Anticoagulan Therapy PDF

A CLINICAL PRACTICE GUIDE
WILLIAM E. DAGER, PharmD, BCPS (AQ Cardiology), FCSHP,

FCCP, FCCM, FASHP, MCCM
Pharmacist Specialist, UC Davis Medical Center
Clinical Professor of Medicine, UC Davis School of Medicine
Sacramento, California
Clinical Professor of Pharmacy
UC San Francisco School of Pharmacy
San Francisco, California
Clinical Professor of Pharmacy, Touro School of Pharmacy
Vallejo, California
MICHAEL P. GULSETH, PharmD, BCPS, FASHP

Program Director for Anticoagulation Services
Department of Pharmaceutical Services
Sanford USD Medical Center
Sioux Falls, South Dakota
Clinical Associate Professor
University of South Dakota Sanford School of Medicine
EDITH A. NUTESCU, PharmD, MS CTS, FCCP

Associate Professor, Department of Pharmacy Systems,
Outcomes and Policy
Director, Center for Pharmacoepidemiology and
Pharmacoeconomic Research
University of Illinois at Chicago, College of Pharmacy
Co-Director, Personalized Medicine Program
University of Illinois Hospital and Health Sciences System
(UI-Health)
Chicago, Illinois
1
Any correspondence regarding this publication should be sent to the publisher,
American Society of Health-System Pharmacists, 4500 East West Highway, Suite 900,
Bethesda, MD 20814, attention: Special Publishing.
The information presented herein reflects the opinions of the contributors and
advisors. It should not be interpreted as an official policy of ASHP or as an endorse-
ment of any product.
Because of ongoing research and improvements in technology, the information and

its applications contained in this text are constantly evolving and are subject to the
professional judgment and interpretation of the practitioner due to the uniqueness
of a clinical situation. The editors and ASHP have made reasonable efforts to ensure
the accuracy and appropriateness of the information presented in this document.
However, any user of this information is advised that the editors and ASHP are not
responsible for the continued currency of the information, for any errors or omissions,
and/or for any consequences arising from the use of the information in the document
in any and all practice settings. Any reader of this document is cautioned that ASHP
makes no representation, guarantee, or warranty, express or implied, as to the
accuracy and appropriateness of the information contained in this document and
specifically disclaims any liability to any party for the accuracy and/or completeness
of the material or for any damages arising out of the use or non-use of any of the
information contained in this document.
Acquisitions Editor: Beth Campbell

Editorial Project Manager: Ruth Bloom
Production Manager: Johnna Hershey
Cover & Page Design: David Wade
Composition: Carol Barrer
Library of Congress Cataloging-in-Publication Data

Names: Dager, William E., editor. | Gulseth, Michael P., editor. | Nutescu, Edith A.,
editor. | American Society of Health-System Pharmacists, issuing body.
Title: Anticoagulation therapy : a clinical practice guide / [edited by] William E. Dager,
Michael P. Gulseth, Edith A. Nutescu.
Other titles: Anticoagulation therapy (Dager)
Description: Second edition. | Bethesda, Maryland : American Society of Health-
System Pharmacists, [2018] | Includes bibliographical references and index.
Identifiers: LCCN 2017052407 | ISBN 9781585284894 (pbk. : alk. paper)
Subjects: | MESH: Anticoagulants--therapeutic use | Thromboembolism--drug therapy
Classification: LCC RM335 | NLM
© 2018, American Society of Health-System Pharmacists, Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any

means, electronic or mechanical, including photocopying, microfilming, and record-
ing, or by any information storage and retrieval system, without written permission
from the American Society of Health-System Pharmacists.
ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.;

registered in the U.S. Patent and Trademark Office.
ISBN: 978-1-58528-489-4
10 9 8 7 6 5 4 3 2 1
DEDICATION
Without the continuous support and encouragement from family, colleagues, students,
and residents, this book—now in its second edition—could never have come to fruition.
To all the patients who have needed our services and desire to learn and improve
their care.
Edith
To my parents who instilled a work ethic and passion to serve others. For my wife
Karen and children William R, Jessica, and Laura for their constant encouragement
and understanding throughout the years: I am forever grateful.
Bill
To my parents, Daniel and Constance Gulseth: Thank you for showing me the path
to take on life—living faithfully, cherishing family, and pursuing worthy opportunities.
Michael
CONTENTS
Contributors..........................................................................................................................vii
Preface...................................................................................................................................xi
Acknowledgments.................................................................................................................xiii
Abbreviations........................................................................................................................xv
Part I. Anticoagulation Medication Management

1. Introduction to Anticoagulation Management...............................................................3
William E. Dager, Michael P. Gulseth, and Edith A. Nutescu
2. Warfarin..........................................................................................................................13
Ann K. Wittkowsky
3. Unfractionated Heparin..................................................................................................35
William E. Dager
4. Low Molecular Weight Heparin and Fondaparinux........................................................65
Zachary Stacy and Sara K. Richter
5. Parenteral Direct Thrombin Inhibitors............................................................................85
William E. Dager and A. Joshua Roberts
6. Thrombolytic Considerations When Used with Anticoagulants......................................107
Toby C. Trujillo and Tyree H. Kiser
7. Direct Oral Anticoagulants.............................................................................................131
Allison E. Burnett and Candice L. Garwood
8. Anticoagulation Reversal: Part I—Pharmacology of Agents Used for Reversal..............163
Lance J. Oyen and Scott A. Chapman
9. Anticoagulation Reversal: Part II—Clinical Application...................................................183
William E. Dager
10. Transitions in Care—Periprocedural Bridging and Transitions Between Agents.............223
Jessica Rimsans, Katelyn W. Sylvester, and John Fanikos
11. Considerations in Special Populations............................................................................251
Thaddaus Hellwig and William E. Dager
Part II. Conditions Requiring Anticoagulation Therapy

12. Venous Thromboembolism Prevention...........................................................................283
Paul P. Dobesh and Kelsey Aker
13. Venous Thromboembolism Treatment............................................................................313
Snehal H. Bhatt and Michael P. Gulseth
14. Atrial Fibrillation............................................................................................................347
Daniel M. Witt
15. Acute Coronary Syndromes............................................................................................363
Sarah A. Spinler
16. Prosthetic Heart Valves..................................................................................................393
Douglas C. Anderson
v
CONTENTS (continued)
17. Mechanical Circulatory Support Devices........................................................................405
Christopher Paciullo, Laura Baumgartner, and Lauren Roller
18. Heparin-Induced Thrombocytopenia..............................................................................423
William E. Dager
19. Pregnancy.......................................................................................................................449
Nancy L. Shapiro
20. Pediatrics........................................................................................................................481
Kirsten H. Ohler
Part III. Practical Measuring, Monitoring, and Coagulation Laboratory

Insights
21. Coagulation Laboratory Considerations.........................................................................507
Robert C. Gosselin and Maureen A. Smythe
22. Thrombophilias...............................................................................................................549
Jessica B. Michaud and Canice A. Coan
Part IV. Essentials for Practice Success

23. Models and Standards of Anticoagulation Care Delivery...............................................577
Nathan P. Clark and Paul B. Shaw
24. Regulatory and Practice Resources................................................................................605
Michael P. Gulseth and William E. Dager
Appendixes
Appendix A. Coagulation Cascade............................................................................................... 617
Appendix B. Agents Implicated in Drug-Induced Thromboembolic Diseases.............................. 618
Appendix C. Nutrition Influence on Anticoagulation.................................................................... 623
Appendix D. Anticoagulants in Management of Ischemic Stroke or
Transient Ischemic Attacks........................................................................................................ 625
Appendix E. Citrate Anticoagulation............................................................................................. 627
Appendix F. Examples of Available Bleeding Definitions.............................................................. 629
Appendix G. Types of CNS Hemorrhage...................................................................................... 631
Appendix H. Disseminated Intravascular Coagulation.................................................................. 632
Appendix I. Nondrug Causes of Thrombocytopenia.................................................................... 633
Appendix J. Drug-Related Causes of Thrombocytopenia............................................................. 634
Appendix K. Examples of Transfusion-Related Reactions............................................................. 637
Appendix L. Considerations for Transitioning from aPTT to Anti-Xa
to Manage Heparin Therapy..................................................................................................... 638
Appendix M. PIONEER AF-PCI..................................................................................................... 641
Appendix N. Betrixaban APEX Trial.............................................................................................. 642
Index......................................................................................................................................643
vi
CONTRIBUTING EDITORS
WILLIAM E. DAGER, PharmD, BCPS (AQ CARDIOLOGY), FCSHP, FCCP, FCCM,
FASHP, MCCM
Pharmacist Specialist, UC Davis Medical Center
Clinical Professor of Medicine
UC Davis School of Medicine
Sacramento, California
UC San Francisco School of Pharmacy
San Francisco, California
Touro School of Pharmacy
Vallejo, California
MICHAEL P. GULSETH, PharmD, BCPS, FASHP

Program Director for Anticoagulation Services
Department of Pharmaceutical Services
Sanford USD Medical Center
University of South Dakota Sanford School of Medicine
EDITH A. NUTESCU, PharmD, MS CTS, FCCP

Associate Professor
Department of Pharmacy Systems, Outcomes and Policy
Director, Center for Pharmacoepidemiology and Pharmacoeconomic Research
University of Illinois at Chicago, College of Pharmacy
Co-Director, Personalized Medicine Program
University of Illinois Hospital and Health Sciences System (UI-Health)
Chicago, Illinois
CONTRIBUTORS
Kelsey Aker, PharmD Laura Baumgartner, PharmD, BCPS, BCCCP

Critical Care Pharmacist Assistant Professor, Department of Clinical
Department of Pharmaceutical and Nutritional Sciences
Care Touro University California College of Pharmacy
Nebraska Medicine Vallejo, California
Omaha, Nebraska
Snehal H. Bhatt, PharmD, FASHP, BCPS
Douglas C. Anderson, PharmD, DPh (AQ-Cardiology)
Professor and Chair Associate Professor of Pharmacy Practice
Department of Pharmacy Practice MCPHS University
Cedarville University School of Pharmacy School of Pharmacy–Boston
Cedarville, Ohio Boston, Massachusetts
vii
CONTRIBUTORS (continued)
Allison E. Burnett, PharmD, PhC, CACP Robert C. Gosselin, CLS
Antithrombosis Stewardship Pharmacist Clinical Laboratory Scientist
University of New Mexico Hospital Hemophilia Treatment Center
Clinical Assistant Professor Division of Hematology/Oncology
University of New Mexico College of Pharmacy UC Davis Health System
Albuquerque, New Mexico Sacramento, California
Scott A. Chapman, PharmD Thaddaus Hellwig, PharmD, BCPS

Associate Professor Associate Professor
Experimental and Clinical Pharmacology South Dakota State University
University of Minnesota College of Pharmacy and Allied Health
College of Pharmacy Professions
Minneapolis, Minnesota Sanford USD Medical Center
Nathan P. Clark, PharmD, FCCP, BCPS
Clinical Pharmacy Supervisor Tyree H. Kiser, PharmD, FCCM, FCCP, BCPS
Anticoagulation and Anemia Management Associate Professor
Services Department of Clinical Pharmacy
Kaiser Permanente Colorado University of Colorado Skaggs School of
Aurora, Colorado Pharmacy and Pharmaceutical Sciences
Aurora, Colorado
Canice A. Coan, PharmD, BCACP
PCMH Pharm Case Management Coordinator Jessica B. Michaud, PharmD, BCPS
Clarkson Family Medicine, Brentwood Village, Clinical Pharmacist
and Chalco Rheumatology Clinic
UNMC COP Clinical Assistant Professor - Anticoagulation & Medication Therapy Clinic
Pharmacy Practice Froedtert & Medical College of Wisconsin
Nebraska Medicine Milwaukee, Wisconsin
Nebraska Medical Center
Omaha, Nebraska Kirsten H. Ohler, PharmD, BCPS, BCPPS
Paul P. Dobesh, PharmD, FCCP, BCPS Program Director, PGY2 Pediatric Pharmacy
(AQ Cardiology) Residency
Professor of Pharmacy Practice Department of Pharmacy Practice
College of Pharmacy University of Illinois at Chicago, College of
University of Nebraska Medical Center Pharmacy
Omaha, Nebraska Clinical Pharmacist, Neonatal Intensive Care
Univeristy of Illinois Hospital & Health Sciences
John Fanikos, RPh, MBA System
Executive Director of Pharmacy Chicago, Illinois
Brigham and Women’s Hospital
Department of Pharmacy Services Lance J. Oyen, PharmD, BCPS, FCCM, FCCP
Boston, Massachusetts Associate Chief Pharmacy Officer - Clinical
Services & Research, Department of
Candice L. Garwood, PharmD, FCCP, BCPS Pharmacy
Associate Professor (Clinical) Associate Professor of Pharmacy, Mayo College
Eugene Applebaum College of Pharmacy and of Medicine
Health Sciences, Wayne State University Mayo Clinic
Detroit, Michigan Rochester, Minnesota
viii
Christopher Paciullo, PharmD, BCCCP, FCCM, Maureen A. Smythe, PharmD, FCCP
FCCP Anticoagulation Specialist
Pharmacy Manager Department of Pharmaceutical Services
Emory University Hospital Midtown Beaumont Hospital
Atlanta, Georgia Royal Oak, Michigan
and
Sara K. Richter, PharmD, BCPS Professor (Clinical)
Assistant Professor, Pharmacy Practice Department of Pharmacy Practice
St. Louis College of Pharmacy Wayne State University
St. Louis, Missouri Detroit, Michigan
Jessica Rimsans, PharmD, BCPS Sarah A. Spinler, PharmD, FCCP, FAHA,

Clinical Specialist FASHP, AACC, BCPS (AQ-Cardiology)
Department of Pharmacy Professor Emeritus
Brigham and Women’s Hospital Philadelphia College of Pharmacy
Boston, Massachusetts University of the Sciences
Philadelphia, Pennsylvania
A. Joshua Roberts, PharmD, BCPS
(AQ Cardiology) Zachary Stacy, PharmD, MS, FCCP, BCPS
Senior Clinical Pharmacist Associate Professor of Pharmacy Practice
University of California St. Louis College of Pharmacy
Davis Medical Center St. Louis, Missouri
Associate Clinical Professor of Pharmacy
University of California Katelyn W. Sylvester, PharmD, CACP, BCPS
San Francisco School of Pharmacy Pharmacy Manager
San Francisco, California Department of Pharmacy
Brigham and Women’s Hospital
Lauren Roller, PharmD, BCCCP Boston, Massachusetts
Assistant Professor
Department of Clinical Sciences Toby C. Trujillo, PharmD, FCCP, FAHA, BCPS
Touro University California (AQ Cardiology)
Vallejo, California Associate Professor
University of Colorado
Nancy L. Shapiro, PharmD, FCCP, BCACP, Skaggs School of Pharmacy and Pharmaceutical
CACP Sciences
Clinical Associate Professor Clinical Specialist - Anticoagulation/Cardiology
Pharmacy Practice University of Colorado Hospital
Coordinator and Clinical Pharmacist Aurora, Colorado
Antithrombosis Clinic
PGY2 Ambulatory Care Residency Director Daniel M. Witt, PharmD, FCCP, BCPS
University of Illinois at Chicago Professor and Chair, Pharmacotherapy
Chicago, Illinois Assistant Dean of Clinical Affairs
University of Utah
Paul B. Shaw, PharmD, BCPS L. S. Skaggs Pharmacy Institute
Clinical Pharmacy Supervisor - Cardiology Salt Lake City, Utah
Kaiser Permanente Colorado
Lafayette, Colorado
ix
Ann K. Wittkowsky, PharmD, CACP, FASHP,
FCCP
Director, Anticoagulation Services
UWMedicine Department of Pharmacy
Clinical Professor
University of Washington School of Pharmacy
Seattle, Washington
x
PREFACE
Ensuring the safe and appropriate use of anticoagulants continues to be major

challenge. Despite the release of the direct-acting oral anticoagulants (DOACs), which
many hoped would improve patient safety, in 2016 the U.S. Food and Drug Administra-
tion (FDA) Adverse Event Reporting System received 18,878 reports of anticoagulant-
related serious injury and 3018 deaths.1 In a recent study by the Centers for Disease
Control and Prevention, anticoagulants accounted for 17.6% of all U.S. emergency
department visits, and nearly half of these patients needed to be hospitalized. 2 The
increasing complexity of patients and advances in technologies, such as cardiac circula-
tory devices, has made anticoagulant management approaches even more challenging.
We (the editors) are clinicians and face the challenge of using anticoagulants in a safe
and effective way on a daily basis. From this experience, we decided now was the
right time to update our practical guide on anticoagulation drug therapy. Our goal is
to give the clinician quick access to evidence-based and/or expert opinion information
for the challenging clinical situations they may face.
New features of this second edition include:

• Extensive new information on the DOACs—most agents were not approved when the first
edition was written
• Expanded information on anticoagulation reversal due to the release of DOACs and
expanded options in management
• Five new chapters on the following topics:
{{ Use of anticoagulants, including DOACs, in special patient populations
{{ Use of anticoagulants in patients with mechanical devices
{{ Anticoagulation care delivery standards, regulatory issues, and practice
resources beyond this text
• Three new appendixes covering:
{{ Nutritional influences with anticoagulation, types of central nervous system
hemorrhage, and transitioning heparin measurements using the anti-factor
Xa instead of the aPTT
As with the first edition, the book is:

• Light on text. The amount of “book style text” was intentionally minimized so a clinician
did not have to read a whole chapter to find the “one nugget” they were seeking.
• Heavy on tables/figures. Our hope is that this allows the clinician to rapidly find the answers
they are seeking.
• Easy to find key points. Clinical pearls and highlighted key references make it easy to find
critical information.
• Easy to digest. The use of bullets and clinical pearl examples both present the information
in a succinct fashion, and highlight how the information applies to real-life care.
• Comprehensive. Although no text can cover every foreseeable topic, this book covers a
lot of the potential challenges that clinicians face.
xi
PREFACE (continued)
• Expertly written. All the authors are experts in the areas in which they are writing, and all
chapters were carefully reviewed by the editors including the chapters written by other
editors.
• Applicable to patients across the continuum of care. This book covers topics as diverse as
how to care for the ambulatory patient in need of anticoagulation bridging for an invasive
procedure to the pediatric patient on extracorporeal membrane oxygenation.
• Useful to a broad scope of disciplines. This handbook was intentionally designed to be a
useful guide for clinicians in any discipline caring for patients on anticoagulation therapy.
The editors are deeply indebted to the authors who were again willing to take on one
more project and provide their expertise to improve the care of patients receiving
anticoagulation therapy. We can never repay them for the time they took away from
family and other professional commitments.
Finally, as with the first edition, we must say thank you to all clinicians who tackle the
challenges these medications pose on a daily basis. There is no such thing as a “safe”
anticoagulant, yet your efforts are what ensure that these agents are used “safely” and
in an evidence-based fashion. For that, we wish to thank you on behalf of your patients.
William E. Dager
Michael P. Gulseth
Edith A. Nutescu
References
1. Part II: oral anticoagulants—the nation’s top risk of acute injury from drugs. Acute Care ISMP
Medication Safety Alert! July 27, 2017;22(15):1-4.
2. Shehab N, Lovegrove MC, Geller AI, et al. U.S. Emergency Department Visits for Outpatient
Adverse Drug Events, 2013–2014. JAMA. Nov 22 2016;316(20):2115-2125.
xii
ACKNOWLEDGMENTS
The editors would like to acknowledge the assistance provided by these individuals
during the preparation of the two editions of this handbook. Your contributions are
greatly appreciated.
Lydia D. Chen, PharmD

Lynnette Coolidge, PharmD
Jessica L. Dager
William R. Dager
Ashley Hansen, PharmD
Hahyoon Kim, PharmD
Amy J. Schwinghammer, PharmD
Samantha N. VanAcker, PharmD
xiii
ABBREVIATIONS
A apixaban
AAOS American Association of Orthopedic Surgery
AAP American Academy of Pediatrics
ACA anticardiolipin antibody (also often abbreviated as aCL)
ACC American College of Cardiology
ACC/AHA American College of Cardiology/American Heart Association
ACCP American College of Chest Physicians
ACS acute coronary syndrome
ACT activated clotting time
AF atrial fibrillation
AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management
AHA American Heart Association
AHA/ASA American Heart Association/American Stroke Association
AIS arterial ischemic stroke
ALL acute lymphoblastic leukemia
ALT alanine aminotransferase
AMI acute myocardial infarction
AP antiplatelet
APC activated protein C
APLA antiphospholipid antibody syndrome (also often abbreviated APS and APLS)
syndrome
APLAs antiphospholipid antibodies
aPTT activated partial thromboplastin time
ASA aspirin
ASSENT Assessment of the Safety and Efficacy of a New Thrombolytic
AST aspartate aminotransferase
AT antithrombin
AUC area under the serum concentration versus time curve
AVR aortic valve replacement
BID twice daily dosing
BMI body mass index
BP blood pressure
xv
ABBREVIATIONS (continued)
CABG coronary artery bypass graft
CAD coronary artery disease
CAP College of American Pathologists
CBC complete blood count (including platelets)
CBS cystathionine-β-synthase
CHD coronary heart disease
CI confidence interval
CLIA Clinical Laboratory Improvement Amendments
CLSI Clinical Laboratory Standards Institute (formerly NCCLS or National Committee on Clinical
Laboratory Standards)
Cmax maximum serum concentration
CPK creatinine phosphokinase
CPR cardiopulmonary resuscitation
CrCl creatinine clearance
CRRT continuous renal replacement technique
CRUSADE Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with
Early implementation of the ACC/AHA guidelines
CSCT colloidal-silica clotting time
CT computed tomographic
CVA cerebrovascular accident
CVAD central venous access device
CVL central venous line
D dabigatran
D5W 5% dextrose in water
DBP diastolic blood pressure
Dec decrease
DIC disseminated intravascular coagulation
dL deciliter
DOAC direct-acting oral anticoagulant
dPT dilute prothrombin time
dRVVT dilute Russell’s viper-venom time
DTI direct thrombin inhibitor
xvi
DVT deep vein thrombosis
ECG electrocardiogram
ECLS extracorporeal life support
ECMO extracorporeal membrane oxygenation
ELISA enzyme-linked-immunosorbent assay
Enox enoxaparin
EU European Union
FDA Food and Drug Administration
FFP fresh frozen plasma
FVL factor V Leiden mutation
GAGs glycosaminoglycans
GCS Glasgow Coma Scale
GCS graduated compression stockings
GI gastrointestinal
Gp llb/llla glycoprotein llb/llla receptor
GUSTO global use of strategies to open occluded coronary arteries
HAT heparin-associated thrombocytopenia (nonimmune mediated)
Hct hematocrit
Hgb hemoglobin
HIT heparin-induced thrombocytopenia (immune mediated)
HITTS heparin-induced thrombocytopenia thrombosis syndrome (immune mediated)
hr hour
HR-ACT high response activated clotting time
HR heart rate
HTN hypertension
IBD inflammatory bowel disease
ICD implantable cardioverter defibrillator
ICH intracranial hemorrhage
IgG (IgA, etc.) immune globulin G, etc.
IM intramuscular
Inc increase
xvii
INR international normalized ratio
IPC intermittent pneumatic compression
ISI International Sensitivity Index
ISTH International Society of Thrombosis and Haemostasis
IUGR intrauterine growth restriction
IV intravenous
IVC inferior vena cava
KCT kaolin clotting time
kD kilodalton
kg kilogram
kg/m2 kilogram/meter squared
LA lupus anticoagulant
LIA latex immunoassay
LMWH low molecular weight heparin
LR ACT low range activated clotting time
LV left ventricular
mg milligrams
Mg magnesium
MI myocardial infarction
min minutes
mL/min milliliter/minute
MODS multiple organ dysfunction syndrome
MRI magnetic resonance imaging
MTHFR methylene-tetrahydrofolate reductase
MVP mechanical valve prosthesis
MVR mitral valve replacement
NA not applicable
NHP normal human plasma
NIBSC National Institute of Biological Standards and Controls
NINDS National Institute of Neurological Disorders and Stroke
NPSG National Patient Safety Goal
xviii
NS normal saline
NSAIDs nonsteroidal anti-inflammatory drugs
NSR normal sinus rhythm
NSTE non-ST-segment elevation
NSTEMI non-ST-segment elevation myocardial infarction
OR operation room
PAD peripheral arterial disease
PCC prothrombin complex concentrate
PCI percutaneous coronary intervention
PE pulmonary embolism
PF-4 platelet factor 4
PICC peripherally inserted central catheter
Plt platelet
POC point of care
PPH primary pulmonary hypertension
PRBCs packed red blood cells
PT prothrombin time
Pt yr patient-year
R rivaroxaban
RACE RAte Control vs. Electrical cardioversion for persistent atrial fibrillation study
RCT randomized clinical trial
rFVIIa recombinant factor VII activated
RRR relative risk reduction
rt-PA recombinant tissue plasminogen activator
RVT renal vein thrombosis
SBP systolic blood pressure
SC subcutaneous
SCAI Society for Cardiac Angiography and Interventions
SCD sickle cell disease
SCr serum creatinine
sec seconds
xix
SOB shortness of breath
sub-Q subcutaneous
SRA serotonin release assay
SSC Scientific Subcommittee (part of ISTH)
SSRI selective serotonin reuptake inhibitors
STEMI ST-segment elevation myocardial infarction
T1/2 elimination half life
TAVR transcatheter aortic valve replacement
TBW total body weight
TE thromboembolism
TEE transesophageal echocardiography
THR total hip replacement
TIA transient ischemic attack
TIMI thrombolysis in myocardial infarction
TKR total knee replacement
TMA thrombotic microangiopathy
Tmax time to maximum serum concentration
TNK tenecteplase
tPA tissue plasminogen activator
TPN total parenteral nutrition
TT thrombin time
TTE transthoracic echocardiography
UFH unfractionated heparin
units International Units
Vit K vitamin K or phytonadione
VKA vitamin K antagonist
VKOR vitamin K epoxide reductase
VTE venous thromboembolism
vWF von Willebrand’s factor
WARSS/APASS Warfarin vs. Aspirin Recurrent Stroke Study/Antiphospholipid Antibodies in Stroke Study
WHO World Health Organization
xx
PART I.
ANTICOAGULATION
MEDICATION
MANAGEMENT
1. Introduction to Anticoagulation Management
2. Warfarin
3. Unfractionated Heparin
4. Low Molecular Weight Heparin and Fondaparinux
5. Parenteral Direct
Thrombin Inhibitors
6. Thrombolytic
Considerations When
Used with Anticoagulants
7. Direct Oral Anticoagulants
8. Anticoagulation Reversal: Part I—

Pharmacology of Agents Used for Reversal
9. Anticoagulation Reversal:
Part II—Clinical Application
10. Transitions in Care—Periprocedural

Bridging and Transitions Between Agents
11. Considerations in Special Populations
1
Chapter
1
INTRODUCTION TO
ANTICOAGULATION
MANAGEMENT
William E. Dager, Michael P. Gulseth, and Edith A. Nutescu
INTRODUCTION
In the anticoagulation therapy setting, clinicians are faced with the challenge of
utilizing agents that inherently have a small therapeutic window and the potential
for medication mishaps when not used appropriately. However, this risk is balanced
against the need to prevent against or treat thrombosis, which can also have life-
altering consequences. Therefore, clinicians utilizing anticoagulants must not only
have a firm grasp of the pharmacology and pharmacokinetics of those agents, but
they must also be current with the evidence regarding their use and understand
how an individual patient’s characteristics can influence management decisions.
This practice guide, first published in 2011, was developed with these challenges
in mind and with the goal to seed thoughts and provide information that assists
clinicians in ensuring the safe and optimal use of anticoagulants. The advent of
new agents and advances in anticoagulation therapy management led to the
development of this second edition. Each chapter provides key concepts based
on the literature and on the authors’ clinical experiences when evidence is more
limited. New chapters include considerations in special populations with a focus
on renal failure, obesity, and cancer, and on mechanical devices. A new section
focuses on the essentials for practice success that includes models and standards
in anticoagulation care delivery as well as regulatory and practice resources.
Expert panels’ evidence-based recommendations are included when available. This
practice guide is intended as a supplement to the clinician’s judgment by providing
quick insights and clinical pearls that can assist in the decision-making process.
JOINT COMMISSION’S NATIONAL PATIENT

SAFETY GOALS FOR ANTICOAGULATION,
2017 VERSION (NPSG 03.05.01)1
• Because of the high incidence of reported adverse event rates associated with anti-
coagulation therapy or suboptimal approaches to prevention of venous thrombo-
embolism (VTE), several regulatory agencies have initiated processes to address
their concerns. One example is the Joint Commission’s National Patient Safety Goals
3
4 Anticoagulation Therapy
(NPSGs). The primary goal of the anticoagulation NPSGs is to reduce the likeli-
hood of patient harm associated with anticoagulant therapy.
• The full text and requirements of the NPSGs can be found at https://www.
jointcommission.org/hap_2017_npsgs/.
• The NPSGs are driven by the frequency of reported adverse events associated
with anticoagulation therapy. Thus, newer agents, or infrequently used agents,
may not as of yet received as much attention or regulatory oversight. This does
not necessarily make their use any less challenging, and they could be included
in the future if safety reports warrant it.
TABLE OF USEFUL RESOURCES

See Table 1-1 for useful resources involving anticoagulation therapy.
TOOLS FOR SUCCESS
Considerations in Applying Professional Organizations’

Expert Evidence-Based Guidelines to Patient Care
• Expert panels representing the American College of Chest Physicians (ACCP)
and the American Heart Association (AHA) [published in conjunction with the
American College of Cardiology (ACC)] have provided evidence-based recom-
mendations to aid clinicians in selecting appropriate patient care. In specific
situations, other agencies may independently publish guidelines that include
antithrombotic therapy. Often, these guidelines are considered the final word;
however, multiple guidelines on the same topic (especially when there may be
disagreements) can create some controversy and confusion. Adherence to these
guidelines ignores how an individual patient situation may cause variance from
the guidelines. It should be kept in mind that such guidelines are established
based on the strength of available evidence. In many cases, evidence or trials
may not have included certain situations or populations or perhaps published
negative experiences. Clinicians need to view and use these guidelines as they
are intended—evidence-based tools designed (or developed) to aid in patient
care and not to replace clinical judgment.
• The following tables explain the evidence ranking system of both the ACCP and
AHA guidelines. These evidence grades are mentioned extensively in subsequent
chapters. See Tables 1-2 and 1-3.
Considerations When Evaluating Clinical Trials Involving

Anticoagulants
• Clinical trials have frequently preselected inclusion and exclusion criteria that
create a focus for the concept being studied. In many cases with anticoagula-
tion therapy, patient groups (advanced age, bleeding history, organ dysfunc-
tion, critically ill, hypercoagulable condition) initially excluded from the clinical
trials may receive the therapy. Clinicians should consider that trials serve as a
foundation to managing thrombosis, but that excluded populations may respond
differently to a given therapy.
INTRODUCTION TO ANTICOAGULATION MANAGEMENT 5
TABLE 1-1: Resources Involving Anticoagulation Therapy

Reference Web Site Comment
ACCP http://journal.publications. The oldest and most established evidence-

guidelines chestnet.org/SS/ based guideline involving antithrombotic
Antithrombotic_Guideline. therapy. Although the 9th and previous
aspx editions were all developed and published
at the same time, the 10th edition will have
chapters/topics published at various times.
AHA guidelines http://professional. The American Heart Association regularly

heart.org/professional/ published guidelines that cover different
GuidelinesStatements/ arterial disease states, often in conjunction
searchresults.jsp with other societies.
ASHP https://www.ashp.org/ The American Society of Health-System

Pharmacy-Practice/ Pharmacists provides a resource center that
Pharmacy-Topics/ is helpful for pharmacists and clinicians who
Anticoagulation manage anticoagulation therapy.
Anticoagulation http://www.acforum.org/ Multidisciplinary professional organization for

Forum those who manage anticoagulation therapy;
helpful clinical resources are posted on the
site.
Clinical Trials. http://www.clinicaltrials.gov/ The site describes current clinical trials

gov conducted.
ClotCare http://www.clotcare.com/ Regularly updated site mainly focuses on

keeping professionals abreast of cutting-edge
information involving antithrombotic therapy;
site also contains helpful information for
patients.
FDA http://www.fda.gov/ The FDA regularly posts alerts concerning

marketed medications and materials that are
reviewed by advisory committees.
PubMed http://www.ncbi.nlm.nih. Excellent free site available for searching

gov/pubmed/ Medline from the United States National
Library of Medicine.
ACCP: American College of Chest Physicians, AHA: American Heart Association, ASHP: American
Society of Health-System Pharmacists, FDA: U.S. Food and Drug Administration
• Anticoagulants or reversal therapies may frequently be used in conditions where

the agent has not been adequately explored. The limited evidence with such
“off-label” use should be employed with caution and with consideration that
the optimal dose, duration, or approach to their use in such settings has not
been determined.
• In many situations, current approaches to anticoagulation regimens have evolved
based on postmarketing experiences. Populations originally excluded in the
clinical trials may provide signals on how therapies may need to be adapted.
In some settings, limited single-center case reports where no additional infor-
mation exists may drive practice. In others, concepts based in theory but not
TABLE 1-2: Interpreting the ACCP Antithrombotic and

Thrombolytic Therapy Evidence-Based Clinical Practice
Guidelines Evidence Grades2-4*
Grade of Recommendation Quality of Evidence Implications
(recommendation
strength/evidence grade)
1A Consistent findings are from Recommendation applies

randomized clinical trials (RCTs) or to most patients in most
extremely strong evidence from situations.
observational studies.
1B RCTs have important limitations Recommendation applies

or strong evidence from to most patients in most
observational studies. situations.
1C At least one important outcome Recommendation applies

has been assessed in case series, to most patients in many
observational studies, or from situations.
seriously flawed RCTs; indirect
evidence also can be used.
2A Consistent findings are from The appropriate treatment

RCTs or have extremely strong may vary based on patient/
evidence from observational society values.
studies.
2B RCTs have important limitations The appropriate treatment

or strong evidence from may vary based on patient/
observational studies. society values.
2C At least one important outcome Other treatment options

has been assessed in case series, may be equally desirable.
observational studies, or from
a seriously flawed RCT; indirect
evidence also can be used.
Ungraded Consensus-Based The desirable consequences

Statement (New) probably outweigh the
undesirable consequences in
most settings, but there is little
evidence. Recommendations are
more suggestions in the absence
of any rigorous clinical trials or
assessments of the issue.
*Grade 1 recommendations are considered “strong” recommendations, and Grade 2 are

considered “weak” recommendations. Grade A evidence comes from RCTs or observational
studies with very large effects. Grade B evidence comes from RCTs with limitations or strong
evidence from observational trials. Grade C evidence comes from observational trials or RCTs
with major limitations. The Grades of Recommendations, Assessment, Development and
Evaluation (GRADE) approach is utilized.5
ACCP: American College of Chest Physicians
TABLE 1-3: Interpreting the ACC/AHA Evidence Grades Used in

Scientific Statements6
Grade of Recommendation Quality of Evidence
(class/evidence grade)
1 (A) Strong recommendation that a treatment or procedure is

helpful; robust supporting data.
1 (B) Strong recommendation that a treatment or procedure is

helpful; more limited supporting data.
1 (C) Strong recommendation that a treatment or procedure is

helpful; largely based on expert opinion, standard of care, or
case studies.
IIa (A) Recommendation that a treatment or procedure is helpful;

available data contain some conflicting evidence.
IIa (B) Recommendation that a treatment or procedure is helpful;

available data contain some conflicting evidence.
IIa (C) Recommendation that a treatment or procedure is helpful;

largely based on expert opinion, standard of care, or case
studies.
IIb (A) Recommendation that a treatment or procedure may be

considered; supporting data contain significant conflicting
evidence.
IIb (B) Recommendation that a treatment or procedure may be

considered; available data contain significant conflicting
evidence.
IIb (C) Recommendation that a treatment or procedure may be

considered; largely based on expert opinion, standard of
care, or case studies.
III (A) Recommendation that a treatment or procedure should not

be considered; robust supporting data.
III (B) Recommendation that a treatment or procedure should not

be considered; based on more limited supporting data.
III (C) Recommendation that a treatment or procedure should not

be considered; largely based on expert opinion, standard of
care, or case studies.
ACC/AHA: American College of Cardiology/American Heart Association
yet validated [e.g., overlapping parenteral anticoagulants for 2 additional days

after the international normalized ratio (INR) on warfarin is over 2] are utilized.
• When reviewing data derived from observations collected from registries, the
reviewer should consider the voluntary structure and potential cleaning of data
prior to submission to eliminate any perception of poor management. The coding
of the information prior to being extrapolated may also create certain bias or
limitations on the quality of the research.
• See Table 1-4.
Meta-Analysis Interpretation Cautions

• Guidelines strive to incorporate the best evidence available when developing
recommendations. This can frequently be influenced by meta-analysis that
explores similar trials. However, trials may not be published, particularly small
negative trials. This can create a literature base that is influenced by positive
outcomes. In some cases, single large trials may dominate the observations.
Such data basis should utilize concepts such as funnel plots to describe any
potential bias in the data base. (See reference 7 for an example of how this can
help detect publication bias.)7
• Differences in the approach to the study and the patients actually studied may
have influenced the variable results reported in the meta-analysis. These trials,
while having enough power to detect small treatment effects, often include a
diverse population of patients by design.
• Medical advances in both technology and management approaches over time
can independently influence outcomes. Because trials included in a meta-analysis
are usually conducted during different time periods, it can create challenges in
interpreting the results.
“Real World” Data Interpretation Cautions

• The increased availability of large claims-based databases and clinical registries
has resulted in evaluation and dissemination of the treatment effectiveness and
safety of medication use in the community.
• Compared to randomized clinical trials (RCTs), these observational studies have
the advantage of evaluating more “real life” outcomes because patient selec-
tion is much less sanitized.
• One of the major disadvantages of these observational analyses is the potential
of unmeasured confounding factors and selection bias despite sophisticated
econometrics and pharmacoepidemiology statistical techniques.
• We encourage readers to, whenever possible, use RCTs to make treatment
decisions keeping in mind any limitations as it relates to the patient’s situation.
Also, it is recommended to use real-world observational data to help decide
if the treatment effect and safety profile seen in the RCTs is consistent when
studied in less controlled population-based studies.
• Extreme caution should be taken with real-world data when comparing agents
that have not been compared head-to-head in RCTs due to possible confound-
ing and bias.
Treat the Patient and Consider All of the Patient’s

Potential Needs
• Each patient is unique, and clinicians will combine their knowledge and experi-
ence along with resources, such as this practice guide, to derive and adapt
anticoagulation therapy. In many cases, deficiencies in the information used
TABLE 1-4: Additional Considerations When Evaluating Clinical

Trials
Consideration Comment
Population studied • The inclusion and exclusion criteria describe who was or was not
studied in the analysis. Be sure the patients you are considering for
therapy based on the trial would have been included.
• The number of eligible subjects versus those actually studied can
also describe potential challenges in repeating the observations in
the general population.
Methods • The methods should be cross-compared to the study’s setting.

For example, ethnic differences in a region or the assay used may
create results with some limitations when implemented in a different
setting.
• They should clearly state the design and how the management
strategy was provided. In some cases, the methods may have been
published separately or provided in supplemental materials. Also
note the challenges in enrolling patients, including potential delays
in randomization and consent where the trial’s implementation may
have been delayed and other therapies initially used.
Results • Many of the new trials involving anticoagulants are “noninferiority”

in design. If the medication is found to be “noninferior” to the
comparator, be sure to carefully review the noninferiority criteria to
ensure it is appropriate. Also, when compared to warfarin, how well
controlled was the warfarin?
• Carefully consider the clinical significance of the primary endpoint
of the trials. For example, many orthopedic trials commonly include
venographically derived asymptomatic DVT, which many would argue
is not as clinically significant as symptomatic DVT/PE. These results
may be statistically significant, but that is very different than clinically
significant.
• Data should be carefully assessed for robustness. Were any signals
present, suggesting different outcomes within the study population?
Who was excluded? Was additional analysis done to confirm the
primary endpoint findings or conclusions made?
• Was any subgroup analysis included in the initial study design,
or was it derived post hoc to create a positive spin on the study?
Caution should be exercised if considering application of the post
hoc analysis to patient care.
• When assessing a clinical observation or reported result, consider
the potential error in the data. Single, unexpected, or atypical
observations should be confirmed with additional analysis.
• Trends in data that support a result create a higher level of
confidence than the single outlier.
Limitations Be sure the study clearly identifies the limitations of the analysis.
The study should attempt to describe how the limitations affect
interpretation/application of the results. It is also helpful if they have
done additional data analysis to assess the impact of the limitations.
Summary/ Be sure the conclusion is appropriate considering the data and their
conclusion limitations. Often, conclusions overreach the observed result, ignoring
important limitations, which could potentially harm patients if applied
without this consideration.
DVT: deep vein thrombosis, PE: pulmonary embolism

limit its application. Laboratory results or other surrogate markers may not be
validated to hard outcomes of bleeding, thrombosis, morbidity, or death. Quality
of life or limitations such as the ability to be adherent to the management plan,
affordability of the therapy, or monitoring can influence management plans.
{{ Observations away from the bedside may not always agree with
the patient presentation. For example, increasing the level of
anticoagulation based on laboratory results may not be optimal
if the patient is bleeding. The laboratory test is intended to lend
assistance in determining appropriate patient management and
must not be interpreted apart from the individual patient’s situation.
Caution should be considered with the management of anticoagu-
lation therapy when assessing information solely from a computer
screen, even in facilities with the most advanced electronic medical
record systems. Critical information (bleeding, consideration for an
lumbar puncture, potential invasive procedures) may be missed,
due to delay in availability or omission of information. This can limit
the level of care provided. Where possible, bedside or face-to-face
assessments and communication can provide additional information
in real time (current).
{{ Just because something is ordered does not mean the intended
therapy is carried out. Handing out a prescription or order where
hurdles to fulfill the prescription exist may delay or prevent therapy.
A classic example is the patient never filling the prescription when
he or she leaves the hospital.
{{ Even when a patient is handed a dose, this does not always equate
to the patient taking it. In time, this may be discovered by a lack
of INR response to warfarin. One consideration is to ensure the
therapy is administered by requesting a nurse/family member to
witness swallowing of the medication.
{{ When arranging ambulatory anticoagulation patient care follow-
up, has the treatment team determined if the patient can get the
prescribed follow-up laboratory monitoring? Is he or she capable
of utilizing the medication prescribed, including injectables? Is the
patient able to afford the prescribed medication regimen? Long-
term regimens should be assessed for financial feasibility, and any
barrier for potential failure identified and addressed. Consider
engaging the community pharmacist in the patient’s care so he or
she can help to ensure a smooth transition.
{{ Communication is critical. All stakeholders need to be aware of any
potential gaps in the therapy when identified.
• The level of patient acuity should be considered. Clinical trials may not have
explored critically ill patients, yet the therapy may be regularly used in such
a population. Management plans may at times be short term and should be
adapted as changes occur. In many cases, therapy involves multiple agents
or changing settings. A management plan should consider both short- and
long-term goals, and what options are available. Sometimes, the agent chosen
in a management plan may not be the one that is “best” based on evidence,
but instead the agent that is most likely to succeed considering the patient’s
individual situation.
{{ Often, newer agents may be preferable; but if they are financially

prohibitive for the patient, they could lead to suboptimal results.
{{ Patients are often moving in or out of different care settings during
therapy, which can influence the choice of agents utilized in the
management plan.
{{ Management should consider how the patient is clinically changing
in interfering factors (e.g., interacting drugs or disease states) and
adapt as necessary.
{{ When the situation is unclear or rapidly changing, consider short-
term decisions and closer/more frequent assessments.
• Practitioners who also have practice management responsibilities should strive
to break down transitional care barriers that lead to unsafe care.
{{ When patients are admitted, it is important to obtain an accurate
medication history. This is particularly critical regarding their
antithrombotic drug therapy, which is often taken from electronic
records and may not be current with the patients’ actual regimen.
Effects may last for several days after the last dose was taken,
especially if conditions that reduce elimination are present.
{{ Patients being discharged should be promptly handed off to the
responsible managing clinician, with critical information relayed.
The clinician needs to understand how the inpatient care experience
may have influenced the patients’ antithrombotic therapy needs.
This is a particularly high-risk time period in the patients’ therapy,
and too often patients do not understand their individual manage-
ment plans, leading to adverse drug events. Further, it is common
for the medication reconciliation process to not be completed
correctly at discharge. For example, patients can be put back on
their home warfarin dosing (assuming it was correctly identified
at admission!), which is no longer clinically appropriate consider-
ing their condition at discharge. Others may revise the regimen
based on an altered response during an acute illness (elevated INR
during acute decompensated heart failure or an infection), and
not re-adjust the dose back once the patient’s baseline has been
reestablished (heart failure or infection resolved). In this situation,
a period of catch up may occur after discharge.
{{ Upon discharge from an acute care setting, consider not only includ-
ing key follow-up information but also identifying the managing
party to have the information sent to them.
• Each patient is unique and, hence, a special population. However, generalizations
of certain clinical situations create a special management population. Examples
include elderly patients, pediatric patients, critically ill patients, patients with
certain concurrent disease states, patients with a hypercoagulable condition, and
patients with multiple indications for anticoagulation, impaired organ function,
presence of mechanical devices, etc. These patient populations are frequently
discussed in this text. In some selected settings where information may not
directly fit within a specific chapter, it may be found in the Appendix section.
REFERENCES
1. The Joint Commission National Patient Safety Goals. 2018; https://www.
jointcommission.org/assets/1/6/NPSG_Chapter_HAP_Jan2018.pdf. Accessed May 10,
2018.
2. Diekemper RL, Patel S, Mette SA, et al. Making the GRADE: CHEST Updates its
methodology. Chest. 2018 Mar;153(3):756-759.
3. Guyatt GH, Norris SL, Schulman S, et al. Methodology for the development of
antithrombotic therapy and prevention of thrombosis guidelines: Antithrombotic
Therapy and Prevention of Thrombosis. 9th ed. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):53S-70S.
4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST
Guideline and Expert Panel Report. Chest. 2016;149(2):315-352.
5. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3. Rating the
quality of evidence. J Clin Epidemiol. 2011;64(4):401-406.
6. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the
management of patients with non-ST-elevation acute coronary syndromes: executive
summary: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;130(25):2354-2394.
7. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis
in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch
Intern Med. 2007;167(14):1476-1486.
2
Chapter
WARFARIN
Ann K. Wittkowsky
INTRODUCTION
Vitamin K antagonists (VKAs), including warfarin, have been the core of oral anti-
coagulation for decades. Warfarin is used for stroke prevention in atrial fibrillation,
prevention of valvular thrombosis in biologic and mechanical valve replacement,
and prevention and treatment of deep vein thrombosis, pulmonary embolism, and
other manifestations of venous and arterial thromboembolism. Due to a narrow
therapeutic index, highly variable dose response and the significant impact of
diet, disease, and drugs on warfarin pharmacokinetics and pharmacodynamics, it
is an agent that requires frequent monitoring and dosage adjustment to maintain
its efficacy and safety.
PHARMACOLOGY1
Warfarin and other VKAs act by inhibition of the hepatic synthesis of vitamin
K dependent clotting factors II, VII, IX, and X. These clotting factors (and the
anticoagulant substances protein C and protein S) become biologically active
by gamma-carboxylation involving vitamin KH2. In a vitamin K hepatic recycling
process that maintains a continuous supply of vitamin KH2 for clotting factor
synthesis, vitamin KH2 is oxidized to vitamin KO and subsequently converted to
vitamin K by vitamin K epoxide reductase (VKOR) and then back to vitamin KH2 by
vitamin K1 reductase. Warfarin inhibits VKOR and vitamin K1 reductase, resulting
in accumulation of biologically inactive vitamin KO and a reduction in vitamin K
dependent clotting factor synthesis. The full anticoagulant effect of warfarin occurs
when previously activated clotting factors are depleted at rates consistent with their
biologic half-lives, typically within 5–10 days (Table 2-1, Figure 2-1, Figure 2-2).
PHARMACOKINETICS/PHARMACODYNAMICS3
Warfarin is a racemic mixture of R and S enantiomers that differ with respect to
elimination half-life, metabolism, pathways of oxidative metabolism, and potency
(Table 2-2). The pharmacokinetic and pharmacodynamic properties of other VKAs
available outside the United States are quite different from those of warfarin
(Table 2-3).
Pharmacogenomic characteristics influence warfarin dosing requirements in a
number of ways.4 Genetic variations in CYP2C9 genotype can influence the clear-
13
TABLE 2-1: Proteins and Half-life

Vitamin K Dependent Proteins Elimination Half-life
Factor II 42–72 hr
Factor VII 4–6 hr
Factor IX 21–30 hr
Factor X 27–48 hr
Protein C 8 hr
Protein S 60 hr
TABLE 2-2: Differences in R and S Enantiomers

R-Warfarin S-Warfarin
Elimination half-life 45 hr (20–70 hr) 29 hr (18–52 hr)
Metabolism 40% reduction 10% reduction

60% oxidation 90% oxidation
Oxidative metabolism 1A2>3A4>2C19 2C9>3A4
Potency 1 (reference) 2.7–3.8 × R-warfarin
TABLE 2-3: Other K Antagonists

Acenocoumarol Phenprocoumon
Elimination half-life R: 9 hr R: 5.5 days

S: 0.5 hr S: 5.5 days
Oxidative metabolism R: 2C9>2C19 R: 2C9

S: 2C9 S: 2C9
1/3 eliminated unchanged
Potency R more active due to faster S 1.5–2.5 × more potent

clearance of S than R
ance of warfarin, leading to lower-than-average warfarin dosing requirements

in patients who are CYP2C*1/*2, CYP*1/*3, and CYP*2/*3 heterozygotes, and
even lower dosing requirements in CYP*2/*2 and CYP*3/*3 homozygotes. The
*2 and*3 alleles are the primary dysfunctional alleles in patients of European
ancestry, and the *3 allele is most prevalent in patients of Asian ancestry.
Additional polymorphisms, including *5, *6, *8 and *11 alleles, have been
observed in patients of African ancestry.
Haplotype for VKORC1 influences warfarin responsiveness. A minor A
allele in a specific regulatory region of VKORC1, with highest frequency
WARFARIN 15
1 mg Pink 5 mg Peach
2 mg Lavender 2.5 mg Green
FIGURE 2-1. Jantoven Brand Warfarin Tablets

This color scheme is also used for other brands of warfarin and can be used to
determine a patient’s tablet strength and dose.
Source: Used with permission of Upsher-Smith Laboratories, Inc., Maple Grove, MN.
3 mg Tan 4 mg Blue
6 mg Teal 7.5 mg Yellow 10 mg White
FIGURE 2-1. (continued)

100 100
90 90
80 80
70 Warfarin steady-state 70
concentration achieved
60 60
50 50
40 40
of clotting factors
30 30
% Normal concentration
20 20
% Warfarin steady-state achieved
10 10
0 0
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Time (hours)
 = factor II ;  = factor VII; = factor IX;  = factor X ; x = warfarin.
FIGURE 2-2. Coagulation Factor Decline Over Time

Source: Reprinted with permission from Eckhoff CD, DiDomenico RJ, Shapiro NL. Initiation warfarin therapy: 5 mg versus 10 mg. Annals of
Pharmacotherapy, © 2004; 38:2115-21; reprinted by permission of SAGE Publications, Inc.
WARFARIN 17
in Asians, is associated with lower gene expression and significantly lower

warfarin dose requirements than are seen in patients with the G allele.
Numerous investigations have confirmed that CYP2C9 and VKORC1
genotypes account for 10-45% of variability in warfarin dosing requirements.
A number of dosing algorithms that incorporated CYP2C9 genotype and
VKORC1 haplotype have been investigated, with results suggesting that
pharmacogenetics-guided warfarin dosing might be a promising advance
in clinical care. But recent randomized trials have demonstrated conflicting
results with regard to the influence of genomic-guided dosing on a surrogate
endpoint (time in therapeutic range), and no trial has evaluated meaningful
clinical endpoints. As a result, the use of genetic testing to guide warfarin
dose determination is not a routine component of clinical care.
• W
hen warfarin therapy is started, initial INR
(international normalized ratio) test results
reflect elimination of factor VII. However, the
anticoagulant effect of warfarin is not established
until factors II and X are eliminated. Thus,
when treating acute thrombosis, a bridge with
a traditional immediate-acting anticoagulant
(heparin, LMWH, fondaparinux) is necessary.
• D
ue to the long half-life of warfarin, every dose
taken within the last 7 days must be considered
when making dosing decisions. However,
doses taken 2–3 days ago will have the most
prominent effect on the current day’s INR, and
these require careful consideration when making
further dosage adjustments.
Vitamin K Interactions3
Changes in dietary vitamin K intake can alter response to warfarin therapy.
Accordingly, patients should be instructed to recognize foods high in vitamin
K and to maintain a stable and consistent intake of high vitamin K-containing
foods. Examples of foods high in vitamin K are listed below (Table 2-4). The
USDA Food Composition database can be searched to obtain a thorough
list of foods containing vitamin K. This database is available at: https://ndb.
nal.usda.gov/ndb/nutrients/index.
WARFARIN 19
TABLE 2-4: Sample Foods High in Vitamin K

Broccoli Lettuce
Brussels sprouts Kale
Cabbage Mustard greens
Chard Parsley
Chives Scallions
Collard greens Spinach
Endive Turnip greens
• Hospitalized patients often have changes in

diet, causing fluctuating warfarin requirements
and dosing that is distinctly different from their
outpatient requirements. Further, enteral and
parenteral nutritional supplements containing
vitamin K further complicate matters. It is
important for clinicians to follow changes
in feeding rates and diets as these influence
warfarin dosing.
Disease State Interactions

Numerous disease states influence the pharmacokinetics and pharmaco-
dynamics of warfarin (Table 2-5). Progression and improvement in these
factors can influence warfarin dosing requirements and should be considered
when evaluating INR response to warfarin therapy.
• P
atients who experience acute liver dysfunction
(hypotensive episodes, liver metastasis, etc.)
while in the hospital will be extremely sensitive
to warfarin. Vigilance is necessary when
managing warfarin in these patients (daily
INRs and warfarin adjustments), and sometimes
holding warfarin until liver function recovers is
required. Close consultation with the attending
physician is advised in these situations.
• A n elevated INR in patients with hepatic
disease does not assure a particular degree of
anticoagulation, as it is associated with broad
impairment of clotting factor synthesis rather
than specific drug-induced changes in vitamin K
dependent clotting factors.
(continued)
TABLE 2-5: Drug-Disease State Interactions3

Clinical Condition Effect on Warfarin Therapy
Advanced age Increased sensitivity to warfarin due to reduced vitamin K stores and/or
lower plasma concentrations of vitamin K dependent clotting factors
Pregnancy Teratogenic; avoid exposure during pregnancy
Lactation Not excreted in breast milk; can be used postpartum by nursing

mothers
Alcoholism • Acute ingestion: inhibits warfarin metabolism, with acute elevation

in INR
• Chronic ingestion: induces warfarin metabolism, with higher dose
requirements
Liver disease • Possible coagulopathy induced by decreased production of

clotting factors, with baseline elevation in INR
• Possible reduced clearance of warfarin
Renal disease Reduced activity of CYP2C9, with lower warfarin dose requirements
Heart failure Reduced warfarin metabolism due to hepatic congestion
Cardiac valve Enhanced sensitivity to warfarin postoperatively due to

replacement hypoalbuminemia, lower oral intake, decreased physical activity, and
reduced clotting factor concentrations after cardiopulmonary bypass
Nutritional status Changes in dietary vitamin K intake (intentional or as the result of

disease, surgery etc.) alter response to warfarin
Use of tube feedings Decreased sensitivity to warfarin, possibly caused by changes in

absorption or vitamin K content of nutritional supplements
Thyroid disease • Hypothyroidism: decreased catabolism of clotting factors

requiring increased dosing requirements
• Hyperthyroidism: increased catabolism of clotting factors causing
increased sensitivity to warfarin
Smoking and tobacco • Smoking: may induce CYP1A2, increasing warfarin dosing
use requirements
• Chewing tobacco: may contain vitamin K, increasing warfarin
dosing requirements
Obesity Increased warfarin dosing requirements observed inconsistently in

obese and morbidly obese patients
Fever Increased catabolism of clotting factors, causing acute increase in INR
Diarrhea Reduction in secretion of vitamin K by gut flora, causing acute increase

in INR
Acute infection/ Increased sensitivity to warfarin

inflammation
Malignancy Increased sensitivity to warfarin by multiple factors
INR: international normalized ratio

WARFARIN 21
• T
hyroid status is often not a clinical concern
unless thyroid status is changing. In other
words, stable levothyroxine patients in euthyroid
status should be treated like patients without
thyroid issues. Hypothyroid patients initiated
on levothyroxine or having levothyroxine dose
increases may require warfarin dose reduction.
Patients undergoing hyperthyroid treatment will
likely require warfarin dose increases.
• P
reviously stabilized warfarin patients often
have elevated INRs when admitted with
decompensated heart failure. This often requires
holding or reducing their warfarin dose by about
50% for 1–2 days after admission, but as they
diurese and improve, they often require their
previous warfarin dose. Clinicians are often
reluctant to resume previous dosing, thinking
“the dose made them go high,” overlooking the
acute illness as the cause rather than the dose.
As with all warfarin patients, it is important for
the clinician to understand the patient’s complete
clinical status and not just “treat the numbers.”
Drug-Drug Interactions5
Numerous prescription and nonprescription drugs as well as natural/herbal
products interfere with the pharmacokinetics and/or pharmacodynamics of
warfarin. The addition or discontinuation of interacting agents can profoundly
impact warfarin dose-response and requires that current medication use be
evaluated routinely in patients taking warfarin so that appropriate monitor-
ing and dosage adjustments may occur. Timely management can avoid
significant interactions and allow for interacting drugs to be used concur-
rently with warfarin. There is considerable variability in the time of onset,
extent of influence, and time of offset of drug interactions with warfarin,
requiring individualization of dosing and monitoring any time a potentially
interacting medication is started, stopped, or used on an as-needed basis
(Tables 2-6 and 2-7).
TABLE 2-6: Warfarin Drug Interactions
Target Effect Response Examples (Noninclusive)
Clotting Increased synthesis Decreased INR Vitamin K

factors
Decreased synthesis Increased INR Broad spectrum antibiotics
Increased catabolism Increased INR Thyroid hormones
Decreased catabolism Decreased INR Methimazole Propylthiouracil

Warfarin Inhibition Increased INR Acetaminophen Allopurinol Amiodarone Azole antifungals

metabolism
Cimetidine Fluoroquinolones Macrolides Metronidazole
Propafenone SSRIs Statins Sulfa antibiotics
Induction Decreased INR Barbiturates Carbamazepine Doxycycline Griseofulvin
Nafcillin Phenytoin Primidone Rifampin
Hemostasis Additive antithrombotic effects Increased bleeding risk Aspirin NSAIDs Salicylates GPIIb/IIIa inhibitors
Additive anticoagulant response Increased bleeding risk Heparin LMWH Direct thrombin inhibitors Thrombolytics
Absorption Reduced Decreased INR Cholestyramine Colestipol Sucralfate
Unknown Decreased INR Ascorbic acid Azathioprine Corticosteroids Cyclosporin
Increased INR Androgens Clofibrate Cyclophosphamide Gemfibrozil
INR: international normalized ratio, LMWH: low molecular weight heparin, NSAIDs: non-steroidal anti-inflammatory drugs, SSRIs: selective serotonin reuptake inhibitors
WARFARIN 23
TABLE 2-7: Indications and Goal INR1

Indication Target INR (range)
Atrial fibrillation 2.5 (2–3)
Atrial flutter 2.5 (2–3)
Cardioembolic stroke 2.5 (2–3)
Left ventricular dysfunction 2.5 (2–3)
Myocardial infarction 2.5 (2–3)
Venous thromboembolism (treatment and prophylaxis) 2.5 (2–3)
Valvular heart disease 2.5 (2–3)
Valve replacement, bioprosthetic 2.5 (2–3)
Valve replacement, mechanical Also see Chapter 16
Aortic, bileaflet 2.5 (2–3)
Aortic, other 3 (2.5–3.5)
Mitral, all 3 (2.5–3.5)
Other mechanical devices See Chapter 17
• P
atient and medical staff education on warfarin
interactions reduces hospital admissions by
improving warfarin management and preventing
warfarin misadventures. Hospital admissions
secondary to warfarin drug interactions provide
an opportunity to educate the prescriber, patient’s
outpatient pharmacy, and the patient on
interaction screening.
• I nteractions involving inhibition of S-warfarin
metabolism are more severe and may require
preemptive warfarin dose adjustments or
interchange to safer alternatives. Interactions
involving the less potent R-isomer can often be
managed by daily INR monitoring and usually
cause less dramatic INR elevations.
(continued)
• C
learly determining if a medication, even those
known to interact, caused an INR elevation in
hospitalized patients is difficult because acute
illnesses may also elevate the INR. A good
example is a patient receiving metronidazole for
Clostridium difficile colitis. When an INR bump
occurs, is it from the metronidazole, the severe
diarrhea, poor vitamin K intake, or all of the
above? Often it is a combination of factors, and
the presumed “drug interaction” may become less
pronounced as the patient recovers from illness.
DOSE MANAGEMENT
Dosage Form Availability

Warfarin is available in brand (Coumadin), branded generic (Jantoven), and
various unbranded generic formulations that are 100% bioavailable. The
tablets, which can be crushed, are color coded to identify strength. The
10-mg tablet contains no dyes and can be used for patients in whom dye
allergies are suspected or confirmed (Table 2-8).
Initiation Dosing
After obtaining a baseline INR, which can be used to identify patients with
underlying coagulopathy, warfarin therapy is initiated at a starting dose. Two
general methods of warfarin initiation dosing are available.
TABLE 2-8: Tablet Strengths and Colors (see Figure 2-1)

Tablet Strength Color
1 mg Pink
2 mg Lavender
2.5 mg Green
3 mg Tan
4 mg Blue
5 mg Peach
6 mg Teal
7.5 mg Yellow
10 mg White
WARFARIN 25
Average Daily Dosing Method3,6

Although dosing requirements vary considerably among patients, from as
little as ≤1 mg/day to ≥20 mg/day to reach a therapeutic INR of 2–3, the
average dosing requirement is approximately 5 mg daily. The average daily
dosing method for warfarin initiation uses a starting dose of 5 mg daily,
with subsequent dosing adjustments guided by INR response. A well-known
algorithm uses two 5-mg doses and day 3 INR to guide doses on days 3 and
4, following by a day 5 INR to guide doses on days 5–7. An institutional hybrid
using 5 mg daily for 3 days (2.5 mg daily for patients with factors known to
increase sensitivity to warfarin) is described below. This type of initiation is
useful for outpatients, in which daily INR monitoring is inconvenient and can
also be a reasonable starting point for inpatients that are otherwise clinically
stable (Table 2-9).
Flexible Initiation Dosing Nomograms3,7-9
For inpatients, in which daily INR monitoring is available, a flexible initiation
nomogram can be helpful. Several algorithms have been developed that
utilize daily INR results to guide warfarin dosing for the first 4–6 days of
therapy. These algorithms may begin with either a 5-mg or 10-mg starting
dose, but 10-mg initiation typically results in a higher likelihood of over-
anticoagulation.
It is critical to appreciate that warfarin dosing nomograms/algorithms have
most often been developed and validated in stable, healthy outpatients.
Many of these studies have significant exclusion criteria (such that a majority
of hospitalized patients were not included) and provide no information on
whether or not changes in interacting drugs were included or considered.
Dosing nomograms offer a reasonable starting point for warfarin dose adjust-
TABLE 2-9: Warfarin Initiation Nomogram

Nonsensitive Patients Sensitive Patients
Initial dose 5 mg every day × 3 days 2.5 mg every day × 3 days
First INR
<1.5 7.5–10.0 mg every day × 2–3 days 5–7.5 mg every day × 2–3 days
1.5–1.9 5 mg every day × 2–3 days 2.5 mg every day × 2–3 days
2–3 2.5 mg every day × 2–3 days 1.25 mg every day × 2–3 days
3.1–4 1.25 mg every day × 2–3 days 0.5 mg every day × 2–3 days
>4 Hold until INR <3 Hold until INR <3
Subsequent dosing Continue dose escalation and frequent monitoring until lower limit of
and monitoring therapeutic range is reached.
INR: international normalized ratio, x: times

• C
linicians need to identify factors that may
increase sensitivity to warfarin when initiating
therapy, including interacting medications,
elderly, race, malnutrition, and disease states
like heart failure, acute infections, etc. For these
reasons, acutely ill patients starting warfarin
should be initiated on lower doses such as 2.5–3
mg of warfarin per day.
ments but should never be used in an “absolute” manner. Thorough patient

assessment and clinical judgment are imperative components of warfarin
dose management.
BRIDGING ANTICOAGULATION
Due to the prolonged onset of action of warfarin, it is sometimes necessary
to overlap with a short-acting anticoagulant, typically IV heparin or sub-Q
low molecular weight heparin. This overlap is often referred to as bridging.
When treating acute thrombosis, bridging continues for a minimum of 5 days
and until the INR is greater than the lower limit of the goal INR range. When
no acute thrombosis is involved, bridging can be discontinued once the INR
reaches the lower limit of the therapeutic range, with no minimum duration.
Maintenance Dosing3
Once the therapeutic INR range has been reached and warfarin therapy is
essentially at steady state, dosing adjustments are based on routine INR
monitoring and assessment of factors that may have resulted in the INR being
below, within, or above the therapeutic range. Dosing adjustments are based
on percent changes in the weekly (or in some cases, daily) dose, taking into
consideration the tablet size available to the patient. As with initiation therapy
algorithms, maintenance therapy algorithms must be used with considerable
clinical judgment. When the INR test result is unexpected or does not fit the
clinical context, laboratory error should be considered (Table 2-10).
When CYP2C9 and/or VKORC1 genotype information is available for a
patient, these parameters can be incorporated into determining warfarin
maintenance dose. The Clinical Pharmacokinetics Implementation Consortium
provides recommendations and algorithms based on available evidence.10
Frequency of INR Monitoring1,3

Frequency of monitoring should be guided by clinical considerations (e.g.,
initiation versus maintenance dosing, stable versus unstable therapy) as well
as by practical issues (e.g., patient convenience, vacations, weekends). If
followup intervals need to be extended for a particular circumstance, a more
conservative dosing strategy may be warranted (Table 2-11).
WARFARIN 27
TABLE 2-10: Warfarin Maintenance Dosing Nomogram

For Goal INR 2–3 Adjustment For Goal INR 2.5–3.5
INR <1.5 • Consider a booster dose of 1.5–2 times INR <2

daily maintenance dose.
• Consider resumption of prior maintenance
dose if factor causing decreased INR is
considered transient (e.g., missed warfarin
dose/s).
• If a dosage adjustment is needed, increase
maintenance dose by 10–20%.
INR 1.5–1.8 • Consider a booster dose of 1.5–2 times INR 2–2.3

daily maintenance dose.
dose/s).
INR 1.8–1.9 • No dosage adjustment may be necessary INR 2.3–2.4

if the last two INRs were in range; if there
is no clear explanation for the INR to be
out of range; and if, in the judgment of the
clinician, the INR does not represent an
increased risk of thromboembolism for the
patient.
• Consider a booster dose of 1.5–2 × daily
maintenance dose.
dose/s).
INR 2–3 • Desired range INR 2.5–3.5
INR 3.1–3.2 • No dosage adjustment may necessary if INR 3.6–3.7

the last two INRs were in range; if there
is no clear explanation for the INR to be
out of range; and if, in the judgment of
the clinician, the INR does not represent
an increased risk of hemorrhage for the
patient.
dose if factor causing elevated INR is
considered transient (e.g., acute alcohol
ingestion).
• If a dosage adjustment is needed, decrease
(continued)
TABLE 2-10: (Continued)

For Goal INR 2–3 Adjustment For Goal INR 2.5–3.5
INR • Consider holding ½ –1 dose. INR 3.8–3.9

3.3–3.4 • Consider resumption of prior maintenance
ingestion).
• If a dosing adjustment is needed, decrease
INR • Consider holding 1 dose. INR 4–4.4

3.5–3.9 • Consider resumption of prior maintenance
ingestion).
INR ≥4* • Hold until INR <upper limit of therapeutic INR ≥4.5
range.
• Consider use of minidose oral vitamin K.
ingestion).
*For management of critically elevated INR and/or serious bleeding, see Table 2-12.
INR: international normalized ratio, x: times
• D
ata on how often INRs are required in the
inpatient setting are scarce. Considering the
instability of patients in high acuity settings,
increased probability of medication interactions,
and changes in dietary intake of vitamin K,
many hospitals often have policies requiring
daily INRs and daily warfarin dosing. This
ensures patients, at least in theory, are reassessed
daily.
• M
any hospitals standardize their warfarin
administration time to the evening, so dose
adjustments can be made the same day as an
INR check and to match when most patients take
warfarin at home.
WARFARIN 29
TABLE 2-11: Frequency of Monitoring by Clinical Setting

Clinical Setting Frequency of Monitoring
Initiation therapy Inpatient initiation Daily
Outpatient flexible initiation Daily through day 4, then within

3–5 days
Outpatient average daily dosing Every 3–5 days until INR >lower
method limit of therapeutic range, then
within 1 week
After hospital discharge If stable, within 3–5 days

If unstable, within 1–3 days
First month of therapy At least weekly
Maintenance therapy Medically stable inpatients Every 1–3 days
Medically unstable inpatients Daily
After hospital discharge If stable, within 3–5 days

If unstable, within 1–3 days
Routine followup in medically Every 4–12 weeks

stable and reliable patients
Routine followup in medically Every 1–2 weeks

unstable or unreliable patients
Dose held today for significant In 1–2 days

over-anticoagulation
Dosage adjustment today Within 1–2 weeks
Dosage adjustment ≤2 weeks ago Within 2–4 weeks
Management of Nontherapeutic INRs with or without

Complications1,11
Although general guidelines are available for the management of patients
with nontherapeutic INRs as well as bleeding or thromboembolic compli-
cations, some practical issues should be considered too. For patients with
limited access to healthcare or who live in remote areas, it may be advis-
able to prescribe several tablets of oral vitamin K to have available on an
“as needed” basis. Patients with a significant degree of variability in INR
response may benefit from same-daily dosing of warfarin (5 mg every day,
5.5 mg every day, etc.) rather than alternating dosing (e.g., 7.5 mg Mondays
and Friday, and 5 mg all other days), as well as supplementation with mini-
dose vitamin K (50–100 mcg orally using commercial products available in
health food stores as dietary supplements). Most importantly, the clinical
context of out-of-range INRs needs to be considered before any interven-
tion is made (Table 2-12).
TABLE 2-12: Management Strategies for Complications of

Warfarin Therapy
Clinical Scenario Strategy
Thromboembolic recurrence despite Treat with full intensity heparin/LMWH/fondaparinux

adequate anticoagulation with warfarin or switch to a direct-acting oral anticoagulant with or
without bridging depending on agent selected.
INR <1.5 • Increase maintenance dose if appropriate.

• Avoid bridging for a single subtherapeutic INR.
Elevated INR <4.5 and no evidence of Hold warfarin until INR < upper limit of therapeutic
bleeding range.
INR 4.5-10 and no evidence of • Hold warfarin until INR < upper limit of
bleeding therapeutic range.
• Consider low dose oral vitamin K.
>10 and no evidence of bleeding • Hold warfarin until INR < upper limit of
therapeutic range.
• Give low dose oral vitamin K.
Serious or life threatening bleeding • Hold warfarin.

• Give 4-factor prothrombin complex concentrate
for rapid reversal. See Chapters 8 and 9.
• Give vitamin K 5-10 mg IV by infusion. See
Chapters 8 and 9.
INR: international normalized ratio, LMWH: low molecular weight heparin
• I njectable vitamin K can be given orally when

doses less than 2.5 mg are desired. Many
hospital pharmacies use parenteral vitamin K for
oral administration due to the high cost of oral
vitamin K tablets.
HEMORRHAGIC RISK ASSESSMENT12-17

Bleeding is the most significant adverse effect associated with warfarin
therapy. Several scoring systems have been developed to assess the risk
of major bleeding in patients taking warfarin. These scoring systems can
be helpful in determining risk versus benefit of oral anticoagulation and
in guiding the management of over-anticoagulation in individual patients
(Table 2-13).
WARFARIN 31
TABLE 2-13: Bleeding Risk Scoring Systems

Scoring System Criteria Point Scores Risk of Major Bleeding
Outpatient AGE >65 1 point Score Major bleeding

bleeding risk 0 0.8%/pt yr
index (validated History of GI bleed 1 point 1–2 2.6%/pt yr
in outpatients 3–4 9.7%/pt yr
taking warfarin) History of stroke 1 point
One or more of diabetes, 1 point

Hct <30, Scr >1.5, or
recent MI
HEMORR2HAGES Hepatic or renal disease 1 point Score Major bleeding

(validated in 0 1.9%/pt yr
AF patients) Ethanol abuse 1 point 1 2.5%/pt yr
2 5.3%/pt yr
Malignancy 1 point 3 8.4%/pt yr
4 10.4%/pt yr
Older (age >75) 1 point
≥5 12.3%/pt yr
Reduced platelet count or 1 point
function
Rebleeding risk 2 points
Hypertension (uncontrolled) 1 point
Anemia 1 point
Genetic factors (CYP2C9 1 point

polymorphism)
Excessive fall risk 1 point
Stroke 1 point
HAS-BLED Hypertension 1 point Score Major bleeding

(validated in 0 1.13%/pt yr
AF patients) Abnormal renal or hepatic 1−2 points 1 1.02%/pt yr
function 2 1.88%/pt yr
3 3.74%/pt yr
Stroke 1 point 4 8.7%/pt yr
≥5 12.5%/pt yr
Bleeding 1 point
Labile INRs 1 point
Elderly (age >65) 1 point
Concurrent antiplatelet/ 1−2 points

NSAIDs or alcohol use
(continued)

Scoring System Criteria Point Scores Risk of Major Bleeding
ATRIA Anemia 3 points Score Major bleeding

(validated in 0–3 0.8%/pt yr (low risk)
AF patients) Severe renal disease 3 points 4 2.6%/pt yr
(intermediate risk)
Age >75 2 points 5–10 5.8%/pt yr (high
risk)
Prior bleeding 1 point
Hypertension 1 point
Findings from Recent major bleeding 2 points Score Major bleeding

REITE Registry 0 0.1%/pt yr (low risk)
(validated in Creatinine >1.2 mg/dL 1.5 points 1–4 2.8%/pt yr
patient with (intermediate risk)
acute venous Anemia 1.5 points >4 6.2%/pt yr (high
thrombo- risk)
Cancer 1 point
embolism)
Pulmonary embolism 1 point
Age >75 years 1 point
AF: atrial fibrillation, GI: gastrointestinal, Hct: hematocrit, INR: international normalized ratio,
MI: myocardial infarction, NSAIDs: nonsteroidal anti-inflammatory drugs, Pt yr: patient year, Scr:
serum creatinine
• P
atient education on bleeding: minor nose bleeds,
gum bleeding after brushing, and increased
bruising are common for warfarin patients.
However, they may also indicate an elevated
INR in a patient not used to these experiences
while therapeutic on warfarin. Patients require
education on how to manage these symptoms
and advice on specific symptoms requiring
medical attention. Patients prone to minor nose
bleeds should be informed of nasal moisturizers
that reduce this occurrence. Patients tend to
bruise easily on warfarin; however, bruises
should not continue to grow after several days.
• R
ed or brown urine as well as red or black
tarry stools are often symptoms of more serious
bleeding. These require medical attention and
INR check. Patients with hemorrhoids or frequent
constipation may have blood on toilet paper.
Stool softeners can be helpful in this situation.
These symptoms, however, should also be
WARFARIN 33
evaluated by a physician in patients recently

starting warfarin or for those not having this
problem previously. Positive stool guaiacs and
red or black tarry stools can be symptoms of a
more serious condition such as malignancy or
the result of excessive anticoagulation. Warfarin
patients who develop occult gastrointestinal
(GI) bleeding have a 5–25% chance of finding
a malignant source with further evaluation.
Any bleeding regardless of source, which doesn’t
resolve quickly with minor attention, requires
medical attention and check of the INR.
REFERENCES AND KEY ARTICLES*

*1. Ageno W, Gallus AS, Wittkowsky AK, et al. Oral anticoagulant therapy: Antithrombotic
Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e89S-e119S.
2. Eckhoff CD, DiDomenico RJ, Shapiro NL. Initiation warfarin therapy: 5 mg versus 10
mg. Ann Pharmacotherapy. 2004;38:2115-2121.
*3. Wittkowsky AK. Warfarin. In: Murphy JE, ed. Clinical Pharmacokinetics. 6th ed.
Bethesda, MD: ASHP; 2017.
4. Johnson JA, Cavallari LH. Warfarin pharmacogenetics. Trends Cardiovasc Med.
2015;15:33-41.
*5. Wittkowsky AK. Drug interactions with oral anticoagulants. In: Colman RW, Marder VJ,
Clowes AW, et al. Hemostasis and Thrombosis. Basic Principals and Clinical Practice.
5th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
6. Kovacs MJ, Anderson DA, Wells PS. Prospective assessment of a nomogram for
the initiation of oral anticoagulant therapy for outpatient treatment of venous
thromboembolism. Pathophysiol Haemost Thromb. 2002;32:131-133.
7. Fennerty A, Dolben J, Thomas J, et al. Flexible induction dose regimen for warfarin and
prediction of maintenance dose. Br J Med. 1984;288:1268-1270.
8. Roberts GW, Helboe T, Nielsen CBM, et al. Assessment of an age-adjusted warfarin
initiation protocol. Ann Pharmacotherapy. 2003;37:799-803.
9. Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better. Ann Intern Med.
1997;127:332-333.
10. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation
Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin
Pharmacol Ther. 2011;90:625-629.
*11. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of
antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis. 9th
ed. American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e152S-e184S.
12. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting
risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105:91-99.
13. Aspinall SL, DeSanzo BE, Trilli LE, et al. Bleeding risk index in an anticoagulation
clinic: assessment by indication and implications for care. J Gen Intern Med.
2005;20:1008.
14. Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting
hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart
J. 2006;151:713-719.
15. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to
assess 1 year risk of major bleeding in patients with atrial fibrillation. The Euro Heart
Survey. Chest. 2010;138:1093-1100.
16. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated
hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
J Am Coll Cardiol. 2011;58:395-401.
17. Ruiz-Gimenez N, Suarez C, Gonzalez R, et al. Predictive variables for major bleeding
events in patients presenting with documented acute venous thromboembolism.
Findings from the REITE Registry. Thromb Haemost. 2008;100:26-31.
3
Chapter
UNFRACTIONATED HEPARIN
William E. Dager
INTRODUCTION
Unfractionated heparin (UFH) is one of the most commonly used parenteral
anticoagulants. Heparin is used in a wide variety of settings to prevent or treat
thromboembolism. It can be used systemically, instilled in catheters, used to sustain
device functions, or coat artificial surfaces and lines to prevent thrombotic compli-
cations. As one of the oldest anticoagulant agents in use, many of its applications
developed over time and had limited assessment of efficacy from rigorous trials.
Despite availability of newer anticoagulants, UFH remains frequently used due to
its quick onset and offset and ease to reverse.
PHARMACOLOGY1,2
• UFH is a highly sulfated mucopolysaccharide, heterogeneous compound of which
one-third contains the pentasaccharide unit responsible for anticoagulant activity.
• UFH is an indirect-acting anticoagulant that forms a complex with antithrombin, increas-
ing the affinity and anticoagulant activity of antithrombin against clotting factors IIa
(18 saccharide sequence required) and Xa (5 saccharide sequence required). Factors
IXa, XIa, and XIIa are also inactivated.
• At higher concentrations, heparin chains unrelated to the pentasaccharide sequence
can catalyze thrombin by inhibiting thrombin via heparin cofactor II, or separately by
factor Xa generation through antithrombin and heparin cofactor II.
• UFH will not dissolve a formed clot but will prevent its propagation and growth.
• No differences in antithrombotic activity have been demonstrated between the various
UFH preparations.
INDICATIONS
Approved indications for UFH are listed in Table 3-1.
PHARMACOKINETICS/PHARMACODYNAMICS
The pharmacokinetic properties of UFH are listed in Table 3-2.
• The pharmacokinetics of UFH can be altered by factors such as age, thromboembolism
location, hepatic or renal impairment, and obesity.
35
TABLE 3-1: Approved Indications for Unfractionated Heparin

• Anticoagulant in blood samples for laboratory purposes
• Anticoagulant in blood transfusions, extracorporeal circulation, dialysis procedures
• Atrial fibrillation with embolism
• Diagnosis and treatment of acute and chronic consumptive coagulopathies (disseminated
intravascular coagulation [DIC])
• Prevention of clotting in arterial and cardiac surgeries
• Prophylaxis and treatment of peripheral arterial embolism
• Prophylaxis and treatment of venous thromboembolism
• The activated partial thromboplastin time

(aPTT)/anti-factor Xa activity from UFH can
be checked to verify appropriateness of the
dose for a particular treatment dosing interval.
For subcutaneous administration with higher
treatment goals, a 12-hour (trough) value can
be assessed. If this value is too low, an 8-hour
dosing interval may be considered. Similarly, if
an 8-hour trough value is in the upper portion
of the target range or higher, a 12-hour dosing
interval can be considered for ease of use. A
repeat trough value can be considered to validate
the regimen. Risk assessment for thrombosis,
bleeding, and compliance should be considered
when determining a subcutaneous dosing
regimen.
• Intramuscular administration is not
recommended due to erratic absorption and risk
of hematoma formation.
Change in Calibrators for UFH and Potency

In 2009, the United States Pharmacopeia (USP) updated the monograph for
heparin to be consistent with the World Health Organization (WHO) standards.
This update resulted in up to a 10% reduction in heparin potency (potency
per USP unit of heparin was up to 10% less than International Units). This
conversion created a concern among clinicians for a potential underdosing
of heparin. Consensus to date suggests that impact of this change on clinical
outcomes is minimal.6
UNFRACTIONATED HEPARIN 37
TABLE 3-2: Pharmacokinetic Properties of UFH3-5

UFH Properties Comment
Source Extracted from porcine intestinal mucosa or beef lung (currently

not available in the United States).
Molecular weight (daltons) Mean 15,000 (range 3,000–30,000)
Bioavailability Oral: UFH administered orally is not absorbed by the

gastrointestinal tract.
Intravenous: 100%—Rapid onset of anticoagulation action can
occur with an IV bolus followed by a continuous infusion; in
some situations (e.g., during cardiac procedures), IV bolus doses
may be repeated to maintain desired effects.
Subcutaneous: Highly variable (10–80%); generally,
approximately 20–30% but can be up to 80% with high doses.
• Because of the nonspecific binding of UFH to various
cellular proteins and cells and unpredictable sub-Q
bioavailability, notable inter- and intra-patient variability in
anticoagulant dose-response can occur.
• Bioavailability when given sub-Q may decrease when
vasoconstrictors are in use or in the critically ill in general.
• Effects from sub-Q injections typically have duration of
activity lasting 8–12 hr.
Activated clotting factors Factors IIa, IXa, Xa, XIa, XIIa
inhibited
Binding to proteins other Nonspecific binding to proteins and other cells; presence of
than target heparin-binding proteins, including acute phase reactants, can
vary in concentration during acute illness and affect the aPTT.
Ratio anti-Xa activity: 1:1

anti-IIa activity
Onset of action Rapid if sufficient amounts administered; IV faster than sub-Q.
Primary route of elimination Enzymatic degradation at low doses and renal at higher dose;
both zero-order and first-order processes can be present.
Clearance (Cl): 0.015–0.12 L/hr/kg
Higher clearance can occur in the setting of pulmonary
embolism.
Half-life (Sub-Q route) 30–150 min (dependent on dose and administration site, with
slower clearance at higher doses); may be slightly prolonged in
liver disease and end stage renal disease.
Volume of distribution 0.07 L/kg (range 0.04–0.14 L/kg); typically reflects blood
volume; distribution into the tissues can occur with large doses
(during cardiac bypass surgery).
Effects of protamine Complete neutralization
aPTT: activated partial thromboplastin time, hr: hour, IV: intravenous, L: liters, kg: kilograms,
sub-Q: subcutaneous, UFH: unfractionated heparin
INITIATING THERAPY
UFH is usually administered parenterally by intravenous (IV) or subcutaneous
injection. In some situations, heparin may be used by other purposes (such as
a bath) for instruments used in procedures, flushes in surgical processes, or
as a coating of dialyzers prior to use. It can also be imbedded into catheter
linings during their manufacture or locally infused to keep devices functional
(e.g., Impella catheters, see Chapter 17).
UFH for Flushing Catheters

• Saline and heparin are frequently instilled into catheters to keep them from
clotting. Saline is the preferred agent in peripheral IV lines.
• Depending on the manufacturer of the peripherally inserted central catheter
(PICC) line, heparin may or may not need to be instilled.
• The concentration and volume of heparin instilled will vary between catheters
with suggestions potentially provided by the catheter’s manufacturer. The lowest
amount of heparin to maintain patency should be considered (see Table 3-3
for examples).
• When using in the same line as an agent that is incompatible with heparin,
consider flushing first with saline prior to instilling the other agent.
• In some cases, high amounts of heparin are used—where the possibility of a
sufficient amount reaching the circulation to cause systemic anticoagulant effects
should be considered.
TABLE 3-3: Examples of Uses of Heparin Locks in Adults for

Selected Devices
Device Heparin Volume
Midline 10 units/mL 3 mL
PICC, non-tunneled and tunneled 10 units/mL 5 mL
Port 100 units/mL 3–5 mL

• Line flushing during percutaneous coronary

intervention (PCI): 200 units of IV heparin was
used to flush catheters in individuals receiving
fondaparinux undergoing PCI in the OASIS 5
trial to reduce thrombosis on the guidewire.7
Recent observations suggest that narrow target-
specific agents (e.g., fondaparinux and direct
acting oral anticoagulants) may not adequately
protect artificial surfaces from thrombosis
formation.
• he lack of more specific anticoagulants to
T
protect mechanical surfaces compared to heparin
may relate in theory to heparin’s effects of factors
XI and XII.
ADMINISTRATION: INTRAVENOUS OR
SUBCUTANEOUS
Bolus Dosing
• A bolus is typically used when immediate anticoagulation is necessary. If immedi-
ate anticoagulation is not required (i.e., active thromboembolism is not present),
a bolus may not be necessary.
• Dosing guidelines may consider specifying a maximum bolus and infusion rate
that triggers an additional assessment step for safety to prevent unintended
excessive doses of heparin (see Dose Capping section).
• Continuous IV infusion is preferred over intermittent IV boluses. Intermittent
bolus injections result in high peak anticoagulant levels that may be associated
with a higher risk of major bleeding.
• Dosing of UFH is generally based on patient’s weight (see Table 3-4).
{{ Weight-based UFH dosing regimens are more likely to exceed
the therapeutic aPTT threshold in the first 24 hours after initiating
treatment compared to more traditional dosing regimens, such as
a 5,000-unit bolus dose followed by an infusion administered at
1,000 units/hr.8
{{ For continuous infusion, the dose and target aPTT/anti-Xa may
depend on the indicated use (Table 3-5).
{{ UFH products are available in a wide variety of concentrations.
Solutions for injection range from 1,000 units/mL to 20,000 units/
mL, while flushes may include 1 unit/mL to 100 units/mL. Institu-
tional use of different concentrations should be avoided as much as
possible to minimize medication errors and ensure patient safety.
TABLE 3-4: Evidence Supporting Weight-Based Dosing

Compared to a Preset Bolus and Infusion Rate and the
Importance of Achieving Minimal aPTT Targetsa,8
N = 115 (VTE = 80)
Time Standard UFH Weight-based UFH P value

Bolus: 5,000 units Bolus: 80 units/kg
Continuous Infusion Continuous Infusion
started at 1,000 units/hr 18 units/kg/hr (total
body weight)
24 hr aPTT
Therapeutic 35% 57% <0.001
Subtherapeutic 58% 15% <0.001
Supratherapeutic 7% 27% <0.001
48 hr aPTT
Therapeutic 44% 65% <0.001
Subtherapeutic 49% 18% <0.001
Supertherapeutic 8% 18% <0.001
Minor/major bleeding 2% / 1% 2% / 0% NS
Recurrent VTE (3 months) 8 / 32 (25%) 2 / 41 (5%) 0.02
a
The key points of this analysis were that using a weight-based approach (using total body
weight) led to a higher incidence of aPTT values within or above the target range in the first
24–48 hours without increasing bleeding instances but decreasing recurrent VTE events five
fold. Some observations have linked increased bleeding to frequent excessive aPTT values or
higher doses during prolonged courses of therapy, suggesting some caution regarding frequent
supratherapeutic values beyond 48 hours.9,10
aPTT: activated partial thromboplastin time, hr: hours, NS: nonsignificant, UFH: unfractionated
heparin, VTE = venous thromboembolism
Dose Capping
• Adjusted and total body weight to a certain maximum dose should be consid-
ered to minimize potential excessive anticoagulation. The amount can vary
between indications.
{{ Bolus: Outside of arterial disease or during surgical procedures,
bolus doses beyond 4,000–5,000 units may not add any clinical
benefit and should be avoided.
{{ Large bolus doses may not be necessary to get a sufficient antico-
agulation effect. In one analysis, 3,000 units of heparin prior to
cardiac catheterization produced therapeutic aPTT values, with half
exceeding 140 seconds. Low values were only seen if the dose was
<32 units/kg (weight >92 kg).11
TABLE 3-5: Dosing Considerations for the Initiation of UFH1,14-16

Indication Bolus Dose Maintenance Dose
IV VTE treatment (DVT 80 units/kg (or 5,000 18 units/kg/hr; aPTT range

or PE) units) established by laboratory;
Lower doses (e.g., calibrated to correspond to
2000 units) have been anti-factor Xa activity of 0.3–0.7
suggested as an option. International Units/mL
PCI (with GP IIb/IIIa 50–70 units/kg Additional bolus doses

inhibitor) (common target low response
ACT 200–250 sec)
PCI (without GP IIb/ 70–100 units/kg Target ACT may depend on

IIIa inhibitor) the device and if a high or low
range card is used. Different
tests (e.g., Hemochron,
MedTronic, HemoTec) and card
range will give notably different
values. See Table 3-9.
Acute STEMI 60 units/kg 12 units/kg/hr

(patients receiving Max: 4,000 units Max: 1,000 units/hr
full-dose rt-PA) (common target aPTT 50–70
sec)a for at least 48 hr or until
revascularization
Acute STEMI 40 units/kg 7 units/kg/hr

(combination Max: 3,000 units Max: 800 units/hr
regimen with rt-PA) (common target aPTT 50–70
(See Chapter 6) sec)a
STEMI 60 units/kg 12 units/kg/hr (maximum 1000

Max: 4,000 units units) initially, adjusted to
maintain aPTT at 1.5–2 (e.g.,
50–70 sec) times control for 48
hr or until revascularization
Unstable angina or 60 units/kg 12 units/kg/hr

NSTEMI Max: 4,000 units Max: 1,000 units/hr; some
institutions use a higher
threshold to achieve target
ranges earlier
Stroke Historically has been In the early phase of an acute

avoided due to ischemic stroke, heparinization
bleeding concerns. or use of anticoagulation is not
Currently, consensus and generally recommended (Class
recommendations for III A). Use of heparin should
bolus dosing of heparin in be avoided for a minimum of
acute stroke are lacking. 24 hours after thrombolytic
therapy (Class III B). Overall,
use of heparin in acute stroke
has not shown to impact
outcomes. Some potential
exceptions, however, may exist
(see below).
(continued)

Indication Bolus Dose Maintenance Dose
Sub-Q DVT prophylaxis 5,000 units every 8–12 hr

(Note: q 12 hr dosing intervals
may be considered in low/
moderate risk, elderly, low
weight)
Dose in obesity unknown - See
Chapter 10
VTE treatment 250 units/kg (or 17,500 250 units/kg every 12 hr

(DVT or PE, with units)
monitoring)
VTE treatment 333 units/kg 250 units/kg every 12 hr

(DVT or PE, without
monitoring)
IM IM administration should be avoided because of frequent hematomas.

a
aPTT range will depend on the reagent’s sensitivity to heparin unique to each laboratory. aPTT
target range selection of VTE treatment may consist of the middle to upper portion of the
anti-factor Xa activity calibration. Anti-factor Xa activity targets with concurrent thrombolytic
therapy or ACS are unclear. See Chapter 6 (Table 6-6) for heparin dosing recommendations when
thrombolytic therapy is used.
ACT, activated clotting time, aPTT: activated partial thromboplastin time, DVT: deep vein
thrombosis, GP: glycoprotein, hr: hour, IM: intramuscular, IV: intravenous, kg: kilogram, NSTEMI,
non-ST elevation myocardial infarction, PCI, percutaneous coronary intervention, PE: pulmonary
embolism, q: every, rt-PA: recombinant tissue plasminogen activator, sec: second, STEMI: ST
segment elevation myocardial infarction, sub-Q: subcutaneous, VTE: venous thromboembolic
event
• Infusions: Depending on the situation, infusions for systemic anticoagulation

are typically initiated at 12–18 units/kg/hr, but may go up to 25 units/kg/hr.12
Capping the initial allowed infusion rate, unless otherwise specifically justified,
can avoid unintended or excessive dosing. On occasion, higher infusion rates
adjusted based on aPTT or anti-Xa activity may be needed.
{{ It has been suggested that the risk of bleeding may increase when
daily doses exceed 31,000 units/day.13
{{ In acute coronary syndromes (ACS), daily doses >1,667 units/hr
(>40,000 units/day) may not need to be adjusted upward when
the aPTT remains low if the measured anti-factor Xa activity is at
least 0.35 units/mL. In the American Heart Association non-ST
segment elevation myocardial infarction (AHA NSTEMI) guideline,
the maximum bolus of 60 units/kg is 4,000 units and infusion of
12 units/kg/hr up to 1,000 units is suggested followed by dosing
adjustment per established nomogram.14,15
• S etting a maximum “capped” dose for both the

bolus dose and separately the infusion rate may
avoid dosing errors that might occur from an
incorrect weight (or units such as pounds for kg),
or extra digit (500 units intended but 5,000 units
ordered). Capped doses may be different based
on the indicated use. Lower capped doses may
be considered in the setting of ACS compared to
PE. Higher doses may occur in the setting of PE
secondary to enhanced elimination.
• C
ommon order sets should be considered where
possible, especially if for the same indication. All
areas where adjusted dose heparin is used should
be easy to identify and revised as aPTT assay
reagents change.
• W
hen restarting anticoagulation in a patient
who recently received UFH, titration difficulties
may be avoided by considering the previous
dose required to reach and maintain therapeutic
values. Acute changes in clinical status, different
therapeutic goals, and safety concerns must also
be carefully assessed.
Fixed-dose UFH subcutaneous for VTE treatment has been explored while
transitioning to warfarin. No heparin-induced thrombocytopenia (HIT) was
observed; however, the course was relatively short.
In the setting of acute stroke, heparinization may not influence outcomes.
But in the following situations, it may be considered:
• Atrial fibrillation with intracardiac chamber thrombus on echocardiography
• Cerebral venous sinus thrombosis
• Presence of artificial valves, thrombus in the left atrium or ventricle, or recent
(past month) myocardial infarction
• Symptomatic dissection of the arteries providing blood flow to the brain after
CT scan has ruled out central nervous system hemorrhage
• Symptomatic intracranial or extracranial arteriosclerotic stenosis with crescendo
transient ischemic attacks or early progressive stroke
• Basilar artery occlusion
• Presence of established hypercoagulable states (Note: Nongenetic hypercoagu-
lable conditions at the time of the acute event may be misleading.)
TABLE 3-6: Estimating a Subcutaneous Heparin Regimen When

Transitioning from an IV Infusion in Treatment of VTE
• Dose subcutaneously administered q 12 hr = [last IV infusion rate/hr × 24] [1.2] / 2 (for
twice daily – every 12 hour dosing)
• “[1.2]” reflects the approximately 20% loss of bioavailability with the subcutaneous route.
• The common 250 units/kg every 12 hr dose for VTE treatment was determined by this
approach; 20% over the common 18 units/kg/hr IV infusion rate used in VTE.
hr: hour, IV: intravenous, VTE: venous thromboembolism, x: times
Transitioning from Intravenous to Subcutaneous UFH

• Depending on dose, onset of effect occurs within 1–2 hours with peak effect
achieved around 3 hours. Several days may be required to reach steady-state
pharmacodynamics for assessing values when subcutaneous UFH is given in full
therapeutic doses.
• Due to the lower and variable bioavailability of the subcutaneous route of
administration, higher doses of UFH should be initiated to attain therapeutic
anticoagulation effect quickly.
• For VTE treatment, target aPTT values (or equivalent anti-factor Xa activity of
0.3–0.7 units/mL) at 6 hours post administration should be considered (Table
3-14).16
• I n selected treatment situations where a low

molecular weight heparin (LMWH) may not be
an available option, UFH can be administered
subcutaneously every 8–12 hours. The dose can
be estimated from the IV infusion rate in Table
3-6. It may take several days for the aPTT
to reach steady state. The risk for HIT with
long-term subcutaneous UFH is not known. If
bleeding at injection sites is observed, consider
checking an aPTT and also checking the size of
the needle used.
• D
oses of 5,000 units every 8 hours in elderly,
low-weight individuals may yield aPTT values
close to or in the therapeutic range.
Use of UFH in Selected Procedures and Weight

Considerations
Dosing heparin in selected procedures is further described in Table 3-7 with
Table 3-8 providing some insights on trials exploring the obese population.
See Tables 3-7 and 3-8 for specific examples of UFH in selected procedures
and weight-based dosing.
TABLE 3-7: Examples of UFH Dosing in Selected Invasive

Procedures for Adults17-20
Indication Initial Bolus Dose Maintenance Dose
IV CABG 80–350 units/kg Target HR-ACT 250 to >400 sec

administration
On-pump CABG 250–400 units/kg Target HR-ACT 2.5 x baseline or
≥400 sec
Off-pump CABG 180 units/kg 3,000 units every 30 min

(with aspirin 600 (target HR-ACT ≥350 sec)
mg PR)
Vascular 100–150 units/kg 50 units/kg every 45–50 min

reconstruction
Cardiac AF ablation Heparin bolus Heparin infusion to sustain an

(50–150 units/kg). ACT of 300–400 sec. Target ACT
Timing may be (low range) 300–350 sec may be
operator preference considered with a higher goal to
but should be 400 sec if enlarged atria present.
administered prior Target range may be ACT range
to or immediately card and test used dependent
following transseptal (see Table 3-9). Post-procedure
puncture in AF. protamine can be considered—
If on warfarin, sheaths may be removed
higher heparin when ACT below 160–200 sec.
requirements may Anticoagulation agent chosen
occur if INR is below post-procedure is dependent
2 versus above 2. on the clinician’s choice. Due to
concerns for bleeding—lower
intensity anticoagulation (e.g.,
enoxaparin 0.5 mg/kg) may
be considered until bleeding
concerns subside.
Dialysis (normal 50 units/kg 500–1,500 units/hr

bleeding risk) (target LR-ACT 80% above
baseline)
Dialysis (increased 10–25 units/kg 250–500 units/hr

bleeding risk) (target LR-ACT 40% above
baseline)
(continued)

Indication Initial Bolus Dose Maintenance Dose
Other Impella (see May depend on Purge solution of dextrose

Chapter 17) the device inserted, 20% and heparin 50 units/mL
and several types is used to locally keep device
of Impellas are from clotting. Adjustments
available. in purge rate part of device
For insertion on programming. Higher purge
the left side, the rates may increase the heparin
following has been delivered and affect concurrent
suggested: systemic heparin therapy
Inserting requirements.
guidewire—ACT System infusion rate will need
goal >250 sec. to account for heparin given
Systemic heparin— both IV and through the purge
ACT of 160–180 sec solution.
suggested. For aPTT Lower heparin concentrations
monitoring, may within the purge (12.5 units/
depend on assay mL or 25 units/mL) can be
reagent sensitivity. employed if aPTT values are
One approach above desired range.
suggested an aPTT
60–80 sec using For Impella RP for the
a 12-unit/kg/hr right side of the heart,
infusion rate to start a separate approach to
with a 60-unit/kg heparinization has been
optional bolus. suggested. See manufacturers’
If receiving a recommendations. aPTT goals
GP IIb/IIIa agent, may not have been assessed
can insert guidewire and adjusted for different
at ACT value of 200 reagent sensitivities to heparin.
sec or higher.
Dialysis (very high Rinse dialyzer with Rinse dialyzer intermittently with
bleeding risk or 5,000–20,000 units saline (target blood flow ≥250
active bleeding) and flush with 0.5–2 mL/min).
L saline.
Hypothermia Therapeutic In general, protocols or

hypothermia may guidelines for dosing heparin
slow down the during hypothermia may
clotting cascade. require an adjustment to lower
Goals may be doses (e.g., ~50% reduction)
different with depending on the clinical
hypothermia during situation and temperature
surgery versus post- goals. The dose may need to
cardiac arrest. subsequently increase as the
patient is being warmed.
ACT: activated clotting time, AF: atrial fibrillation, aPTT: activated partial thromboplastin time,
CABG: coronary artery bypass graft, hr: hours, HR-ACT: high range-activated clotting time, IV:
intravenous, kg: kilograms, L: liters, LR-ACT: low range-activated clotting time, min: minutes, mL:
milliliters, PR: per rectum, sec: seconds
TABLE 3-8: Weight Considerations for UFH Dosing in Obesity

Source Observation
Raschke R et al. 8
See Table 3-4 (actual body weight [ABW] used)
Yee W et al.18 ABW more likely to get aPTT in range by 24 hr
Median infusion rate: 13 units/kg/hr
Morbidly obese: potential for severe overdose at 18 units/kg/hr
Max bolus: 10,000 units; Max infusion: 1,500 units/hr
Max weight: 184 kg (this patient therapeutic at 1,700 units/hr)
Rosborough TK19 anti-factor Loading dose (units): 450 × estimated blood volume (liters)
Xa activity monitoring Initial infusion (units/hr): 344.335 + estimated blood volume
(liters) × 257.962 – (age in years × 4.951)
Estimated blood volume: (liters)
Males: (0.3669 × height m3) + (0.03219 × wt kg) + 0.6041
Females: (0.3561 × height m3) + (0.03308 × wt kg) + 0.1833
Weight: median 77 kg (range 30 – 184 kg)
Myzienski AE et al.21 Literature review and case report in a 388-kg patient suggests a
dosing weight of IBW + 0.4 [ABW – IBW]
Riney JN et al.22 For aPTT similar to anti-factor Xa activity 0.3–0.7 units/mL
BMI ≥40 kg/m2: 11.5 units/kg/hr (mean wt 141 ± 32 kg)
BMI 25–39.9 kg/m2: 12.5 units/kg/hr (mean wt 89 ± 16 kg)
Normal: 13.5 units/kg/hr (mean wt 62 ± 11 kg)
Fan J et al.23 aPTT targets were achieved faster with heparin infusions based
on adjusted body weight over actual body weight. Use of actual
body weight dosing was associated with higher bleeding rates.
ABW: actual (total) body weight, aPTT: activated partial thromboplastin time, hr: hours, IBW: ideal
body weight, kg: kilograms, m3: cubic meters, UFH: unfractionated heparin, wt: weight, x: times
• The amount of heparin required to maintain a hemodialysis circuit is variable

depending on the approach (e.g., intermittent, extended duration, continuous),
the properties of the dialysis circuit, and the patient.
• Some hemodialysis machines are programmed to use preselected heparin
concentrations (i.e., 1,000 units/mL) for continuous infusions.
• Heparin requirements may be lower in extended daily dialysis (~650 units/
hr) compared to continuous renal replacement therapy (approximately 1,100
units/hr).
• Fewer patients on extended duration dialysis may require heparin compared to
continuous renal replacement therapy (CRRT).
• Consider using total body weight with a preselected maximum infusion rate cap
(i.e., 2,000 units/hr) that subsequently triggers an additional assessment to limit
unintended excessive dosing.
• B
ecause obesity is a risk factor for VTE, it is
important to achieve adequate anticoagulation as
soon as possible. The volume of distribution for
heparin correlates to blood volume and thus creates
a risk for overshooting targets in the very obese
patient (BMI ≥40 kg/m2 or >200 kg) if weight-
based dosing is not capped or adjusted accordingly.
Dosing caps can be considered to reduce the risk of
excessive anticoagulation; however, aPTT (or anti-
factor Xa activity) should be carefully measured
and infusions promptly adjusted to achieve targets
as soon as possible in the setting of an acute
thromboembolic event. Table 3-8 provides insights
on how to approach heparin dosing in this setting.
• A s the patient’s weight increases, the amount of heparin
required on a unit/kg per body weight may decline.
• a PTT and anti-factor Xa assay monitor may not
correlate in obesity.
MONITORING AND DOSING ADJUSTMENTS

Clinical Challenge—Transitioning from an Oral Anti-Xa
Agent to Heparin Infusion
Presence of an oral anti-Xa agent (e.g., apixaban, rivaroxaban, edoxaban,
betrixaban) in the system can elevate the heparin calibrated anti-Xa values. It is
unclear if the total anti-Xa activity with the combined agents provides the same
degree of anticoagulation as each agent individually and carries the potential
for initially under-dosing or down titration of unfractionated heparin in the
first few days of therapy, or at least the need to titrate up the heparin infusion
as the oral agents’ effects wear off. The effects of the oral agents, including
shorter acting apixaban, may last for over 48 hours from the last dose, with
the occasional rare case of longer effects if a long-acting agent, high levels,
or a notable reduction in clearance is present. Consider adding both aPTT
and anti-Xa activity as baseline laboratory assessments prior to starting the
heparin infusion. One option may be manage with the aPTT until the DOAC
effects have dissipated. Presence of a high baseline aPTT and INR may suggest
excessive DOAC effects present. In high thrombosis risk situations (e.g., new
STEMI and post thrombolysis), the risk of bleeding and recurrent thrombosis
should be evaluated. Should heparin be continued (e.g., 2–3 days post lytic)
when an oral anti-Xa agent had recently been administered, anti-Xa values
may be elevated and drive either holding or lowering heparin infusion rate.
Consider using the aPTT to manage the heparin infusion and capping how low
the infusion rate may go and assess for thrombosis or bleeding.
TABLE 3-9: Laboratory Tests Used in the Monitoring of UFH*a

Test Monitoring Considerations
aPTT Target range will vary between assays depending on the lot of each reagent
used; the aPTT is typically used for lower intensity of heparin anticoagulation
effects such as prophylaxis to VTE treatment; this assay can identify presence
of diminished response to UFH if antithrombin deficiency is present.
aPTT values obtained via central venous access devices may yield higher
values than by venipuncture.
Anti-factor Xa As with the aPTT, anti-factor Xa activity calibrated to heparin is an alternative

activity assay for measuring lower intensity of heparin anticoagulation effects such as
prophylaxis to VTE treatment; this assay can identify presence of diminished
response to UFH if high factor VIII concentrations are present.
Anti-factor Xa assays may or may not add antithrombin into the process and
potentially yield different results. (See Table 3-10)
Low response Typically used in cardiac interventional procedures such as PCI; measures the
ACT intermediate range of heparin anticoagulation; ACT values may vary between
tests. (Hemochron values yield higher results than MedTronic values in the
upper part of the ACT range.)
High response Used during high ranges of heparinization such as during cardiopulmonary
ACT bypass; may not detect presence of heparin at concentrations used to treat
VTE.
Protamine See Chapter 21

a
titration
*See Appendix L: Considerations for Transitioning from aPTT to Anti-Xa to Manage Heparin
Therapy.
ACT: activated thrombin time, aPTT: activated partial thromboplastin time, PCI: percutaneous
coronary intervention, UFH: unfractionated heparin, VTE: venous thromboembolism
• T
arget ACT ranges may depend on the device,
specific test, and if a high or low range card
is used. Different tests (e.g., Hemochron,
MedTronic, HemoTec) and card ranges (high vs.
low) will give notably different values. The ACT
range established for each test specifically should
be used instead of a standard range. See Table
3-9.
TABLE 3-10: Target Anti-factor Xa Activity Level Considerations

for Selected Indications Using UFH24,a
Indication Target Anti-Factor Xa Activity Level
VTE prophylaxis 0.1–0.3 units/mL
VTE treatment 0.3–0.7 units/mL
ACS Target values vary. 0.35–0.7 units/mL as well as 0.3–0.55 units/mL

have been proposed (not validated) and may depend on concurrent
therapies (i.e., thrombolytics) used.
Pregnancy 0.35–0.7 units/mL can be considered; however, the target may

depend on the setting such as during pregnancy, during delivery and
use of spinal catheters, and the post-partum period.
a
Note: These values have not been validated for changes in heparin requirements, bleeding, or
thrombosis outcomes in clinical observations or trials. Anti-Xa activity values over 0.7 units/mL
have been associated with increased bleeding events.
ACS: acute coronary syndrome, mL: milliliters, VTE: venous thromboembolism
• D
ata on the optimal approach to heparin
management are limited. Some data describe
using a weight-based approach or a set minimal
dose or having aPTT in target range within 24
hours as factors associated with a reduced risk
for thrombosis (Table 3-11).
• M
ost trials comparing UFH to LMWH for VTE
treatment used set aPTT ratios for heparin.
Given the more sensitive heparin assays now in
use, underdosing of UFH may have been present
compared to current doses derived from aPTT
ranges determined by anti-factor Xa activity
titration. This may have created a bias favoring
LMWH in clinical trials that compared LWMH
to UFH targeting a predetermined aPTT (60–80
sec) vs. more sensitive assays to heparin (e.g.,
aPTT target 80–110 sec for anti-factor Xa
activity of 0.3–0.7 units/mL).28
• S tudies establishing the aPTT range for many
devices may not have accounted for different assay
reagent sensitivities.
• E
xamples of heparin dosing using aPTT or anti-
Xa in VTE treatment are described in Tables
3-12, 3-13, 3-14.
TABLE 3-11: Trials Achieving a Therapeutic aPTT in the First

24–48 Hours after Initiating UFH Lower Risk of Recurrent
VTEa
Studies UFH Dose VTE Recurrence
Raschke R Weight-based vs. See Table 3-4

19928 5,000 unit-bolus and Weight-based had a fivefold lower incidence of
24,000 units/24 hr recurrent VTE at 3 months.
Hull 199725 aPTT over therapeutic range at 24 hr: 23.3%

incidence
The incidence of recurrent VTE is significantly lower
with aPTT in the therapeutic range at 24 hr.
Outlines importance of aPTT reaching target range
early.
Anand 1996 30,000 units/24 hr aPTT subtherapeutic 24 hr: 6.3%

Five Trials26 aPTT over lower therapeutic limit: 7%
Outlines that if 30,000 units/day are provided, no
evidence of improved efficacy observed with earlier
aPTT in range.
Anand 1997 5,000 bolus + ≥1,250 Low aPTT: odds 1.3 vs. therapeutic aPTT (at 24 and
Three Trials27 units/hr 48 hr) p = 0.56
Suggests the value of infusing at least 1,250 units/hr.
a
Controversy: It is unclear if an aPTT value within the target range at 24–48 hours or if daily doses
24,000–30,000 units are used lead to different outcomes. Lower daily doses and subtherapeutic
aPTT values in the setting of acute thromboembolism may be associated with increased recurrent
thromboembolism.
aPTT: activated partial thromboplastin time, hr: hours, VTE: venous thromboembolism
TABLE 3-12: Adjusted Dosing Nomogram Example for

Continuous Heparin Infusions Using the aPTT in VTE
Treatmenta
APTT (sec) Dose Adjustment Comments
Weight-Based Non-Weightb Based
<35 Bolus 40–80 units/kg Bolus 2,500–5,000 Consider bolus

Increase by 3 units/ units option if emergent
kg/hr Increase by 200–250 anticoagulation is
units/hr necessary.
35–49 Bolus 20–40 units/kg Bolus 1,000–2,500

Increase by units
2 units/kg/hr Increase by
100–200 units/hr
50–59 (50–70; see Increase by Increase by

Clinical Pearl below) 1 unit/kg/hr 50–100 units/hr
60–90c (70–90; see No change No change

Clinical Pearl below)c
91–105 Decrease by Decrease by

1 unit/kg/hr 50–100 units/hr
106–125 Decrease by Decrease by Option: Hold 30–60

2 units/kg/hr 100–200 units/hr minutes
>125 Decrease by Decrease by Option: Hold 1–2 hr

3 units/kg/hr 200 units/hr
a
Each nomogram should consider the reagent range used in each lab specific to the test and
reagent lot. This sample nomogram assumes an aPTT treatment range of 60–90 seconds based
on anti-factor Xa activity titration of 0.3–0.7 units/mL for VTE treatment. The aPTT range has to be
calibrated by each laboratory and will vary between lots of even the same reagent (see Chapter
21). The final nomogram for order sets should have specific numbers instead of a range. Smaller
bolus dosing may be an option.
b
Dose increase of 50–100 units/hr may depend on the patient weight.
c
Institution-specific therapeutic aPTT range of 60–90 seconds is equivalent to a plasma heparin
concentration of 0.3–0.7 anti-factor Xa activity units/mL or 0.2–0.4 units/mL by protamine
titration. Range may vary depending on the assay sensitivity to heparin for a particular reagent
and adjusted as reagent sensitivity to heparin changes. Repeat aPTT 4–8 hours post-rate change;
4 hours if no bolus; 6–8 hours if a bolus is administered (see Figure 3-1).
Note: In patients very sensitive to heparin and on very low doses, the titration scale may need
to be for smaller quantities for titrating to avoid large % changes in the dose with adjustments
(e.g., rate at 400 units/hr and adjustment of 100 and 200 units/hr is a 25–50% change. Consider
adjusting to 50–100 units/hr if not using a weight-based approach).
aPTT: activated partial thromboplastin time, hr: hour, kg: kilogram, VTE: venous
thromboembolism
TABLE 3-13: Adjusted Weight-Based Dosing Nomograms for

Continuous Heparin Infusions Using the Anti-Factor Xa Activity
in VTE Treatmenta,29
Anti-Factor Xa Dose Adjustment Comment
Activity (units/mL)
≤0.2 Bolus 26–30 units/kg Option: Consider bolus if emergent

Increase rate 3–4 units/kg/hr anticoagulation is necessary.
0.21–0.29 Bolus 15 units/kg Option: Consider bolus if emergent

Increase rate 2 units/kg/hr anticoagulation is necessary; option 0.21–
0.39 if higher levels of anticoagulation
desired where target range started at a
higher value such as 0.4 units/mL.
0.3–0.7 No change Option: 0.3–0.55 if bleeding is a notable

concern.
0.71–0.8 Decrease 1 unit/kg/hr
0.81–0.99 Decrease 2 units/kg/hr Option: Hold 30–60 min if notable

bleeding risks present.
≥1 Hold infusion 1–2 hr

Decrease 3 units/kg/hr
a
Repeat anti-factor Xa activity 4–8 hours after infusion rate change. Earlier draw (4–6 hours) can be
done if no bolus (see Figure 3-1). Once two consecutive anti-factor Xa activity levels are 0.3–0.7
units/mL, draw every 24 hours.
hr: hours, kg: kilograms, VTE: venous thromboembolism
• T
he upper end of the titration curve may be
selected for the aPTT range to ensure adequate
anticoagulation in acute VTE treatment (in this
example, 70–90 sec).
• I n patients who are at high risk for bleeding and
lower risk for thrombosis, the aPTT or anti-Xa
target range can be set at the lower part of the
target range (e.g., anti-Xa of 0.3 to 0.5 units/mL).
Timing of aPTT or Anti-Factor Xa Draw During Continuous

Infusion Heparin after a Bolus Dose of Heparin
• The bolus dose may influence measured aPTT/anti-factor Xa values up to 8 hours
depending on the amount administered.
• aPTT or anti-Xa activity assessments shortly after a bolus may suggest a higher
degree of anti-coagulation than provided by the continuous infusion alone.
• Depending on the amount of a bolus (dashed line in Figure 3-1) administered,
the aPTT/anti-factor Xa will rise to a point higher than achieved by the continuous
infusion (dotted line in Figure 3-1). The measured value (solid line in Figure 3-1)
in this situation will then drop over time to a value reflective of the infusion rate.
TABLE 3-14: Sample Adjusted Dosing Nomogram for

Subcutaneous Heparin in VTE Treatment
aPTT (seconds) Dosing Adjustment Next aPTT
Below 40 Increase by 36–48 units/kg q 12 hr 6–8 hr post dose
40–59 Increase by 24–36 units/kg q 12 hr 6–8 hr post dose
60–90 No change Next morning, then daily (less

frequent monitoring may be
required with long-term use)
91–103 Decrease by 6–12 units/kg q 12 hr 6–8 hr post dose
104–124 Decrease by 12–24 units/kg q 6–8 hr post dose

12 hr
Over 124 Decrease by 24–36 units/kg q 6–8 hr post dose

12 hr
aPTT: activated partial thromboplastin time, hr: hours, kg: kilograms, q: every
• Initial dose is 250 units/kg subcutaneous administered every 12 hr (or 17,500 units
every 12 hr).
• For change from IV to subcutaneous administration, see Table 3-6.
• aPTT should be drawn at 6–8 hr (mid-interval) after dose.
• In pregnancy, an 8- or 12-hr aPTT can be considered to determine if the dosing interval
needs to be changed to every 8 hr dosing (if on every 12 hr dosing) or every 12 hours
dosing (if on every 8 hour dosing) is feasible; institution-specific therapeutic range of
60–90 sec is equivalent to anti-factor Xa activity titration of 0.3–0.7 anti-factor Xa activity
units/mL or 0.2–0.4 units/mL by protamine titration.
• F
igure 3-1 describes the influence of the bolus
dose on measured aPTT (or anti-factor Xa
activity) and subsequent dosing adjustments.
Early aPTT/anti-factor Xa measures after a
bolus dose may be higher than observed should
no bolus have been administered. This may
lead to no dosing adjustment or a downward
adjustment. The subsequent aPTT (or anti-
factor Xa activity) may then be below the target
range, creating a delay in reaching target values.
Checking aPTT values earlier than 6 hours after
initiating the UFH infusion may be requested to
determine if an adequate infusion rate is present
(aPTT value close to baseline). UFH bolus doses
of >5,000 units can also have an effect on aPTT
values drawn up to 8 hours later.
Bolus
80
Measured aPTT
60
aPTT
40
Infusion
2 hr 4 hr 6 hr 8 hr
Time
FIGURE 3-1. Bolus Dosing and Impact on Timing Laboratory

Values for Adjusting a Continuous Infusion
Heparin Resistance1
• Lack of a measurable heparin response in the absence of administering an
antidote can occur secondary to reduced antithrombin (benefit of the aPTT
assay), excessive factor VIII, or fibrinogen (benefit of anti-factor Xa activity assay).
Consider checking that the dose is being infused correctly into the patient as
ordered (one trick is to check the volume administered during the shift prior
to the lab draw and if it matches the prescribed administration rate). Consider
checking an alternative assay (anti-factor Xa if using aPTT), antithrombin, factor
VIII, and fibrinogen with infusion rates above 25 units/kg/hr and subtherapeutic
assay measurements. If additional clarification is required, consider a low range
ACT or sending samples to an outside lab for validation.
• Patients with acute thrombosis may frequently need higher UFH dose require-
ments to attain therapeutic effect as these patients have been noted to elimi-
nate UFH more rapidly, possibly because of increased binding to acute phase
reactants.
{{ Lower aPTT and anti-factor Xa activity values may occur during
awake periods compared to when asleep.30
Although saline is commonly used during hemodialysis, heparin or sodium
citrate may be used to prevent thrombosis formation in the circuit. See Table
3-15 as an example for using heparin in continuous renal replacement therapy
(CRRT). Dosing approaches may vary between different approaches to CRRT.
TABLE 3-15: UFH Dosing Adjustments in Continuous Renal

Replacement Therapya,31
APTT (sec) Dose Adjustments
<35 Bolus 1,000–2,500 units

Increase by 200 units/hr
35–49 Bolus 1,000 units

Increase by 50–100 units/hrb
50–65c No change
66–75 Decrease by 50–100 units/hrb
76–90 Decrease by 100–200 units/hr

Option: Hold 30–60 min
>90 Decrease by 200 units/hr

Option: Hold 1–2 hr
a
Each nomogram should consider the reagent range used in each laboratory. The aPTT range
has to be calibrated by each laboratory and will vary between lots of even the same reagent (see
Chapter 18). Initial bolus doses of 25 units/kg (range 10–30 units/kg) followed by an infusion of
5–10 units/kg/hr (range 5–25 units/kg/hr) is one approach.Target aPTT should be a minimum of
1.5 times control or as established within the 0.3–0.7 units/mL anti-factor Xa activity calibrations.
Variations may exist between dialysis therapies.
b
Dose increases or decreases of 50–100 units/hr may depend on the patient weight and
sensitivity to heparin.
c
Institution-specific therapeutic aPTT range of 45–75 seconds is equivalent to a plasma heparin
concentration of 0.3–0.7 anti-factor Xa activity units/mL or 0.2–0.4 units/mL by protamine
titration. Range described is within (but more narrow) than the 0.3 to 0.7 units/mL, but may vary
depending on the assay sensitivity to heparin for a particular reagent.
hr: hour, min: minutes
• Repeat aPTT 4–8 hours post-rate change; 4 hours if no bolus; 6–8 hours if a
bolus has been administered.
• Survival of filter and heparin requirements may depend on the material (filter)
used.
• Auto-anticoagulated patients at high risk of bleeding may not undergo anti-
coagulation of the circuit.
• Regional heparin (patients with high bleeding risk and filter life span is too short
to accept): continuous UFH (500 units/mL) into arterial line (i.e., 9 × blood flow
[mL/min]). Continuous infusion protamine (5 mg/mL) into venous line starting
at a 1:100 (protamine 1 mg/100 units UFH). Check circuit aPTT (arterial line
post-UFH) and patient aPTT (arterial line pre-heparin). Target circuit aPTT is >55
seconds, and patient aPTT <45 seconds.
• a PTT or anti-factor Xa activity values can vary

during a 24-hour period secondary to a potential
pharmacokinetic effect. Values can be higher
during sleeping periods (early a.m.) compared
to during awake hours.30 Dosing increases and
decreases may subsequently occur. For prolonged
infusions and frequent daily dosing adjustments,
the infusions ordered may be modified (i.e.,
measuring the aPTT or anti-factor Xa
activity at the same time each day) to simplify
management.
• I f resistance to UFH is suspected, check an
aPTT value shortly after a bolus dose to see
if a measure response occurs. If no response
(increase in aPTT or anti-factor Xa activity) is
noted, for example 15–30 minutes after an IV
bolus dose, the assay may need to be checked
(run anti-factor Xa activity off the aPTT, ACT)
or an alternative approach to anticoagulation
considered. If the patient is antithrombin (AT)
deficient, consider a direct-acting anticoagulant.
Extracorporeal Membranous Oxygenation (ECMO) or

Extracorporeal Life Support (ECLS) (See Chapter 17)
• Infusion rates may be center-specific. Initial infusion rates of 20 units/kg/hr
have been used.
• Infusion rates over 60 units/kg/hr have been associated with diminished
outcomes.
• Can lead to a drop in antithrombin (AT) level. Impact of replacing AT on heparin
requirements unknown, but a change in UFH doses is not commonly seen after
AT administration.
• Dosing adjustments may be done by bedside ACT (typically every 1–2 hours).
• Infusion rates and target goals may depend on the age of the patient, circuit,
bleeding concerns, and cannulation site.
• Unclear if the aPTT/anti-factor Xa or ACT is the best test and may vary between
centers. Correlation between assays is not strong.
• Monitoring should include visual inspection of the circuit for any signs of clot
formation (see Chapter 17).
• D
uring ECLS/ECMO, the measured ACT or
aPTT may vary without changes in the infusion
rate. If one is not corresponding to dosing
adjustments, consider adding the other for
conformation. For pediatric patients, small pedi-
tubes can be used to minimize blood loss. Make
sure the correct ACT test is used consistently.
Impella (See Chapter 17)
TABLE 3-16: Drug Incompatibilities with Heparin

Alteplase Droperidol Levorphanol tartrate
Amikacin Ergonovine maleate Methylprednisolone
Amobarbital Erythromycin Mitoxantrone
Amphotericin B Deoxychoate Filgrastim Morphine sulfate
Atropine Gentamicin Nesiritide
Chlordiazepoxide Haloperidol deconate Norepinephrine bitartrate
Ciprofloxacin Haloperidol lactate Orphenadrine citrate
Clarithromycin Hyaluronidase Pentamidine
Codeine Hydrocortisone sodium Phenytoin sodium
Cytarabine phosphate Polymyxin B sulfate
Daunorubicin Hydroxyzine HCl Prochlorperazine
Diazepam Idarubicin HCl Promethazine
Doxorubicin Kanamycin sulfate Quinupristin/dalfopristin
Doxycycline Levofloxacin
SIDE EFFECTS, PRECAUTIONS, AND

CONTRAINDICATIONS
Side effects, precautions, and contraindications to UFH are listed in Table
3-17.
Adverse Effects—Clinical Considerations
• Excessive aPTT or Anti-Xa Activity: Result could be a hemidiluted sample,
especially if the INR is unexpectedly elevated or hemoglobin or hematocrit
(Hgb/HCT) is lower. Consider repeating by peripheral phlebotomy.
• Presence of an oral anti-Xa inhibitor may substantially elevate the measured
anti-Xa activity.
• Continued unexpected values: Check the bag concentration used or vial concen-
tration; verify that patient received it or cross-check using an alternative assay
such as a low range ACT, anti-factor Xa activity, aPTT, or INR. Some individuals
for unexplained circumstances may not respond to a particular assay.
TABLE 3-17: Side Effects, Precautions, and Contraindications to

UFH
Side Effects Precautions Contraindications
• Bleeding • Drug interactions including • History (recent) of

• Hypersensitivity oral anticoagulants and heparin-induced
platelet inhibitors thrombocytopenia
• Local irritation
• Fatal medication errors • Inability to obtain
• Thrombocytopenia,
• Hemorrhage: blood coagulation
HAT, HIT, HITTS (see
tests at appropriate
Chapter 18) {{ Bleeding disorders
intervals
• Long-term use: {{ Subacute bacterial
• Severe
{{ Alopecia endocarditis
thrombocytopenia
{{ Elevated AST/ALT {{ Active ulcerative GI
• Suspected intracranial
diseases
{{ Hyperkalemia hemorrhage
{{ Continuous GI tube
{{ Osteoporosis • Uncontrolled active
drainage
{{ Priapism bleeding except
{{ Severe HTN when due to DIC (see
{{ History of hemorrhagic Appendix H)
stroke
{{ Recent invasive
procedures, including
spinal anesthesia
{{ Concomitant platelet
inhibitors
{{ Recent GI bleeding
{{ Severe liver disease
{{ Age >60 yr
• Heparin resistance (>25,000
units/24 hr)
• Hypersensitivity
• Hyperkalemia
• Osteoporosis
• Thrombocytopenia, HAT, HIT,
HITTS
ALT: alanine aminotransferase, AST: aspartate aminotransferase, DIC: disseminated intravascular

coagulation, GI: gastrointestinal, HAT: heparin-associated thrombocytopenia, HIT: heparin-
induced thrombocytopenia, HITTS: heparin-induced thrombocytopenia thrombosis syndrome,
hr: hour, HTN: hypertension, yr: years
• I f the correct amount of heparin being

administered is unclear, consider replacing with
a new bag or syringe that has been verified for
accuracy and re-measure laboratory.
• B
leeding: Consider turning off the infusion;
reverse with protamine or other blood products as
necessary..31
• R
eversal: See Chapter 9. Post administration
of protamine, a heparin rebound from tissue
redistribution back into the plasma can occur
after very high doses (cardiothoracic surgery),
warranting repeat protamine administration
and assessment of continued anticoagulation
effects by aPTT or anti-factor Xa activity
measurements.32
Heparin-Induced Thrombocytopenia (See Chapter 18)
SPECIAL POPULATION CONSIDERATIONS

• Low-weight/elderly: Low-weight or elderly patients can potentially be more
sensitive or responsive to UFH. Preset or fixed, non-weight-based dosing thus
has the potential for higher than expected levels of anticoagulation.
• Obesity: See Table 3-8.
• Pregnancy: See Chapter 19.
• Pediatrics: See Chapter 20.
• Heparin-induced thrombocytopenia: See Chapter 18.
• Mechanical devices: See Chapter 17.
• Combined with thrombolysis: See Chapter 6.
• Reversal required: See Chapters 8 and 9.
TABLE 3-18: ACCP 2012 Recommendations for Platelet Count

Monitoring of UFH and LMWH33,a
ACCP 2012 Guidelines for Platelet Count Monitoring
Heparin Risk Platelet Count Level

Monitoring
Yes >1% Every 2 or 3 days from 2C

day 4 to day 14 (or until
heparin is stopped,
whichever occurs first)
Yes <1% Not recommended 2C
Yes UFH past 100 days Baseline and within 24 hr Suggested,

if feasible not graded
Yes Acute inflammatory reaction Request immediate Suggested,

(30 min) after an IV bolus (fever, platelet count to assess not graded
chills and/or cardiorespiratory for acute onset HIT
symptoms such as hypertension,
tachycardia, dyspnea, chest pain,
cardiorespiratory arrest)
ACCP 2012 Guidelines for Platelet Count Monitoring
Heparin Risk Platelet Count Level

Monitoring
Within 30 min Anaphylactoid reaction Immediate and compare 1C

of UFH bolus to prior count
Therapeutic Every 2–3 days (day 4–14 2C

UFH or until stopping UFH)
Prophylactic Postoperative Every other day (day 4–14 2C

UFH (HIT risk >1%) or until stopping heparin)
Prophylaxis Medical/OB (HIT risk 0.1% to 1%) Every 2–3 days (day 4–14 2C
or until stopping heparin)
Medical/OB or UFH catheter flush Not recommended 2C

(HIT risk 0.1% to 1%)
Note: The 2015 ACCP guidelines did not address specifics on heparin dosing.
a
HIT: heparin-induced thrombocytopenia, hr: hour, LMWH: low molecular weight heparin, OB:
obstetric, UFH: unfractionated heparin

*1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrom-
botic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest
Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl
2):e24S-e43S.
2. Kandrotas RJ. Heparin pharmacokinetics and pharmacodynamics. Clin
Pharmacokinet. 1992;22:359-374.
3. Lexi-Comp Inc. Heparin. Accessed August 3, 2017.
4. Roberts J, Dager W. Heparin, low-molecular-weight heparin and fondaparinux. In:
Murphy J, ed. Clinical Pharmacokinetics. 6th ed. Bethesda, MD: American Society of
Health-System Pharmacists; 2017.
5. Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low
molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous
and subcutaneous administration. Thromb Res. 1985;39:631-636.
6. Smythe MA, Nutescu EA, Wittkowsky AK. Changes in the USP heparin monograph and
implications for clinicians. Pharmacotherapy. 2010;30:428-431.
7. Yusuf S, Mehta SR, Chrolavicius S, et al.; Fifth Organization to Assess Strategies in
Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin
in acute coronary syndromes. N Engl J Med. 2006;354:1464-1476.
*8. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram
compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern
Med. 1993;119:874-881.
9. Walker AM, Jick H. Predictors of bleeding during heparin therapy. JAMA. 1980;244:
1209-1212.
10. Anand SS, Yusuf S, Pogue J, et al.; Organization to Assess Strategies for Ischemic
Syndromes Investigators. Relationship of activated partial thromboplastin time to
coronary events and bleeding in patients with acute coronary syndromes who receive
heparin. Circulation. 2003;107:2884-2888.
11. Laslett L, White R. Predictors of the effect of heparin during cardiac catheterization.
Cardiology. 1995;86:380-383.
12. Cipolle RJ, Rodvold KA. Heparin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied
Pharmacokinetics: Principles of Therapeutic Drug Monitoring. 2nd ed. Spokane, WA:
Applied Therapeutics; 1986:908-943.
13. Morabia A. Heparin doses and major bleedings. Lancet. 1986;1:1278-1279.
14. O’Gara PT, Kushner FG, Ascheim DD, 2013 ACCF/AHA guideline for the management
of ST-elevation myocardial infarction: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2013;61(4):e78-140.
management of patients with non-ST-elevation acute coronary syndromes: executive
Task Force on Practice Guidelines. Circulation. 2014;130:2354-2394.
*16. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for venous
thromboembolic disease: Antithrombotic Therapy and Prevention of Thrombosis. 9th
Chest. 2012;141(suppl 2):e419S-e494S.
17. Tanaka KA, Thourani VH, Williams WH, et al. Heparin anticoagulation in patients
undergoing off-pump and on-pump coronary bypass surgery. J Anesth. 2007;21:297-
303.
18. Yee WP, Norton LL. Optimal weight base for a weight-based heparin dosing protocol.
Am J Health-Syst Pharm. 1998;55:159-162.
19. Rosborough TK, Shepherd MF. Achieving target anti-factor Xa activity with a heparin
protocol based on sex, age, height, and weight. Pharmacotherapy. 2004;24:713-719.
20. Briceno DF, Villablanca PA, Lupercio F, et al. Clinical Impact of Heparin Kinetics
During Catheter Ablation of Atrial Fibrillation: Meta-Analysis and Meta-Regression. J
Cardiovasc Electrophysiol. 2016 Jun;27(6):683-693.
21. Myzienski AE, Lutz MF, Smythe MA. Unfractionated heparin dosing for venous
thromboembolism in morbidly obese patients: case report and review of the literature.
Pharmacotherapy. 2010;30:105e-112e.
22. Riney JN, Hollands JM, Smith JR, et al. Identifying optimal initial infusion rates for
unfractionated heparin in morbidly obese patients. Ann Pharmacother. 2010;44:1141-
1151.
23. Fan J, John B, Tesdal E. Evaluation of heparin dosing based on adjusted body weight
in obese patients. Am J Health-Syst Pharm. 2016;73:1512-1522.
*24. Olson JD, Arkin CF, Brandt JT, et al.; College of American Pathologists Conference
XXXI on Laboratory Monitoring of Anticoagulation Therapy. Laboratory monitoring of
unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122:782-788.
25. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower
limit of the APTT therapeutic range and recurrent venous thromboembolism during
heparin treatment for deep vein thrombosis. Arch Intern Med. 1997;157:2562-2568.
26. Anand SS, Bates S, Ginsberg JS, et al. Recurrent venous thrombosis and heparin
therapy: an evaluation of the importance of early activated partial thromboplastin time
results. Arch Intern Med. 1999;159:2029-2032.
27. Anand S, Ginsberg JS, Kearon C, et al. The relation between the activated partial
thromboplastin time response and recurrence in patients with venous thrombosis
treated with continuous intravenous heparin. Arch Intern Med. 1996;156:1677-1681.
28. Raschke R, Hirsh J, Guidry JR. Suboptimal monitoring and dosing of unfractionated
heparin in comparative studies with low-molecular-weight heparin. Ann Intern Med.
2003;138:720-723.
29. Smith ML, Wheeler KE. Weight-based heparin protocol using anti-factor Xa
monitoring. Am J Health-Syst Pharm. 2010;67:371-374.
30. Decousus HA, Croze M, Levi FA, et al. Circadian changes in anticoagulant effect of
heparin infused at a constant rate. Br Med J. 1985;290:341-344.
31. Fischer KG. Essentials of anticoagulation in hemodialysis. Hemodial Int. 2007;11:178-
189.
32. Teoh KH, Young E, Blackall MH, et al. Can extra protamine eliminate heparin
rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg.
2004;128(2):211-219.
33. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced
thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
American College of Chest Physicians Evidence-based Clinical Practice Guidelines.
Chest. 2012;141(suppl 2):e495S-e530S.
4
Chapter
LOW MOLECULAR WEIGHT

HEPARIN AND FONDAPARINUX
Zachary Stacy and Sara K. Richter
INTRODUCTION
The low molecular weight heparins (LMWHs) and the synthetic pentasaccharide,
fondaparinux, offer several advantages over unfractionated heparin (UFH). Enoxa-
parin and dalteparin were approved in the United States in 1993 and 1994, respec-
tively, followed by fondaparinux in 2001. Tinzaparin was approved and available in
2000, but was subsequently withdrawn from the market in 2011. These injectables
have been traditionally used as prophylaxis for venous thromboembolism or as a
bridge therapy to therapeutic oral anticoagulation. Based on their relative ease
of dosing and monitoring, these agents frequently replace UFH in many clinical
situations. This chapter will focus on those agents currently available in the United
States, including enoxaparin, dalteparin, and fondaparinux.
PHARMACOLOGY AND PHARMACOKINETICS1-9

Traditionally, unfractionated heparin was the parenteral anticoagulant used in the
inpatient setting. Active unfractionated heparin compounds are composed of an
inconsistent number of sugars, each ending in a specific pentasaccharide sequence.
Using a consistent and shorter sequence of sugars improved the variability in the
anticoagulant effect, giving rise to fractioned LMWH products.
Mechanism of Action
• LMWHs and fondaparinux are indirect inhibitors of clotting factors requiring antithrom-
bin to exert an anticoagulant effect (Figure 4-1).
• A specific pentasaccharide sequence binds to antithrombin to potentiate its activity.
• LMWHs inhibit both Factor Xa and IIa (thrombin) activity.
• Fondaparinux selectively inhibits only Factor Xa.
• Refer to Tables 4-1 and 4-2 for comparison of the specific clotting factors inhibited.
65
AT AT AT Xa AT Thrombin
UFH
AT AT Xa AT Thrombin
LMWH
AT Xa AT Thrombin
AT
Fondaparinux
FIGURE 4-1. Mechanism of Action for LMWH and

Fondaparinux in Comparison to UFH
AT: antithrombin, LMWH: low molecular weight heparin, UFH: unfractionated heparin
Source: Adapted from Weitz J. Low molecular weight heparins. N Engl J Med.
1997;337:688–698. Copyright ©1997 Massachusetts Medical Society. Used with
permission from Massachusetts Medical Society.
TABLE 4-1: Commercially Available Agents in the United States

Drug Therapeutic Generic Version Product Source Clotting Factors
Class Available Inhibited
Dalteparin LMWH No Chemical or Xa>IIa

(Fragmin) enzymatic
depolymerization
of UFH
Enoxaparin LMWH Yes Chemical or Xa>IIa

(Lovenox) enzymatic
depolymerization
of UFH
Fondaparinux Pentasaccharide Yes Chemical synthesis Xa

(Arixtra)
LMWH: low molecular weight heparin, UFH: unfractionated heparin

LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX 67
TABLE 4-2: Pharmacologic and Pharmacokinetic Properties of

LMWH and Fondaparinux
Property Dalteparin Enoxaparin Fondaparinux
Molecular weight (daltons) 5,000 4,500 1,728
Anti-Xa: anti-IIa 2.7:1 3.8:1 100% anti-Xa
Subcutaneous bioavailability ~87% ~100% ~100%
Volume of distribution 40–60 mL/kg 4.3 L 7–11 L
Protein binding (outside target) Limited Limited Limited
Time to peak concentration ~ 4 hr 3–5 hr ~ 2–3 hr

(subcutaneous route)
Primary route of elimination Renal Renal Renal
Half-life (subcutaneous route) 3–5 hr 4.5–7 hr 17–21 hr
Effects of protamine Partial neutralization Partial neutralization No effect
• Because fondaparinux is a synthetic product, it

may be an option in individuals with allergies to
animal products or in those who have religious
preferences to avoid select animal-derived
products.
INDICATIONS, DOSING, AND

ADMINISTRATION1-10
Route of Administration
• Due to their quick onset of action, LMWHs and fondaparinux can be initiated
and administered via the subcutaneous (sub-Q) route for most indications.
• Intravenous bolus doses have been used in the setting of acute arterial throm-
bosis and in hemodialysis to protect against thrombosis of the dialysis circuit.
• Refer to Table 4-3 for FDA-approved dosing and route of administration recom-
mendations.
Dosing
• When dosing LMWHs and fondaparinux, remember the following:
{{ Actual body weight should be used for dose determination (see
Special Populations for Guidance in Obese and Underweight
Patients section).
{{ Restricting doses to a maximum limit or dose capping is not recom-
mended when treating acute venous thromboembolism because it
may lead to underdosing in obese patients.
TABLE 4-3: FDA-Approved Indications and Recommended

Doses for LMWHs and Fondaparinux
FDA-Approved Enoxaparina Dalteparinb Fondaparinuxc
Indications
CrCl >30 mL/min CrCl <30 mL/min
VTE prophylaxis 30 mg sub-Q q 30 mg sub-Q q 2,500 units 2.5 mg sub-Q q

after hip 12 hr initiated 24 hr sub-Q given 4–8 24 hr initiated
replacement 12–24 hr after hr after surgery, 6–8 hr after
surgery surgery then 5,000 units surgery
or sub-Q q 24 hr
40 mg sub-Q q or
24 hr initiated 5,000 units
10–12 hr prior to sub-Q q 24 hr
surgery initiated the
evening prior
(10–14 hr prior)
to surgery

after hip fracture 12 hr initiated 24 hrd sub-Q given 4–8 24 hr initiated
surgery 12–24 hr after hr after surgery, 6–8 hr after
surgeryd then 5,000 units surgery
sub-Q q 24 hrd

after knee 12 hr initiated 24 hr sub-Q given 4–8 24 hr initiated
replacement 12–24 hr after hr after surgery, 6–8 hr after
surgery surgery then 5,000 units surgery
sub-Q q 24 hrd

after abdominal 24 hr initiated 24 hr sub-Q 1–2 hr 24 hr initiated
surgery 1–2 hr prior to prior to surgery 6–8 hr after
surgery then 2,500 surgery
units 12 hr after
surgery followed
by 5,000 units
sub-Q q 24 hr
VTE prophylaxis 40 mg sub-Q q 30 mg sub-Q q 5,000 units 2.5 mg sub-Q

in acute medical 24 hr 24 hr sub-Q q 24 hr q 24 hrd
illness
Treatment of 1 mg/kg sub-Q q 1 mg/kg sub-Q q 100 units/kg 5 mg sub-Q q

VTE (DVT +/- 12 hr 24 hr sub-Q q 12 hrd 24 hr if weight
PE) or or <50 kg
1.5 mg/kg sub-Q 200 units/kg 7.5 mg sub-Q q
q 24 hre sub-Q q 24 hr 24 hr if weight
for 1st month, 50–100 kg
then 150 units/ 10 mg sub-Q q
kg sub-Q q 24 24 hr if weight
hr for months >100 kg
2 to 6f
(continued)

FDA-Approved Enoxaparina Dalteparinb Fondaparinuxc
Indications
CrCl >30 mL/min CrCl <30 mL/min
Unstable angina 1 mg/kg sub-Q 1 mg/kg sub-Q 120 units/kg 2.5 mg sub-Q
or non-Q-wave q 12 hrg q 24 hr sub-Q q 12 hr q 24 hrd
MI (maximum dose Note: UFH
10,000 units) was added
to prevent
thrombus
formation on
the guidewire
(see Table 3-4)
Acute STEMI If <75 years of If <75 years of Not Not

age: age: recommended recommended
30 mg single IV 30 mg single IV for this for this
bolus plus a bolus plus a indication. indication.
1 mg/kg sub-Q 1 mg/kg sub-Q
dose followed by dose followed by
1 mg/kg sub-Q 1 mg/kg sub-Q
q 12 hr (first two q 24 hr (first two
sub-Q doses sub-Q doses
capped at capped at
100 mg) 100 mg)
If ≥75 years of If ≥75 years of

age: age:
0.75 mg/kg 1 mg/kg sub-Q
sub-Q q 12 hr q 24 hr (no bolus)
(no bolus, first
two sub-Q doses
capped at 75 mg)
hr: hour, IV: intravenous, MI: myocardial infarction, PE: pulomonary embolism, Q: every, STEMI:
ST-segment elevation myocardial infarction, sub-Q: subcutaneous, UFH: unfractionated heparin,
VTE: venous thromboembolism
a
Enoxaparin dose conversion is 10 mg = 1,000 units (e.g., 30 mg = 3,000 units).
b
Dalteparin should be used with caution in patients with a CrCl <30 mL/min.
c
Fondaparinux is contraindicated in patients with a CrCl <30 mL/min and should be used with
caution when CrCl 30–50 mL/min.
d
Non-FDA approved for indication.
e
The 1.5 mg/kg dose should be avoided in obesity, pediatrics, pregnancy, and renal impairment.
Dosing regimen approved for VTE treatment in patients with malignancy.
f
g
An additional 30 mg IV bolus with the first sub-Q dose has been studied in clinical trials.
• I nitiation of therapy for acute indications should

be prompt.
• A dministration times should be scheduled to
reduce potential for missed or late doses.
• C
linicians should be aware that fluctuations in
weight may require dose adjustment.
• L
MWHs and fondaparinux are available in
color-coded, prefilled, and graduated and
non-graduated syringes. Rounding the dose to
a convenient syringe size may be considered.
Doses available in graduated syringes should be
rounded only to the nearest 0.1 mL. See Table
4-4 for commercially available syringe and vial
sizes.
• When rounding to the nearest syringe size, clinically
significant changes in dose can occur when
rounding in low-weight individuals (<50 kg).
For example, rounding down to a 40 mg syringe of
enoxaparin in a 45 kg patient represents an 11%
dose reduction as compared to rounding down
to an 80 mg syringe in an 85 kg patient, which
represents only a 6% dose reduction.
Administration
• For subcutaneous administration, patients may self-inject only if their physicians
determine that it is appropriate and with medical follow-up, as necessary. Proper
training in subcutaneous injection technique should be provided (see Patient
Education section).
• Subcutaneous administration should be alternated between the left and right
anterolateral and left and right posterolateral abdominal wall.
• For intravenous enoxaparin injection, the multiple-dose vial should be used.
When administered intravenously, enoxaparin should not be mixed or co-admin-
istered with other medications.
TABLE 4-4: Commercially Available Strengths/Formulations of

LMWH and Fondaparinux in the United States
Enoxaparin Dalteparin Fondaparinux
Dose/ Packaging Dose/ Packaging Dose/ Packaging

Concentration Color Concentration Color Concentration Color
30 mg/0.3 mL Medium 2,500 Blue 2.5 mg/0.5 mL Blue

Blue units/0.2 mL
40 mg/0.4 mL Yellow 5,000 Orange 5.0 mg/0.4 mL Orange

units/0.2 mL
60 mg/0.6 mLa Orange 7,500 Green 7.5 mg/0.6 mL Pink

units/0.3 mL
80 mg/0.8 mLa Brown 10,000 units/ Peach 10 mg/0.8 mL Purple

1 mLa
100 mg/1 mLa Black 12,500 Gray

units/0.5 mL
120 mg/0.8 mLa Purple 15,000 Purple

units/0.6 mL
150 mg/1 mLa Navy Blue 18,000 Yellow

units/0.72 mL
300 mg/3 mL Red 95,000 Teal

multidose vial units/3.8 mL
Graduated prefilled syringes.

a
units: International Units
COMMON SIDE EFFECTS, PRECAUTIONS,

AND CONTRAINDICATIONS7-9,11-13
The most common side effect associated with LMWH and fondaparinux
is minor and major bleeding. Minor bleeding events, such as ecchymosis
and epistaxis, occur more frequently than major bleeds such as hematuria,
hematomas, and hemorrhages. Major bleeding event rates are dependent
on the medical indication and intensity of anticoagulation. UFH is associ-
ated with major bleeding rates of 5–10% when used for the prophylaxis
or treatment of venous thromboembolism. Comparatively, major bleeding
rates are 2–4% with enoxaparin and fondaparinux. Management of bleeding
may include temporary discontinuation of the medication to reversal with
protamine and clotting factor concentrates. Non-bleeding adverse effects
occur infrequently, including thrombocytopenia and hyperkalemia. Table 4-5
summarizes and compares the possible contraindications and side effects of
the LMWHs and fondaparinux.
TABLE 4-5: Side Effects, Precautions, and Contraindications of

LMWH and Fondaparinux
LMWH Fondaparinux
Contraindications/ Side Effects Contraindications/ Side Effects

Precautions Precautions
• Hypersensitivity • Bleeding • Hypersensitivity • Bleeding

• Active major • Thrombo- • Active major • Thrombo-
bleeding cytopeniaa bleeding cytopeniaa
• Thrombo- • Spinal and • Thrombocyto- • Spinal and
cytopenia epidural penia associated epidural
associated with hematomasb with a positive hematomasb
a positive in • Hyperkalemia in vitro test for
vitro test for (suppression antiplatelet
antiplatelet of aldosterone antibody in the
antibody in the production) presence of
presence of fondaparinux
LMWH • Neuraxial
• History of anesthesia
or current • Bacterial
heparin-induced endocarditis
thrombocytope-
• CrCl <30 mL/
nia (HIT)
min
• Neuraxial
• Body weight
anesthesia
<50 kg (prophy-
laxis)
• Catheter tip
thrombosisc
a
See Thrombocytopenia section for additional information.
b
See Neuraxial Procedures section for additional information.
c
Guiding-catheter thrombosis has occurred when fondaparinux was used as the sole anticoagulant
during percutaneous coronary intervention (PCI); therefore, an adjunct anticoagulant with
antithrombin activity (e.g., UFH) is recommended during PCI. It must take into account whether
glycoprotein IIb/IIIa antagonists have been administered. Use of fondaparinux during primary PCI
is not recommended.
CrCl: creatinine clearance, LMWH: low molecular weight heparin
Thrombocytopenia
• Cases of LMWH-induced thrombocytopenia and thrombosis (similar to heparin-
induced thrombocytopenia [HIT]) have been observed. Use is not recommended
in patients with current HIT due to high cross-reactivity to heparin-platelet
factor-4 antibody. Avoid in patients with history of HIT, especially if administered
within 100 days of HIT episode because heparin-platelet factor-4 antibodies
may still be present.
• Rare cases of thrombocytopenia with thrombosis similar to HIT have also been
reported with fondaparinux administration; however, fondaparinux use has
also been reported in patients with current or history of HIT due to a lack of an
immune-mediated effect on platelets.
• Discontinue therapy and consider alternative treatment if platelets are <100,000/

mm3, platelets decrease 50% from baseline, and/or thrombosis develops.
Reversal
• Protamine sulfate can be used as a partial reversal agent for the effects of LMWH
(neutralizes approximately 60% of the anti-Factor Xa activity). Refer to Table
4-6 for recommended dosing of protamine.
• There is no specific antidote for reversal of fondaparinux.
TABLE 4-6: Dosing of Protamine for the Reversal of LMWH

Timing of LMWH Dose Protamine Dosea
Last dose given in previous 8 hours 1 mg of protamine for every 1 mg (100 units) LMWH
Last dose given in previous 8–12 hours 0.5 mg of protamine for every 1 mg (100 units)
LMWH
Last dose given more than 12 hours ago Use of protamine is not recommended
a
Repeated doses of protamine 0.5 mg for every 1 mg (100 units) LMWH may be considered if
anti-Xa level remains elevated or if bleeding continues.
LMWH: low molecular weight heparin, units: International Units
RECOMMENDATIONS FOR TIMING IN

PATIENTS UNDERGOING NEURAXIAL
PROCEDURES12
The use of anticoagulants in patients undergoing neuraxial anesthesia or
spinal puncture poses a significant risk for epidural and spinal hematoma.
Bleeding complications involving the spine can result in long-term or perma-
nent paralysis. The time since the previous dose and/or next dose relative
to the catheter placement or spinal puncture should be carefully considered
(Table 4-7).
TABLE 4-7: Considerations of Use of LMWH or Fondaparinux

Administration with Neuraxial Proceduresa
Anticoagulant Minimum Minimum Minimum Minimum
Time Between Time Between Time Between Time Between
Anticoagulant Insertion of Anticoagulant Removal of
Dose and Spinal Needle Dose and the Epidural
Insertion of or Placement Removal of Catheter and
Spinal Needle of Epidural the Epidural Anticoagulant
or Placement Catheter and Catheter Dose
of Epidural Anticoagulant (provided
Catheterb Dose hemostasis has
been achieved)
Therapeutic or 36–48 hr Avoid while Ideally avoid 2 hr

prophylactic doses catheter is in while catheter is
of fondaparinux place. in place.
Therapeutic 24 hr If considered,
doses of LMWH then just before
(enoxaparin or the next dose
dalteparin) and when
anticoagulant
Prophylactic 10–12 hr effect is at
doses of LMWH minimum.
(enoxaparin or
dalteparin)
See Chapter 10, Table 10-7.

a
b
Longer elimination times will be required in patients with impaired renal function.
LMWH: low molecular weight heparin
MONITORING1,4,7-10,14-15
• LMWHs and fondaparinux have a predictable anticoagulant dose response and
wide therapeutic windows; thus, routine dosage adjustments and monitoring of
anticoagulation activity are not required in the majority of patients.
• The prothrombin time/international normalized ratio (PT/INR), activated partial
prothrombplastin time (aPTT), and activated clotting time (ACT) are inappro-
priate laboratory markers to monitor the anticoagulant effect, as they are only
minimally affected by LMWHs and fondaparinux.
• LMWHs have minimal effect on Factor IIa; thus, limited prolongation of aPTT
may be seen in cases of LMWH overdoses.
• Refer to Table 4-8 for specific monitoring parameters and laboratory draw times.
TABLE 4-8: Monitoring Parameters for LMWH and

Fondaparinux
Baseline (prior to initiation of therapy) Ongoing (every 3–4 days in inpatient setting)
CBC (specifically hemoglobin and platelets) CBC (specifically hemoglobin and platelets)
Serum creatinine Serum creatinine
Creatinine clearance Creatinine clearance
Role of Anti-Factor Xa Monitoring (see Chapter 21)

• This is not routinely recommended due to lack of clinical outcomes data.
• This may be useful and considered in certain high-risk situations such as the
following:
{{ Morbid obesity (weight >190 kg or body mass index >40 kg/m2)
(see Chapter 11)
{{ Very low body weight (weight <50 kg)
{{ Significant renal impairment (CrCl <30 mL/min) (see Chapter 11)
{{ Neonates and pediatric patients (see Chapter 20)
{{ Pregnant women (see Chapter 19)
{{ Patients who receive extended therapy (>1 month)
• When measuring anti-Factor Xa peak activity, the sample should be obtained
after steady-state concentrations of the LMWH or fondaparinux are attained,
usually after the third to fourth dose. Refer to Table 4-9 for a sample LMWH
dosing nomogram using anti-Factor Xa peak levels.
• The anti-Factor Xa activity assay for fondaparinux has to be specifically calibrated
for fondaparinux, and many laboratories do not offer this option.
• Anti-Factor Xa activity levels should be collected during peak drug concentra-
tions (typically occur approximately 4 hours after a subcutaneous dose). Refer
to Table 4-10 for indication-specific goals for anti-Factor Xa peak levels.
• Trough anti-factor Xa activity levels may be useful to rule out drug accumulation,
such as in patients with renal failure, and are typically measured just prior to the
next dose of the LMWH or fondaparinux.
TABLE 4-9: Sample LMWH Twice-Daily Dosing Nomogram

Based on Peak Anti-Factor Xa Activity for VTE Treatment
Peak Anti-Factor Xa Dose Modification When to Repeat Anti-Factor Xa
Activity Level Activity Level
<0.35 units/mL Increase dose by 25% 4 hr after next dose
0.35–0.49 units/mL Increase dose by 10% 4 hr after next dose
0.5–1 units/mL No dose adjustment needed Next day, then in 1 week, then
monthly
1.1–1.5 units/mL Decrease dose by 20% Before next dose
1.6–2 units/mL Hold 3 hr, then decrease dose Before next dose and 4 hr after next
by 30% dose
>2 units/mL Hold until level <0.5 units/mL, Before next dose and q12 hr until
then decrease dose by 40% level <0.5 units/mL
LMWH: low molecular weight heparin, VTE: venous thromboembolism

Source: Adapted from Monagle P, Michelson AD, Bovill E, et al. Antithrombotic therapy in
children. Chest. 2001;119 (suppl 1):344S–370S. Used with permission from Elsevier ©2001.
TABLE 4-10: Goal Anti-Factor Xa Activity Levels Based on

Indication
Indication Goal Anti-Factor Xa Level (peak)a
• Prevention of VTE • 0.2–0.4 units/mL
• Treatment of VTE • 0.6–1 units/mL

a
Goal peak levels are assuming twice daily dosing. For once daily dosing, higher goal peak levels
of 1–2 units/mL have been suggested, but data are limited.
PATIENT EDUCATION7-9
• Patients should be provided with written and verbal instructions prior to receiv-
ing LMWH or fondaparinux as an outpatient.
• Some institutions provide patient education kits that contain demonstration
syringes, supplies, and instructions for patient education prior to use in the
outpatient setting.
Patients should be informed of the following:
• The site of administration should be rotated.
• Squirting out of the air bubble in syringes can lead to more bruising at the injec-
tion site and/or not all of the dose being administered. Priming the needle is
not recommended prior to injection.
• It may take longer than usual to stop bleeding.
• Bruising and/or bleeding may occur more easily.

• Unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark
red spots under the skin) should be reported to their physician immediately.
• Their physicians and dentists should be made aware that they are taking LMWH
or fondaparinux.
• Other medications, including some over-the-counter medications, may increase
the risk of bleeding and/or bruising (e.g., antiplatelets, NSAIDs).
• Refer to Table 4-11 for a list of steps in the self-administration of LMWH and/
or fondaparinux.
TABLE 4-11: Steps for Self-Injection of LMWH or Fondaparinux

Step Instruction
1 Wash and dry hands thoroughly.
2 Sit or lie in a comfortable position, so that you can see your abdomen.
3 Choose an area on the right or left side of your abdomen, at least 2 inches from your
belly button or scars.
4 Clean the injection site with an alcohol swab, and let air dry.
5 Remove the needle cap by pulling it straight off the syringe and discard it in a sharps
collector.a
6 Hold the syringe like a pencil in your writing hand.b
7 With your other hand, pinch an inch of the cleansed area to make a fold in the skin.
Insert the full length of the needle straight down—at a 90º angle—into the fold of
skin.
8 Press the plunger with your thumb until the syringe is empty.
9 Pull the needle straight out at the same angle that it was inserted and release the skin
fold.
10 Carefully activate the needle’s safety shield.
11 Place the used syringe in a sharps collector.a

a
Some manufacturer discharge kits are equipped with a sharps collector. If one is not provided, it
may be purchased or patients can be educated to use any hard, plastic container (e.g., milk jug,
laundry detergent container).
b
If a dose adjustment is necessary, carefully discharge solution to the desired dose before
administration.
SPECIAL POPULATIONS4,13,16
Pregnancy and Pediatrics

The pharmacokinetics of LMWH and fondaparinux vary in pregnant women
and pediatric patients. Adjustments to dosing regimens may be necessary in
these patients due to differences in the volume of distribution, metabolism,
and clearance. Therefore, therapeutic drug monitoring is recommended in
these special populations more frequently than the general patient population.
Dosing and monitoring of LMWH and fondaparinux in pregnancy and
pediatric patients will be covered in Chapters 19 and 20, respectively.
Morbid Obesity Dosing Considerations for VTE

Due to a larger volume of distribution in patients who are morbidly obese,
adjustments to dosing regimens may be necessary. The definition of morbidly
obese may vary from one institution to another and may be based on body
weight or body mass index. Additionally, therapeutic drug monitoring is
recommended more frequently in obese patients than the general patient
population. Dosing and monitoring of LMWH and fondaparinux in obese
patients will be covered in Chapter 11.
• T
otal body weight appears to be a good predictor
for dosing of LMWHs and fondaparinux in obese
patients.
• S etting a maximum dose (dose capping) is not
recommended when treating patients for VTE.
This practice may result in underdosing, putting
patients at risk for thrombotic complications.
• F
ondaparinux 10 mg sub-Q daily is approved
for VTE treatment in patients weighing >100
kg. There are not sufficient data to support
dose adjustments in obese patients for VTE
prophylaxis.
• W
hen using LMWHs for VTE prophylaxis, a
25–30% dose increase or weight-based dosing of
50 units/kg/day may be considered.
• F
or enoxaparin, the 1.5 mg/kg sub-Q daily
dosing strategy should be avoided in obese
patients with VTE.
(continued)
• I n all obese patients, consider anti-Factor

Xa monitoring to assess dosing of LMWH or
fondaparinux. See Monitoring section for more
information.
Dosing Considerations in Underweight Patients

• For VTE prophylaxis, fondaparinux is contraindicated in patients weighing <50 kg.
• For VTE treatment, fondaparinux 5 mg sub-Q daily is recommended for patients
weighing <50 kg.
• Fixed prophylactic doses of LMWH or fondaparinux in underweight patients (<50 kg)
may result in drug accumulation and increased risk of bleeding complications.
Consider anti-Factor Xa monitoring to assess dosing of LMWH and fondaparinux
in this patient population. Also see Monitoring section for more information.
Dosing Considerations in Renal Dysfunction

Because LMWHs and fondaparinux are renally eliminated, reduced elimina-
tion can result in increased drug concentrations and an increased bleeding
risk. The actual degree of accumulation is different for the various LMWHs
and fondaparinux as there are differences in their pharmacologic profiles.
Refer to Table 4-12 for a description in how these pharmacokinetic changes
impact the dosing and monitoring. Additional considerations in renal impair-
ment are discussed in Chapter 11.
Considerations in Oncology Patients

Special LMWH dosing should be considered in patients with malignancy.
These agents may be preferred for chronic management due to their inhibi-
tion of tissue factor pathway inhibitor. Although malignancy increases the
risk for thrombosis, bleeding risk may also be increased in these patients
with special attention placed on platelet count. For dosing and monitoring
of LMWH and fondaparinux in oncology patients, see Chapter 11.
TABLE 4-12: Dosing and Monitoring Considerations for LMWH

and Fondaparinux in Renal Impairmenta
Anticoagulant Pharmacokinetic Dosing and Monitoring Package Insert
Considerations Recommendations Recommendations
Dalteparin CrCl <30 mL/ CrCl <30 mL/min b: CrCl <30 mL/minb: Use with
min b: No No dose adjustment caution.
accumulation needed up to 1 week
noted up to 1 with prophylaxis doses;
week of therapy. for treatment doses,
consider monitoring
CrCl 30–50 anti-Factor Xa activity.
mL/min: No
accumulation For use >1 week:
noted. Consider monitoring of
anti-Factor Xa activity
and adjust dose if
accumulation is noted.
CrCl 30–50 mL/min:

No dose adjustment
needed.
Enoxaparin CrCl <30 mL/ CrCl <30 mL/minb: CrCl 20–30 mL/minb:
min b: 40−50% Consider a 40−50% Prophylaxis, 30 mg sub-Q
accumulation dose decrease and daily; treatment, 1 mg/
noted subsequent monitoring kg sub-Q daily. See below
of anti-Factor Xa for CrCl <20 requiring
CrCl 30–50 mL/ activity. hemodialysis.b
min: 15−20%
accumulation CrCl 30–50 mL/min:
noted. Consider a 15−20%
dose decrease with
prolonged use (>10–14
days) and subsequent
monitoring of anti-
Factor Xa activity.
Fondaparinux CrCl <30 mL/ CrCl <30 mL/min: CrCl <30 mL/min:
min b: 55% Contraindicated in this Contraindicated.
accumulation population.
noted. CrCl 30–50 mL/min: Use with
CrCl 30–50 mL/ caution.c
CrCl 30–50 min: If prolonged
mL/min: 40% use (>10 days), drug
accumulation accumulation may occur
noted. and dosing adjustment
may be necessary.
Could consider
measurement of
to guide with dose
adjustment.
(continued)

a
The use of an anti-Factor Xa activity measurement to adjust dosing in the setting of renal
insufficiency has not been validated, and it is at best a controversial practice. Trough anti-Factor-
Xa activity measurements have been considered to assess potential accumulation in patients at
increased risk for bleeding.
b
Data are very limited in patients with a CrCl <20 mL/min. In patients on hemodialysis, limited
data are only available for thrombosis prevention in the dialysis circuit but not for the prevention
and/or treatment of venous or arterial thrombosis. UFH is the agent of choice in patients
on hemodialysis or with a CrCl <20 mL/min. In one comparative single center assessment,
enoxaparin 0.6–0.7 units/kg daily (range 0.4−1 units/kg with no measuring of anti-Factor Xa
activity) was safe and effective in transitioning patients requiring hemodialysis to warfarin.17 CrCl
measurements in the clinical trials may have used total body weight and, thus, estimate a value
higher than estimated when using the ideal body weight.
c
Care should be exercised when fondaparinux is used for an extended time (>7–10 days) in
patients with moderate renal impairment (CrCl 30–50 mL/min, as accumulation of the drug has
also been reported in these patients at a rate of approximately 40%).
CrCl: creatinine clearance, sub-Q: subcutaneous
• L
MWHs are preferred over warfarin, UFH,
and fondaparinux for acute and chronic
anticoagulation in the setting of cancer-related
thrombosis. Benefits are primarily seen in non-
metastatic disease.
• D
osing strategies of enoxaparin 1 mg/kg twice
daily or dalteparin 200 units/kg once daily
during the first 4 weeks have been suggested to
provide a more aggressive level of anticoagulation
when the risk of recurrent thrombosis is the
greatest.
• D
alteparin is the only LMWH with an FDA-
approved indication for treatment of venous
thrombosis in the setting of cancer.
• B
enefits of efficacy or safety of LMWH use
beyond 6 months have not been established at
this time.
Dosing Considerations in the Elderly

• Before sending an elderly patient home on a LMWH or fondaparinux, consider
dexterity, eyesight, and ability to self-inject.
• In addition to age, renal function and weight change over time. See dosing and
monitoring considerations above.
Dosing Considerations in Critically Ill Patients

• Bioavailability for LMWH can be reduced in the setting of edema, hypotension,
or active vasopressor use.
• In selected situations, critically ill patients may have low levels of antithrombin
(i.e., large trauma, renal failure), thereby reducing the level of anticoagulation.
Anti-Factor Xa activity measurements using an assay that incorporates antithrom-
bin may not identify it (see Chapter 21).
• No clear data exist on guiding subsequent dose adjustments for these situations.

*1. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrom-
botic Therapy and Prevention of Thrombosis. 9th ed. American College of Chest
Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):
e24S-e43S.
2. Weitz JI. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-699.
3. Haines ST, Witt D, Nutescu EA. Venous thromboembolism. In: DiPiro J, Talbert R, Yee
G, et al. eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY:
McGraw-Hill; 2008:331-372.
*4. Nutescu EA, Dager W. Heparin, low molecular weight heparin, and fondaparinux. In:
Gulseth M, ed. Managing Anticoagulation Patients in the Hospital. Bethesda, MD:
ASHP; 2007:177-202.
5. Nutescu EA, Haines ST, Wittkowsky AK. Venous thromboembolism. In: Chisholm-Burns
M, Schwinghammer T, Wells B, et al., eds. Pharmacotherapy Principles and Practice.
4th ed. New York, NY: McGraw-Hill; 2016:163-192.
6. Hirsh J, O‘Donnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin:
current and future advances. Circulation. 2007;116(5):552-560.
7. Lovenox [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2013. http://products.
sanofi.us/lovenox/lovenox.html. Accessed March 19, 2017.
8. Fragmin [package insert]. New York, NY: Pfizer; 2015. http://labeling.pfizer.com/
ShowLabeling.aspx?id=2293. Accessed March 19, 2017.
9. Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009. http://
www.accessdata.fda.gov/drugsatfda_docs/label/2009/021345s019lbl.pdf. Accessed
March 19, 2017.
10. Nutescu EA, Wittkowsky AK, Dobesh PP, et al. Choosing the appropriate antithrombotic
agent for the prevention and treatment of VTE: a case-based approach. Ann
Pharmacother. 2006;40:1558-1571.
11. Linkins LA, Dans AL, Moores LK, et al. Antithrombotic Therapy and Prevention of
Thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical
Practice. Chest. 2012; 141(2)(suppl 2):e495S-e530S.
12. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient
receiving antithrombotic or thrombolytic therapy. Reg Anesth Pain Med. 2010;35:64-
101.
13. Lim W, Dentali F, Eikelboom JW, et al. Meta-analysis: low-molecular-weight
heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med.
2006;144:673-684.
14. Monagle P Michelson AD, Bovill E, et al. Antithrombotic therapy in children. Chest.
2001;119 (suppl 1):344S-370S.
*15. Laposata M, Green D, Van Cott EM, et al. College of American Pathologists Conference
XXXI on Laboratory Monitoring of Anticoagulant Therapy: the clinical use and
laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and
related compounds, and argatroban. Arch Pathol Lab Med. 1998;122:799-807.
*16. Nutescu EA, Spinler SA, Wittkowsky AK, et al. Low molecular weight heparins in renal
impairment and obesity: available evidence and clinical practice recommendations
across medical and surgical settings. Ann Pharmacother. 2009;43:1064-1083.
17. Pon TK, Dager WE, Roberts AJ, White RH. Subcutaneous enoxaparin for therapeutic
anticoagulation in hemodialysis patients. Thromb Res. 2014;133:1023-8.
5
Chapter
PARENTERAL DIRECT THROMBIN

INHIBITORS
William E. Dager and A. Joshua Roberts
INTRODUCTION
The parenteral direct thrombin inhibitors (DTIs) act independent of antithrombin
and are typically used in situations where unfractionated heparin (UFH) is not
recommended or contraindicated such as heparin-induced thrombocytopenia,
antithrombin deficiency, or in the setting of acute coronary syndromes. This class
of agents works differently than other anticoagulants, despite similar laboratory
assessments. Further, due to more limited experience with their use, it is important
to approach their management and laboratory assay target ranges as independent
of observations with other anticoagulants. There are currently two parenteral DTIs
available in the United States—bivalirudin and argatroban. Lepirudin and desirudin
are no longer available.
PHARMACOLOGY1-2
• The activity of thrombin can be inhibited by currently available DTIs that bind directly
to either the catalytic (active) site or substrate recognition site (exocite 1). Thrombin
also contains a heparin-binding site (exocite 2).
• All commercially available DTIs directly bind to the catalytic (active) site on thrombin
responsible for enzymatic activity.
• Binding to the catalytic (active) site on thrombin inhibits several actions of thrombin
including cleavage of fibrinogen and platelet activation, both of which are involved
in thrombus formation.
• Bivalent DTIs (bivalirudin, desirudin, and lepirudin) also bind to the substrate recogni-
tion (exocite 1) on thrombin where fibrinogen can bind.
• DTIs do not bind to exocite 2, and thus are capable of inhibiting the effects of thrombin
bound to fibrin (clot bound thrombin).
• DTIs can also block thrombin’s ability to activate platelets as well as stimulate granule
release, surface receptor expression and aggregation, and a plethora of other factors
that mediate vascular integrity.
• Lepirudin and desirudin are able to tightly bind to thrombin and can lead to prolonged
inhibition. These agents are no longer available.
• Bivalirudin is enzymatically cleaved by thrombin. This results in loss of activity that is
primarily independent of renal or hepatic function. Its effects may not last in stagnant
85
blood. Increased elimination can occur with hemofiltration.

• The onset of bivalirudin on activated clotting time (ACT) values occurs within
5–10 minutes after a bolus.
• Dabigatran etexilate is an oral DTI (see Chapter 7 for further details).
• See Table 5-1 for further pharmacokinetic/pharmacodynamics information.
TABLE 5-1: Pharmacokinetics of Available Parenteral Direct
Thrombin Inhibitors3-5
Agent Argatroban Bivalirudin
Source Synthetic Analog of hirudin
Route of administration IV IV
Plasma half-life (healthy subjects) 31–51 min 25 min
Primary elimination route Hepatic Enzymatic
Fraction excreted unchanged in the urine 16% 20%
Effect on INR Moderate Mild

(depends on the amount of DTI present; this may
correlate to an elevation in the aPTT or ACT level in the
sample)
ACT: activated clotting time, aPTT: activated partial thromboplastin time, IV: intravenous, min:
minutes
Parenteral DTIs are most commonly used in acutely ill patients who may have reduced organ
function and elimination.
Time to steady-state may take longer, and effects may last more than a few hours after stopping
the infusion.
DOSING/ADMINISTRATION
• Post-marketing experiences have suggested lower dosing approaches than those
used in clinical trials, especially in acutely ill patients.
• The initial dosing regimen for a DTI will depend on the indication for anticoagula-
tion, clinical presentation of the patient, and the desired intensity of parenteral
anticoagulation, similar to how heparin is utilized (Tables 5-2, 5-3, and 5-4).
• Specific factors that may influence the dosing and target ranges include the
following:
{{ Presence of thrombosis, acute thrombosis—consider higher doses
with aPTT target ranges of 2–2.5x normal baseline initially (2–3x
normal baseline for argatroban).
Note: The higher aPTT target for argatroban is based on the targets
set in the original ARG 911 trial. No trial was done for bivalirudin
in heparin-induced thrombocytopenia (HIT); however, published
single-center experiences in over 1,000 individuals typically follow
PARENTERAL DIRECT THROMBIN INHIBITORS 87
the 1.5–2.5 x normal baseline aPTT as set in the lepirudin heparin-

associated thrombocytopenia (HAT) trials.
{{ Presence of active bleeding or risk factors for bleeding—consider
lower doses or use the lower end of the aPTT target range (1.5−2
for bivalirudin or 1.5−2.5 x normal baseline for argatroban 2 x
normal baseline).
• Note that ACT readings with a DTI may vary between low and high response
assay methods.
• For argatroban, there is poor correlation between the aPTT and hemoclot
thrombin inhibitor assay. When using assays independent of methods used in
trials, consider if improved accuracy of measuring the agent has an impact on
actual outcomes for bleeding or thrombotic complications.6,7
TABLE 5-2: Dosing and Administration of DTIs for Selected

Indications3,5,8-16
Indications Argatroban Bivalirudin
HIT: typical IV dosing • Has FDA indication • No FDA indication in HIT.
(See Chapter 15) • No bolus Multiple single center
experiences published.
• Prescribing information: The approved dose
2 mcg/kg/min listed in the prescribing
• Average dose in trials 1.6 information is in ACS,
mcg/kg/min. Subsequest which is much higher
published experiences than used in HIT.
have observed doses • Typically no bolus
lower than 2 mcg/kg/min
in general. Rarely used at Bolus: 0.2 mg/kg (in
rates >3 mcg/kg/min. cases of life-/limb-
threatening thrombosis)
• Maximum dose 10 mcg/
kg/min • Starting doses:
• In acutely/critically ill CrCl >60 mL/min:
patients, starting doses 0.12–0.15 mg/kg/hr
of 0.5–1.2 mcg/kg/min • aPTT target 1.5–2.5 x
have been used. control
• Reduce dose in hepatic
failure.
• aPTT target 1.5–3 x
baseline. Maximum of
100 sec.
(continued)

Indications Argatroban Bivalirudin
ACS/PCI/PTCA • Bolus: 350 mcg/kg IV Pre-PCI (early invasive
Avoid drawing INR values • Infusion: 25 mcg/kg/min strategy)
during the use of these higher IV dosing • Bolus: 0.1 mg/kg IV
doses as high false positive • Infusion: 0.25 mg/
• Low Range ACT target:
values will occur. kg/hr IV until PCI or
300–450 sec
angiography14
• If low range ACT
<300 sec, can consider PCI
adjusting upward to as • Bolus: 0.75 mg/kg IV
high as 40 mcg/kg/min • No adjustment needed if
• If ACT >450, consider CrCl >29 mL/min
adjusting infusion rate as • 0.5 mg/kg IV if receiving
low as 15 mcg/kg/min pre-PCI infusion
• Infusion: 1.75 mg/kg/
hr IV (CrCl ≥30 mL/min)
for up to 4 hours post
procedure (CrCl 15–29
mL/min: 1 mg/kg/hr)13
Post-PCI (continued infusion)
• 0.2 to 0.25 mg/kg/hr IV
for up to 12 to 20 hours
post PCI
• With GPIIb/IIIa inhibitors: • Removal of closure

250 mcg/kg IV bolus device, with a aPTT
followed by an infusion target of approximately
of 25 mcg/kg/min 65–70 sec
IV targeting ACT of • ACT target: None
275–450 sec; for ACT
• CrCl <30 mL/min:
<275 sec, a 150-mcg/kg
1 mg/kg/hr IV
IV bolus is given.
• Dialysis: 0.25 mg/kg/hr IV
Unstable angina • N/A • Infusion: 0.2 mg/kg/hr IV
ACS: acute coronary syndrome, ACT: activated clotting time, aPTT: activated partial
thromboplastin time, CrCl: creatinine clearance, FDA: U.S. Food and Drug Administration, HIT:
heparin-induced thrombocytopenia, hr: hour, INR: international normalized ratio, IV: intravenous,
kg: kilograms, mcg: micrograms, min: minutes, N/A: not applicable, PCI: percutaneous coronary
intervention, PTCA: percutaneous transluminal coronary angioplasty, sec: seconds, x: times
TABLE 5-3: Renal, Hepatic, and Hepatorenal Failure

Anticoagulation Dosing under HIT Conditions3,15-19
Modifying Argatrobana Bivalirudin
Factor
Hepatic dose • Child-Pugh score >6 (see • Eliminated enzymatically

adjustments Chapter 11) or total bilirubin and may only need minor
>1.5 mg/dL adjustment for hepatic function.
• Reduce dose to less than or
equal to 0.5 mcg/kg/min
Renal dose • Renal dysfunction dose • Eliminated enzymatically and

adjustments adjustment unclear. Reduced may not need large adjustment
elimination observed in renal for renal dysfunction alone.
(Hemodialysis impairment may be from the (Critically ill may require doses
See Table 5-4) kidney influencing selected on lower end of the range.)
metabolic pathways. • Removed by hemodialysis and
• No apparent effect of HD on ultrafiltration
elimination • CrCl >60 mL/min: 0.12–0.15
• A dosing decrease of 0.1–0.6 mg/kg/hr
mcg/kg/min for every 30-mL/ • CrCl 30–60 mL/min: 0.08–0.1
min drop in CrCl in HIT has (range 0.06–0.13 reported)
been reported. mg/kg/hr
• CrCl <30 mL/min: 0.05–0.08
mg/kg/hr
• Substantially removed during
HD
Hepatorenal • Prolonged effects • Eliminated enzymatically and

dose • Start with low dose then titrate may not need major adjustment
adjustments up for hepatic function.
• Assume initial aPTT is not
steady state
Monitoring • 1.5–3 x controlb • 1.5–2.5 x controlb

goal aPTT
a
Argatroban is generally preferred over lepirudin in severe renal failure. Bivalirudin may have
pharmacokinetic advantages in concurrent hepatic and renal failure.
b
Use patient’s baseline aPTT value as the control. The institution’s mean aPTT value can be used if
there is no baseline value.
aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, HD: hemodialysis, HIT:
heparin-induced thrombocytopenia, x: times
TABLE 5-4: Considerations for Dosing DTIs in

Hemodialysis12,18,20-25
Agent Consideration in Hemodialysis (see Table 15-3)
Argatroban • Unclear if dose adjustments are necessary as reports are not consistent.
• For anticoagulation to maintain the circuit during intermittent HD only,
three regimens have been studied and found equivalent:
{{ 250 mcg/kg IV bolus at the start of hemodialysis with an additional
250 mcg/kg bolus allowed 2 hr later if ACT <140% of baseline
{{ 250 mcg/kg IV bolus followed by 2 mcg/kg/min
{{ 2 mcg/kg/min IV infusion started 4 hr prior to HD with target ACT
140–180 sec
• CRRT: 100 mcg/kg IV bolus and 0.5 mcg/kg/min IV infusion. In the post-
cardiac surgery population using CVVH, a dose of 0.25 mcg/kg/min IV
infusion has been reported.
Bivalirudin • When using bivalirudin for therapeutic use (not just to maintain the
circuit), it is important to consider that some is dialyzed off, likely
necessitating an increase in the rate. The optimal management strategy
may depend on the duration of hemodialysis and aPTT value maintained,
along with the risk of thrombosis formation during HD. Consider aPTT
2 hr into HD to assess a need to temporarily increase the infusion rate
during prolonged dialysis (>8 hours).
Initial dose
• For treatment of HIT or antithrombin deficiency, consider the following:
{{ Intermittent hemodialysis: 0.03–0.07 mg/kg/hr IV infusion
{{ Extended duration hemodialysis: 0.06–0.09 mg/kg/hr IV infusion
{{ CRRT: 0.06–0.07 mg/kg/hr IV infusion (range 0.03–0.1 mg/kg/hr)
• As an alternative to heparin during intermittent dialysis only (no acute
thrombosis), start at ~0.03 mg/kg/hr. For CRRT: consider checking aPTT
and consider the lower end of the range (~1.5–2 x baseline).
{{ Note: Based on total body weight and for infusing during and off
dialysis.a
Note: Bivalirudin is removed during hemodialysis, so consider the following:
• During intermittent or extended hemodialysis, avoid drawing aPTT
during or within 2 hours post-dialysis until the serum concentrations have
recovered.
• Administration of bivalirudin pre-filter in CVVH may decrease the
incidence of occlusion of the hemofilter.
• If CRRT is stopped, an aPTT should be considered and re-evaluation if the
bivalirudin dose needs to be lowered.
a
Target aPTT may depend on the dialysis circuit and frequency of thrombosis-related
complications. An aPTT of 1.5–2 x baseline aPTT can be considered in place of heparin if
concurrently treating for HIT.
~: approximately, ACT: activated clotting time, aPTT: activated partial thromboplastin time, CRRT:
continuous renal replacement therapy, CVVH: continuous venovenous hemofiltration,
HD: hemodialysis, HIT: heparin-induced thrombocytopenia, sec: seconds, x: times
Argatroban Dosing in HIT (See Chapter 18)

• Asians often need lower doses (1 mcg/kg/min).
{{ Lower than doses observed in Hispanic or
African Americans.26
• C
ritically ill patients often need lower doses
than package insert recommendations.
{{ 0.6 mcg/kg/min versus noncritical
1.4 mcg/kg/min.8
{{ Mean doses of 0.22 mcg/kg/min have been
reported.7
• I f weight >50% ideal body weight (IBW):
Initiate at 1 mcg/kg/min.
MONITORING (SEE TABLE 5-5)

TABLE 5-5: Target aPTT Range in the Setting of HIT
aPTT Range (Bivalirudin) Clinical Setting
Lower: 1.5–2 x baseline • Argatroban: 1.5–2.5 x baseline

• Isolated HIT, AT deficiency or treatment of
thromboembolic complications when increased bleeding
concerns are present
Higher: 2–2.5 x baseline • Argatroban: 2–3 x baseline
• HITTS and limited risk for bleeding
AT: antithrombin, HIT: heparin-induced thrombocytopenia, HITTS: heparin-induced
thrombocytopenia thrombosis syndrome, x: times
Clinical Pearls in Managing and Monitoring DTI Regimens (See Tables 5-5,
5-6, and 5-7)
• D
ifferences in sensitivities for aPTT reagents
between heparin or DTI may occur and, thus,
the target aPTT range for a DTI will not be the
same as heparin nor the same between different
DTIs. Furthermore, due to differences in aPTT
assays, the target range for a DTI will likely
vary between institutions.
• A cutely ill patients such as those with renal,
hepatic, or cardiac dysfunction may reach target
aPTT values at a dose notably lower than
observed in the clinical trials.
• B
ecause most published dosing experiences are
based on aPTT monitoring, not serum DTI
concentrations, the actual dosing observed may
be different due to differences in aPTT assays.
• B
ivalirudin dosing in acute coronary syndromes
(ACS): the target ACT in the Replace II ACS
trial was a bolus to maintain the ACT over
225 seconds. In subsequent ACS trials, ACT
monitoring of the bivalirudin was not required.27
• E
ffects of bivalirudin on the ACT can be seen
within minutes of a bolus.
• A ny DTI and no acute thrombosis and concerns
for bleeding present: Consider targeting aPTT
ratio of 1.5 to 2 x baseline (1.5−2.5 x baseline
argatroban) to minimize bleeding risks. Because
a higher incidence of thrombosis was seen in the
lepirudin trials, if half the aPTT values were
below 1.5 x control, lower targets may not be
preferred.
• A lthough more consistent results have been
observed with alternative assays to monitor DTI
infusions compared to the aPTT, reductions in the
incidence of bleeding or thrombosis with their use
has not been established, and they were not used
in the clinical trials that led to market approval.
(continued)
• A lterations in dosing requirements may be

necessary as the dynamic clinical presentation
of the patient changes. Measured aPTT values
should take this under consideration, and the
infusion rate should be adjusted to prevent
undershooting or overshooting target goals (see
Figures 5-1 and 5-2).3
TABLE 5-6: Sample Adjustment Scale for a DTIa

Agent _________________
Start infusion at ____________ (__________/hr) Baseline aPTT ________________

Draw aPTT________ hr after starting infusion Baseline INR _________________
Draw aPTT/INR/CBC every morning while on infusion Call physician if the rate exceeds
_________________________
aPTT Rate adjustment Rate adjustment Repeat aPTT Comment

by percentage
Less than Increase infusion Increase infusion 4–6 hr

__________ sec rate by 40% rate
__________
________ to Increase infusion Increase infusion 4–6 hr

_________ sec rate by 20% rate
_____________
Goal aPTT No change No change Draw aPTT/INR

___________ every morning
____________ Decrease infusion Decrease 4–6 hr

to rate by 20% infusion
__________ sec rate _________
Greater than Decrease infusion Decrease 4–6 hr b

For low infusion
__________ sec rate by 40% infusion rates (defined
rate __________ based on agent)
Hold for 1–2 hrb and aPTT >100
Hold for 1–2 hrb sec (could vary
based on hospital
reagent), hold 2
hr; if at a higher
rate (defined
based on agent),
hold 1 hr
Clinical thrombosis: Target 2–2.5 x baseline for bivalirudin (2–3 x baseline argatroban).
No apparent clinical thrombosis: Target aPTT 1.5–2/2.5 x baseline.
Rate adjustment units (mg/hr, mcg/kg/min, mg/kg/hr) can vary between institutions and the
agent used.
For argatroban: When using argatroban, adjust initial dose in the following fashionb:
• Asian: 1 mcg/kg/min
• Hepatic impairment (Child-Pugh >6): 0.5 mcg/kg/min
• Critically ill: 0.6–1 mcg/kg/min
• Critically ill with multisystem organ impairment: 0.2–0.5 mcg/kg/min
• See Table 18-14
aPTT target determined by agent, baseline value, and presence of thrombosis.

a
b
Use dry weight for calculations in anasarca.
aPTT: activated partial thromboplastin time, CBC: complete blood count, hr: hours, INR:
international normalized ratio, sec: seconds
TABLE 5-7: Monitoring Considerations When Initiating and

Adjusting a DTI Regimen
Initiating DTI
• Draw baseline aPTT and INR if not previously done; if a true baseline aPTT is not possible,
use laboratory normals to help set targets.
• Evaluate renal, liver, and cardiac function for potential reasons to reduce the dose.
• Initiate DTI depending on target goals and indication for use.
Monitoring DTI (see Figures 5-1 and 5-2)

• Draw aPTT at a predetermined time within 2–6 hr to reduce the risk of overtargeting or
undertargeting the selected aPTT goal. Note that the initial value reported may not be at
steady-state in acutely ill patients.
• Adjust dose upward any aPTT value notably below a ratio of 1.5 X baseline.
• Consider adjusting the dose downward if the upper end of the target range is noted
shortly after initiating the infusion, or above prior to achieving steady state.
• Follow thrombosis progression, platelet count (HIT), patient, and HCT (or hemoglobin) for
any evidence of bleeding.
• If an INR was drawn before starting warfarin while on the DTI, consider an aPTT with it to
determine amount of DTI effect on the INR.
• A flattening of the aPTT dose response curve has been observed at higher degrees
of anticoagulation intensity with minimal change in the aPTT as the DTI concentration
increases (see Chapter 21).
• The ACT has been used in situations where a higher degree of anticoagulation may
be required, such as invasive cardiac or selected surgical procedures (e.g., coronary
intervention, cardiopulmonary bypass, or ECLS).
• The DTI can independently elevate the INR value by interfering with the assay in the
laboratory. Absent of warfarin, this should not be interpreted as an elevated degree of
anticoagulation. The degree of effect on the INR often correlates with the concentration
of the DTI present, which is also represented by the intensity of rise in the aPTT. At higher
doses, a more pronounced elevation in the INR for any DTI can occur. Argatroban generally
leads to the largest INR elevations followed by bivalirudin and then lepirudin, which has the
least effect on INR. Stopping DTI therapy after seeing an INR over 2 without considering
the effect of DTI on INR is a very common clinical error that needs to be prevented.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, DTI: direct
thrombin inhibitor, ECLS: extracorporeal life support, HCT: hematocrit, HIT: heparin-induced
thrombocytopenia, INR: international normalized ratio, x: times
Low Clearance
aPTT
2.5–3 X control
Moderate Clearance
1.5 X control
High Clearance
2 hr 4 hr
FIGURE 5-1. Considerations for Measuring aPTT Values at the

Initiation of a DTI Infusion
The initial aPTT may depend on plasma clearance. An early aPTT in the upper end of the
target range might signal a reduced ability to eliminate the DTI.
aPTT
Ratio
2.5–3 X control
1.5 X control
time
Dose ↑ Dose ↑
FIGURE 5-2. Optional Approach to Titrating DTI Infusion into

the Target Range in the Presence of Notable Bleeding Concerns
The dotted line represents potential aPTT values above the target in the setting of
reduced DTI elimination that is not recognized early in the course of therapy. The
solid line describes a strategy of starting a lower infusion rate and titrating upward to
minimize risk of overshooting the target when notable bleeding concerns are present.
Source: Adapted from Dager WE. Considerations for drug dosing post coronary artery
bypass graft surgery. Ann Pharmacother. 2008;42:421-424. Copyright© 2008. Reprinted
by permission of SAGE Publications.
• D
ue to the potential flattening of the aPTT at
high concentrations of DTI, following the INR
in conjunction with the aPTT can be considered
when very high doses of DTI are given. You may
be experiencing this flattening of the aPTT dose-
response curve if the aPTT is not rising with
increasing DTI doses but the INR is continuing
to increase. In this situation, since the serum
level of the DTI is likely still rising, the INR and
thrombin time (TT) may now be a guide for
assessing dosing titrations.
• I n situations of confirmed HIT and lack of
platelet response, consider reassessing target
aPTT values and dosing titration scale.
Transitioning from a DTI to
warfarin3,12,16,17,20-22,27-33
Note: aPTT and INR responses to a DTI and
warfarin separately vary between assays (see Table
5-8).
• D
raw a baseline INR and aPTT on DTI
therapy alone.
• I nitiate warfarin and identify a desired
1.5–2 point increase in the INR or pick a
preselected INR, which considers the DTI-
induced INR prolongation (with minimal
change in the aPTT).
• O
nce the desired number of overlap days and
desired platelet recovery has occurred and
the INR target is reached, hold the DTI for
4–8 hours and recheck the INR and aPTT.
• A
fter withholding the DTI and the subsequent
INR is over 2 with an aPTT close to baseline
(indicating the DTI has largely cleared), then
the DTI can be discontinued. It may take
longer for the effects of a DTI to diminish if
a very low infusion rate has been used and
aPTT values are in the target range, as this
suggests slower drug elimination (Figure 9-2).
(continued)
If the INR is less than 2 or in the lower portion

of the INR range with a continued notable
elevation in the aPTT, restarting the DTI
infusion may be necessary.
• A
nother option may be the use of
chromogenic factor X (not anti-Xa activity)
or factor II to assess if an adequate
anticoagulation response with warfarin has
occurred.30-32
{{ Factor X <11% = INR >3.5
{{ Factor X of 11% to 42% ~INR 2–3.5
{{ Factor X >42% = INR <2
{{ Factor II targets of 20% to 35% ~INR 2–3
Note: Slight differences in the percent range can occur
between assay methods.
SPECIAL POPULATIONS
TABLE 5-8: Influence of Direct Thrombin Inhibitors on Selected
Assays31
Agent Effect
Argatroban • Increased protein C and protein S

• Increased dRVVT
• Decrease fibrinogen, factor II, and factor
IX
Bivalirudin • Increased protein C and protein S
• False positive lupus anticoagulant ratios
• Decreased factor IX
No effect: D-dimer; Von Willebrand’s factor; chromogenic plasminogen, antithrombin (slight
elevation observed).
dRVVT: dilute Russel viper venom test (test for present of lupus anticoagulant)
Coronary Artery Bypass Grafting and Procedures

Requiring Cardiopulmonary Bypass
• HIT is rare with the exception of recent exposure to heparin.
• Heparin is the anticoagulant of choice in coronary artery bypass grafting (CABG)
with a pump unless patient has reasons not to use.
• Suggested management options if patient requires CABG when heparin contra-
indicated:
{{ Delay procedure until heparin antibody cannot be detected (several
months).
{{ Use alternative anticoagulant.
• Suggested alternative anticoagulant dosing during CABG under HIT conditions:
{{ DTI infusion rates post-open heart surgery may be lower than in the
pre-operative setting as organ function and, thus, elimination may
be diminished. Platelet count most likely will drop after surgery.
• Because bivalirudin can be cleaved and

inactivated by thrombin in stagnant blood,
blood clotting in small pockets outside the
circulation within the surgical field—unlike
with heparin—does not suggest insufficient
anticoagulation.
Mechanical Circulatory Devices36,37

Heparin is commonly used in the setting of mechanical circulatory support
to sustain blood flow and prevent clotting of the circuit (see Chapter 17).
Some components of using DTIs in this setting are discussed in Chapter 17.
In situations where heparin is not an option and an alternative short-acting
anticoagulant is required, parenteral DTIs may be considered. Dosing and
goals of therapy will depend on the need for either sustaining the circuit or
independent. systematic anticoagulation of the patient.
Goals of Therapy
• May be different for sustaining the circuit, and monitoring may be based on
assessment of clotting within the circuit (e.g., extracorporeal life support [ECLS]),
function of the device (e.g., ventricular assist devices).
• Laboratory assessment of the DTI should still occur to make sure excessive
anticoagulation effects and potential complications such as systemic bleeding
are identified.
• It is unclear what the target goals are and which test (aPTT or ACT) should be
used because information is limited based on single-center case reports or small
case series (if any information at all).
TABLE 5-9: DTI Dosing Considerations for Open Heart Surgical

Procedures12,34,35
Agent Pump Systemic Infusion Suggested Adjustment
Priming Bolus Rate During Target (if needed)
CABG (High
Range ACT)
Bivalirudin 50 mg to 1 mg/kg 2.5 mg/kg/hr Maintain Rate: +/– 0.25

with pumpa priming ACT: mg/kg/hr
solution ≥2.5 x or
baseline Intermittent
bolus: 0.1–0.5
mg/kg; stop 20
min before going
off pump
Bivalirudin – 0.75 mg/kg 1.75 mg/kg/hr ACT: Rate: +/– 0.25

without >300 sec mg/kg/hr
pumpa or
Intermittent
bolus: 0.1–0.5
mg/kg; stop 15
min before flow
restored down all
grafts
Argatroban 50 mcg/kg 100 mcg/kg 5–10 mcg/ ACT:

with pumpb kg/min 300–400 sec
Argatroban 5 mg 2–5 mcg/kg/ ACT:

without min >200 sec
pumpb
a
Hemofiltration can be used to decrease bivalirudin concentrations at end of procedure. In the
CHOOSE-ON trial, 50 mg was added to the priming solution with a 1-mg/kg bolus followed by
2.5 mg/kg/hr until 15 minutes before planned going of cardiopulmonary bypass.34 ACT values
targeted 2.5 x baseline or more. Additional bolus doses of 0.1–0.5 mg/kg could be used for
subtherapeutic ACT. With the initiation of recirculation, reconnect arterial and venous lines, clamp
arterial filter, infuse residual blood, refill CPB with saline, recirculate and add a 50-mg bolus
followed by continuous infusion of 50 mg/hr into the circuit until determined that CPB was not
necessary to reestablish.
b
Limited case reports with argatroban. Anticoagulation with argatroban has shown to be
inconsistent in CABG cases.
• Cessation of anticoagulant: commonly done prior to restoration of flow to grafts.
• If using a cell-saver device during procedure for bivalirudin, add 1 part citrate 3–4% to 6−8
parts blood to prevent clotting in the reservoir.
• Because bivalirudin is enzymatically cleared, elimination may be severely impaired during
episodes of hypothermia and may lead to some accumulation. Depending on observed ACT
measures, the infusion may actually need to be held.
• Hypothermia induced during surgery may shut down the clotting cascade. Depending on the
situation, anticoagulation may need to be reduced or turned off.
ACT: activated clotting time, CABG: coronary artery bypass graft, CPB: cardiopulmonary bypass,
x: times
• The management goals should be clearly defined at the initiation of a DTI, and
should include reassessments and revisions as needed.
• In situations where the device requires consistent anticoagulation, the DTI should
be started at the same time heparin would have been, with frequent assessments
until the revised target range is achieved.
Additional consideration to note: Circulatory support devices can also
cause thrombocytopenia, so caution and careful assessment should occur
for changing to a DTI for suspected HIT.
Use in Pediatric Patients (see Table 5-10)

Consider alternative anticoagulant dosing in pediatric patients under HIT
conditions:
• Body weight may be correlated with clearance.
• Dosing in infants or neonates is unclear.
• Higher doses may be required during ECLS or invasive procedures, including
cardiac surgery.
TABLE 5-10: Dosing Considerations for DTIs in Pediatric

Patients
Agent Dose
Argatroban • In normal hepatic function, doses similar to observations in adults may
apply; younger patients <6 months may have lower clearance and require
a lower dose; higher doses may be used in selected situations.
Bivalirudin • A bolus of 0.1–0.25 mg/kg has been used.

• Infusion rate 0.15 ± 0.07 mg/kg/hr (average ranges between 0.05 and
0.31 mg/kg/hr have been observed).
Use in Pregnant and Lactating Patients (see Table 5-11)
TABLE 5-11: Direct Thrombin Inhibitors in Pregnancy and

Lactation
Drug Pregnancy Risk Pregnancy Information Lactation Information
Category
Bivalirudin B Although animal studies Excretion in breast milk

have not shown harm unknown; use caution.
to the fetus, safety and
efficacy for use in pregnant
women have not been
established. Bivalirudin is
used in conjunction with
aspirin, which may lead to
maternal or fetal adverse
effects, especially during
the third trimester. Use
during pregnancy only if
clearly needed.
Argatroban B Adverse events were not Excretion in breast

observed in animal studies milk unknown/not
and there are no adequate recommended.
and well-controlled studies
in pregnant women.
Argatroban should be used
in pregnant women only if
clearly needed.
SIDE EFFECTS, PRECAUTIONS,

CONTRAINDICATIONS (SEE TABLE 5-12)
TABLE 5-12: Side Effects, Precautions, and Contraindications

Argatroban Bivalirudin
Side Effects >10% >10%

Cardiovascular—chest pain, Cardiovascular—hypotension
hypotension Central nervous system—pain,
Gastrointestinal—gastrointestinal headache
bleed Gastrointestinal—nausea
Genitourinary—genitourinary bleed Neuromuscular and skeletal—back
and hematuria pain
1−10% 1−10%
Cardiovascular—atrial fibrillation, Cardiovascular—hypertension,
angina, bradycardia, CABG- bradycardia, angina
related bleeding, cardiac arrest, Central nervous system—insomnia,
cerebrovascular disorder, myocardial anxiety, fever, nervousness
infarction, myocardial ischemia, Gastrointestinal—vomiting,
vasodilation, ventricular tachycardia, dyspepsia, abdominal pain
thrombosis Genitourinary—urinary retention
Central nervous system—fever,
headache, intracranial bleeding pain
Dermatologic—skin reactions
Gastrointestinal—abdominal pain,
diarrhea, nausea, vomiting
Genitourinary—urinary tract infection Hematologic—major hemorrhage;
Hematologic—hemoglobin transfusion required,
decreased, hematocrit decreased thrombocytopenia
Local—bleeding at injection or access Local—injection site pain
site Neuromuscular and skeletal—pelvic
Neuromuscular and skeletal—back pain
pain
Renal—abnormal renal function
Respiratory—dyspnea, cough,
hemoptysis, pneumonia
Miscellaneous—sepsis, infection
Precautions Patients with increased risk of • Thrombus formation
hemorrhage: • Preexisting disease states
• Bleeding disorders associated with increased risk
• GI ulcers hepatic impairment of bleeding
• Lumbar puncture • Elderly patients; increased risk
• Major surgery of bleeding events
• Severe hypertension • Avoid IM use due to increased
• Spinal anesthesia risk of bleeding
Contraindications • Overt major bleeding • Active major bleeding

• Hypersensitivity to argatroban • Hypersensitivity to bivalirudin
or its components
CABG: coronary artery bypass graft, GI: gastrointestinal, IM: intramuscular


1. Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother. 2003;4:653-666.
2. Mann MJ, Tseng E, Ratcliffe M, et al. Use of bivalirudin, a direct thrombin inhibitor,
and its reversal with modified ultrafiltration during heart transplantation in a patient
with heparin-induced thrombocytopenia. J Heart Lung Transplant. 2005;24:222-225.
*3. Dager WE, Dougherty JA, Nguyen PH, et al. Heparin-induced thrombocytopenia:
a review of treatment options and special considerations. Pharmacotherapy.
2007;27:564-587.
4. Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin-inhibitors:
bivalirudin, lepirudin and argatroban, on prothrombin time and INR measurements.
Am J Clin Path. 2004;121:593-599.
*5. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced
Chest. 2012;141(suppl 2):e495S-e530S.
6. Keyl C, Zimmer E, Bek MJ, Wiessner M, et al. Argatroban pharmacokinetics and
pharmacodynamics in critically ill cardiac surgical patients with suspected heparin-
induced thrombocytopenia. Thromb Haemost. 2016;115(6):1081-1089.
7. Beiderlinden M, Treschan TA, Görlinger K, Peters J. Argatroban anticoagulation in
critically ill patients. Ann Pharmacother. 2007 May;41(5):749-754. Erratum in: Ann
Pharmacother. 2007;41(7):1320.
8. Keegan SP, Rolik EM, Ernst NE, et al. Effects of critical illness and organ failure on
therapeutic argatroban dosage requirements in patients with suspected or confirmed
heparin-induced thrombocytopenia. Ann Pharmacother. 2009;43:19-27.
9. Ansara AJ, Arif S, Warhurst RD. A weight-based argatroban dosing nomogram for the
treatment of heparin induced thrombocytopenia. Ann Pharmacother. 2009;43:9-18.
10. Lubenow N, Eichler P, Leitz T, et al. Lepirudin for prophylaxis of thrombosis in
patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3
prospective studies. Blood. 2004;104:3072-3077.
11. Huhle G, Hoffmann U, Hoffmann I, et al. A new therapeutic option by subcutaneous
recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a
pilot study. Thromb Res. 2000;99:325-334.
*12. Hassell K. The management of patients with heparin-induced thrombocytopenia who
require anticoagulant therapy. Chest. 2005;127:1S-8S.
13. 2015 ESC guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation: Task Force for the Management
of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment
Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-
315. doi:10.1093/eurheartj/ehv320.
14. Amsterdam EA, Wegner NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the
management of patients with non-ST-elevation acute coronary syndromes: a report of
the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation. J Am Coll Cardiol. 2014;64(24):e139-228.
15. Tsu L, Dager W. Bivalirudin dosing adjustments for reduced renal function with or
without hemodialysis in the management of heparin-induced thrombocytopenia. Ann
Pharmacother. 2011;45:1185-1192.
16. Runyan CL, Cabral KP, Riker RR, et al. Correlation of bivalirudin dose with creatinine
clearance during treatment of heparin-induced thrombocytopenia. Pharmacotherapy.
2011;31:850–856.
17. Hursting MJ, Murray PT. Argatroban anticoagulation in renal dysfunction: a literature
analysis. Nephron Clin Pract. 2008;109:c80–c94.
18. Fischer KG. Hirudin in renal insufficiency. Semin Thromb Hemost. 2002;28:467-482.
19. van Cott EM, Roberts AJ, Dager WE. Laboratory monitoring of parenteral direct
thrombin inhibitors. Semin Thromb Hemost. 2017 [Epub ahead of print].
20. Kiser TH, Burch JC, Klem PM, et al. Safety, efficacy, and dosing requirement of
bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy.
2008;28:1115-1124.
21. Kiser TH, Fish D. Evaluation of bivalirudin treatment for heparin-induced
thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction.
Pharmacotherapy. 2006;26:452-460.
22 Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in
hemodialyzed end-stage renal failure patients. Thromb Haemost. 1997;77:650-655.
23. Grouzi E. Update on argatroban for the prophylaxis and treatment of heparin-induced
thrombocytopenia type II. J Blood Med. 2014;5:131-141.
24. Murray PT, Reddy BV, Grossman EJ, et al. A prospective comparison of three
argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney
Int. 2004;66:2446-2453.
25. Klingele M, Bomberg H, Lerner-Gräber A, et al. Use of argatroban: experiences in
continuous renal replacement therapy in critically ill patients after cardiac surgery. J
Thorac Cardiovasc Surg. 2014;147:1918-1924.
26. Hursting MJ, Verme-Gibboney CN. Risk factors for major bleeding in patients with
heparin-induced thrombocytopenia treated with argatroban: a retrospective study. J
Cardiovasc Pharmacol. 2008;52:561-566.
27. Lincoff AM, Bittl JA, Harrington RA, et al. REPLACE-2 Investigators. Bivalirudin
and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned
glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2
randomized trial. JAMA. 2003;289:853-863.
28. Dager WE. Considerations for drug dosing post coronary artery bypass graft surgery.
Ann Pharmacother. 2008;42:421-424.
29. Arpino PA, Hallisey RK. Effect of renal function on the pharmacodynamics of
argatroban. Ann Pharmacother. 2004;38:25-29.
30. Brown PM, Hursting MJ. Lack of pharmacokinetic interactions between argatroban
and warfarin. Am J Health-Syst Pharm. 2002;59:2078-2083.
31. Gosselin RC, King JH, Janatpour KA, et al. Comparing direct thrombin inhibitors
using aPTT, ecarin clotting times, and thrombin inhibitor management testing. Ann
Pharmacother. 2004;38:1383-1388.
32. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict
the international normalized ratio in patients transitioning from argatroban to warfarin.
33. Trask A, Gosselin RC, Diaz J, et al. Warfarin initiation and monitoring with clotting
factors II, VII and X levels. Ann Pharmacother. 2004;38:251-256.
34. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in
patients with previous or acute heparin-induced thrombocytopenia and heparin
antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83:572-577.
*35. Greinacher A. The use of direct thrombin inhibitors in cardiovascular surgery in patients
with heparin-induced thrombocytopenia. Semin Thromb Hemost. 2004;30:315-327.
36. Bain J, Flannery AH, Flynn J, Dager W. Heparin induced thrombocytopenia with
mechanical circulatory support devices: review of the literature and management
considerations. J Thromb Thrombolysis. 2017;44(1):76-87.
37. Crouch MA, Kasiraja V, Cahoon W, et al. Successful use and dosing of bivalirudin
after temporary total artificial heart implantation: a case series. Pharmacotherapy.
2008;28:1413-1420.
6
Chapter
THROMBOLYTIC
CONSIDERATIONS WHEN USED
WITH ANTICOAGULANTS
Toby C. Trujillo and Tyree H. Kiser
INTRODUCTION
Today thrombolytic agents such as recombinant tissue plasminogen activator
(rt-PA), reteplase, and tenecteplase (TNK) are crucial agents in the treatment of
acute myocardial infarction (AMI), stroke, venous thromboembolism (VTE) (includ-
ing massive pulmonary embolism [PE]), and peripheral arterial thrombosis as well
as other unique thromboembolic conditions. Their ability to dissolve clot, as
opposed to preventing clot expansion, is a key distinguishing characteristic from
other anticoagulant agents, which makes them valuable options when immediate
nonsurgical reperfusion of an occluded vessel is warranted. Despite their clinical
utility, thrombolytic agents carry a high risk of bleeding, especially intracranial
hemorrhage. Patient selection must be carefully considered to optimize the risk−
benefit ratio with these agents.
PHARMACOLOGY AND PHARMACOKINETICS1-9

• Four thrombolytic agents are commercially available in the US: streptokinase, rt-PA
(alteplase [Activase]), reteplase (Retavase), and TNK (TNKase). Each of these agents
has distinct pharmacologic properties that impact their clinical use (see Table 6-1).
Mechanism of Action
• All of the available agents exert their effect on the endogenous fibrinolytic system by
converting plasminogen to plasmin through hydrolysis of the arginine−valine bond in
plasminogen. Plasmin cleaves fibrin and fibrinogen leading to clot dissolution, as well
as degrading the procoagulant factors V and VIII.
• Urokinase and streptokinase produce plasminogen activation on a systemic level,
leading to global activation of plasminogen to plasmin. With doses used for systemic
effects, plasmin may be depleted and fibrin/fibrinogen degradation products may
produce a systemic anticoagulant effect.
• Recombinant t-PA, reteplase, and TNK are all fibrin-specific thrombolytic agents. As
such, minimal amounts of plasminogen are converted to plasmin in the absence of
fibrin leading to a more localized thrombolytic effect.
107
• Of note, in patients with plasminogen levels significantly below normal (e.g.,

<50%) at therapy initiation, the therapeutic response from an exogenously
administered thrombolytic agent may be blunted or less than expected.
• Thromboelastography (See Chapter 21, Coagulation Laboratory Considerations)
can be used to assess the level and duration of thrombolysis. It can be a useful
tool to determine if adequate lysis is present when attempting to dissolve a
thrombus, but cannot be used to determine if thrombolytic dosage is too high.
Pharmacologic and Clinical Properties of Thrombolytics
TABLE 6-1: Characteristics of Available Thrombolytic Agents

Property Urokinase+ Streptokinase Alteplase Reteplase Tenecteplase
(rt-PA) (TNK)
Molecular weight, 35 47 70 39 70
kD
Half-life, min 13–20 23 4–8 14–18 23–37
Fibrin specificity Minimal Minimal Moderate Moderate High
Potential No Yes No No No
antigenicity
Plasminogen Direct Indirect Direct Direct Direct

binding
FDA-approved PE MI, PE, DVT MI, PE, MI MI

indications stroke,
catheter
occlusion
Patency with TIMI NA 40–50% 46–75% 60–63% 63%

Grade 3 flow* – 90
min
Currently not commercially available in the United States.

+
*TIMI Grade 3 flow (see Table 6-3): complete perfusion defined by normal flow, which fills
the distal coronary bed completely. TIMI Grade 0 flow is no perfusion, with Grades 1 and 2
representing partial perfusion of the myocardium.
DVT: deep venous thrombosis, FDA: U.S. Food and Drug Administration, MI: myocardial
infarction, PE: pulmonary embolism, TIMI: thrombolysis in myocardial infarction
INDICATIONS, DOSING, AND

ADMINISTRATION10-44
• Depending on the half-life of the compound being used, administration is either
by single or multiple intravenous (IV) boluses or through a continuous IV infusion
given for a specified time frame (see Table 6-2).
• Catheter flush is for localized (catheter-related) thrombosis.
• Devices (e.g., ultrasound-accelerated thrombolysis catheters, mechanical circu-
latory support).
THROMBOLYTIC CONSIDERATIONS WHEN USED WITH ANTICOAGULANTS 109
• M
any thrombolytic agents are dosed on body
weight (actual body weight); therefore, obtaining
an accurate weight prior to the initiation of
therapy is crucial to optimize therapy.
• A small bolus of fluid (50–100 mL normal
saline) should follow the administration of a
thrombolytic dosed for systemic effects to ensure
the entire dose is delivered to the patient and no
drug is remaining in the IV line.
• I n more emergent situations, it is important to
set up in advance the lytic to be used, dose, and
location of the drug including sustaining an
adequate supply for a given indication/situation.
MONITORING10-21
Monitoring Parameters in ST Segment Elevation

Myocardial Infarction (STEMI)
• General
{{ Baseline activated partial thromboplastin time (aPTT), prothrombin
time/International Normalized Ratio (PT/INR), hematocrit, platelet
count, fibrinogen (streptokinase therapy)
{{ Coagulation parameters during therapy: aPTT, PT/INR, fibrinogen
level (streptokinase)
{{ Vital signs (blood pressure, heart rate [BP, HR]) at baseline and
during therapy
{{ Bleeding, especially during planned invasive procedures, while
lytic state is in effect
• Therapeutic
{{ Resolution of electrocardiogram (ECG) changes
{{ Resolution of chest pain
{{ Appearance of reperfusion arrhythmias
{{ Early cardiac enzyme peak (primarily creatinine phosphokinase
[CPK])
{{ Infarct artery patency—TIMI flow (see Table 6-3)
• Toxicity/adverse effects
{{ Clinical evidence of bleeding (vascular access site, hematuria, GI
bleeding, positive stool guaiac)
{{ Intracranial bleeding—impaired cognitive, motor, or sensory
function on neurologic exam
TABLE 6-2: Recommended Doses for Thrombolytic Agents by Patient Population
Patient Group Urokinase Streptokinase Alteplase (rt-PA) Reteplase Tenecteplase (TNK)
STEMI NA IV: 1.5 million units given Accelerated infusion 10 units IV over 2 min; give Dose based on weight and
Note: The lytic agent IV over 60 min regimen: Patients ≤67 kg: second 10-unit dose IV 30 given as IV bolus over 5
should be administered give 15 mg IV over 1–2 min, min later unless serious sec; total dose should not
within 30 min. Intracoronary: then 0.75 mg/kg IV over bleeding or anaphylaxis is exceed 50 mg
20,000 units bolus, then 30 min, then 0.5 mg/kg IV present
2,000–4,000 units/min for over 1 hr <60 kg: 30 mg
30–90 min 60–69 kg: 35 mg
Patients >67 kg: 100 mg IV 70–79 kg: 40 mg
over 1.5 hr; give 15 mg over 80–89 kg: 45 mg

1–2 min, 50 mg over 30 ≥90 kg: 50 mg
min, then 35 mg over 1 hr
3-hr infusion regimen:

Patients <65 kg: 1.25 mg/
kg over 3 hr; give 60% of
total dose in first hr with 6%
to 10% as an IV bolus, then
20%/hr for the next 2 hr
Patients ≥65 kg: 100 mg

IV over 3 hr; give 60 mg 1
hr with 6–10 mg as an IV
bolus, then 20 mg/hr for
the next 2 hr
(continued)
PE Load: 4,400 units/ Load: 250,000 units/kg IV Full dose: 100 mg over 10 units IV over 2 min; give Full dose: 30−50 mg
kg IV over 10 min over 30 min 2 hr (10 mg bolus with second 10-unit dose IV (weight dependent) single
remaining 90 mg over 2 hr) 30 min later unless serious intravenous bolus
Maintenance: Maintenance: bleeding or anaphylaxis
4,400 units/kg/hr IV 100,000 units/kg/hr IV Half dose: 50 mg over present >60 kg: 30 mg
for 12 hr for 24 hr 2 hr (10 mg bolus with ≥60 to <70: 35 mg
remaining 40 mg over ≥70 to <80: 40 mg
2 hr) <50 kg, the total dose ≥80 to <90: 45 mg
is calculated as 0.5 mg/kg, ≥90 kg: 50 mg
which is given as a 10-mg
initial bolus followed by the Catheter-directed therapy
remainder over 2 hr after failed systemic lysis:
Or One single report found
50 mg IVP and heparin success with a range
initiated immediately with a of 5–20 mg total dose
2,000−5,000 bolus followed administered, in 2.5-mg
by a infusion 10 unit/kg/hr increments
for 24–30 hr unless aPTT
> target range on heparin
already or received a
LMWH dose within 12 hr
Catheter-directed therapy
after failed systemic lysis:
One single report found
success with a range of
10–30 mg total dose
administered, in 5–10 mg
increments (see Chapter 13)
(continued)
DVT Load: 4,400 units/ Load: 250,000 IUs/kg IV Catheter-directed therapy: NA NA

kg IV over 10 min over 30 min No single dosing regimen
has proven superior to
Maintenance: Maintenance: others; dosing options from
4,400 units/kg/hr IV 100,000 units/kg/hr IV small reports include
for 12 hr for 72 hr
• 0.01 mg/kg/hr (max
20 mg in 24 hr) for up
to 96 hr
• 5-mg bolus, followed
by 0.01-mg/kg/hr
infusion
• 10-mg bolus, followed
by 1–2 mg/hr infusion
See Chapter 13
(continued)
Ischemic stroke NA NA Within 3–4.5 hr of NA Phase 2 trial only compared

symptoms. The maximum to alteplase
dose is 90 mg.
0.1 mg/kg bolus
Patients ≥100 kg: Give Or
0.9 mg/kg (90 mg is the 0.25 mg/kg bolus
maximum dose), for which
10% (9 mg) is given as a Both doses resulted in
bolus over 1 min and 90% improved reperfusion via
(81 mg) is then infused over CT angiography compared
60 min. to 0.9 mg/kg alteplase
Patients <100 kg: Give

0.9 mg/kg, for which 10%
(0.09 mg/kg) is given as
a bolus over 1 min. The
balance of the dose (0.81
mg/kg) is then infused over
60 min.
(continued)
Catheter occlusion 5,000 units/2 mL NA 2 mg instilled into the NA NA

in each IV catheter catheter and retained for 30
lumen over 1–2 min; min to 2 hr; may repeat in 2
dwell time 1–4 hr hr if catheter still occluded
then remove;
flush catheter with
0.9% NaCl prior
to reconnecting
tubing; may repeat

with 10,000 units if
catheter does not
clear
Peripheral arterial 240,000 units/ NA Weight based infusion— One small case series of NA
occlusion (intra-arterial) hr for 2 hr, then 0.02–0.1 mg/kg/hr for up 15 patients used a dosing
administration)* 120,000 units/ to 36 hr regimen of 0.5–1.0 units/hr
hr for 2 hr, then Or for 12–32 hr29
60,000 units/hr for Non weight-based infusion
20 hr or 120,000 ranging from 1–10 mg/ A larger case series of 26
units/hr IV for 2 hr, with 2.5 and 5 mg/hr patients used a dose of
hr, then 60,000 most common doses used; 0.5–2 units/hr (mean
units/hr until clot is duration variable from 2–24 0.9 units/hr) up to a total
dissolved hr or until clot resolution dose of 20 units (means
Or 20.1 units ± 5.5)30
120,000 units/hr IV
for up to 48 hr A third case series in 81
patients used 0.5 units/hr
infusion for an average of
19.5 hr and a total dose of
10.3 units31
(continued)
Pleural effusion/empyema 250,000 units/100 mL NS 10 mg in 30 mL NS instilled NA NA

instilled intrapleurally for intrapleurally for 1 hr every
2–4 hr 12 hr for 3 days (6 doses
total). 5 mg of DNase can
be instilled intrapleurally for
1 hr either concurrently or 1
to 2 hr after the rt-PA.
Or
25 mg in 100 mL NS,
divided in two 60 mL-
syringes. Instill intrapleurally
daily for 3 days. The chest
tube is clamped for the
first hour and suction was
applied for 2 hr
(continued)
Prosthetic heart valve 4,400 units/kg IV 150,000 units to 250,000 10 mg IV bolus, then 90 mg NA NA
thrombosis bolus over 30 min, IIU loading dose IV over IV over 3–5 hr
then 4,400 units/hr 30 min, then 100,000
Or units/hr IV TEG can be used to
1.5 million units Or assess the level of lysis.
given IV over 3 hr 1.5 million units given IV An ultrasound can be
over 3 hr done to determine if the
clot has dissolved and

the TPA infusion can be
discontinued.
Mechanical circulatory Various regimens exist; data

support devices (see are limited to case series
Chapter 17 for additional (may depend on the device)
information)#
10 mg IV bolus, then 1 mg/
min for 20 min, then 1 mg/
hr for up to 24 hr
10−20 mg IV bolus, then

remaining dose (usually
10–50 mg) over 2−4 hr
10–50 mg IV bolus
1 mg/min intraventricularly
(left ventricle cavity) over
20–50 min
(continued)
Ultrasound-facilitated, 1 mg/hr for 24 hr with a

catheter-directed, low- unilateral catheter
dose thrombolytics Or
1 mg/hr/catheter for 12 hr
with bilateral catheters$
Frostbite 1 mg/hr intra-arterial 0.15–0.5 mg/hr intra-arterial 0.25–0.5 mg/hr intra-arterial

catheter administration catheter administration catheter administration
(dose divided by number
of limbs)
*Few randomized trials exist investigating the use of intra-arterial thrombolysis in the setting of peripheral arterial disease. As such, dosing strategies in this population are
highly variable as evidenced by the various dosing strategies provided for each agent. Clinicians may encounter dosing regimens that are not accounted for here.
#
Optimal use of thrombolytics in mechanical circulatory support devices requires further study. Data are limited to retrospective case reports or case series. Various regimens
and routes of therapy have been attempted. Choice of strategy should weigh the risks and benefits for each individual patient (see Chapter 17—Mechanical Circulatory
Support Devices).
$
Catheter-directed ultrasound-accelerated (e.g., EKOS catheter) thrombolysis dose and duration varies. Common doses are 0.5–1 mg/hr into each catheter. Doses may be
titrated up or down depending on patient response and laboratory values (e.g., fibrinogen). Common infusion durations are 8–24 hours in length.
DVT: deep vein thrombosis, hr: hour, IV: intravenous, PE: pulmonary embolism, TEG: thromboelastography, TPA: tissue plasminogen activator, units: International Units
TABLE 6-3: Thrombolysis in Myocardial Infarction (TIMI)

Grade Flow—Grading of Coronary Blood Flow During
Coronary Angiography
TIMI Grade Description
TIMI 0 - no perfusion No antegrade flow beyond the point of occlusion
TIMI 1 - penetration without perfusion Faint antegrade coronary flow beyond the occlusion
with incomplete filling of the distal coronary bed
TIMI 2 - partial perfusion Delayed or sluggish antegrade flow with complete

filling of the distal territory
TIMI 3 - complete perfusion Normal flow with complete filling of the distal
territory
Angiographic TIMI flow grade of the infarct artery is estimated before and after completion
of coronary balloon angioplasty according to four grades of flow (TIMI 0–3). PAMI (Primary
Angioplasty in Myocardial Infarction) investigators provided the description of TIMI 3 as
“opacification of the vessel within three cardiac cycles.”
Monitoring Parameters in PE/DVT

• General
{{ Baseline aPTT, PT/INR, hematocrit, platelet count, fibrinogen
(streptokinase therapy)
{{ Vital signs (BP, HR) at baseline and during therapy
{{ Oxygen saturation and hemodynamic parameters
• Therapeutic
{{ Resolution of symptoms: shortness of breath (SOB), chest pain, leg
pain, improved hemodynamics
{{ Resolution of ECG changes
{{ Improved right ventricular function on echocardiogram
• Toxic
{{ Clinical evidence of bleeding (vascular access site, hematuria,
gastrointestinal [GI] bleeding, positive stool guaiac)
{{ Intracranial bleeding: impaired cognitive, motor or sensory function
on neurologic exam
• I n selected situations (e.g., arterial clots or clots

on heart valves) where common management
approaches are not feasible, alteplase doses (see
Table 6-2 for indication) can be considered with
assessment tools such as ultrasound, peripheral
pulses to assess the impact of the therapy. A
baseline thromboelastography (TEG) along with
a follow-up TEG (assessing the lytic portion

of the curves towards the end of the test) during
therapy can be used to assess the presence of
lysis and determine any adjustments in the
management regimen.
Monitoring Parameters in Stroke

• General
{{ Baseline aPTT, PT/INR, hematocrit, platelet count
{{ Coagulation parameters during therapy: aPTT, PT/INR
• Therapeutic
{{ Resolution of symptoms: neurologic deficits at presentation
• Toxic
{{ Intracranial bleeding: impaired cognitive, motor, or sensory function
on neurologic exam
Monitoring Parameters in Catheter Occlusion

• Therapeutic
{{ Aspiration of blood or catheter contents
• Toxic
Monitoring Parameters in Peripheral Arterial Occlusion

• General
{{ Baseline aPTT, PT/INR, hematocrit, platelet count, fibrinogen
(streptokinase therapy)
• Therapeutic
{{ Resolution of symptoms: leg pain, lower extremity ischemia,
restored perfusion
{{ Angiographic evidence of improvement
• Toxic
{{ Intracranial bleeding: impaired cognitive, motor, or sensory function
on neurologic exam
SIDE EFFECTS, PRECAUTIONS, AND

CONTRAINDICATIONS10-15
Review of absolute and relative contraindications for thrombolytic therapy
should also take place prior to administration. These criteria should be easily
retrieved to ensure rapid assessment (see Table 6-4).
TABLE 6-4: Contraindications to Thrombolytic Therapy

Absolute Contraindications
• Any prior ICH

• Known structural cerebral vascular lesion (e.g., arteriovenous malformation)
• Known malignant intracranial neoplasm (primary or metastatic)
• Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours of
symptom onset
• Suspected aortic dissection
• Active bleeding or bleeding diathesis (excluding menses)
• Significant closed-head or facial trauma within 3 months
• Intracranial or intraspinal surgery within 2 months
• Severe uncontrolled hypertension (unresponsive to emergency therapy)
• For streptokinase, prior treatment within the previous 6 months
Relative Contraindications
• History of chronic, severe, poorly controlled hypertension

• Significant hypertension on presentation (SBP >180 mmHg or DBP >110 mmHg)
• History of prior ischemic stroke greater than 3 months, dementia, or known intracranial
pathology not covered in contraindications
• Traumatic or prolonged (greater than 10 minutes) CPR or major surgery (within less than 3
weeks)
• Recent (within 2–4 weeks) internal bleeding
• Noncompressible vascular punctures
• Pregnancy
• Active peptic ulcer
• Oral anticoagulant therapy*
*Current guidelines published in 2018 note that the use of IV alteplase in patients taking a direct
thrombin inhibitor or direct-acting oral anti-Xa inhibitor has not been firmly established, but may
be harmful (IIIC recommendation). IV alteplase should not be administered to patients taking
direct thrombin inhibitors or direct factor Xa inhibitors unless laboratory tests such as aPTT, INR,
platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays
are normal or the patient has not received a dose of these agents for >48 hr (assuming normal
renal metabolizing function). (Alteplase could be considered when appropriate laboratory tests
such as aPTT, INR, ecarin clotting time, thrombin time, or direct factor Xa activity assays are
normal or when the patient has not taken a dose of these ACs for >48 hr and renal function is
normal.) For patients receiving warfarin with a INR ≤1.7 who present in the 3- to 4.5-hr window, IV
alteplase appears safe and may be beneficial (IIB recommendation).
CPR: cardiopulmonary resuscitation, DBP: diastolic blood pressure, ICH: intracranial hemorrhage,
SBP: systolic blood pressure
RISK OF BLEEDING9-15,45,46
Patient Characteristics That Increase the Risk of Bleeding

with Thrombolytic Agents
• In patients experiencing stroke and myocardial infarction, the most important
bleeding complication is intracranial hemorrhage (ICH) (see Table 6-5).
• Due to the low number of patients who have been enrolled in randomized
clinical trials for PE (<2,000 total patients), the actual incidence of ICH as well
as risk factors for bleeding are less well defined compared to acute coronary
syndrome (ACS) and stroke.
• Risk factors for bleeding are heavily dependent on the indication for throm-
bolysis, with patients treated for stroke having a much higher rate of ICH than
patients experiencing STEMI.
• Characteristics predicting increased bleeding in patients with stroke:
{{ Larger neurologic deficit has been associated with a higher rate
of ICH
{{ Older age has in some, but not all, analyses been associated with
a higher rate of ICH
{{ Diabetes
{{ Higher doses of thrombolytic agents
• Characteristics predicting increased bleeding in patients with STEMI:
{{ Older age
{{ Lower body weight
{{ Prior stroke
{{ Increased systolic or diastolic pressure
{{ Female gender
Risk of Intracranial Hemorrhage Between Agents
TABLE 6-5: Rates of Intracranial Hemorrhage Observed in

Various Patient Populations
Urokinase Streptokinase Alteplase Reteplase Tenecteplase
(rt-PA) (TNK)
STEMI: NA— STEMI: 0.6% in STEMI: 0.7% for STEMI: 0.8% STEMI: 0.9% for
Contemporary GUSTO I trial rt-PA vs. 0.6% for reteplase TNK vs. 0.9% for
information not for streptokinase vs. 0.4% for rt-PA in ASSENT
available PE: N/A— in GUSTO I trial streptokinase in II study
Contemporary INJECT trial
PE: NA— information not PE: 3% for rt-PA PE: 2% for
Contemporary available vs. 0.3% for IV 0.6% for tenecteplase vs.
information not UFH reteplase vs. 0.2% for placebo
available DVT: NA 0.4% for rt-PA in
DVT: NA GUSTO III trial DVT: NA
DVT: NA Stroke: NA
Stroke: 6.4% for PE: NA Stroke: NA
Stroke: NA rt-PA vs. 0.6%
for placebo DVT: NA
symptomatic
ICH within 36 hr Stroke: N/A
in NINDS t-PA
study
DVT: deep vein thrombosis, ICH: intracranial hemorrhage, NA: not applicable, NINDS: National
Institute of Neurological Disorders and Stroke, PE: pulmonary embolism, STEMI: ST-segment
elevation myocardial infarction
DOSING AND MONITORING STRATEGIES

FOR ANTICOAGULANT/ANTIPLATELET
AGENTS TO MINIMIZE RISK OF BLEEDING
AND OPTIMIZE OUTCOME9-15, 24-27
The use of adjunctive antithrombotic therapy (antiplatelet and anti-thrombin
agents) is often necessary to maintain patency of the affected artery or vein.
However, specific recommendations exist for how and when adjunctive
therapies should be initiated in different indications. It is crucial to ensure
adjunctive therapies are timed appropriately in relation to thrombolytic
administration to optimize safety and efficacy (see Table 6-6).
TABLE 6-6: Dosing of Antithrombotic Agents with Thrombolytic Therapy
Patient Group ASA or ASA + Clopidogrel UFH LMWH Fondaparinux Bivalirudin
STEMI ASA: 162–325 mg initial Bolus: 60 units/kg, Enoxaparin is the preferred 2.5 mg sub-Q once daily NA
dose using chewable maximum dose 4,000 units agent and should be started in conjunction with
formulation; maintenance given in conjunction with thrombolytic agent; therapy
dose 81–325 mg daily Continuous IV infusion: fibrinolytic agent for a should be continued for
12 units/ kg/hr, maximum minimum of 48 hr and minimum of 48 hr and
Clopidogrel: Loading initial rate of 1,000 units/hr ideally up to 8 days. ideally up to 8 days;
dose of 300–600 mg contraindicated in patients
may be considered in UFH should be given Patients <75 yr: 30-mg IV with a CrCl <30 mL/min
patients <75 yr of age; in conjunction with bolus followed by 1 mg/kg
loading dose should be thrombolytic agents for a sub-Q q 12 hr (maximum of
omitted in patients ≥75 yr; minimum of 48 hr; patients 100 mg for first two doses)
maintenance dose of 75 receiving fibrin specific
mg daily agents such as rt-PA, Patients >75 yr: No IV
reteplase, and TNK should bolus, therapy should be
Recommended for all receive UFH; patients 0.75 mg/ kg sub-Q q 12 hr
patients for up to 14 days receiving streptokinase (maximum of 75 mg for first
if no subsequent PCI is should receive UFH only two doses)
performed. if at high risk of systemic
emboli (AF, LV, thrombus). Any patient with CrCl <30
mL/min, regardless of age:
Maintenance dose should
be 1 mg/kg sub-Q q 24 hr
(continued)
PE NA Bolus: 80 units/kg, no Standard treatment doses Minimal data are avail- No data available regarding
recommended maximum of LMWH agents apply able regarding using concomitant administration;
dose fondaparinux with systemic however, in a patient with
Continuous IV infusion: 18 Enoxaparin 1 mg/kg sub-Q thrombolysis in PE; active HIT and PE, consider
units/ kg/hr, no recom- q 12 hr or daily for patients however, if used, standard a dose of 0.15–0.25 mg/
mended maximum dose. with a CrCl 20−30 mL/min treatment doses for VTE kg/hr, titrated to an aPTT
Therapy may be started (maximum of 75 mg for first could be considered: of 1.5–2.5 x control and
with or continued when two doses). Caution with continued until warfarin
thrombolytic therapy is CrCl <20 mL/min due to ≤50 kg: 5.0 mg sub-Q therapy is therapeutic;
initiated; alternatively, it lack of data in this popula- once daily these recommend doses
is reasonable to initiate tion. come from ACS and HIT
therapy after thrombolysis 51–100 kg: 7.5 mg data (see Chapter 18 on
has been administered; Dalteparin 200 units/kg sub-Q once daily HIT)
in patients who had UFH sub-Q once daily or 100
interrupted for thrombolytic units/kg sub-Q q 12 hr; >100 kg: 10 mg
administration, consider caution in patients with sub-Q once daily
the following approach to CrCl <20 mL/min
restarting UFH:
• Check the aPTT at the Tinzaparin 175 units/kg
end of lytic infusion sub-Q once daily; caution
• If aPTT is <2 x control, in patients with CrCl <20
restart UFH at previous mL/min
infusion rate with no
bolus Therapy may be started
with or continued when
• If aPTT >2 x control,
thrombolytic therapy is
recheck in 4 hr and
initiated; alternatively it
if acceptable, restart
is reasonable to initiate
UFH
therapy after thrombolysis
Catheter-directed or local has been administered.
thrombolysis: See DVT (continued)
DVT NA Systemic thrombolysis: Systemic thrombolysis: Systemic thrombolysis: No data available regarding
Follow recommendations Follow recommendations Follow recommendations concomitant administration;
for PE for PE for PE however, in a patient with
active HIT and PE, would
Catheter-directed or Catheter-directed or local Catheter-directed or local recommend a dose of 0.15–
local thrombolysis: UFH thrombolysis: Minimal thrombolysis: Minimal 0.25 mg/ kg/hr, titrated to
dosing in this setting information available, information available; an aPTT of 1.5–2.5 x control
is not standardized; recommend utilizing dosing recommend utilizing dosing and continued until warfarin
often lower intensities strategies found under PE strategies found under PE therapy is therapeutic;
of anticoagulation were these recommended doses
reported in studies as come from ACS and HIT
compared to standard DVT/ data (see Chapter 18 on
PE dosing (often <1,000 HIT)
units/hr); in addition, goal
aPTT used in the literature
include 1.2–1.7 x baseline,
1.5–2.5 x baseline, up to
80–100 sec
(continued)
Ischemic stroke ASA: Therapy initiation Therapeutic IV alteplase should not be NA NA
should be withheld for a anticoagulation with UFH administered to patients
minimum of 24 hr after is not recommended in who have received a LMWH
the administration of the previous 48 hr, or treatment dose within
thrombolysis; thereafter, 24 hr after thrombolysis the previous 24 hr (IIIB
ASA 325 mg as an initial for ischemic stroke; UFH recommendation). Older
dose is recommended for VTE prophylaxis may guidelines suggested it
be initiated 24 hr after was reasonable to start a
Clopidogrel: A dose thrombolysis. Caution is LMWH for VTE prophylaxes

of 75 mg daily is only advised if considering after thrombolysis, and wait
recommended if ASA administering a bolus dose; 24 hr after alteplase to start
cannot be used with the boluses are frequently treatment doses. Note:
same timing constraints as omitted post-ischemic Patients with substantial
discussed above stroke. renal failure may have
prolonged LMWH effects
where a longer hold prior
to the procedure may be
considered.
Catheter NA NA NA NA NA
occlusion
(continued)
Peripheral NA UFH generally administered NA NA NA
arterial occlusion concomitantly with intra-
(intra-arterial) arterial thrombolytic;
administration) dosing in trials generally
consisted to a 3,000–5,000
unit bolus, followed by
a 600–1,000 units/hr
continuous infusion titrated
to a defined goal aPTT.
Pleural effusion/ NA NA NA NA NA
empyema
Prosthetic valve NA NA NA NA NA
thrombosis
Frostbite IV heparin infusion titration

to aPTT of approximately
50–70 sec, but varies based
on aPTT reagent utilized
ACS: acute coronary syndrome, aPTT: activated partial thromboplastin time, ASA: aspirin, CrCl: creatinine clearance, DVT: deep vein thrombosis, HIT: heparin-induced
thrombocytopenia, hr: hour, IV: intravenous, LMWH: low molecular weight heparin, NA: not applicable, PCI: percutaneous coronary intervention, PE: pulmonary embolism,
sec: seconds, sub-Q: subcutaneous, UFH: unfractionated heparin, units: International Units, VTE: venous thromboembolism, x: times

1. Verstraete M. Third-generation thrombolytic drugs. Am J Med. 2000;109:52-58.
2. Tsikouris JP, Tsilouris AP. A review of available fibrin-specific thrombolytic agents used
in acute myocardial infarction. Pharmacotherapy. 2001;21(2):207-217.
3. Stringer KA. Biochemical and pharmacologic comparison of thrombolytic agents.
Pharmacotherapy. 1996;16(5, part 2):119-126.
4. Simpson D, Siddiqui AA, Scott LJ, et al. Reteplase. A review of its use in the
management of thrombotic occlusive disorders. Am J Cardiovasc Drugs.
2006;6(4):265-285.
5. Modi N, Eppler S, Breed J, et al. Pharmacokinetics of a slower clearing tissue
plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction.
Thromb Haemost. 1998;79:134-139.
*6. Morse MA, Todd JW, Stouffer GA. Optimizing the use of thrombolytics in ST-segment
elevation myocardial infarction. Drugs. 2009;69(14):1945-1966.
7. Tanswell P, Modi N, Combs D, et al. Pharmacokinetics and pharmacodynamics of
tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet.
2002;41(15):1229-1245.
8. Todd JL, Tapson VF. Thrombolytic therapy for acute pulmonary embolism. Chest.
2009;135:1321-1329.
9. Wittkowsky AK, Nutescu EA. Thrombosis. In: Alldredge BK, Corelli RL, Ernst ME, et
al., eds. Koda-Kimble and Young’s Applied Therapeutics: The Clinical Use of Drugs.
10th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012.
*10. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the
management of ST-elevation myocardial infarction: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
Circulation. 2013;127:e362-e425.
*11. Kearon C, Akl E, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST
12. Witt D, Clark N. Venous thromboembolism. In: DiPiro J, Talbert RL, Yee GC, et al.,
eds. Pharmacotherapy. 9th ed. New York, NY: McGraw-Hill; 2015.
*13. Kernan WN, Ovbiagele B, Black HR, et al; on behalf of the American Heart Association
Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical
Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of
stroke in patients with stroke and transient ischemic attack: a guideline for healthcare
professionals from the American Heart Association/American Stroke Association. Stroke.
2014;45:2160-2236.
14. del Zoppo GJ, Saver JL, Jaunch EC, et al. Expansion of the time window for treatment
of acute ischemic stroke with intravenous tissue plasminogen activator. Stroke.
2009;40:2945-2948.
15. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy
for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
Chest. 2012;141(suppl 2):e601S-e636S.
16. Semba CP, Bakal CW, Calis KA, et al. Alteplase as an alternative to urokinase. Advisory
panel on catheter-directed thrombolytic therapy. J Vasc Interv Radiol. 2000;11(3):279-
287.
17. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular
surgery as initial treatment for acute arterial occlusion of the legs. N Engl J Med.
1998;338(16):1105-1111.
18. Ponec D, Irwin D, Haire WD, et al. Recombinant tissue plasminogen activator
(alteplase) for restoration of flow in occluded central venous access devices: a double
blind placebo-controlled trial—the cardiovascular thrombolytic to open occluded lines
(COOL) efficacy trial. J Vasc Interv Radiol. 2001;12(8):951-955.
19. Semba CP, Murphy TP, Bakal CW, et al. Thrombolytic therapy with the use of alteplase
(rtPA) in peripheral arterial occlusive disease: review of the clinical literature. J Vasc
Interv Radiol. 2000;11(2 Pt 1):149-161.
20. Sugimoto K, Hofmann LV, Razavi MK, et al. The safety, efficacy, and
pharmacoeconomics of low-dose alteplase compared with urokinase for catheter-
directed thrombolysis of arterial and venous occlusions. J Vasc Surg. 2003;37(3):512-
517.
21. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study
Group. N Engl J Med. 1985 Apr 4;312(14):932-936.
22. Chin NK, Lim TW. Controlled trial of intrapleural streptokinase in the treatment of
pleural empyema and complicated parapneumonic effusions. Chest. 1997;111:275-279.
*23. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the
management of patients with valvular heart disease: executive summary: a report of
Guidelines. J Am Coll Cardiol. 2014;63(22):2438-2488.
24. Baekgaard N, Broholm R, Just S, et al. Long-term results using catheter-directed
thrombolysis in 103 lower limbs with acute iliofemoral venous thrombosis. Eur J Vasc
Endovasc Surg. 2010;39(1):112-117.
25. Vik A, Holme PA, Singh K, et al. Catheter-directed thrombolysis for treatment of
deep venous thrombosis in the upper extremities. Cardiovasc Intervent Radiol.
2009;32(5):980-987.
26. Enden T, Kløw NE, Sandvik L, et al.; CaVenT study group. Catheter-directed
thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an
open randomized, controlled trial reporting on short-term patency. J Thromb Haemost.
2009;7(8):1268-1275.
27. Kuo WT, van den Bosch MA, Hofmann LV, et al. Catheter-directed embolectomy,
fragmentation, and thrombolysis for the treatment of massive pulmonary embolism
after failure of systemic thrombolysis. Chest. 2008;134(2):250-254.
28. Davidian MM, Powell A, Benenati J, et al. Initial results of reteplase in the treatment of
acute lower extremity arterial occlusions. J Vasc Interv Radiol. 2000;11:289-294.
29. Ouriel K, Katzen B, Mewissen M, et al. Reteplase in the treatment of peripheral arterial
and venous occlusions: a pilot study. J Vasc Interv Radiol. 2000;11:849-854.
30. Hanover TM, Kalbaugh CA, Gray BH. Safety and efficacy for the treatment of acute
arterial occlusion: complexity of the underlying lesion predicts outcome. Ann Vasc Surg.
2005;19:817-822.
31. Robertson I, Kessel DO, Berridge DC. Fibrinolytic agents for peripheral arterial
occlusion. Cochrane Database Syst Rev. 2010;3:CD001099.
32. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with
heparin alone in patients with submassive pulmonary embolism. N Engl J Med.
2002;347(15):1143-1150.
*33. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk
pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411.
*34. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with
thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277.
35. Rahman NM, Maskell, NA, West A, et al. Intrapleural use of tissue plasminogen
activator and DNase in pleural infection. N Engl J Med. 2011;365(6):518-526.
36. Thommi G, Shehan JC, Robison KL, et al. A double blind randomized cross over trial
comparing rate of decortication and efficacy of intrapleural instillation of alteplase vs
placebo in patients with empyemas and complicated parapneumonic effusions. Respir
Med. 2012;106(5):716-723.
37. Gonzaga T, Jenabzadeh K, Anderson CP, et al. Use of intraarterial thrombolytic therapy
for acute treatment of frostbite in 62 patients with review of thrombolytic therapy in
frostbite. J Burn Care Res. 2015 epub ahead of print.
38. Saeed D, Maxhera B, Albert A, et al. Conservative approaches for Heartware ventricular
assist device pump thrombosis may improve the outcome compared with immediate
surgical approaches. Interact Cardiovasc Thorac Surg. 2016;23:90-95.
39. Stulak, J, Dunlay S, Sharma S, et al. Treatment of device thrombus in the HeartWare
HVAD: success and outcomes depend significantly on the initial treatment strategy. J
HeartLungTransplant. 2015;34:1535-1541.
40. Kamouh A, John R, Eckman P. Successful treatment of early thrombosis of HeartWare
left ventricular assist device with intraventricular thrombolytics. Ann Thorac Surg.
2012;94:281-283.
41. Piazza G, Hohlfelder B, Jaff M, et al. A prospective, single-arm, multicenter trial of
ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and
submassive pulmonary embolism. The SEATTLE II Study. J Am Coll Cardiol Intv.
2015;8:1382-1392.
42. Shahjouei S, Tsivgoulis G, Shahripour RB, et al. Safety of intravenous thrombolysis
among stroke patients taking new oral anticoagulants—case series and systematic
review of reported cases. J Stroke Cerebrovasc Dis. 2015;24(12):2685-2693.
43. Cappellari M, Bovi P. Intravenous thrombolysis for stroke in patients taking non-VKA
oral anticoagulants: an update. Thromb Haemost 2015;113:440-444.
44. Hankey G, Norrving B, Hacke W, et al. Management of acute stroke in patients taking
novel oral anticoagulants. Int J Stroke. 2014;9(5):627-663.
45. Meijer KM, Schulman S. Determinants of bleeding risk in patients on antithrombotic
and antifibrinolytic agents. Semin Thromb Hemost. 2008;34(8):762-771.
46. Holbrook A, Schulman S, Witt DM, et al. Antithrombotic and thrombolytic therapy
for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
Chest. 2012;(suppl 2):e152S-e184S.
7
Chapter
DIRECT ORAL ANTICOAGULANTS

Allison E. Burnett and Candice L. Garwood
INTRODUCTION
Since 2010, four direct oral anticoagulants (DOACs) have become commercially
available in the United States: dabigatran, a direct thrombin inhibitor (DTI); and
rivaroxaban, apixaban, and edoxaban, which are direct factor Xa (FXa) inhibitors
(Table 7-1). The availability of DOACs has significantly changed the therapeutic
TABLE 7-1: Commercially Available Direct Oral Anticoagulants1-6,*

Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of Direct FIIa Direct FXa inhibitor Direct FXa inhibitor Direct FXa inhibitor
action (thrombin) inhibitor
Manufacturer Boehringer- Bayer with Ortho Pfizer with Bristol Daiichi Sankyo
Ingelheim McNeil Myers Squibb
Brand name(s) Pradaxa Xarelto Eliquis Savaysa (U.S.)

Lixiana (non-U.S.)
Approved Post-operative VTE Post-operative VTE Post-operative VTE Post-operative

indications prevention in knee prevention in knee prevention in knee VTE prevention
or hip arthroplasty** or hip arthroplasty or hip arthroplasty in knee or hip
arthroplasty****
VTE treatment VTE treatment VTE treatment
and prevention of and prevention of and prevention of VTE treatment
recurrence recurrence recurrence and prevention of
recurrence
Stroke and Stroke and Stroke and
systemic embolism systemic embolism systemic embolism Stroke and
prevention in prevention in prevention in systemic embolism
non-valvular atrial non-valvular atrial non-valvular atrial prevention in
fibrillation fibrillation fibrillation non-valvular atrial
fibrillation
Acute coronary
syndrome***
*Betrixaban, another direct factor Xa inhibitor, was recently FDA-approved for extended prophylaxis
among medical patients. Due to the recency of approval and the limited uptake in clinical practice to
date, this agent will not be discussed in this chapter.
**In the United States, dabigatran is approved only for post-operative VTE prophylaxis in hip arthroplasty.
***European Union only.
****Japan only.
FIIa: thrombin, FXa: Factor Xa, VTE: venous thromboembolism
131
landscape of anticoagulation. Clinician familiarity with these agents, particu-

larly their markedly different pharmacologies compared to conventional
therapies, is needed for optimal patient care (Table 7-2). This chapter will
provide a concise overview of the pharmacology, safety, and efficacy data
as well as some practical management aspects pertaining to DOACs. Refer
to other chapters in this book for additional information regarding optimal
DOAC management.
• B
ased on safety and efficacy data from large,
randomized controlled trials (Table 7-3) of
over 100,000 patients,7-17 these agents are
now preferred over conventional therapies
(e.g., vitamin K antagonists, low-molecular-
weight heparins) for common anticoagulation
indications (e.g., non-valvular atrial
fibrillation, non-cancer-associated venous
thromboembolism).18-20
PHARMACOLOGY
The DOACs possess intrinsic anticoagulant activity and do not require
binding to cofactors to exert their effect. Thus, they are considered direct
anticoagulants. Because of their small molecular size (~500 daltons) and
lack of binding to bulky cofactors, DOACs are able to penetrate coagula-
tion complexes on phospholipid surfaces and inhibit both clot-bound and
free-floating thrombin. Each DOAC inhibits a single serine protease target
(dabigatran inhibits thrombin [FIIa]; rivaroxaban, apixaban, and edoxaban
inhibit FXa) within the common pathway of the coagulation cascade (Figure
7-1). This specificity provides several practical advantages of DOACs over
conventional anticoagulation therapies.21
• C
ompared to conventional anticoagulants (e.g.,
heparins, warfarin) that inhibit multiple serine
proteases within the coagulation cascade, the
DOACs inhibit a single procoagulant target.
This increased specificity provides a linear dose
response and wide therapeutic index, allows for
fixed dosing, and precludes the need for routine
monitoring of the anticoagulant effect of DOACs
in most patients.
DIRECT ORAL ANTICOAGULANTS 133
Phase of Coagulation Drug

coagulation pathway
TF/VIIa
Initiation
IX, XI,XII
X
PL, Ca+2
Amplification
IXa
VIIIa
Apixaban
Xa Rivaroxaban
Edoxaban
Va
Protein C PLT
II PLT
TM PLT
IIa
Dabigatran
Propagation
Fibrinogen Fibrin
FIGURE 7-1. Mechanism of Action of the Direct Oral

Anticoagulants
Ca+2: calcium ions, PL: phospholipid, PLT: platelet, TM: thrombomodulin, TF: tissue
factor, II, IX, X, XI, XII: inactive clotting factors, IIa, Va, VIIa, VIIIa, IXa, Xa: activated
clotting factors
OF WARFARIN AND THE DOACS1-4,21
TABLE 7-2: Comparison of the Pharmacokinetics and

Pharmacodynamics of Oral Anticoagulants
PK/PD Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Parameter
Target(s) IIa, VIIa, IXa, IIa Xa Xa Xa

Xa
Prodrug No Yes No No No
Bioavailability 80–100 6.5 (pH 80 50 62

(%) dependent)
Volume of 10 50–70 50 23 >107

distribution
(L)
Peak effect 4–5 days 1.5–3 hr 2–4 hr 1–3 hr 1–2 hr
Half-life* 40 hr 12–17 hr 5–9 hr 9–14 hr 10–14 hr
Renal None 80% 33% 25% 35–50%

elimination
Protein >99% 35% 90% 87% 55%

binding
Dialyzable No Yes No No Possible
Interactions Numerous P-gp 3A4, P-gp 3A4, P-gp P-gp
Coagulation Yes No No No No
monitoring
Lab measure INR aPTT PT Anti-Xa Anti-Xa

TT, dTT, ECT Anti-Xa
Antidote Vitamin K Idarucizumab No No No
*In patients with normal renal function.

anti-Xa: anti-Factor Xa, aPTT: activated partial thromboplastin time, dTT: dilute thrombin
time, ECT: ecarin clotting time, hr: hour, INR: international normalized ratio, L: liters, P-gp:
p-glycoprotein efflux transporter, PT: prothrombin time, TT: thrombin time, 3A4: cytochrome P450
3A4, IIa: thrombin, Xa: Factor Xa, VIIa: factor VIIa, XIa: factor XIa
COMPLETED AND ONGOING PHASE III

TRIALS OF DOACS22
See Table 7-3: Phase III Clinical Trials of DOACs beginning on the next page.
TABLE 7-3: Phase III Clinical Trials of DOACs
Anticoagulation Dabigatran Rivaroxaban Apixaban Edoxaban
Indication
Completed Ongoing Completed Ongoing Completed Ongoing Completed Ongoing
Prevention of VTE RE-NOVATE RECORD-1 ADVANCE-3 STARS-E3

in THR RE-NOVATE II RECORD-2 STARS-JV
EPCAT II
Prevention of VTE RE-MODEL RECORD-3 ADVANCE-1

in TKR RE-MOBILIZE RECORD-4 ADVANCE-2
EPCAT II
Prevention of VTE in MAGELLAN MARINER ADOPT

acute medical illness
Treatment of VTE RE-COVER EINSTEIN-DVT AMPLIFY HOKUSAI

RE-COVER II EINSTEIN-PE
Extended treatment RE-SONATE EINSTEIN-EXT RENOVE AMPLIFY-EXT RENOVE

for prevention of RE-MEDY EINSTEIN- COVET COVET
VTE recurrence CHOICE
Splanchnic vein NCT02627053

thrombosis
Cerebral venous RE-SPECT CVT

thrombosis
(continued)
Indication
Cancer-associated NCT03240120 CASSINI CARAVAGGIO HOUKUSAI

thrombosis CALLISTO NCT02585713 VTE CANCER
Outpatient MERCURY PE
treatment of
low-risk PE
APLA-associated RAPS ASTRO-APS

thrombosis
Treatment of VTE in VERDICT VERDICT

renally impaired
VTE treatment in NCT02197416 EINSTEIN Junior NCT02464969 NCT02798471

pediatric patients NCT01895777
Stroke prevention in RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-

NVAF RELY-ABLE AVERROES TIMI 48
NVAF ablation RE-CIRCUIT VENTURE-AF
NVAF cardioversion X-VERT AFTER-CV ENSURE-AF
NVAF and PCI REDUAL-PCI PIONEER AF CAPITAL PCI AF AUGUSTUS ENTRUST-AF-

PCI PCI
(continued)
Indication
NVAF with LA X-TRA

thrombus
Secondary stroke AREST

prevention
Cryptogenic stroke RE-SPECT NAVIGATE ATTICUS

ESUS ESUS
ACS RE-DEEM ATLAS I APPRAISE

ATLAS 2
Elective PCI X-PLORER
Mechanical heart RE-ALIGN

valves
TAVR GALILEO ATLANTIS
Pacemaker or BRUISE- BRUISE- BRUISE-

defibrillator surgery CONTROL-2 CONTROL-2 CONTROL-2
HF and CAD COMMANDER HF
CAD or PAD COMPASS
(continued)
Indication
PAD with VOYAGER PAD

revascularization
NVAF left atrial ADRIFT

appendage closure
NVAF with ESRD AXADIA

on HD RENAL-AF
ACS: acute coronary syndromes, APLA: antiphospholipid antibody syndrome, CAD: coronary artery disease, DOAC: direct oral anticoagulant, ESRD: end-stage renal
disease, HD: hemodialysis, HF: heart failure, LA: left atrium, NVAF: non-valvular atrial fibrillation, PAD: peripheral artery disease, PCI: percutaneous coronary intervention, PE:
pulmonary embolism, TAVR: transcatheter aortic valve replacement, THR: total hip replacement, TKR: total knee replacement, VTE: venous thromboembolism
• C
ompared to warfarin, DOACs have a much
shorter half-life and thus a more rapid onset
and offset of action. Their short time to onset
produces a rapid therapeutic effect in treatment
of acute thrombosis and precludes the need for
bridging therapy around invasive procedures
(see Chapter 10). Their rapid offset requires a
high degree of adherence with therapy to avoid
subtherapeutic levels of anticoagulation.
• A ll of the DOACs are renally eliminated to some
degree. None of the major randomized controlled
trials of DOACs included patients with severe
renal impairment (CrCl <25–30 mL/min via
the Cockcroft-Gault equation using actual body
weight). Therefore, routine use in this population
is not recommended. When considering a patient
for DOAC therapy, careful evaluation of their
renal function at baseline and periodically during
therapy is imperative (see Chapter 11 for further
details).
• I darucizumab is the specific antidote for
dabigatran. Andexanet alfa is approved for
reversing the oral anti-Xa anticoagulants
apixaban and rivaroxaban (see Chapters 8
and 9).
DRUG INTERACTIONS
All of the DOACs are substrates of the P-glycoprotein (P-gp) efflux trans-
porter system. Apixaban and rivaroxaban are also substrates of the hepatic
isoenzyme cytochrome P450 3A4 (CYP 3A4). Inhibition of these pathways
may lead to accumulation of DOACs, whereas induction speeds elimination
of substrates and may lead to lower DOAC plasma concentrations. Available
data on DOAC drug interactions are limited and based solely on pharmaco-
kinetic data. Recommendations for management of studied drug interactions
are provided in DOAC labeling. However, DOAC drug interactions are far
more numerous, and clinicians must routinely use available drug interaction
databases and clinical judgment to assess for interactions significant enough
to warrant a dose adjustment or avoidance of DOAC therapy. Tables 7-4
and 7-5 below summarize management strategies for DOAC interactions.

These lists of inhibitors and inducers are not exhaustive (see Clinical Pearl).
TABLE 7-4: Apixaban and Rivaroxaban (Substrates of P-gp and

CYP3A4) DDI and Management2,3,23
Drug Examples Impact on Suggested
(lists are not Rivaroxaban and Management
exhaustive) Apixaban
P-gp and STRONG Barbiturate, ↓ Decreased levels Rivaroxaban: AVOID

CYP3A4 inducers carbamazepine, USE
phenytoin, rifampin,
St. John’s Wort Apixaban: AVOID
USE
P-gp and STRONG Clarithromycin, ↑ Increased levels Rivaroxaban: AVOID

CYP3A4 inhibitors conivaptan, USE
grapefruit,
itraconazole, Apixaban:
ketoconazole, -If taking 5 mg or 10
posaconazole, mg BID, reduce dose
ritonavir by 50% *
-If taking 2.5 mg BID,
AVOID USE
P-gp and MODERATE Cyclosporine, ↑ Increased levels Rivaroxaban: AVOID

CYP3A4 inhibitors diltiazem, USE if CrCl <80 mL/
dronedarone, min
tamoxifen, verapamil
Apixaban: Use
with caution. No
dose adjustment
recommended
*Based on pharmacokinetic data only—not studied in safety and efficacy trials.

BID: twice daily, CrCl: creatinine clearance based on Cockcroft-Gault, CYP3A4: cytochrome P450
3A4, DDI: drug-drug interactions, mg: milligram, min: minutes, P-gp: permeability-glycoprotein
TABLE 7-5: Dabigatran and Edoxaban (Substrates of P-gp) DDI

and Management1,4,23
Drug Examples Impact on Suggested
(lists are not exhaustive) Dabigatran and Management
Edoxaban
P-gp inducers Barbiturate, carbamazepine, ↓ Decreased Dabigatran:

dexamethasone, phenytoin, levels AVOID USE
rifampin, St. John’s Wort
Edoxaban: AVOID
USE
P-gp inhibitors Amiodarone, carvedilol, ↑ Increased Dabigatran:

clarithromycin, conivaptan, levels AVOID USE if CrCl
cyclosporine, diltiazem, < 50 mL/min
dronedarone, erythromycin,
grapefruit, itraconazole, Edoxaban: VTE
ketoconazole, lapatinib, patients: Reduce
mefloquine, nicardipine, dose from 60 mg
propafenone, quinidine, ritonavir, daily to 30 mg
tacrolimus, tamoxifen, verapamil daily*
*Only applies to VTE indication; does not apply to NVAF.

BID: twice daily, CrCl: creatinine clearance in mL/min based on Cockcroft-Gault, DDI: drug-drug
interactions, NVAF: non-valvular atrial fibrillation, mg: milligram, min: minutes, P-gp: permeability-
glycoprotein, VTE: venous thromboembolism
• W
hen evaluating patients for potential drug
interactions with a DOAC, other potentially
cumulative contributing factors must be
considered in tandem. These include the presence
of multiple drug interactions and factors such as
the patient’s age, weight, and renal function. For
example, if a patient has only a single weak drug
interaction, use of a DOAC might be reasonable.
However, if that same patient had an additional
contributing problematic condition, such as
diminished renal function, advanced age, low
body weight, or obesity, the drug interaction may
bear more significance. Because we have little
real-world clinical experience with the presence
of a combination of contributing factors that
affect DOAC exposure and dose-response and we
have no means to readily monitor DOACs (as we
do with the international normalized ratio (INR)
and warfarin), avoidance of DOACs in these
patients is recommended (see Figure 7-2).
• Often, clinicians will assume a medication is

okay to use with a DOAC if it is not listed as an
interaction in the package insert. Unfortunately,
package inserts often contain only information
on formally studied interactions. Other not listed
medications are frequently problematic and
should be avoided. Any interaction that likely led
to adverse patient outcomes should be reported to
the FDA.
Concomitant
medications
+
Renal impairment
Altered exposure
+ to DOAC
Advanced age
+
Weight extremes
FIGURE 7-2. Interactions That May Alter DOAC Exposure
SAFETY AND EFFICACY OF DOACS

Tables 7-6, 7-7, and 7-8 summarize Phase III clinical trial safety and efficacy
data pertaining to major approved DOAC indications.
TABLE 7-6: Phase III Trials of Prevention of VTE in Orthopedic Surgery24-35
Dabigatran Rivaroxaban
24 25 26 27 28
Study RE-MODEL RE-MOBILIZE RE-NOVATE RE-NOVATE II RECORD 1 RECORD 228 RECORD 329 RECORD 430
N 2067 1896 3494 2055 4541 2509 2531 3148
Design R, DB R, DB R, DB R, DB R, DB, DD R, DB, DD R, DB, DD R, DB, DD
Population TKR TKR THR THR THR THR TKR TKR
DOAC dose 150 mg daily or 150 mg daily or 150 mg daily or 220 mg daily 10 mg daily 10 mg daily 10 mg daily 10 mg daily
220 mg daily 220 mg daily 220 mg daily
Renal dose adjustment Excluded CrCl Excluded Excluded Excluded CrCl Excluded CrCl Excluded CrCl Excluded CrCl Excluded CrCl
(mL/min) <30 CrCl <30 CrCl <30 <30 <30 <30 <30 <30
Enoxaparin dose 40 mg Q 24 hr 30 mg Q 12 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 40 mg Q 24 hr 30 mg Q 12 hr
Treatment duration 6–10 days 12–15 days 28–35 days 28–35 days 35 days Riva: 35 days 10–14 days 10–14 days
Enox: 14 days
Efficacy
Primary endpoint (total Non-inferior Inferior Non-inferior Non-inferior Superior Superior Superior Superior
VTE+ all-cause mortality) (both doses) (both doses)
Safety
Major bleeding ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
Major bleeding + ↔ ↔ ↔ ↔ ↔ ↔ ↔ ↔
clinically relevant non-
major bleeding
(continued)
Apixaban Edoxaban
31 32 33 34
Study ADVANCE-1 ADVANCE-2 ADVANCE-3 STARS E-3 STARS J-V35
N 3195 3057 5407 716 610
Design R, DB, DD R, DB R, DB, DD R, DB, DD R, DB, DD
Population TKR TKR THR TKR THR
DOAC dose 2.5 mg BID 2.5 mg BID 2.5 mg BID 30 mg daily 30 mg daily
Renal dose adjustment (mL/min) Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30 Excluded CrCl <30
Enoxaparin dose 30 mg Q 12 hr 40 mg Q 24 hr 40 mg Q 24 hr 20 mg Q 12 hr 20 mg Q 12 hr
Treatment duration 10–14 days 10–14 days 35 days 11–14 days 11–14 days
Efficacy
Primary endpoint (total VTE+ Inferior* Superior Superior Superior Superior
all-cause mortality)
Safety
Major bleeding ↓ ↔ ↔ ↔ ↔
Major bleeding + clinically ↓ ↔ ↔ ↔ ↔
relevant non-major bleeding
↔ No significant difference between DOAC and comparator therapy.
↓ DOAC significantly lower rate of event versus comparator therapy.
↑ DOAC significantly greater rate of event versus comparator therapy.
*Non-inferiority criteria not met. There was an unexpectedly low event rate (55% of expected event rate) for the primary endpoint.
CrCl: creatinine clearance, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, Enox: enoxaparin, hr: hours, min: minutes, mL: milliliters, N:
number, R: randomized, Riva: rivaroxaban, THR: total hip replacement surgery, TKR: total knee replacement surgery, VTE: venous thromboembolism
TABLE 7-7: Phase III Trials of VTE Treatment and Prevention of Recurrence11-17
Dabigatran Rivaroxaban
Study RE-COVER11 RE-COVER II11 RE-SONATE12 RE-MEDY12 EINSTEIN-DVT13 EINSTEIN-PE14 EINSTEIN-EXT13
N 2539 2589 1343 2856 3449 4832 661
Design R, DB R, DB, DD R, DB R, DB R, open-label R, open-label R, open-label
VTE indication VTE treatment VTE treatment Recurrence Recurrence VTE treatment VTE treatment Recurrence
prevention prevention prevention
Renal dose adjustment (mL/min) Excluded Excluded Excluded Excluded Excluded Excluded Excluded
CrCl <30 CrCl <30 CrCl <30 CrCl <30 CrCl <30 CrCl <30 CrCl <30
DOAC dose 150 mg BID 150 mg BID 150 mg BID 150 mg BID 15 mg BID x 21 15 mg BID x 21 20 mg daily
d; 20 mg daily d; 20 mg daily
Comparator Warfarin* Warfarin* Placebo Warfarin* Warfarin* Warfarin* Placebo
Parenteral “pre-treatment” Yes Yes NA NA No No NA
Efficacy
VTE recurrence or VTE death Non-inferior Non-inferior Superior Non-inferior Non-inferior Non-inferior Superior
Safety
Major bleeding ↔ ↔ Not estimable ↔ ↔ ↓ ↔
Major bleeding + clinically ↓ ↓ ↑ ↓ ↔** ↔** ↔

(continued)
Apixaban Edoxaban
15 16 17
Study AMPLIFY AMPLIFY-EXT HOKUSAI-VTE
N 5395 2486 8240
Design R, DB R, DB R, DB
VTE indication VTE treatment Recurrence prevention VTE treatment
Renal dose adjustment (mL/min) Excluded CrCl <25 Excluded CrCl <25 30 mg daily if CrCl 30–50; excluded CrCl <30
DOAC dose 10 mg BID x 7 d; 5 mg BID 5 mg BID 2.5 mg BID 60 mg daily

Comparator Warfarin* Placebo Placebo Warfarin*
Parenteral “pre-treatment” No NA NA Yes
Efficacy
VTE recurrence or VTE death Non-inferior Superior Superior Non-inferior
Safety
Major bleeding ↓ ↔ ↔ ↔
Major bleeding + clinically ↓ ↔ ↔ ↓**
*Adjusted dose warfarin with INR goal 2−3.

**The principal safety outcome was major bleeding plus clinically relevant non-major bleeding.
CrCl: creatinine clearance, BID: twice daily, d: days, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, hr: hours, mL: milliliters, min: minutes,
N: number, NA: not applicable, R: randomized, VTE: venous thromboembolism
TABLE 7-8: Phase III Trials of Stroke and Systemic Embolism Prevention in Non-Valvular Atrial Fibrillation7-10,36
Study RE-LY7 ROCKET-AF8 ARISTOTLE9 AVERROES36 ENGAGE AF-TIMI 4810
N 18,113 14,264 18,201 5,599 21,105
Design R, blinded dabigatran, open-label R, DB R, DB R, DB R, DB, DD

warfarin
DOAC dose 150 mg BID 110 mg BID 20 mg daily 5 mg BID 5 mg BID 60 mg daily 30 mg daily
Renal dose NA NA 15 mg daily if CrCl 2.5 mg BID if 2 2.5 mg BID if 2 30 mg daily if CrCl 15 mg daily if CrCl
adjustment 30−49 criteria: criteria: 30–50 30–50
(mL/min) Scr ≥1.5 mg/dL Scr ≥1.5 mg/dL
Age ≥80 yr Age ≥80 yr
Wt ≤60 kg Wt ≤60 kg
Renal exclusion CrCl <30 CrCl <30 CrCl <25 CrCl <25 CrCl <30
criteria (mL/min)
Comparator Warfarin* Warfarin* Warfarin* Warfarin* Aspirin 81–324 mg Warfarin* Warfarin*
Efficacy
Stroke or systemic Superior Non-inferior Non-inferior Superior ↓*** Non-inferior Non-inferior

embolism
Ischemic stroke ↓ ↔ ↔ ↔ ↓ ↔ ↑
All-cause mortality ↓ ↔ ↔ ↓ ↔ ↔ ↓
(continued)
Safety
Major bleeding ↔ ↓ ↔** ↓ ↔ ↓ ↓
Intracranial ↓ ↓ ↓ ↓ ↔ ↓ ↓
hemorrhage
Fatal bleeding ↔ ↓ ↓ ↓ ↔ ↓ ↓
GI bleeding ↑ ↔ ↑ ↔ ↔ ↑ ↓
*Adjusted dose warfarin, INR goal 2–3.

**The principal safety outcome in the ROCKET-AF trial was not major bleeding but major bleeding plus clinically relevant non-major bleeding.
***AVERROES was not designed as non-inferiority. Apixaban had a significantly lower rate of the primary endpoint compared with aspirin.
BID: twice daily, CrCl: creatinine clearance, d: days, DB: double bind, DD: double dummy, DOAC: direct-acting oral anticoagulant, GI: gastrointestinal, mL: milliliters, min:
minutes, N: number, NA: not applicable, R: randomized
• D
abigatran 110 mg dose is not approved
for stroke prevention in non-valvular atrial
fibrillation in the United States. However this
dose is approved in Canada and Europe.1
Although DOACs represent a significant advance in our approach to anti-
coagulation therapy, it is important for clinicians to recognize that not all
patients are appropriate DOAC candidates. Patient selection is imperative
for optimizing safety and efficacy of these drugs. Additionally, because there
are now several therapeutic options for anticoagulation, shared decision
making with patients and caregivers is important to promote adherence,
patient satisfaction, and quality of life. Table 7-9 provides suggestions as
to a preferred anticoagulant based on patient characteristics, drug charac-
teristics, and indication for anticoagulation.
PATIENT AND AGENT SELECTION
TABLE 7-9: Clinical Screening Assessment and Considerations

for Oral Anticoagulant Selection
Patient Factor Consideration Recommended Oral Agent
Indication • Non-valvular atrial fibrillation Any oral agent
• Venous thromboembolism Rivaroxaban, apixaban

treatment
• Knee arthroplasty Warfarin, rivaroxaban, apixaban
• Hip arthroplasty Warfarin, rivaroxaban, apixaban,

dabigatran
• Mechanical heart valve replacement Warfarin; DOAC should be

avoided38
• Other indications (not studied) Warfarin
Bleeding risk • History of major GI disease and/or Warfarin, apixaban

GI bleeding event in past year
Significant drug • Ongoing need for concomitant Warfarin

Interactions interacting medications
Dual antiplatelet • Ongoing need for dual antiplatelet Warfarin

therapy therapy
(continued)

Patient Factor Consideration Recommended Oral Agent
Renal • CrCl <30 mL/min Warfarin

dysfunction
• CrCl 30–50 mL/min Dose adjustment required for
rivaroxaban in atrial fibrillation
• CrCl ≥50 mL/min Any oral agent
• CrCl >95 mL/min Any oral agent, except

avoid edoxaban in atrial
fibrillation
Hepatic • Child Pugh A Any oral agent

dysfunction
• Child Pugh B Warfarin, dabigatran
• Child Pugh C Warfarin
Older age • Age ≥75 years old Apixaban, rivaroxaban,

edoxaban, warfarin
• Age <75 years old Any oral agent
Extremes of • Weight <50 kg or >120 kg Warfarin

weight40, 41
Stability on • Time in therapeutic range ≥66% Warfarin

warfarin
• Time in therapeutic range <66% DOAC
(despite good adherence)
Adherence to • Once daily dosing preferred Warfarin, rivaroxaban, edoxaban

medication
• Difficulty with adherence—would Warfarin
benefit from measurable monitoring
and close follow up
• Poor warfarin adherence Warfarin, aspirin; DAPT;

likely poor DOAC candidate
Difficulty • Physical barriers Dabigatran, rivaroxaban,

adhering to • Rural location apixaban, edoxaban
frequent clinic
• Lack of transportation
monitoring
Willingness to • Investigate insurance coverage, Shared decision making with

pay including amount of co-payment patient/caregivers
• Identify any required insurance Verify access to therapy at time
coverage criteria (prior of prescribing
authorization, etc.) Warfarin: potentially lower drug
• Identify eligibility for manufacturer- cost and fewer drug access
sponsored programs (usually issues
requires income statements)
Patient • Weigh options discussing patient Shared decision making with

preferences values and preferences patient/caregivers
CrCl: creatinine clearance, DAPT: dual antiplatelet therapy, DOAC: direct-acting oral
anticoagulant, kg: kilograms
• I n clinical trials for treatment of acute venous

thromboembolism, dabigatran and edoxaban
were studied with 5–10 day parenteral pre-
treatment lead-in.11,12 It is important to note that
this was not overlapping therapy. The patients
in the DOAC arms were switched to dabigatran
or edoxaban after the initial parenteral
anticoagulant was stopped. Rivaroxaban and
apixaban were studied without a parenteral
pre-treatment, thus providing an advantage
of convenience over other agents.13-16 Patients
wishing to avoid the cost and inconvenience of
injections may opt for rivaroxaban or apixaban.
• A ll DOACs carry a black box warning against use
in patients with a mechanical heart valves. The
RE-ALIGN trial found that the use of dabigatran
in patients with mechanical heart valves was
associated with higher rates of thrombosis and
bleeding complications.37
• I n non-valvular atrial fibrillation (NVAF) trials,
both dabigatran and rivaroxaban increased the
risk for gastrointestinal (GI) bleeding compared
to warfarin.7,8 Clinicians may consider avoiding
these agents in patients with a history of GI
bleeding. In addition, dabigatran has a high
rate of dyspepsia, and patients should be
routinely asked about side effects to avoid self-
discontinuation.
• P
atients taking a DOAC plus any combination
of dual antiplatelet therapy (ASA+clopidogrel/
ticagrelor/prasugrel) or higher dose ASA (i.e., >81
mg/daily) were generally excluded from DOAC
clinical trials and have not been extensively
studied. Antiplatelets combined with any type of
anticoagulant will increase bleeding risk. With
warfarin, the INR can be titrated to the lower
end of the goal range in an attempt to minimize
bleeding complications. Emerging evidence and
ongoing trials may provide needed guidance as to
optimal antithrombotic combinations (Table 7-3:
PIONEER PCI, AUGUSTUS, RE-DUAL PCI).
• In those aged ≥75 years, GI bleeding and major

bleeding risk is higher with dabigatran compared
with warfarin.38 Dabigatran is included on the
Beers Criteria for potentially inappropriate
medication use in older patients because safer
alternatives exist.39
• P
atients with extremes in body weight (<50 kg or
>120 kg) make up a small proportion of patients
in the DOAC clinical trials. Due to limited data,
it may be safest to use warfarin until more data in
these patients are available.40, 41
• A meta-analysis of the DOAC trials for atrial
fibrillation found a greater relative reduction
in major bleeding with DOACs when the time
in therapeutic range (TTR) was <66% than
when it was 66% or more. Therefore, patients
well-managed (TTR ≥66%) on warfarin may
not derive advantages for bleeding or efficacy if
switched to a DOAC.42 However, the convenience
of DOACs may increase patient and clinician
satisfaction in appropriately selected patients.
• M
anufacturer sponsored co-pay coupon
cards cannot be used by a patient that has
government-sponsored insurance
(i.e., Medicare, Medicaid, or Tricare).
DOACs are given in fixed doses, but may warrant adjustments for certain
clinical characteristics such as renal function, body weight, or concomitant
drug therapies. Adjustments vary by DOAC, by indication and even by
country. Therefore, clinicians are encouraged to refer to labeled guidance
and to work closely with clinical pharmacists to ensure appropriate dosing
(see Table 7-10).
DOAC DOSING BY U.S. INDICATION
TABLE 7-10: Dosing of DOACs

Drug U.S. Labeled Indication U.S. Labeled Dosing
Dabigatran1
Hip arthroplasty CrCl >30 mL/min: 110 mg daily on first day,
then 220 mg daily
CrCl ≤30 mL/min or on dialysis: Avoid use#
CrCl <50 mL/min with concomitant use of
strong P-gp inhibitors: Avoid use
VTE treatment Initiation of therapy: After 5–10 days of

parenteral pre-treatment
CrCl >30 mL/min: 150 mg BID
Reduction of VTE recurrence CrCl >30 mL/min: 150 mg BID
CrCl ≤30 mL/min or on dialysis: Avoid use#

Non-valvular atrial fibrillation CrCl >30 mL/min: 150 mg BID

CrCl 15–30 mL/min: 75 mg BID*
CrCl <15 mL/min or on dialysis: Avoid use#
CrCl 30−50 mL/min with concomitant use of
strong P-gp inhibitors: 75 mg BID
Rivaroxaban2 Hip arthroplasty CrCl ≥30 mL/min: 10 mg daily with or without

food x 35 days
Knee arthroplasty CrCl ≥30 mL/min: 10 mg daily with or without

food x 12 days

Concomitant use of strong dual inhibitors of
P-gp and CYP3A4: Avoid use
VTE treatment CrCl ≥30 mL/min: 15 mg BID with food

x 21 days; then 20 mg daily with food
Reduction of VTE recurrence CrCl ≥30 mL/min: 20 mg daily with food, or 10

mg daily after at least 6 months of standard
anticoagulant treatment

Non-valvular atrial fibrillation CrCl >50 mL/min: 20 mg daily with food

CrCl 15–50 mL/min: 15 mg daily with food*
(continued)

Drug U.S. Labeled Indication U.S. Labeled Dosing
Apixaban3 Hip arthroplasty 2.5 mg BID x 35 days
Knee arthroplasty 2.5 mg BID x 12 days

VTE treatment 10 mg BID x 7 days; then 5 mg BID
Reduction of VTE recurrence 2.5 mg BID (after 6 months of treatment)

P-gp and CYP3A4: Reduce dose by 50% if
taking 10 mg or 5 mg dose.** Avoid use if
taking 2.5 mg dose.
Non-valvular atrial fibrillation 5 mg BID

2.5 mg BID (if ≥2 of the following: age ≥80
years, weight ≤60 kg, SCr ≥1.5 mg/dL)
taking 5 mg dose.** Avoid use if already taking
2.5 mg dose.
ESRD on dialysis#¥ 5 mg BID

2.5 mg BID (if age ≥80 year and/or weight ≤60 kg)
taking 5 mg dose.** Avoid use if taking 2.5 mg
dose.
Edoxaban4 Non-valvular atrial fibrillation CrCl >95 mL/min: Use is not recommended
CrCl 51–95 mL/min: 60 mg daily
CrCl 15–50 mL/min: 30 mg daily*
Concomitant use of strong P-gp inhibitors: No
dose adjustment necessary.
VTE treatment Initiation of therapy after 5–10 days of

parenteral pre-treatment
CrCl ≥51 mL/min: 60 mg daily
CrCl 15–50 mL/min or weight <60 kg or use of
Specific P-gp inhibitor: 30 mg daily*
*Patients with CrCl <30 mL/min not studied. Dosing for CrCl down to 15 L/min based on
pharmacokinetic modeling.
**Not studied in safety and efficacy trials. Based on pharmacokinetic data only.
#Not recommended. See more detailed information in Clinical Pearls below.
¥FDA-labeled dosing recommendations for ESRD only pertain to non-valvular atrial fibrillation.
The manufacturer does not provide ESRD dosing adjustment recommendations for VTE.
CrCl: creatinine clearance, BID: twice daily, CYP-3A4: cytochrome P450 3A4, ESRD: end stage
renal disease, kg: kilograms, mg: milligrams, mL: milliliters, min: minutes, P-gp: permeability-
glycoprotein, SCr: serum creatinine, x: times
• I n the large Phase III trials of DOACs, renal

function was estimated using the Cockcroft-
Gault equation and actual body weight.
Clinicians should consider using the same
approach in clinical practice when dose adjusting
(or avoiding) DOACs in patients with renal
impairment.
• A lthough apixaban has a labeled indication
for use in NVAF with end-stage renal disease
(ESRD) on hemodialysis, use in this population
is not recommended. This labeling is based on
a single-dose study that did not account for
accumulation in a very small population (n=8
patients).43 Rivaroxaban also has a suggestion
in their labeling that it may be a viable option
in NVAF patients on dialysis, based on a similar
study (n=8, single dose).44 Until more safety data
are available for repeat dosing of DOACs in this
population, use should be avoided in severe renal
impairment.
• A post-hoc subgroup analysis suggests patients
enrolled in the ENGAGE-AF TIMI 48 with
a creatinine clearance > 95 mL/min may
experience decreased efficacy with edoxaban
for the prevention of ischemic stroke compared
with warfarin. Therefore, the FDA labeling
recommends against use of edoxaban in patients
with atrial fibrillation and creatinine clearance
greater than 95 mL/min.4
• I t is important for clinicians to perform DOAC
dose adjustments when needed. However, empiric
dose adjustments that are not based on studied
criteria should be avoided, as this may lead
to suboptimal therapy and increased adverse
events.45-47
PERI-PROCEDURAL MANAGEMENT OF
DOACS
Refer to Chapter 10 for detailed information on peri-procedural manage-
ment of the DOACs.
TRANSITIONING BETWEEN
ANTICOAGULANTS
Refer to Chapter 10 for detailed information on transitioning between
anticoagulants.
MANAGEMENT OF DOAC-ASSOCIATED
CLINICALLY RELEVANT BLEEDING
Refer to Chapters 8 and 9 for detailed information regarding management
of clinically relevant DOAC-associated bleeding.
TRANSITIONS OF CARE
Compelling evidence shows that inadequate care transitions are associated
with suboptimal patient outcomes and a negative financial impact on the
healthcare system. Therefore, national care transitions quality initiatives
have become a major focus for numerous regulatory bodies, including The
Joint Commission.48 High-risk medications, such as anticoagulants, require
vigilance, particularly during care transitions. A systematic approach to
transitions of care is especially critical for DOACs, given the number of
clinical nuances in their use. The DOACs carry indication-specific dosing
recommendations and require dose de-escalations, switches, or adjustments
for a variety of reasons and may require temporary interruption for invasive
procedures. Furthermore, cost and patient access to DOAC therapy are
important transitions of care issues to navigate. Use of a DOAC discharge
checklist (see Table 7-11) is strongly recommended, as it will help to ensure
all key aspects of patient care with DOAC therapy are addressed.
PATIENT COUNSELING PEARLS FOR

OPTIMAL DOAC USE
Tables 7-12 and 7-13 offer key patient counseling points that should aid
clinicians in empowering patients and caregivers and, consequently, promote
the safe and effective use of DOACs.
TABLE 7-11: DOAC Discharge Checklist39,49

• Patient is a good DOAC candidate.
• Assess patient’s eligibility for outpatient treatment.
• Confirm consistent patient access to DOAC for duration of therapy.
• If transitioning to another inpatient care setting (e.g., skilled nursing facility), ensure DOAC
is on formulary.
• DOAC recognized as an oral anticoagulant by patient, caregivers, and providers.
• Provision of thorough DOAC education to patient and/or caregiver in their preferred
language and at an appropriate literacy level.
• Safety net phone number provided to patient/caregiver (who to call with questions).
• Referral or handoff to appropriate provider (anticoagulation clinic, primary care physician,
etc.).
• Time of last drug administration in current setting and time of next scheduled dose in new
setting.
• For VTE patients: Prescribed strategy for appropriate dose change after initial therapy
(either switch to DOAC or DOAC dose de-escalation).
• Consolidated documentation and communication of key anticoagulation information to
next care setting including:
{{ Indication for anticoagulation
{{ Intended duration of therapy
{{ DOAC dose and scheduled time of administration
{{ Contact information for anticoagulation provider
• Follow-up arranged for periodic (every 3–12 months) assessment of the following:
{{ Satisfaction with and tolerance of DOAC therapy
{{ Renal and liver function
{{ Upcoming invasive procedures
{{ New drug interactions or contraindications
{{ Possibility of stopping anticoagulation therapy
TABLE 7-12: General Counseling Points for All DOAC Agents39,48

• Inform provider of all medication changes, including over-the-counter and herbals.
• Avoid taking non-steroidal anti-inflammatory drugs (NSAIDs) while taking anticoagulation
therapy.
• Avoid taking aspirin before discussing its use with provider.
• Carry ‘‘anticoagulant ID wallet card’’ or wear “MedicAlert” bracelet/necklace to alert
emergency medical responders.
• DO NOT stop taking DOAC without a physician order and get prescriptions refilled on
time.
• Communicate any difficulty accessing refills BEFORE running out of medication.
• Report signs and symptoms of bleeding and/or clotting.
• Inform all healthcare providers before invasive procedures or surgery, including dental.
• Inform healthcare provider if pregnant or plan to become pregnant.
• Inform healthcare provider if breastfeeding.
• Notify anticoagulation provider of any hospitalization or emergency department visits.
• Anticoagulation monitoring and follow up are necessary despite no routine coagulation
testing.
TABLE 7-13: DOAC-Specific Patient Counseling Points1-4

Dosing BID Daily BID Daily
Missed dose Take as soon as If taking 15 mg Take as soon Take as soon as

possible on the twice daily for VTE as possible possible same
same day but at induction and 1 same day and day
least 6 hr before dose is missed, continue BID
next scheduled can take 30 mg 1x administration
dose to make up
All other doses:

Take as soon as
possible same day
Food Full glass of water 15 mg and 20 mg: ±food ±food

±food Take with food
10 mg ±food
Storage MUST store in Ambient Ambient Ambient

original container, conditions, can conditions, can conditions, can
keep sealed, use place in pill box place in pill box place in pill box
within 120 days
Crushing Swallow whole; Can crush, mix Can crush, Can crush, mix
do not crush, cut, with food. May suspend in D5W, with food. May
or open. give via NG tube. and give via NG give via NG
tube. tube.
BID: twice daily, hr: hours; mg: milligrams, NG: nasogastric, VTE: venous thromboembolism

1. Dabigatran package insert [Internet]. Available from: http://docs.boehringer-ingelheim.
com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. Accessed March 14, 2017.
2. Rivaroxaban package insert [Internet]. Available from: https://www.xareltohcp.com/
shared/product/xarelto/prescribing-information.pdf. Accessed March 14, 2017.
3. Apixaban package insert [Internet]. Available from: https://packageinserts.bms.com/pi/
pi_eliquis.pdf. Accessed March 14, 2017.
4. Edoxaban package insert [Internet]. Available from: http://dsi.com/prescribing-
information-portlet/getPIContent?productName=Savaysa&inline=true. Accessed
March 14, 2017.
5. European Medicines Agency - Find medicine - Xarelto [Internet]. Available
from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/000944/human_med_001155.jsp&mid=WC0b01ac058001d124. Accessed
March 14, 2017.
6. 20110719_322_E.pdf [Internet]. Available from: http://org.daiichisankyo.com/
media_investors/media_relations/press_releases/detail/005784/20110719_322_E.pdf.
Accessed March 14, 2017.
7. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
9. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients
with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
10. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with
11. Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous
thromboembolism with dabigatran or warfarin and pooled analysis. Circulation.
2014;129(7):764-772.
12. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or
placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-718.
13. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al.
Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med.
2010;363(26):2499-2510.
14. EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral
rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med.
2012;366(14):1287-1297.
15. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous
thromboembolism. N Engl J Med. 2013;369(9):799-808.
16. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous
thromboembolism. N Engl J Med. 2013;368(8):699-708.
17. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso Ma, et al. Edoxaban versus
warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med.
2013;369(15):1406-1415.
*18. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of
atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016 Aug 26;
37(38):2893-2962.
19. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation:
Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American College of
Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl
2):e531S-e575S.
*20. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE Disease: CHEST
guideline and expert panel report. Chest. 2016;149(2):315-352.
21. Ageno W, Gallus AS, Wittkowsky A, Oral anticoagulant therapy: Antithrombotic Therapy
and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-
based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e44S-88S.
22. Home - ClinicalTrials.gov [Internet]. [cited 2016 Oct 18]. Available from: https://
clinicaltrials.gov/.
23. Voukalis C, Lip GYH, Shantsila E. Drug-drug interactions of non-vitamin K oral
anticoagulants. Expert Opin Drug Metab Toxicol. 2016; Aug 26:1-17.
24. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs.
subcutaneous enoxaparin for the prevention of venous thromboembolism after
total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost.
2007;5(11):2178-2185.
25. RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, et al. Oral
thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for
prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty.
2009 Jan;24(1):1-9.
26. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for
prevention of venous thromboembolism after total hip replacement: a randomised,
double-blind, non-inferiority trial. Lancet Lond Engl. 2007;370(9591):949-956.
27. Eriksson BI, Dahl OE, Huo MH, et al. Oral dabigatran versus enoxaparin for
thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A
randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105(4):721-
729.
28. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus
short-term enoxaparin for the prevention of venous thromboembolism after total
hip arthroplasty: a double-blind, randomised controlled trial. Lancet Lond Engl.
2008;372(9632):31-39.
29. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-
2786.
30. Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.
Lancet Lond Engl. 2009;373(9676):1673-1680.
31. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for
thromboprophylaxis after knee replacement. N Engl J Med. 2009;361(6):594-604.
32. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind
trial. Lancet Lond Engl. 2010;375(9717):807-815.
33. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for
thromboprophylaxis after hip replacement. N Engl J Med. 2010;363(26):2487-2498.
34. Fuji T, Wang C-J, Fujita S, et al. Safety and efficacy of edoxaban, an oral factor Xa
inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: The
STARS E-3 Trial. Thromb Res. 2014;134(6):1198-1204.
35. Fuji T, Fujita S, Kawai Y, et al. Efficacy and safety of edoxaban versus enoxaparin for
the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V.
Thromb J. 2015;13:27.
36. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation.
N Engl J Med. 2011;364(9):806-817.
37. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in
patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214.
38. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of
dabigatran compared with warfarin in older and younger patients with atrial
fibrillation: clinical perspective. Circulation. 2011;123(21):2363-2372.
39. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American
Geriatrics Society 2015 Updated Beers criteria for potentially inappropriate medication
use in older adults. J Am Geriatr Soc. 2015;63(11):2227-2246.
40. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants
in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost.
2016;14(6):1308-1313.
*41. Burnett AE, Mahan CE, Vazquez SR, et al. Guidance for the practical management of
the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis.
2016;41:206-232.
42. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety
of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-
analysis of randomised trials. Lancet. 2014;383(9921):955-962.
43. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics,
and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin
Pharmacol. 2016;56(5):628-636.
44. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, pharmacodynamics, and safety
of single-dose rivaroxaban in chronic hemodialysis. Am J Nephrol. 2016;43(4):229-
236.
45. Alexander JH, Andersson U, Lopes RD, et al. Apixaban 5 mg twice daily and clinical
outcomes in patients with atrial fibrillation and advanced age, low body weight, or
high creatinine: a secondary analysis of a randomized clinical trial. JAMA Cardiol.
2016;1(6):673-681.
46. Yao X, Shah ND, Sangaralingham LR, Gersh BJ. Effectiveness and safety of reduced
dose non-vitamin K antagonist oral anticoagulants in patients without severe renal
impairment. Value Health. 2016;19(3):A2.
47. Barra ME, Fanikos J, Connors JM, et al. Evaluation of dose-reduced direct oral
anticoagulant therapy. Am J Med. 2016;129(11):1198-1204.
48. Transitions of Care Portal | Joint Commission [Internet]. Available from: https://www.
jointcommission.org/toc.aspx. Accessed March 14, 2017.
*49. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm
Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in
patients with non-valvular atrial fibrillation. Europace. 2015 Oct;17(10):1467-1507.
8
Chapter
ANTICOAGULATION REVERSAL:
PART I—PHARMACOLOGY OF
AGENTS USED FOR REVERSAL
Lance J. Oyen and Scott A. Chapman
INTRODUCTION
Uncontrolled bleeding in the setting of therapeutic anticoagulation is a risk
associated with all anticoagulation therapy. In addition to holding anticoagulation
therapy, pharmacologic antidotes to anticoagulants and fresh frozen plasma (FFP)
can be administered to reverse the anticoagulant effect. These reversal agents differ
in terms of their target, onset of action, duration of reversal effect, and adverse
effect profile. Such agents may directly antagonize the anticoagulants’ pharma-
cological effects or replace normal coagulation factors (return of hemostasis).
Patients who are receiving anticoagulation therapy are either at high risk for
a thromboembolic event or are being treated for a thromboembolic event and
are, therefore, at greater risk for developing a clot. The greatest concern with
reversal of anticoagulation is the potential for creating a prothrombotic state in
the patient, leading to exacerbated thromboembolic complications. Assessment
of the patient’s need for reversal based on the urgency of the clinical situation,
the associated degree of reversal needed, and the degree to which a patient is
anticoagulated at the time of assessment of the need for reversal will dictate the
reversal approach(s) used. This chapter will review the pharmacologic agents
used for reversal of anticoagulation, including dosing, administration, onset
and duration, and adverse effects associated with anticoagulant reversal agents.
Chapter 9 will discuss patient-specific assessments of reversal strategies used in
anticoagulation therapy.
APPROACHES TO REDUCING THE

PHARMACOLOGIC EFFECTS OF
ANTICOAGULATION
When considering the treatment options to reversing anticoagulation through the
use of reversal agents, the approach to selection of the reversal agent(s) needs to
account for balancing two things: (1) the urgency of the bleeding event, and the
associated emergence of the reversal need with the anticipated timing of response
and degree of reversal response (partial versus complete reversal); and (2) the
163
onset and offset of the reversal agent administered (see Figure 8-1), and as
the bleeding event is related to the clinical situation and mitigating risks in
therapies on exacerbating clots (Table 8-1). An elevated coagulation effect
beyond the desired target level of anticoagulation without bleeding can be
corrected by simply holding the anticoagulant without administration of any
reversal agent (Table 8-2). However, a patient experiencing a life-threatening
bleeding event (i.e., intracranial hemorrhage) or a bleeding event that has
the potential for resulting in permanent disabling consequences (i.e., ocular
bleeding) may require rapid and complete reversal of the anticoagulant effect.
TABLE 8-1: Approaches to Reversing Anticoagulation Effectsa

Approach Consideration
Holding the anticoagulant Goal is hours to days, allowing a natural reduction in

pharmacologic effects.
It depends on urgency to reverse effect and patient’s ability to
eliminate the effects of the agent within the desired time period.
Removing drug If before the drug is absorbed, can administer activated charcoal.
Bivalirudin and dabigatran can be removed by dialysis.
Drug effects may persist if elimination is impaired (organ failure,
drug interactions).
Antidote Administration of an agent that directly inhibits the pharmacologic

effects of an anticoagulant.
Goal is minutes to hours to reduce pharmacologic effects, usually
when a patient is at high risk of harm or that harm is already
occurring.
Establishing hemostasis Administration of an hemostatic agent (i.e., a procoagulant) that

promotes normal coagulation.
Revision of the Goal is to reduce therapy target usually related to changes in risk
anticoagulation approach acceptance.
Usually does not involve an antidote.
a
Note: Approach may include complete or partial reduction of anticoagulation.
ANTICOAGULATION REVERSAL: PART I 165
FFP IV vitamin K
INR PO vitamin K
rFVIIa PCC
Time
FIGURE 8-1. Onset and Offset of Agents to Reverse Warfarin
This figure illustrates the potential rebound in international normalized

ratio (INR) when administering various reversal strategies that have a shorter
duration of effect compared to warfarin. The effects of recombinant factor
VII activated (rFVIIa) and prothrombin complex concentrate (PCC) are rapid;
however, the shorter half-life of clotting factor VII leads to an earlier rebound
compared to PCCs. The hemostatic effects of PCCs may also last more than
a day. rFVIIa may lower the INR slightly further than PCC and is more likely
to get a value below 1.2; however, this may not mean a greater level of
hemostasis. For FFP, there is a delay in the partial effects secondary to the
time to administer and amount given. Rebound from FFP begins shortly after
the end of infusion. For vitamin K, the intravenous (IV) form has an earlier
onset; however, the impact of the oral form begins to catch up at 24 hours.
The degree and timing of rebound may depend on the dose administered
and how high the INR is initially prior to the intervention.
AGENTS TO REVERSE ANTICOAGULATION
TABLE 8-2: Mechanism/Pharmacology/Pharmacokinetics of

Agents for Anticoagulation Reversal1,2
Reversal Mechanism Pharmacokinetics Dose Rebound of
Agent (see also Chapter Anticoagulant
9) Effects
Protamine Combines Onset within 5 See Table 9-9 on 30 min to 18 hr

chemically minutes. use of protamine after protamine.
with heparin Duration is for UFH and Likely with
molecules to irreversible and LMWH. subcutaneous
form inactive dose dependent. dosing
salt. Rebound of associated with
anticoagulation later delivery but
may occur with not related to
subcutaneous loss of effect.
heparin or LMWH
doses.
Fresh frozen Contains all Onset in 1–4 10–20 mL/kg IV ~4–6 hr

plasma (FFP) coagulant hr depending (see Table 9-18)
factors, including on dose and
II, VII, IX, and X magnitude of
but in diluted anticoagulation.
form compared Duration of effect
to other options. 6 hr or less.
Requires
activation of
factors in vivo.
Prothrombin Contains Onset within 25–50 ~12 hr

complex coagulant 10–15 min. International
concentrate factors, including Duration of effect Units/kg IV;
(PCC) II, IX, and X and 12–24 hr. this may vary
some with VII, in Used with between
concentrations vitamin K for products (best
25 x that of FFP. longer reversal of to review your
Requires warfarin. formulary-
activation of specific choice
factors in vivo. to determine
dosing used in
studies) (Table
9-18).
Activated Contains mainly Onset within Warfarin: ~12 hr

prothrombin nonactivated minutes. 500 Units INR <5
complex coagulation Duration 6–24 hr. 1,000 Units INR
concentrates factors II, VII, >5
IX, and mainly DOACs
activated 8–50 units/kg
coagulation (Tables 9-11,
factor VII, 9-12, and 9-17)
(continued)

Reversal Mechanism Pharmacokinetics Dose Rebound of
Agent (see also Chapter Anticoagulant
9) Effects
Coagulation Selective Onset within 10 10–40 mcg/kg IV. 6–12 hr

factor VIIa replacement of minutes. No dose
(recombinant) rFVIIa, which Duration of effect ranging trials
(rFVIIa) activates extrinsic 4–6 hr. are available in
clotting pathway Used with FFP this setting; low
resulting in to limit INR (with doses of 1 mg
thrombin warfarin) rebound have normalized
formation and vitamin K the INR within
extends to 15 minutes
>24 hr. (Table 9-17).
Vitamin K Cofactor Onset 12–24 hr Up to 10 mg Dose dependent

for hepatic with PO or 4–12 IV/PO.
production of hr with IV. Subcutaneous
active factors II, Duration and IM routes not
VII, IX, and X dependent on recommended
warfarin intensity. (as the onset of
INR rebound effect is faster
occurring in days. with PO) (Tables
9-13, 9-14, 9-15,
9-16, and 9-18).
DOACs: direct-acting oral anticoagulants, FFP: fresh frozen plasma, hr: hours; IM : intramuscular,
INR: international normalized ratio, IV: intravenous, LMWH: low molecular-weight heparin, min:
minutes; PO: oral, UFH: unfractionated heparin
• D
oses for use of PCC products for hemophilia
management are based on calculation for each
product and determined by the desired factor IX
level (e.g., 12.5–100 Units factor IX/kg). These
doses are typically larger than those used to
manage anticoagulation reversal (e.g., 25–50
Units factor IX/kg). Thrombosis risk may be
higher in patients receiving these products
for warfarin reversal as compared to young
hemophiliacs because with warfarin, the cause
for the coagulopathy can be eliminated, whereas
in hemophilia the cause for coagulopathy
persists.
CONSIDERATIONS FOR DRUG

ADMINISTRATION
Protamine1,3
• Pregnancy Category 3
• Typically reserved for life-threatening bleeds during unfractionated heparin
(UFH) or low molecular weight heparin (LMWH) therapy or to prevent risks of
bleeding after very large UFH doses.
• Neutralizes the effects of heparin and partially for low molecular weight heparins.
• See Table 9-9 for dosing.
• Infusion rates: 5 mg/min.
• The activated partial prothromboplastin time (aPTT) (or activated clotting time
[ACT]) can be used to assess the effectiveness of protamine sulfate neutralization.
• Neutralization of subcutaneous UFH may require a prolonged infusion of
protamine sulfate.
• Dosage form/storage: 10 mg/mL IV solution. If diluted in 5% dextrose in water
(D5W) or normal saline (NS), it should be used immediately and not stored.
There is no preservative in protamine. For expiration, see above.
• The risks and adverse effects associated with protamine are listed in Table 8-3.
TABLE 8-3: Risks Associated with Protamine Use1,3,4

• Angioedema
• Cardiac effects (hypotension, shock, bradycardia)
• Flushing
• Leucopenia
• Pulmonary edema
• Pulmonary hypertension
• Pulmonary vasoconstriction
• Thrombocytopenia
• Urticaria
Caution: Hypersensitivity reactions are potentially higher in patients with allergy to fish, prior use
of protamine insulin, or prior vasectomy; consider corticosteroids or histamine antagonist to treat
reactions.
Vitamin K (Phytonadione)
• Pregnancy category C.
• The liver needs to be capable of producing clotting factors for vitamin K effec-
tiveness.
• Mechanism of action: Vitamin K (Phytonidione) increases coagulation through
its effects as a cofactor of the microsomal enzyme that catalyzes the activation
of the inactive hepatic precursor of factors II, VII, IX, and X.
TABLE 8-4: Vitamin K Products Commonly Used for Reversal

Dosing Form Administration Considerations Comments
Injectable • Available as 10 mg/mL or 1 • Subcutaneous administration

mg/0.5 mL concentration. not preferred because of erratic
• Physically compatible in NS, absorption and delay in onset of
D5W, or D5WNS. effect compared to IV or PO (see
Table 9-15).
• Administer under light sensitive
conditions (protect from light). • Not recommended as
intramuscular administration
• Recommended to infuse at a
because of potential for
rate not exceeding 1 mg/min.
hematoma since patient is
• Clinical application: Infuse IV in anticoagulated.
50 mL of compatible fluid over
• IV doses of 0.1–0.5 mg appear
30–60 min.
to be as effective as higher
doses to reduce excessive INR
values into the target range, with
over-reversal less likely with the
lower dose.24
• 5–10 mg IV for life-
threatening bleeding where
re-anticoagulation is not an
issue within the next week,
and rebound anticoagulation
presents a significant threat.
• Anaphylactoid (and rarely
anaphylaxis) reactions can occur
(see Table 8-5).
Oral • Available as 5-mg unscored • Clinical application: To give

tablet. doses <5 mg, the intravenous
• IV form can be administered formulation that is diluted
orally (Table 9-13). (cherry syrup is one option)
orally to give a more accurate
dose.5
D5W: dextrose 5% in water, D5WNS: dextrose 5% in normal saline, INR: international normalized
ratio, IV: intravenous, min: minutes, NS: normal saline, PO: oral
TABLE 8-5: Adverse Effects Observed with Parenteral Vitamin K6

• Changes in taste
• Cyanosis
• Dizziness
• Dyspnea
• Flushing sensations
• Hyper bilirubin (newborns)
• Hypersensitivity reactions, including anaphylaxis
• Hypotension
• Pain/swelling/tenderness at injection site
• Profuse sweating
• Rapid and weak pulse
• On repeated injections: Erythematous, indurated, and pruritic plaques have occurred,
rarely progressing to scleroderma-like lesions; most dermatological effects have occurred
following intramuscular injections.
Vitamin K Dispensing
• Dispense IV doses in a piggyback bag to ensure slower infusion rates.
• Use caution with availability of 10-mg vials outside the pharmacy (i.e., available
in the automated dispensing cabinets). If the pharmacy is able to prepare and
dispense a dose (noting that the onset of effect is several hours and that more
rapid-acting agents can be used if necessary), consider the benefits of pharmacy
assessment of the dose and route along with the need for other interventions
to minimize the potential for over- or under-reversal and delay in the use of
other adjuncts (FFP, PCC, or rFVIIa). When pharmacy services are not available,
consider procedures that address safety and dosing concerns.
Fresh Frozen Plasma1,7

• Fluid portion of 1 unit of blood centrifuged, separated, and frozen at –18°C
within 6 hours of collection.
• The general dose for FFP is 10–20 mL/kg.
• A unit typically equals about 250–300 mL of FFP.
• In 1 mL of FFP, there is about 1 unit of each coagulation factor. The INR of FFP is 1.
• The expected response depends on patient’s predose level of coagulation
factors.
• Limitations: Thawing (generally 30 minutes), storage, and donor dependence.
• Primary uses:
{{ For temporary reversal. Partial reversal of warfarin therapy (in
emergency or high risk for bleeding scenarios where anticoagula-
tion must be resolved by replacing vitamin K-dependent factors)
includes risk of rebound anticoagulation occurring 4–6 hours after
dose. It is most commonly administered with adjunctive therapy
such as IV vitamin K and potentially the short-acting concentrated
clotting factors (rFVIIa), especially for subtherapeutic INR reversal
goals and critical bleeding. It may not be necessary, however, if a

PCC is given because the PCC products have a rapid onset and
prolonged duration of effect.
{{ For emergency or high risk for bleeding scenarios. Used where
anticoagulation must be reversed, but where target is still goal
range INR (2–3.5) and not complete reversal.
• Volume associated with FFP may cause volume-related complications (fluid
overload, cardiogenic shock) and limit its utility in a life-threatening bleeding
situation (due to slow rate of administration).
• Volume is benefit in hemorrhagic shock, providing volume in addition to factor
replacement often along with platelets and/or red blood cells.
• Risk of transfusion reaction (see Appendix F) for transfusion-related reactions)
should be monitored.
• Transmission of blood-borne pathogens is very low risk.
Prothrombin Complex Concentrate7,8

• Dosed on factor IX units but take caution that the order for PCC does not confuse
PCC with factor IX, which is a single factor product.8
• PCC or factor IX complex contains factors II, VII, IX, and X, and some also include
proteins C and S. Some are low in factor VII (PCC 3), and others have relatively
equal amounts of all four (PCC 4).9
{{ PCC3: Contains therapeutic concentrations of factors II, IX, and X;
may contain other factors such as protein C, S, and factor VII to
lesser concentrations.
{{ PCC4: Contains therapeutic concentrations of factors II, VII, IX,
and X; may contain other factors such as Protein C or Protein S to
lesser concentrations.
{{ Activated PCC (i.e., FEIBA ®) provides selected clotting factors
(mainly factor VII) in the activated form.1 The proposed advantage of
using activated PCC is that it can work below anti-factor Xa activity
and II in the common pathway of the clotting cascade (thus, after
the sites of activity of the anticoagulants in coagulation cascade).10
{{ Heparin and antithrombin have been added to some PCC products
to minimize accumulation of factor II and X effects, which may last
longer and cause thromboembolism. (KCentra has heparin.)
• Factor components are 25 x more concentrated than that of the plasma concen-
tration.
• Vials contain variable amounts of coagulation factors.
• No refrigeration (except Bebulin VH) or thawing is required, but reconstitution
is necessary. Is convenient to store in dispensing cabinets outside of pharmacy.
• Fluid effects and transfusion reactions are potential adverse reactions, but the
most concerning is thrombosis.
• Rapid administration relative to FFP makes administration simple. See Table
8-6 for maximum infusion rate.
TABLE 8-6: U.S. Coagulation Factor Products: Admixing and Administration20-25
Product KCentra® Bebulin® VH Profilnine® SD FEIBA® NF NovoSeven® RT
CSL Behring Baxter Grifols Baxter Novo Nordisk
(PCC4) (PCC3) (PCC3) (aPCC) (rFVIIa)
Type Non-activated FII, FVII,F Non-activated FII,F IX, Non-activated FII,F IX, and Non-activated II, IX, and X, Factor VII activated
XI, FX and FX FX, with small amount FVII and activated VII (recombinant)
Protein C and S Low amounts of FVII (35 FVII units/100 FIX units) FVIII C:Ag
Reversal of Warfarin; DTIs Warfarin; DTIs Warfarin; DTIs Dabigatran Warfarin; DTIs
anticoagulant(s)-
suggest removing
Dose per vial Variable amounts FIX in Variable amounts of FIX Variable doses Variable doses 1, 2, 5, 8 mg
500 unit-(400–620 units) ~500-unit vials.(480–760 500, 1,000, 1,500 units FIX 500, 1,000, 2,500 units
and 1,000 unit-(800–1,240 units/20 mL vial) FVIII inhibitor bypass
units) vials activity units
Formulation Lyophilized Lyophilized Lyophilized Lyophilized Lyophilized powder for
powder powder powder Freeze-dried powder solution
Diluent to add 20- or 40-mL SWFI 20-mL SWFI 5- or 10- mL SWFI 20- or 50- mL SWFI 1-, 2-, 5-, or 8-mL
histidine diluent
provided
Stored prior to mixing Refrigerator or room Refrigerator Refrigerator or room Refrigerator-PI says room Room temperature
temperature temperature (NTE 77 °F, temperature (NTE 77 °F, (NTE 77 °F, 25 °C)
(NTE 77 °F, 25 °C) 25 °C) 25 °C)
Special dissolution Warm to room Warm to room Warm to room temperature Warm to room Add diluent against vial
temperature prior to temperature prior to prior to mixing; use of temperature prior to wall, NOT onto powder,
mixing; use of transfer mixing; use of transfer transfer set and gentle mixing; use of transfer gentle swirling
set and gentle swirling; set and gentle swirling; swirling; withdrawal with set and gentle swirling;
withdrawal with syringe withdrawal with syringe syringe withdrawal with syringe
(continued)
Product KCentra® Bebulin® VH Profilnine® SD FEIBA® NF NovoSeven® RT
CSL Behring Baxter Grifols Baxter Novo Nordisk
(PCC4) (PCC3) (PCC3) (aPCC) (rFVIIa)
Final concentration FIX ~25 units/mL (20–31 NA NA NA 1,000 mcg/mL

units/mL); varies based 10–60 FIX units/mL 500- and 1,000-unit vial 100 500 IU vial≈25 IU/mL
on actual FIX content in FIX units/mL 1,000-unit and 2,500-unit
each vial 1,500-unit vial 150 FIX units/ vials ≈50 units/mL
mL
Other ingredients Human ATIII Heparin NA NA NA

Heparin
Albumin
Infusion rate Max 8.4 mL/min infusion NTE 2 mL/min NTE 10 mL/min 10 mL/min 2–5 min bolus
0.12 mL/kg/min (~3 units/ NTE 2 units/kg/min
kg/min), up to a maximum
rate of 8.4 mL/min (~210
units/min)
Stability after mixed 4 hr 3 hr 3 hr 3 hr 3 hr
Administration Separate line, not with Not infused with other Not infused with other Separate line, not with Flush with NS only;
information other medication products medication products; medication products; flush other medication products; remove from vial
flush with NS; do not with NS; do not refrigerate flush with NS; plastic Luer with syringe for
refrigerate after mixing after mixing lock syringe (not glass) administration
aPCC: activated prothrombin complex concentrate, °C: degree Celsius, DTI: direct thrombin inhibitor,°F: degrees Fahrenheit, FII: factor II, FIX: factor IX, FVII: factor VII,
FVIII C Ag: factor VIII coagulant antigen, FX: factor X, hr: hours, min: minutes, NA: not applicable, NS: normal saline, NTE: not to exceed, PCC: prothrombin complex
concentrate, PCC3: 3-factor prothrombin complex concentrate, PCC4: 4-factor prothrombin complex concentrate, PI: prescribing information, rFVIIa: recombinant factor VII
(activated), SWFI: sterile water for infusion, units: International Units
• Onset of effects is generally complete reversal of warfarin-induced, elevated

INR within 10–30 minutes.11-14
• Adverse effects:
{{ Allergic reactions.
{{ Transfusion-related reactions (see Appendix F).
{{ Thromboembolism (potentially increased when repeat or high
doses are used).
{{ PCC3 and PCC4 seem similar in rates of thromboembolic events
(both more likely at higher doses).
• HIT (in theory for those products containing heparin—know your formulary
product).
Specific Dosing Considerations for PCC
Warfarin
• See Tables 9-17 and 9-18 regarding warfarin-induced elevation, combinations
of phytonadione, and other products.
• Dosing varies by specific product and studies using the product. In most studies,
25–50 units (factor IX equivalent) per kg or 500 International Units was used.
Be familiar with institution-specific products and be aware of the evidence and
dosing for those agents prior to use.
• Dose based on degree of INR; weight adjusted in combination appears more
effective than standard dosing (e.g., 500 International Units).15
Combined with Other Reversal Agents
• Rebound INR increase can occur in 12–24 hours, especially if used without IV
vitamin K. The addition of vitamin K should be considered (generally 10 mg IV) in
life-threatening, nonsurgically repairable bleeds or with the need for prolonged
complete reversal such as intracranial hemorrhage.
• Phytonadione should be considered in life-threatening or emergent bleeding
situations when using PCC.16
• Intravenous phytonadione is predominately used in emergent situations with
PCC and FFP compared to oral phytonadione.
• FFP with PCC, if using a PCC3, has been suggested to augment factor VII levels.17
• Generally, administration of PCC in the high INR situation can result in low normal
goal range or subtherapeutic anticoagulation (<2).
• The risk for thromboembolic complications may be higher when using PCC and
rFVIIa, either together or in addition to other agents such as aminocaproic acid.
• Understand your options and products available, including dosing and/or avail-
able evidence. Each is different.8
• Several approaches to individualize the PCC dose have been explored.18 The
approach used should consider the agents available, personal experiences with
their use, and published experiences. Multiple approaches have been explored,
and examples are provided below. Dose is based on factor level.
{{ International Units requested = kg weight X (target factor level–
current factor level)19
• Dose based on the observed INR

{{ Recommended dose of PCC4 (KCentra®) for initial INR20
{{ 25 International Units/kg for INR of 2–3.9, max 2,500 International
Units
{{ 35 International Units/kg for INR 4–6, max 3,500 International Units
{{ 50 International Units/kg for INR >6, max 5,000 International Units
Note: Prescribing and randomized trials did not explore use when the INR
is <2; however, in the setting of a severe/urgent bleed or higher risk proce-
dure, a lower INR may be desired and doses of 10–25 units/kg considered.
• I n urgent bleeding situations, mixing several

vials of the PCC in the pharmacy for the total
dose after waiting for the INR to be reported may
delay the onset of therapy. Consider drawing the
INR, and then give the first 1,000 units up front.
Additional PCC can be given depending on the
reported INR and assessment of the patient’s
response to the first 1,000 units.
• P
CCs can contain heparin and may not be
preferred in the setting of heparin-induced
thrombocytopenia.
LMWH/Fondaparinux
• PCC may have a role in reversal.
{{ FEIBA®: The ability of FEIBA to work downstream of anti-factor Xa
activity in the common pathway in the coagulation cascade has
been postulated with limited evidence (in vitro) as an advantage
in reversing anticoagulation when in the presence of an anti-factor
Xa activity inhibitor (in this case, fondaparinux was analyzed in the
referenced publication). Dose of FEIBA® ranges 500 International
Units to 50 units/kg.10
{{ Note: PCC products contain clotting factors. FEIBA ® differs
from other PCCs in that factor VII is in an activated form. The
activated factors may produce immediate thrombin generation
in the presence of an anti-factor Xa activity inhibitor, such as
fondaparinux.10
• KCentra® is labeled by the U.S. Food and Drug

Administration (FDA) for warfarin reversal in the
United States.
• S everal PCC products are currently available.
Be familiar with the products available for use.
Differences between products do exist. Some
are PCC3, where an additional transfusion of
other blood products may be considered. Some
products contain additional substances including
heparin, which may be of concern for patients
with a history of HIT. The duration of effect and
potential for inducing thrombosis may be related
to the dose given. Generally, rFVIIa should be
avoided in individuals receiving a PCC.
Recombinant Activated Factor VII

• Available in vials that contain 1 mg, 2 mg, 5 mg, or 8 mg of coagulation factor
VIIa (recombinant), or rFVIIa.
• A recombinant product is not derived from blood; thus, it can be an option in
patients refusing blood products.
• Common approaches used for hemostasis in presence of an anticoagulant: 10–40
mcg/kg IV, but doses as high as 90 mcg/kg have been used.1,26
{{ Dose may depend on the risk of bleeding complications (higher)
and thrombosis (lower).
{{ No dose ranging trials in this setting are available.
{{ Lower doses (e.g., 1 mg) have recently been explored out of concern
for thromboembolic concerns with the rFVIIa.
• Hemostatic effects observed within 5–15 minutes (allows potential titration to
effects by starting with lower doses if time permits).
• Rebound in the INR for warfarin patients can occur in 6–12 hours when rFVIIa
is used alone. Prolonged reduction in the INR can be accomplished by adding
vitamin K. FFP and IV vitamin K may be a consideration to provide continued
reversal until the full onset of vitamin K effects (see Figure 8-1).
• Observations from a small registry suggest a potential benefit when used with
other antidotes to reestablish hemostasis during LMWH and UFH therapy.27
• No direct comparisons in outcomes evidence to PCC are available.
• Adverse effects with use in non-hemophiliacs list are list in Table 8-7.
TABLE 8-7: Adverse Events Associated with the Use of rFVIIa

Outside Hemophiliacs
Thromboembolism The reported incidence of thromboembolism may be higher than
observed in the hemophiliac population due to increased embolic risks
for embolism.
Black box warnings with off label use:
• Arterial and venous thrombotic and thromboembolic events
following administration of rFVIIa have been reported during
postmarketing surveillance.
• Clinical studies have shown an increased risk of arterial
thromboembolic adverse events with rFVIIa when administered
outside the current approved indications.
• Discuss the risks and explain the signs and symptoms of thrombotic
and thromboembolic events to patients who will receive rFVIIa.
• Fatal and nonfatal thrombotic events have been reported.
• Monitor for signs or symptoms of activation of the coagulation
system and for thrombosis.
Hypersensitivity • Including anaphylaxis.

• Administer only if clearly needed in patients with known
hypersensitivity to rFVIIa or any of its components, or mouse,
hamster, or bovine proteins.24
rFVIIa: recombinant factor VII (activated)
DOAC REVERSAL AGENTS
Direct Thrombin Inhibitor Antidote

Idarucizumab (Praxbind)28
• Is FDA-approved humanized antibody fragment directed at dabigatran (350 x
greater affinity than thrombin).
• Binds free and thrombin-bound dabigatran.
• Is structurally similar to thrombin with no procoagulant activities.
• Dose: 5 gm as two 2.5-gm 50 mL bolus injections administered as consecutive
infusions no more than 15 minutes apart (neutralizes approximately 800–1,000
ng/mL; see Chapter 9).
• Administer within 1 hour of removal from the vial.
• Onset: Completely reverses ecarin clotting time (ECT) and aPTT within
10 minutes of administration.
• Duration: Some patients showed rebound increases in ECT and aPTT within
12 to 24 hours of administration.
• Thrombin time (TT) can be used as a surrogate marker to determine if any
dabigatran effects remain present.
• Hypersensitivity reactions are a concern.
• Sorbitol as an excipient poses risk for serious adverse reaction in those with
hereditary fructose intolerance.
• Adverse effects reported include pyrexia, bronchospasm, hyperventilation, rash,

and pruritus.
• Storage: Store vials in the refrigerator at 2ºC to 8ºC (36ºF to 46ºF). Do not
freeze. Do not shake.
{{ Prior to use, the unopened vial may be kept at room temperature
25°C (77°F) for up to 48 hours, if stored in the original package to
protect from light, or up to 6 hours when exposed to light.
Anti-factor Xa Inhibitor Antidotes

Andexanet Alfa29
• FDA approved modified recombinant factor Xa decoy protein binds factor Xa
inhibitors but lacks pharmacologic anticoagulant activity.
• Neutralizes direct and indirect factor Xa inhibitors (FDA-approved for rivaroxaban
or apixaban reversal).
• Onset: 10 minutes.
• Duration: Approximately 1–2 hours (reversal effects diminish 1 hour after bolus
and 2–3 hours after bolus + infusion).
• Dose (see Tables 8-8 and 8-9 below)
TABLE 8-8: ANDEXXA Dosing Regimens29

Dose Initial IV Bolus Follow-Up IV Infusion
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for up to 120 minutes
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for up to 120 minutes
*The safety and efficacy of more than one dose have not been evaluated.
• The extent of reversal may depend on the initial serum concentration (how long
post the last dose) and presence of factors that may reduce elimination. In such
situations, full reversal may not be achieved.
• Infusions may need to be extended during surgical procedures incurring bleed-
ing risks lasting more than 2 hours.
• Several vials will be required for a dose. Consider developing a process in
pharmacy to limit any delays in the preparation process.
• After stopping the infusion, consider that a rebound in anticoagulation effect
may occur.
TABLE 8-9: Andexanet Dose Based on Rivaroxaban and

Apixaban Dose29
FXa Inhibitor FXa Inhibitor Last Dose Timing of FXa Inhibitor Dose Before
ANDEXXA Initiation
Less Than or Equal to Greater Than 8 hr

8 hr or Unknown
Rivaroxaban ≤10 mg Low dose Low dose
>10 mg or unknown High dose
Apixaban ≤5 mg Low dose
>5 mg or unknown High dose
• Undergoing clinical trials in patients with major bleeding events receiving a

factor Xa inhibitors (NCT:02329327).
{{ Onset of hemostasis may take several hours.
{{ In trials, initiation of therapy after recognition, consent, random-
ization, and administration of agent took several hours, creating a
potential limitation on outcomes.30
• Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO
NOT FREEZE.
• Reconstituted ANDEXXA in vials is stable at room temperature for up to 8 hours,
or may be stored for up to 24 hours at 2°C to 8°C.
• Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8
hours, or may be stored for up to 16 hours at 2°C to 8°C.
Broad Spectrum Reversal Product

Aripazine, Ciraparantag (PER977) (Investigational)31
• Synthetic, small, water-soluble cationic molecule with broad binding activity
against UFH, LMWH, fondaparinux, factor Xa inhibitors, and direct thrombin
inhibitors.
• Dose: Single IV dose of 100–300 mg has been studied.
• Onset: 10 minutes.
• Duration of effect: 24 hours.
See Chapter 9 on considerations for using antidotes when devices or surgi-
cal procedures requiring parenteral anticoagulation prior to the effects of
the antidote wear off.
ANTIFIBINOLYTIC AGENTS—AMINOCAPROIC
ACID AND TRANEXAMIC ACID32,33
• Mechanism of action: Inhibits plasminogen activators and to a lesser degree
through antiplasmin activity.
• Is used prophylactically and therapeutically as a hemostatic agent to control
bleeding and reduce surgical blood loss events including cardiac surgery, hepatic
surgery, postpartum bleeding, knee and hip replacement surgery, sinus, gyneco-
logical and prostate surgery, heavy menstrual bleeding, and tooth extraction in
hemophilia patients. Mouthwash formulas have been used for bleeding gums
post-dental procedures.
• Has prothrombotic risk when administered with other procoagulants (i.e.,
prothrombin complex concentrates, recombinant factor VIIa, anti-inhibitor
concentrates).
Aminocaproic Acid32
• IV dosing: Initial 4–5 gm IV, diluted in 250 mL of D5W or NS, infuse over 1 hour,
followed by 1 g/hour (50 mL/hr) for about 8 hours or until bleeding is controlled.
• PO dosing: Initial 5 g ORALLY during the first hour, followed by 1 gm per hour
ORALLY for 8 hours or until bleeding is controlled.
• Contraindications:
{{ Disseminated intravascular coagulation
Tranexamic Acid33
• Dosing: Varies based on indication.
• Dosing: The CRASH -2 Study34—1 gm IV over 10 minutes, then 1 gm infused
over 8 hours.
{{ Delayed use carries concerns for thrombosis.
• Contraindications:
{{ Acquired defective color vision, since this prohibits measuring one
endpoint that should be followed as a measure of toxicity.
{{ Subarachnoid hemorrhage—anecdotal experience indicates
that cerebral edema and cerebral infarction may be caused by
tranexamic acid in such patients.
{{ Active intravascular clotting.
{{ Hypersensitivity to tranexamic acid or any of the ingredients.
Note: Dosing during operative procedures may be different. Combination

with a concentrated clotting factor may increase the risk for thrombosis.

*1. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev.
2007;21:37-48.
2. Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex
concentrate (FEIBA) for reversal of warfarin-related bleeding. Am J Emerg Med.
2013;31:1251-1254.
3. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic
4. Hiong YT, Tang YK, Chui WH, et al. A case of catastrophic pulmonary vasoconstriction
after protamine administration in cardiac surgery: role of intraoperative
transesophageal echocardiography. J Cardiothorac Vasc Anesth. 2008;22:727-731.
5. Baker P, Gleghorn A, Tripp T, et al. Reversal of asymptomatic over-anticoagulation by
orally administered vitamin K. Br J Haematol. 2006; 133:331-336.
6. Phytonadione (Vitamin K Injection) Product Information. Lake Forest, Il: Hospira, Inc;
2004 November.
7. Goldstein JN, Rosand J, Schwamm LH. Warfarin reversal in anticoagulated-associated
intracerebral hemorrhage. Neurocrit Care. 2008;9:277-283.
8. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients
treated with vitamin K antagonists. Anesthesiology. 2008;109:918-926.
9. Hellstern P, Beeck H, Fellhauer A, et al. Factor VII and activated-factor-VII content of
prothrombin complex concentrates. The PCC Study Group. Vox Sang. 1997;73:155-
161.
*10. Desmurs-Clavel H, Huchon C, Chatard B, et al. Reversal of the inhibitory effect
of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res.
2009;123:796-798.
11. Yasaka M, Oomura M, Ikeno K, et al. Effect of prothrombin complex concentrate
on INR and blood coagulation system in emergency patients treated with warfarin
overdose. Ann Hematol. 2003;82:121-123.
12. Yasaka M, Sakata T, Naritomi H, et al. Optimal dose of prothrombin complex
concentrate for acute reversal of anticoagulation. Thromb Res. 2005;115:455-459.
13. Yasaka M, Sakata T, Minematsu K, et al. Correction of INR by prothrombin complex
concentrate and vitamin K in patients with warfarin related hemorrhagic complication.
Thromb Res. 2003;108;25-30.
14. Markis M, Greaves M, Phillips WS, et al. Emergency oral anticoagulation reversal: the
relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on
correction of the coagulopathy. Thromb Haemost. 1997;77:477-480.
15. van Aart L, Eijkhout HW, Kamphuis JS, et al. Individualized dosing regimen for
prothrombin complex concentrate more effective than standard treatment in the
reversal of oral anticoagulant therapy: an open, prospective randomized controlled
trial. Thromb Res. 2006;118:313-320.
16. Ansell J, Hirsh J, Hylek E, et al. The pharmacology and management of the vitamin K
antagonists: the eighth ACCP conference on antithrombotic and thrombolytic therapy.
Chest. 2008;133(suppl);160S-198S.
17. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal consensus guidelines
on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust.
2004;181:492-497.
*18. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant
therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care.
2010;12:403-413.
19. Boulis N, Bobek M, Schmaier A, et al. Use of factor IX complex in warfarin-related
intracranial hemorrhage. Neurosurgery. 1999;45:1113-1119.
20. Kcentra® (Prothrombin Complex Concentrate [Human]) Product Information.
Kanakee, IL: CSL Behring, LLC; 2014.
21. Bebulin® VH (factor IX complex) Product Information. Westlake Village, CA: Baxter
Healthcare; 2012 July.
22. Profilnine® SD (factor IX complex) Product Information. Los Angeles: Grifols
Biologicals; 2011 August.
23. FEIBA® NF (Anti-Inhibitor Coagulant Complex) Product Information. Westlake Village,
CA: Baxter Healthcare; 2013 November.
24. NovoSeven® RT, Coagulation Factor VIIa (Recombinant) Product Information.
Plainsboro, NJ. Novo Nordisk, Inc; 2015 April.
25. Miyaries MA, Davis K. Newer oral anticoagulants: A review of laboratory monitoring
options and reversal agents in the hemorrhagic patient. Am J Health-Syst Pharm.
2012;69:e28-39.
26. Dager WE, Regalia R, Williamson D, et al. Reversal of elevated international normalized
ratios and bleeding with low-dose recombinant activated factor VIIa in patients
receiving warfarin. Pharmacotherapy. 2006;26:1091-1098.
27. Ingerslev J, Vanek T, Culic S. Use of recombinant factor VIIa for emergency reversal of
anticoagulation. J Postgrad Med. 2007;53:17-22.
28. Praxbind (Idarucizumab) [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc.
Ridgefield, CT; 2015.
29. Andexxa® (coagulation factor Xa [recombinant], inactivated-zhzo). Product
Information. South San Francisco, CA: Portola Pharmaceutials, Inc.; 2018.
30. Connolly SJ, Milling TJ, Eikelboom JW, et al. Andexanet alfa for acute major bleeding
associated with factor Xa inhibitors N Engl J Med. 2016;375:1131-1141.
31. Ansell JE, Bakhru SH, Laulicht BE, et al. Use of PER977 to reverse the anticoagulant
effect of edoxaban. N Engl J Med. 2014;371:2141-2142.
32. Aminocaproic Acid Injection, USP 5 g/20 mL (250 mg/mL) [package insert]. Hospira,
Inc., Lake Forest, IL; 2007.
33. Cyklokapron® tranexamic acid injection [package insert]. Pfizer Injectables. Pharmacia
and Upjohn Co. Division of Pfizer, Inc., New York, NY; 2014.
34. CRASH-2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive
events, and blood transfusion in trauma patients with significant haemorrhage
(CRASH-2): a randomised, placebo-controlled trial. Lancet .2010;376 (9734):23-32.
9
Chapter
ANTICOAGULATION REVERSAL:
PART II—CLINICAL APPLICATION
William E. Dager
INTRODUCTION
Bleeding, or concerns for bleeding during anticoagulation therapy, may at
times create a need to lower or completely reverse the existing intensity of anti-
coagulation. Besides holding the anticoagulant or managing the bleeding directly,
additional agents may be considered to counter the anticoagulant’s effects.
Such agents may directly reverse the anticoagulant’s pharmacological effects or
independently drive normal coagulation (hemostasis). Several drivers for bleed-
ing or bleeding events may be present and should be identified. Multiple factors
are involved in finding the optimal approach to minimize bleeding consequences
while limiting the risk for a thrombotic event. This chapter will provide insights
into developing a strategy for reversing anticoagulation.
REVERSAL CONSIDERATIONS
Questions to Ask When Deciding the Best Approach to

Reverse the Effects of an Anticoagulant
• What is the goal with the reversal?
{{ Stop or just slow active bleeding.
{{ Completely reverse or lower the intensity of anticoagulation (see Figure
9-1).
{{ Prevent a potential bleeding event.
• What is the risk for thrombosis (surgical procedure, use of hemostatic agents, or initial
reason for anticoagulation)?
• How long do we need to reverse?
{{ Can we bridge if necessary (i.e., to warfarin)?
{{ Is there an indication suggesting limited break in anticoagulation desired?
• Is there an active bleed, or high risk situation present?
• Will the reversal plan create additional challenges?
{{ Restarting anticoagulation.
{{ Prolonged hospital stay.
183
Level
of
Effect
Target Range
Potential Rebound
Time
FIGURE 9-1. Goal Anticoagulation Intensity of Reversal Plana

a
Reversal targets may depend on the current use of anticoagulation, and how far the
reversal and intended level of anticoagulation to achieve is. The goal may be partial—
down to the target range (solid line), or some value below the target range (broken
line). Thus, the amount of reversal may depend on the initial level of anticoagulation and
the final target goal to achieve. A rebound may occur if the duration of effect from the
reversal agent is shorter than the anticoagulant.
Considerations During the Development of a Reversal

Plan
End Target Goal
One of the goals of reversal is to not only control and potentially stop the
bleeding, but to also identify and correct the source or cause. In some forms
of bleeding (e.g., gastrointestinal bleeding), full cessation of bleeding using
hemostatic agents may limit the ability to identify and resolve—through other
means—the bleeding source (1) to prevent potential recurrence as well as
(2) to decrease concerns for recurrent events and increase confidence with
re-initiating anticoagulation therapy.
• Possible goal: Slowing the bleed to identify the source and mechanically correct it.
• Reversal plans: Should consider the entire process from initiation of reversal and
ability to re-initiate anticoagulation in a manner that avoids any later avoidable
risks to the patient.
Clinician Considerations
• Pharmacodynamic and pharmacokinetic properties of the anticoagulant and
separately the reversal agent
{{ Onset and offset of effects for each.
Duration of antidote effects shorter than the agent
reversed: Potential for re-bound in anticoagulant effects
(Figure 9-1).
ANTICOAGULATION REVERSAL: PART II 185
Duration of antidote effects longer that the agent

reversed: Potential for resistance to any anticoagulant
neutralized by the antidote until its effects are gone.
Alternative anticoagulants may need to be considered
if re-initiating anticoagulation is necessary before the
effects of the antidote wear off.
Broad spectrum antidotes affecting multiple classes
of anticoagulants may diminish options for restarting
anticoagulation until the effects of the antidote have
sufficiently diminished.
{{ Elimination of either anticoagulant or antidote may be longer in
elderly patients, presence of a selected disease state/organ failure,
or a drug interaction.
• Current degree of anticoagulation
{{ Consider measuring the level of anticoagulation.
{{ Assess the patients’ ability to eliminated anticoagulation effects
from holding alone (Figure 9-2).
• Presence of other drivers for bleeding (e.g., antiplatelet therapy, history of
bleeding, concurrent clinical conditions such as trauma)
{{ Need for an invasive procedure.
{{ Stopping versus slowing bleeding.
{{ Ability to recognize and manage other drivers for bleeding.
{{ The value of education and preventing both short- and long-term
undesirable situations should not be underestimated.
• Target level of anticoagulation after reversal
{{ Full or partial reversal (Figure 9-1).
• Multiple agents possibly used in combination to meet reversal goals
• Desired timing of the onset of anticoagulation reversal
{{ Determining if a reversal agent has been given.
{{ Ability to measure level of anticoagulation effects post-initiation
of reversal therapy.
{{ Determining if a planned invasive procedure can be undertaken,
and will the reversal therapy last until the bleeding risk has suffi-
ciently resolved.
• Desired duration of anticoagulation reversal
{{ Short term (surgical or invasive procedures with short bleeding
risk period).
{{ Long term (chronic bleeding or bleeding risk/impact higher the risk
for thrombosis for a prolonged period).
• Desired outcome of the therapy plan versus the risks (i.e., Is the risk of the active
bleeding or prevention of bleeding high enough to risk the use of agents that
could cause embolic complications?)
Anticoagulant Effect
Rapid
Intermediate
Slow
Time
FIGURE 9-2. Drop in Anticoagulant or Antidote Effects Related

to an Individual’s Ability to Store and Eliminate the Agent
This describes the different decay patterns in anticoagulation effects for variations
in pharmacokinetic and pharmacodynamics effects within the population. Individuals
sustaining typical target goals at very low doses of the agent may have poor elimination
and, thus, require a longer duration of time for the effects to cease compared to those
who require very high doses for the same measured effects where more rapid loss of
effects can occur.
Example: A compliant patient on warfarin 1 mg/day with a INR of 2.5 or on DTI infusion
at 2 mg/hour with a aPTT of 65 seconds would be considered low dose. It could take up
to 10 days for the warfarin to see the INR normalize <1.3 or over 8 hours for the effects
of the DTI (aPTT) to wear off. In contrast, a compliant patient on warfarin 10 mg/daily
with an INR of 2.5 may see the INR normalize below 1.3 as soon as 3 days from the last
dose, or effects of a DTI infusion at 15 mg/hour wear off in 4–6 hours.
• Determine if there is a plan to continue or reinitiate anticoagulation therapy

{{ Has the necessary duration of anticoagulation occurred (e.g., 3
months for a provoked venous thromboembolism [VTE]) where the
potential exists to just end treatment.
• Options to reestablish anticoagulation with prolonged reversal effects for a
given strategy
{{ Example: Patients with a high risk for thrombosis (cancer with
multiple thromboembolic events), end-stage renal failure, and
excessive reversal (≥10 mg vitamin K in a warfarin patient) may
create challenges in reestablishing anticoagulation, especially if
there is no need for continued hospitalization.
• P
atients who arrive with an oral anticoagulant
on board and bleeding may benefit from
measuring the level of anticoagulation present.
If excessive, potential causes should be identified
and determined if the driver is short- or long-
term. If no alteration in the drivers can be
undertaken and the dosing regimen remains
unchanged when restarted, then the same
regimen could result in recurrence of the excessive
level of anticoagulation.
Patient-Specific Considerations
General Considerations for Developing a Reversal Strategy
• What anticoagulant agents are involved?
• Is the patient anemic, thrombocytopenic, or bleeding? How low is the Hgb/Hct?
• Does the patient have risk factors for bleeding?
{{ Are they easy to identify and correct?
• What is the clinical impact of blood loss?
{{ Is the baseline Hgb/HCT sufficient to minimize consequences of
blood loss?
{{ Is the baseline Hgb/HCT low, or is there a situation present limiting
the ability to transfuse?
{{ Do preexisting disease states (pulmonary or cardiac) create
additional clinical risks from blood loss?
• Can the patient be transfused or receive the desired intervention?
• Can the patient handle the transfusion volume (e.g., heart failure patient)?
• I n the setting of a bleeding event outside a central

nervous system (CNS) or closed cavity bleed,
one strategy may be to slow and control the
bleeding. Advantages for this include limiting
the amount of concentrated clotting factors and
risk for thrombosis, or allowing the bleeding to
be assessed (e.g., scope the patient) and then
identify the location and mechanically control
(drain placement) and fix the source of bleeding.
This may lead to a higher level of comfort in
restarting anticoagulation therapy at a later
time.
RISK FACTORS FOR BLEEDING
TABLE 9-1: Risk Factors for Increased Anticoagulant Bleeding1

Category Characteristics
Anticoagulation Organ dysfunction (e.g., hepatic failure, renal failure) creating reduced
capacity for hemostasis to occur
Presence of multiple anticoagulants or antiplatelet agents
Prolonged or persistent anticoagulation effects
Quality of therapy (out of range vs. within goal)
Patient Active or prior bleeding

Acute trauma
Age >70 years old
Alcohol abuse
Anemia
Chronic renal insufficiency
Genetic or acquired coagulopathy disorders
Hypercoagulable state
Malignancy
Organ failure reducing anticoagulant clearance
Previous stroke
Reduced platelet count or function
Severe liver impairment
Uncontrolled hypertension
Procedures Anticoagulation required for the procedure (e.g., bypass, vascular

catheterization)
Drains at site
Invasive procedure disrupting vascular integrity
Recent procedure (bleeding risk is higher closer to surgery)
Vascular irregularities (e.g., aneurysm)
Considerations for Reversing Anticoagulation During

Invasive Procedures
• Closed-cavity (pericardial, spinal, CNS, ocular) regions where small amounts of
blood can pool and create notable risk for complications
• Feasibility to transfuse
• Presence of drains or ability to intervene to manage bleeding
• Adequate duration of anticoagulation reversal
• If use of an anticoagulant is necessary in the

overall management plan (e.g. placement of a
mechanical assist device requiring use of selected
anticoagulants, need to go on cardiopulmonary
bypass), the presence of an antidote may neutralize
or impact necessary laboratory values (for the
anticoagulant) and impair the ability to implement
a critical therapy. The potential for dosing such
procedures emergently should be incorporated into
the management plan and also decisions regarding
reversal and any antidote selection.
REVERSAL OPTIONS
Steps for Developing a Plan to Reverse Anticoagulation

Effects
1. Assess the urgency of the situation (Table 9-2)
{{ Urgent: Reverse immediately.
{{ Semi-urgent: More conservative therapy and titrate to desired
goals.
{{ Non-urgent: Observe, measure, and evaluate. Reverse as necessary
considering titrating to goals.
2. Assess laboratory validity (Do the results accurately describe the situation?)
(see Chapter 21)
{{ Occurrence of an unexpected value (single value not supported by
a trend or clinical explanation).
{{ Does the observed value match the clinical presentation?
Recheck or validate if time permits.
Single unexpected values should be validated.
Consider alternative assays to validate.
{{ Is an interacting factor influencing a result? (see Chapter 21)
{{ Is the value believable? (see Chapter 21)
Dilution of sample
Sample sent or drawn incorrectly (e.g., sample degrada-
tion, alteration)
{{ Is there a false international normalized ratio (INR) elevation? (see
Table 21-7)
Sampling techniques
Lupus anticoagulant
Presence of lupus anticoagulant may falsely
elevate the INR by interfering with the test
and suggest presence of a higher level of
TABLE 9-2: Assessment of the Bleeding versus Thrombosis Risk2
Urgency Syndrome or Indication Timeline Hemostatic Goal Rebound Risk
Urgent Life-threatening or bleeding that may Minutes to hours Onset within minutes to hours for emergent Anticoagulant effects may outlast
lead to death, damage of a vital organ; symptoms (e.g., ICH); normal indices the reversal therapy and rebound.
active bleeding or presumed bleeding achieved rapidly and sustained until Very high levels of an anticoagulant
with hypotension, tachycardia, hematoma, bleeding stabilized. may persist for days.
swollen joints, other signs or symptoms High: Minimize with repeat doses of
that suggest immediate consequences; rapid shorter-acting reversal agent
may include selected emergent invasive and consider combining with agents
procedures where immediate reversal is with prolonged action (e.g., vitamin
necessary. K for warfarin).
Semi-urgent Plan for emergent invasive medical Hours Therapeutic anticoagulation level or Moderate: Reversal should cover
procedure causative of bleeding. lower usually in 12–72 hr; reserve reversal duration of risk window such as
Moderate bleeding with time to manage. for patients with notable risk factors for procedure duration and removal of
bleeding or any shortly planned procedure invasive devices.
is high risk for bleeding.
Non-urgent Presence of bleeding issues that create Hours to days Anticoagulation may be partially or fully Moderate or low: Depends on the
some clinical concerns; however, there may reversed if risk is very high or planned degree for reversal and amount of
be sufficient time to address co-morbid procedure shortly pending. As with urgent reversal therapy administered.
conditions. and semi-urgent bleeding, hemostatic
goals may be achieved by gradually
titrating the hemostatic agent to effect by
using low doses, with the option to repeat,
to minimize the overall dose necessary
to reach goals and risk for subsequent
thrombosis if time permits.
ICH: intracranial hemorrhage

Source: Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice
considerations. Am J Health-Syst Pharm. 2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All rights reserved. Adapted with permission.
anticoagulant effect. This can be validated

by checking the amount of clotting factor II
or X present.
Direct thrombin inhibitor or oral anti-factor Xa antago-
nists
Especially if higher or excessive serum concen-
trations are present
Heparin in absence of a neutralization step by the
laboratory
Hepatic failure
{{ Is there a false activated partial prothromboplastin time (aPTT)
elevation? (see Table 21-7)
Sampling technique
{{ Is there a false anti-factor Xa activity level elevation?
Was the test calibrated to the agent that is being
measured?
Does clinical urgency allow time to recheck the
questioned value prior to implementing a reversal plan?
Are there residual effects from other anti-factor Xa inhibi-
tors (e.g., direct-acting oral anticoagulants [DOACs])?
{{ Can an alternative test confirm the observation?
Heparin: Anti-factor Xa activity, aPTT, activated clotting
time (ACT)
Warfarin: Factor II or Factor X
Direct thrombin inhibitor (DTI): Thrombin time, INR, or aPTT
Anti-factor Xa antagonist: Anti-factor Xa activity
3. Consider clinical reason for reversal and timeline assessment for new goal levels
{{ Have you determined the appropriate approach for the current
issue? (see Table 8-1)
{{ If the patient is bleeding, what is the acute bleeding issue?
What drivers for bleeding are present, and can they be
eliminated or managed?
{{ What is assessment of thrombosis risk with loss of anticoagulation
vs. bleeding concerns? (see Table 9-2)
{{ How fast must the anticoagulant effects be reversed? (see Tables
9-2, 9-3, and 9-4)
If the bleeding event or risk with the procedure is life-
threatening (i.e., intracranial hemorrhage) or capable
of causing permanent disabling consequences (ocular
bleeding), is immediate/urgent reversal necessary?
4. If major bleeding, but not life-threatening bleeding (i.e., drop in hemoglobin, see
Appendix F) is occurring, immediate reversal may or may not be needed depend-
ing on the clinical situation and options available to support the patient’s needs.
{{ What degree of reversal is necessary (complete, partial, or bringing

excessive effects back into a safe value)? (see Tables 9-3, 9-4, and 9-5)
{{ Is complete reversal desired if major bleeding is occurring or is
anticipated to occur (during high-risk planned procedure)?
{{ Is partial reversal to be considered (i.e., INR <2 or <1.5) when
bleeding concerns are present, but not high enough when balanced
with thrombosis concerns to warrant full reversal (common when
using reversal to facilitate lower bleeding risk related procedures)?
Does the intervention require sustaining some bleeding
to identify and repair the source?
{{ Are values excessive, suggesting an undesirable higher level of
anticoagulation present and a need to lower (here, the goal may
be to drop the INR, aPTT, or ACT) back into the target range faster
than would occur simply by holding the agent? (see Figure 9-1)
Reversal Plan Considerations

The reversal should consider the immediate and long-term effects of the
management process. The agent(s) involved, urgency, need for an invasive
procedure, potential risks, and need to re-initiate anticoagulation should be
coordinated from the beginning and communicated.
• Anticoagulant involved: Selected laboratory assays along with review of the
medical record, including medication history, should be completed. If the oral
agent is unknown, then selected assessment tools should be considered to
narrow down to the most likely class of agent involved (Figure 9-3).
• A ssay errors during collection or measuring can

occur. Single critical values could be misleading
compared to values observed with a supporting
trend from previous measurements. If the clinical
presentation does not support the laboratory
measurement, consider rechecking the value prior
to implementing a different management plan.
Adding an alternate confirmatory test may be
considered in selected situations.
FIGURE 9-3. Considerations for the Identification and Reversal

of Oral Anticoagulation (see next page)
a
For PCC in warfarin, the actual body weight (ABW) is used up to 100 kg. For reversing
the DOAC’s, what weight to use has not been determined. Consider that ABW up to
100 kg or IBW as data is emerging that a lower dose strategy (< 20 units/kg) may be an
effective approach.
ABW: actual body weight, aPTT: activated partial thromboplastin time, DOAC: direct-
acting oral anticoagulant, INR: international normalized ratio, FEIBA: anti-inhibitor
anticoagulant complex, IV: intravenous, PO: by mouth, TDC: tunneled dialysis catheter,
TT: thrombin time
Is this patient on an oral anticoagulant? No
Yes
Unclear
Exit algorithm
Is the patient severely
bleeding and needs urgent
Medication History
reversal? TT, aPTT, INR, anti-factor Xa activity
Note: INR and aPTT may be high with excessive DOAC levels
Yes No
Reversal in hours Reversal in 24 hours Does the patient need an invasive procedure?
(Semi-Urgent) (Non-Urgent)
FIGURE 9-3. (Continued)

Hold anticoagulant Hold anticoagulant, consider antidote, reduced dose
Hold anticoagulant, consider supportive
reversal strategies and other supportive management Yes No
or topical hemostatic agents
based on bleeding risk assessment
Urgent reversal-minutes
Hold anticoagulant Exit algorithm
Warfarin Anti-Factor Xa Antagonist

Dabigatran
Measured anti-factor Xa is elevated

INR Elevated INR not elevated Thrombin (TT) Thrombin (TT)
(e.g., 1.4 or higher) normal elevated
Antidote if available,
Vitamin K IV 2–10 mg PCC or aPCC
Consider activated charcoal orally (within a few hours of ingestion), 8 to 50 units/kg ABWa
PCC dosed on ABW (up Exit algorithm Idarucizumab 5 gm IV
to 100 kg) Consider FEIBA 8 to 50 units/kga IV if life threatening bleed
(Lower doses with the option to repeat if necessary
may be an option if time permits)
Hemodialysis: (FEIBA 8 units/kg IV just prior to TDC placement)
REVERSAL PLAN
TABLE 9-3: Considerations for Urgent Reversal of

Anticoagulation Effects
Goal: Minimal active anticoagulation by returning anticoagulation indices to baseline for major
or life-threatening hemorrhage.
• If an immediate surgical procedure associated with a high risk of bleeding complications
or life-threatening bleed, which cannot delay therapy, the choice of reversal and/or
hemostasis therapy with effects in minutes is ideal. This may include both therapy for
emergent reversal, and prevention of rebound of anticoagulant effect.
• The dose of reversal therapy may be adapted to the current intensity of anticoagulation
level if a desire is to avoid prolonged reversal effects when continued concerns for
thrombosis are present; replacement of impaired coagulant factors if necessary for
incomplete reversal with antidotes; for instance, use of rFVIIa, fresh frozen plasma (FFP),
or PPC for emergent hemostasis (not drug antidote) plus 2–10 mg IV vitamin K to prevent
rebound effects in warfarin-induced life-threatening hemorrhage. For DOACs, an antidote
can be considered.
• Generally the goal of reversal is at least 24–72 hours, but as long as life-threatening
bleeding issues are present, long-term anticoagulation may not be an immediate concern.
For instance, with warfarin vitamin K IV 2–10 mg (similar degree of reversal, but longer
effects with the higher doses); reversal may be repeated if necessary; for sub-Q LMWH or
sub-Q UFH, prolonged infusion of protamine may be necessary.
FFP: fresh frozen plasma, IV: intravenous, LMWH: low molecular weight heparin, PCC:
prothrombin complex concentrates, rFVIIa: activated recombinant factor VII, sub-Q: subcutaneous
Note: In the setting an intracranial hemorrhage (ICH) or gastrointestinal (GI) bleed with warfarin
used for stroke prevention in AF or history of VTE, reinitiating warfarin within 1 month has been
associated with a net positive benefit. Bridging (Chapter 10) with a LMWH, while transitioning
back to warfarin in AF, for most situations may not be necessary (see Figures 9-4 and 9-5).
TABLE 9-4: Considerations for Semi-Urgent Reversal of

Anticoagulation Effects
Goal: Lower end of target range for minimally invasive procedure to subtherapeutic goal for
highly invasive, bleeding-inducing procedures; for patients with high bleeding risks (see below),
intensity of new goal may be adjusted to a lower target during the period of increased bleeding
concern. For instance, INR reversal from 6 may be reduced to 2.5–3.5 for patient goal without
other risks, but to perhaps 2–2.5 or lower for the procedure if patient has additional risk factors
for bleeding. This should be balanced with the risk for thrombosis.
• Low-risk procedure or high risk for bleeding: Lower goal range but not complete reversal
of anticoagulant effect; relatively lower dose of reversal therapy and selection of therapy
where rebound effects acceptable.
• Administering rapid-onset agents too far in advance may have minimal reversal effect
secondary to decline in effects and subsequent rebound in level of anticoagulation; for
instance, a common mistake in the use of FFP for a procedure like a pacemaker lead
placement is to infuse until the desired INR is obtained but then have a significant delay
from that time until the procedure occurs, allowing for the INR to rebound (increase).
This can be avoided by initiating FFP or PCC within 4–6 hours prior to the procedure and
continuing it up to the time of the procedure if necessary.
FFP: fresh frozen plasma, INR: international normalized ratio, PCC: prothrombin complex
concentrates
Source: Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding
and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst
Pharm. 2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All
rights reserved. Adapted with permission.
TABLE 9-5: Considerations in Non-Urgent Reversal of

Anticoagulant Effects
• Generally therapeutic level is the goal with minimal intervention (e.g., holding the
anticoagulant; oral vitamin K reversal plus holding the anticoagulant for a short period).
• Generally holding therapy for 3–4 half-lives, accounting for any organ clearance
compromise; for warfarin therapy, holding for 1–2 days and restarting at a lower dose
depending on the initial level of anticoagulation and revised target goals during period
targeting a lower level of anticoagulation.
• Monitor pertinent laboratory tests or clinical features of bleeding; reassess further need for
reversal.
• Decline in anticoagulant effects may be relative to the anticoagulant dose. Patients

receiving higher anticoagulant doses with the same (measured) goal level may be able to
clear out the anticoagulant faster than those on lower chronic doses at the same measured
effect.
Source: Originally published in Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding
and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health-Syst
Pharm. 2013;70:1914-1929. © 2013, American Society of Health-System Pharmacists, Inc. All
rights reserved. Adapted with permission.
FIGURE 9-4. Survival Rates with or without Restarting Warfarin

Anticoagulation in AF Patients Post ICH49
FIGURE 9-5. Resuming Warfarin in AF Patients After a

Gastrointestinal Bleed50
Monitor for Bleeding or Recalcitrant Bleeding
TABLE 9-6: Considerations for Monitoring the Impact of the

Reversal Approach
Factor Monitoring Considerations
Bleeding Vital signs, hematocrit or hemoglobin, platelets

Signs of bleeding: Physical assessment, wound sites, urine,
and stool for occult blood
CT scan, colonoscopy, etc.
Intensity of anticoagulation Agent specific measurements: aPTT, anti-factor Xa activity

(calibrated to agent when possible), INR, ACT, DOAC
drug levels, thrombin time, platelet count, and fibrinogen
(patients with serious bleeding); other tests may be available
depending on the setting and anticoagulant agent (see
Chapter 21).
Some antidotes in development may have limitations on
our ability to detect if the anticoagulant effects have been
removed. Alternative approaches not influenced by the
reversal agent may need to be considered.
Assess potential impact should rebound in anticoagulant
effect occur if using a reversal strategy that has a shorter
duration of effect than the anticoagulant being reversed.
Impaired drug elimination Organ function studies consistent with prolonged

anticoagulation effects after holding because of a reduction
in elimination (LFTs, renal function, cardiac output). For some
agents (warfarin, LMWH, fondaparinux, DOACs, argatroban),
effects can last for days.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, CT: computer
tomography, DOAC: direct-acting oral anticoagulant, INR: international normalized ratio, LFTs:
liver function tests, LMWH: low molecular weight heparin
TABLE 9-7: Factors Impacting Extent and Speed of Reversal

Factors Consideration
Assessment of risk for • Thrombotic event (TE) history, number, location, and
thrombosis severity of the event(s)
• Recent TE event (provoked versus unprovoked)
• Hereditary risk factors/hypercoagulable state
• Risk score (example: CHADS2, CHADS-VASC2) for stroke-
related risk in AF (see Chapter 14)
• Mechanical devices (ECLS, LVAD) may require continuous
anticoagulation effects
Requirement of bridge • Ability to provide a bridging agent should be assessed (see

therapy prior to a procedure Chapter 10)
when thrombosis concerns • Ability to afford bridging agent and desired duration
are notable
• Safety of the therapy or related risks
• Ability to provide follow-up management
• Patient ability to administer
• Dose adjusted for organ function
• Bleeding risk with continued anticoagulation effect at time
of the procedure
Patient risk factors for • Additional invasive procedures

continued or worsening • Continuous presence of independent drivers for bleeding
bleeding (not reversal)
• Additional complications may be a concern should
angina/ACS, altered
continued bleeding or drop in Hgb/Hct occur
mental status, pulmonary
insufficiency, dialysis efficacy
Magnitude/intensity of • Current intensity of anticoagulant effects

current anticoagulation • Degree of reversal (Figure 9-1)
effect
• Return super therapeutic to target goals
• Goal below target or return to baseline
Dose of anticoagulation Higher doses of the anticoagulant required to maintain typical

agent therapy targets may drop faster (possible increase in clearance);
e.g., the INR may drop faster in patients requiring higher weekly
warfarin dosing than those on low weekly doses (Figure 9-2).3
Estimation of patient’s • Pharmacokinetics of the anticoagulant

ability to eliminate the • Note: In acute or chronic illness, advanced age, etc., the
anticoagulant elimination half-life may be notably longer than reported
in prescribing information typically derived from a healthier
population.
• Presence of organ dysfunction
• Ability to expedite reversal
{{ Antidote (protamine, vitamin K, idarucizumab)4-8
{{ Hemofiltration (bivalirudin, dabigatran)9-10
{{ Caution with charcoal if risk for aspiration early
post-ingestion
(continued)

Factors Consideration
Predictability of reversal • Route of administration

agent effects • Bioavailability
• Dose–response relationship
ACS: acute coronary syndrome, ECLS: extra corporeal life support, Hct: hematocrit, Hgb:
hemoglobin, INR: international normalized ratio, LVAD: left ventricular assist device
TABLE 9-8: Considerations for Measuring and Reversing

Parenteral Anti-Factor Xa Agents
Anticoagulant Examples of Pharmacologic Comment
Laboratory Assays Reversal Agents
to Consider
Unfractionated aPTT or anti-factor Protamine For urgent situations: Effects

heparin Xa (UFH calibrator) of heparin dissipate several
hours after holding. Post
cardiopulmonary bypass,
an aPTT rebound may be
detected up to 6 hours out
requiring an additional dose
of protamine (~25 mg).
LMWH Anti-factor Xa Protamine Partial reversal of effects

typically drawn 4 with protamine. Degree of
hr post dose in reversal and ability to reduce
selected situations bleeding is unclear.
(LMWH calibrator)
Fondaparinux Anti-factor Xa has Unclear One in vitro assessment

been proposed, showed a greater impact with
but no known effect an aPCC compared to rFVIIa.
on outcomes. Not
recommended
at this time.
(No current
FDA-approved
fondaparinux
calibrator)
aPCC: activated prothrombin complex concentrates, aPTT: activated partial thromboplastin

time, FDA: U.S. Food and Drug Administration, LMWH: low molecular weight heparin, rFVIIa:
recombinant activated factor VII
AGENT-SPECIFIC CONSIDERATIONS
Unfractionated Heparin
• The half-life is relatively short (60–90 minutes) with effects typically lost 3–4 hours
after stopping IV infusion but potentially longer with large doses (e.g., after large
[>2,000 units] boluses, cardiac procedures, or subcutaneous administration).11
• Subcutaneous administration effects typically last 8–12 hours.
{{ Pharmacologic effects rapidly reversed with protamine (see Table
8-2).7
{{ Rebound anticoagulation effects from redistribution of UFH from
tissues can occur after reversal with protamine when circulating
unfractionated heparin (UFH) persists, or after large doses used
during cardiopulmonary bypass.
• Monitoring by aPTT or anti-factor Xa activity with normal therapeutic dosing or
ACT when very high intensity dosing (e.g., catheterization lab, operating room).
Note: Return to baseline on high range ACT may still yield a venous thrombo-
embolism (VTE) treatment target aPTT value.
{{ ACT (low and high range) is used to measure higher levels of heparin
related anticoagulation.
{{ aPTT or anti-factor Xa activity level may be necessary to determine
full reversal.
{{ Pharmacologic effects rapidly reversed with protamine (see Table
9-9).
PARENTERAL ANTI-FACTOR Xa ACTIVITY

ANTAGONISTS (LOW MOLECULAR WEIGHT
HEPARINS AND FONDAPARINUX)
Low Molecular Weight Heparins

• Half-life of low molecular weight heparins (LMWHs) is 3–5 hours with effects
typically lasting 12–24 hours (may be longer in patients with renal impairment).
• Value of anti-factor Xa activity monitoring in the setting of reversal has not been
established.
Note: 1 mg enoxaparin ~100 anti-factor Xa activity units
• Protamine partially neutralizes LMWH, with only ~60% effective2
{{ Dosing (see Table 9-9)
• Bleeding recalcitrant to protamine or imminent life-threatening bleeding, rFVIIa
(dose not established), or PCC can be considered. Low doses may be effective
to achieve goals and allow titration to effect as onset is rapid (minutes). Repeat
doses of protamine may need to be considered if activity is prolonged from
reduced elimination in renal insufficiency.
• Andexanet alfa, an agent that can potentially neutralize LMWH, is available but
FDA approved only for reversing apixaban and rivaroxaban. No standard dosing
guidance is provided for LMWH reversal at this time.
TABLE 9-9: Protamine for Reversal of Heparins7,12,17

Agent Dose Comment
Unfractionated • For IV heparin: Because the half-life of IV heparin is

heparin Protamine 1 mg/100 units relatively short (~60–90 min) with effects
of heparin, maximum of dissipating rapidly after stopping the IV
50 mg at rate not to infusion, consider calculating the dose
exceed 5 mg/min; if of protamine sulfate from the amount
>60 min after holding the of heparin administered within the
UFH infusion, preceding few hours.
0.5 mg/100 units; if
>2 hr, 0.25 mg/100 units; Can add the total amount of heparin
may give additional administered over the past 3 hours if no
protamine if warranted recent bolus (> 8 hours past the bolus) as
after at least 10 min. the amount of heparin to neutralize.
• Higher doses of protamine
are used to reverse heparin After an IV UFH bolus and bleeding (or
effects after high doses high risk): 1 mg/100 units of UFH if aPTT
during cardiopulmonary at goal; 1.5 mg/100 units of UFH if the
bypass surgeries. aPTT is elevated.
• For subcutaneous heparin
Infuse at 5 mg/min.
(treatment dosing):
25–50 mg IV infusion
After large doses in cardiac bypass
over 8–16 hr (with
graft surgery and initial protamine
bleeding/high risk of
reversal, redistribution of heparin out
bleeding: aPTT at goal,
of tissues to the plasma may lead to a
use 25 mg; if elevated
rebound heparin effect where additional
aPTT, use 50 mg and
protamine may be considered when
recheck aPTT)—see
bleeding concerns are present.11
Chapter 8.
Neutralization of sub-Q UFH may require
a prolonged infusion of protamine sulfate
or repeat doses (e.g. in 4 hr depending
on how long it has been since the sub-Q
dose and how high the aPTT/anti-Xa
level is) until sufficient loss of effects.
The APTT/anti-Xa activity (or ACT) can

be used to assess the effectiveness of
protamine sulfate neutralization.12
LMWH • Protamine 1 mg/100 anti- Tinzaparin >dalteparin >enoxaparin

factor Xa activity units IV (in order of effect) for neutralization by
at 5 mg/min within 8 hr protamine; any clinical significance of
of dose. this between agents is unknown.12
• If 8 hr or more after dose, Enoxaparin 1 mg ~100 anti-factor Xa

0.5 mg/100 anti-factor Xa activity units.
activity units.
• Consider repeat dose of
0.5 mg/100 anti-factor Xa
activity units if bleeding
continues.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, hr: hours, IV:
intravenous, sub-Q: subcutaneous, UFH: unfractionated heparin
Fondaparinux
• Long half-life (17–21 hours).
• Monitoring of anti-factor Xa activity level requires a fondaparinux-specifically
calibrated anti-factor Xa assay value to determine if reversal is not established.
• No definitive antidote data, but some limited short-term effect may exist with
rFVIIa and may be a consideration in life-threatening situations.13-15 Activated
PCC (FEIBA™) hypothetically may have an effect (see PCC section below).16
• Protamine does not bind to fondaparinux and may not effectively reverse its
effects given the lack of sites on the molecule to elicit an effect, and similar
hypersensitivity precautions would still be a concern.
Concentrated Clotting Factors—LMWH/Fondaparinux
• Prothrombin complex concentrates (PCC) may have a role in protamine recal-
citrant reversal.16
FEIBA: The ability of FEIBA to work downstream of anti-factor Xa activity in the
common pathway in the coagulation cascade has been postulated with limited
in vitro evidence as an advantage in reversing anticoagulation when in the
presence of an anti-factor Xa activity inhibitor (fondaparinux analyzed). Dose
of FEIBA proposed is 25 units/kg. However, lower doses may be effective to
achieve hemostatic target goals.
Note: PCC products contain clotting factors. FEIBA differs from other PCCs in
that some of the factors present are already in an activated form (Chapter 8). The
activated factors may produce immediate thrombin generation in the presence
of an anti-factor Xa activity inhibitor.16
CONSIDERATIONS FOR DRUG

ADMINISTRATION
• Protamine: Typically reserved for life-threatening bleeds during UFH or LMWH
therapy or to prevent risks of bleeding after very large UFH doses.
• Chapter 8 contains information on the specific reversal agents.
• Protamine can be administered undiluted in emergency situations, but dilution
in dextrose in 5% water (D5W) or normal saline (NS) is preferred.
DIRECT THROMBIN INHIBITORS

• Parenteral DTIs used concomitantly with warfarin may elevate the INR value
above warfarin’s anticoagulation effects.
{{ Elevated INR values secondary to DTIs in the absence of warfarin
may not reflect excessive loss of systemic vitamin K-dependent
clotting factors but a false positive influence on the assay; thus,
vitamin K should not be used for reversal if no warfarin has been
given.
The INR, aPTT, ecarin clotting time, or thrombin time may also be
elevated with oral DTIs. The INR’s ability to reflect a level of anti-
coagulant effect is unclear. As the DTI concentration rises, depend-
ing on the sensitivity of the assay, the INR can eventually rise.
Elevated INR values may actually suggest excessive anticoagulation
if no other causes are present (e.g., liver failure, DOACs).
If the prothrombin time (PT)/INR and aPTT are difficult to interpret
to assess loss of DTI effects, a thrombin time can be considered.
• Prolonged effect due to reduced elimination in impaired cardiac, hepatic, or
renal function requires extended monitoring for recurrent bleeding or ongoing
bleeding risk.
• In patients with normal organ function, the parenteral DTIs half-life is short
(~30–60 minutes depending on the product) and effects will minimize within
3–4 hours of stopping.
{{ DTIs administered by the subcutaneous (sub-Q) or oral route may
have longer durations of actions.
{{ A thrombin time may be a separate means to confirm decline of
anticoagulant effects.
Parenteral Direct Thrombin Inhibitors (Argatroban,

Bivalirudin)
Parenteral direct thrombin inhibitors in general have a relatively short half-
life in healthy individuals. In the presence of organ failure, elimination may
be impaired and take a substantially longer time (>24 hours in selected
settings) to be removed. Little information is available on the reversal of the
parenteral DTI (Table 9-10).
• Argatroban: No clear reversal agent or antidote is known. Elimination is hepatic,
but also reduced in renal failure (see Chapter 5). In severe organ failure, effects
may last several days.
• Bivalirudin: No reliable data on reversal agents; however, low-dose rFVIIa has
been used along with ultrafiltration with some effect.9,18 More data are needed
to verify this concept. Elimination is primarily enzymatic with some liver and
renal clearance. In hypothermia, elimination may be reduced.
• Therapeutic responses on lower doses may suggest decreased elimination and
longer periods of time for the effects to decline (see Figure 9-2).
DIRECT-ACTING ORAL ANTICOAGULANTS

• DTIs (dabigatran).
• Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, betrixaban).
• Shorter half-life in patients with normal organ function compared to warfarin
(range 5–37 hours depending on the product).
{{ Effects may be prolonged in patients with renal, hepatic, or cardiac
dysfunction.
• Significant drug interactions with P-gp and/or CYP3A4.

Parenteral Direct Thrombin Inhibitors
Anticoagulant Examples Reversal Comment
of Common Approach
Laboratory Assays
to Consider
Argatroban • aPTT Effective means to reverse

• ACT in argatroban have not been
selected established.
cardiac
procedures.
Chromogenic
IIa and dilute
thrombin time
have been
explored
in limited
settings.
Bivalirudin • aPTT Hemofiltration10 Limited evidence suggests

• ACT in that rFVIIa (e.g., 1–2 mg) may
selected reverse effects.19 Theory is that
cardiac the thrombin burst caused by
procedures. rFVIIa is creating the enzymatic
means to cleave apart and
inactivate bivalirudin. This
has not been explored or
validated under more rigorous
assessments. Based on case
observations.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, rFVIIa: recombinant
activated factor VII
• Monitoring of anticoagulant effects (see Table 9-11).

{{ PT/INR may not be elevated beyond the baseline values at thera-
peutic doses, and may be elevated with excessive serum concen-
trations from reduced elimination or overdose. Thrombin time (TT)
and ecarin clotting time (ECT using a ECA assay) are prolonged by
dabigatran only.20,21
{{ aPTT may be more sensitive than the PT (INR) to dabigatran.
{{ PT (INR) may be more sensitive than aPTT to anti-factor Xa agents.
TABLE 9-11: Considerations for Measuring and Reversing Direct-Acting Oral Anticoagulants5,6,22,23
Laboratory Reversal Agents
Assays to
Consider
Dabigatran Thrombin time, • Idarucizumab • For minor bleeding: Monitor and re-check laboratory tests and assess bleeding.
aPTT, INR, and, • aPCC or PCC • Semi-urgent major bleeding: Consider idarucizumab and if hemostasis desired in an active bleeding patient
if available, within a few hours, can consider low dose PCC or aPCC (approximately 8 units/kg) or tranexamic acid.
• Hemodialysis
dabigatran
• Urgent life-threatening bleeding: Idarucizumab 5-gm IV bolus with a consideration of adding a aPCC initial
level using ECA
dosed between 8–25 units/kg and titrated to effect with the option for additional doses (up to ~50 units/
or dTT assay
kg) total if hemostasis targets are not achieved and patient is still unstable or tranexamic acid at physician’s
approaches
discretion in traumatic non-ICH bleeding. Hemodialysis may be a secondary consideration in rare situations.
If very high dabigatran levels are present (>800–1000 ng/mL), additional idarucizumab may be necessary.24
INR may be
elevated • In the setting of an ICH: aPCC doses of 25–50 units/kg have been suggested with reported experiences
at high ranging for 8 units/kg to >50 units/kg. It is not clear what dose is necessary for optimal effect and may
concentrations depend on the timing for onset of the bleed and the location of the bleeding event (Appendix H). Doses <25
units/kg have been effectively used in single center case series with no apparent increased risk in thrombosis
compared to FFP noted.25,26
• In the setting of a major or life-threatening active bleeding: When idarucizumab alone may not achieve
bleeding management targets, the addition of aPCC at doses ranging from 8–25 units/kg or tranexamic acid
can be considered at the discretion of the treating physician. There are no supporting data on when or how
to combine a prohemostatic agent with idarucizumab with life-threatening bleeding events. Data are limited
relative to an effective approach for managing active bleeding.
• Idarucizumab will directly neutralize dabigatran, limiting the need for hemodialysis as a means to expedite
removal of drug. Onset of hemostasis may take several hours (in bleeding patients noting that time of data
collection may have influenced observations) for the cessation of bleeding.
• Note: Dose to fully neutralize excessively high dabigatran levels not established.
• Hemodialysis can remove dabigatran depending on the amount present in the plasma. Drug levels have
been shown to rebound upon cessation of hemodialysis from tissue to plasma redistribution and rebound
rise in plasma levels; therefore, prolonged dialysis may be considered in selected situations (see Table 9-12).
Can consider low-dose FEIBA™ (~8 units/kg) just prior to catheter placement for hemodialysis.25
Laboratory Reversal Agents
Assays to
Consider
Rivaroxaban, aPTT, PCC or aPCC Data on the agent and dose to reverse the effects of oral anti-factor Xa agents have not been established. Not
apixaban, chromogenic Andexanet Alfa dialyzable.
edoxaban anti-factor • Minor bleeding: Monitor any bleeding, re-check laboratory tests, and re-assess any need for a intervention.
Xa (consider • Semi-urgent—major bleeding: Andexanet Alfa, PCC, or aPCC starting at low doses.
calibrating to
• Emergent life-threatening bleed: Andexanet Alfa, PCC, or aPCC—8–50 units/kg.

agent involved).
UHF and LMWH • Some limited data have observed positive effects with low-dose aPCC (FEIBA™) 8–12 units/kg. If time
calibrators can permits (non-ICH), can consider starting with a low dose and titrate to treatment goals. In the setting of an
be used, but ICH, the dose of PCCs is unclear. 25–50 units/kg are commonly recommended; however, use of lower doses
results may vary has been reported.23
aPCC: activated prothrombin complex concentrates (FEIBA is a product example), aPTT: activated partial thromboplastin time, dTT: dilute thrombin time, ECA: ecarin
clotting assay, ICH: intracranial hemorrhage, INR: international normalized ratio, PCC: prothrombin complex concentrates
• H
emostatic agents do not directly reverse DOACs,
but can drive hemostasis indirectly. The dose
has never been determined and may be situation
dependent. Because they create an independent
risk for thrombosis, the lowest effective dose may
be desirable. Given that the onset of effects from
these agents are rapid (in minutes), if semi-rapid
hemostasis is considered necessary, low doses can be
considered initially if time permits and titrated with
additional doses until target goals (prevention or
stabilization of bleeding) are achieved.
• In the setting of intracranial hemorrhage (ICH), guidelines from the Neurocritical

Care Society recommend 50 units/kg of a PCC. Lower doses have been reported
in case reports or case series.22
Overdose of DOAC: In the setting of an overdose, bleeding if not already
occurring may not happen until invasive procedures such as lines, etc., are
placed.
Dabigatran
• Dabigatran half-life is longer than parenteral DTIs (12–17 hours).
• In the presence of organ failure, effects of all DTIs may last longer after holding
secondary to slower elimination.
• Dabigatran etexilate is approximately 80% renally cleared.
• Idarucizumab: A U.S. Food and Drug Administration (FDA)-approved antidote
specifically designed to reverse dabigatran (see Chapter 8).
{{ The recommended dose is a 5-gm IV bolus. Available in 2.5 gm in
50-cc vials with each vial infused over 5 minutes.
{{ Idarucizumab reverses most concentrations of dabigatran for up to
24 hours in most patients.
A 5-gm dose may not fully reverse very high concentra-
tions. In such situations, a second dose may be necessary
for complete reversal of effects.24
{{ Onset of reversal is immediate.
{{ Has no prothrombotic effects—It is unclear if additional adjunct
may be needed to stop active life-threatening bleeding.
{{ In presence of bleeding and need for urgent reversal, data support-
ing preferred options between concentrated clotting factors or
tranexamic acid to establish hemostasis are unknown.
{{ Hemodialysis can remove dabigatran (see Table 9-12).23,27-30
{{ Drug interactions with the oral agents may prolong their effects.
{{ A TT may be a separate means to confirm decline of anticoagulant
effects.
TABLE 9-12: Considerations for the Removal of Dabigatran by

Hemodialysis23,27-30
Consideration Comment
Develop an approach in advance for Limit any logistical delays or barriers to initiating
implementing emergent hemodialysis hemodialysis.
for the removal of dabigatran. Coordination in advance if transferring the patient
to a higher level care facility.
Establish an approach to assessing Consider: TT, ECT, dilute TT. Declining values can
adequate drug removal. Determine indicate removal of dabigatran; however, some
which assays will be used to measure the may be normal at therapeutic levels (aPTT, INR). A
removal of dabigatran. normal TT may suggest sufficient removal.
Note: The use of more than one testing approach
may help confirm observations.
Consider associated bleeding risks with Low-dose aPCC (FEIBA) ~ 8 units/kg immediately
insertion of the dialysis catheter. prior to insertion of the dialysis catheter has been
reported to be used safely.
Initiate dialysis at a tolerable flow rate In most case reports, a rebound in dabigatran
(e.g., 400–500 mL/min). After a few concentrations was observed after stopping
hours, the rate can be reduced to allow hemodialysis and notably less than two-thirds was
removal of drug redistributing from removed in the first 2 hr. Initial dialysis blood flow
tissue compartments to the plasma. The rates of 200 mL/min removed 49% compared to
duration of dialysis may depend on the 59% at 400 mL/min in one analysis of hemodialysis
amount of dabigatran in the system, the for 4 hr. Initial dabigatran plasma concentrations
patient’s ability to tolerate hemodialysis, were approximately 159 ng/mL. Duration of
hemodialysis approach, blood flow rate, hemodialysis may be a strong predictor of overall
and assay results confirming adequate removal.
removal. In one case report of a 9-gm overdose with a
dabigatran concentration of 1,560 ng/mL—CVVHF
x 32 hr successfully removed dabigatran—observed
extraction ratio was approximately 0.2.
aPTT: activated prothrombin thromboplastin time, CVVHF: continuous veno-veno hemofiltration,

dTT: dilute thrombin time, ECA: ecarin clotting assay, FEIBA: factor eight inhibitor bypassing
agent, INR: international normalized ratio, TT: thrombin time
• Hemodialysis: Dabigatran pharmacokinetic studies exploring effects of hemo-

dialysis used a single dose model and did not allow for tissue distribution and
over-estimated removal within the first 2 hours. Longer periods of hemodialysis
or even continuous renal replacement therapy may be necessary to remove
dabigatran depending on initial serum concentrations.
• The TT is a very sensitive test for presence of DTI such as dabigatran. A normal
TT may suggest adequate loss of effect after holding or undergoing hemodialy-
sis. Availability of idarucizumab should limit the need for hemodialysis as line
placement, etc., carries additional risks.
Anti-Factor Xa Antagonists—Potential Antidotes

• The duration of oral anti-factor Xa antagonists’ effects can be days, especially in
the setting of organ failure with diminished elimination and potential accumula-
tion to higher serum concentrations, or in the setting of an overdose.
• Plasmapheresis has been successfully used in case reports (apixaban).31

• Additional antidotes are in development (see Chapter 8).
• Initial studies currently available are primarily in non-urgent bleeding or
non-bleeding settings.
• Measuring intensity of anticoagulation: It is unclear what laboratory approaches
can be used to determine the loss of anticoagulants effects sufficient enough
to stop the antidote.
• Andexanet Alfa is available (see Chapter 8). Dosing and amount of reversal may
depend on the agent, time since the last dose, and level of anticoagulant effect
present if elimination impaired or in an excessively anticoagulated setting. For
use during surgical procedures with high bleeding risks, the andexanet alfa
infusion may need to be continued during the period of bleeding risk, which
could be longer than the 2 hours studied as the effects rapidly wear off after
stopping the infusion.
Clinical Consideration: In the setting of administering an antidote, the effects
of any anticoagulant neutralized will continue until the effects of the antidote
wears off. If the same class of neutralized anticoagulant (e.g., heparin) must
be emergently required (e.g., placing patient on extra corporeal life support
[ECLS]), it may be difficult to establish and measure the necessary level of
anticoagulation. If possible, delay the procedure until the effects of the
antidote wear off or consider an anticoagulant that is not neutralized (see
Tables 9-11 and 9-12).
• W
hen using an antidote to reverse a DOAC, the
amount reversed will depend on the concentration
of drug in the plasma and tissues and the
amount of antidote administered (molar ratio).
High DOAC levels may not be fully reversed
with approved antidote doses. Higher antidote
doses may be necessary for full reversal. For
dabigatran, 800–1000 ng/mL is reversed by 5 gm
idarucizumab.24 In the setting where complete
dabigatran reversal is desired with an initial
notably elevated INR prior to administration of
a 5 gm idarucizumab dose, a follow up thrombin
time may assist in determining any need for an
additional dose.
• F
or andexanet alfa, the dose studied in clinical
trials was agent dependent; however, patients
with excessively high levels of apixaban may
require a higher dose andexanet alfa for full
reversal.
WARFARIN
• Long half-life of factors II, VII, IX, and X, and protein C and protein S (see Table 2-1).
• Monitoring of reversal of warfarin using INR. Timing of monitoring the INR after
reversal agent(s) administered depends on the reversal strategy used, the speed
of the onset of reversibility effects, and urgency of need for reversal.
• Time to reversal and duration of reversal agent effects and potential for rebound
in the INR vary depending on the strategy used for reversal (See Figure 8-1).
• Monitor PT/INR; in selected cases, Factor II, VII or X can be measured.
VITAMIN K (PHYTONADIONE)
Factors to Consider in Determining a Vitamin K Reversal Dose

• Pregnancy category C.
• The liver needs to be capable of producing clotting factors.
• At higher initial INR values, small changes in clotting factors create larger changes
in the subsequent INR value. Very small amounts of vitamin K (e.g., 0.25–1 mg
IV) can drop a critical INR value (>6) to the target range or lower.32
• It may take more vitamin K to reverse the INR <2 or 1.5 because a greater number
of active clotting factors are needed per INR unit change (see Chapter 21).
• Large doses of fat-soluble vitamin K can delay reinitiating anticoagulation with
warfarin for days to weeks, potentially requiring bridge therapy; as the severity
of the bleeding increases, the importance of prolonged reversal may diminish
when extended duration of low INRs is desirable.33
• Individuals very sensitive to warfarin dose responses may potentially have larger
INR declines compared to less sensitive patients for the same vitamin K dose.34
• At higher initial INR values, small changes in clotting factors create larger changes
in the subsequent INR value.
• The parenteral form of vitamin K can be given orally with similar effects on the
INR. This can also allow the use of smaller doses to prevent excessive reversal
(see Table 9-13).
TABLE 9-13: Assessment of Intravenous Vitamin K

Formulation Administered Orally for Non-Urgent Reversal of
Anticoagulation44
Initial INR 8 to 11.9 12 to 20 Over 20
Vitamin K dose 2.5 mg 5 mg 5 mg
Day 1 (~14 hr)–INR 3.5 3 2.9

• % INR 2–4.9 77% 52% 44%
• % INR <2 8% 17% 29%

Note: Differences in clotting factors present between an INR of 8 to >20 is very small.
Elevated INR
outcomes (see Table 9-14).35

No Bleeding Present, but
reversal with vitamin K may not alter

• If no invasive procedure is planned,
TABLE 9-14: Assessment of 1.25 mg Vitamin K Orally versus Placebo in Reversal If INR Values Between 4.5–10
in Non-Bleeding Patients35
Outcome Day 7 Day 30 Day 90
Vitamin K Placebo p Vitamin K Placebo p Vitamin K Placebo p
Any bleeding 7.9% 9.2% 0.52 11.5% 12.7% 0.63 15.8% 16.3% 0.86
Major bleeding – – – – – – 2.5% 1.1% 0.22
Thromboembolism 0.3% 0.3% 1.00 0.6% 0.3% 0.62 1.1% 0.8% 0.72
Death 0 0.3% 1.00 0.3% 1.4% 0.22 2.0% 1.9% 0.94

Procedure/Surgery Planned—INR Reversal Within Hours

• Intravenous (IV) phytonadione provides a faster decrease in the INR over oral
with some effects observed as early as 4–6 hours after IV administration.4 In
the situation where an emergent drop in anticoagulation that day is desired,
IV vitamin K may be used to reduce degree of anticoagulation for a period of
time after the procedure, but it may not facilitate reaching goals prior to the
procedure. A more rapid-acting agent may be needed to achieve reversal goals
within the same day.
• Both the IV and oral (PO) route work faster than intramuscular (IM) (risk for
hematoma) and sub-Q (Table 9-15).
TABLE 9-15: Reversal of Warfarin with Oral versus

Subcutaneous Vitamin K46
Mean INR 1 mg Oral 1 mg Subcutaneous
N = 26 N = 25
Initial INR 5.6 6.2
INR day 1 2.9 4.2
INR day 2 2.2 3.1
INR day 3 2.7 2.8

Note: PO appears to work faster, minimizing any reasons for administering by the SC route.
• Oral phytonadione provides a decrease in the INR starting within 24 hours (see
Table 9-16).
TABLE 9-16: Reversal of Warfarin with IV versus PO Vitamin K

(Initial INR 6-10)45
INR 2.5 mg Orally 0.5 mg Intravenous
Target INR 2–4 6 hr: 0% 6 hr: 46%

12 hr: 35% 12 hr: 67%
24 hr: 87% 24 hr: 67%
% INR <2 at 24 hr 9% 29%
% INR >4 at 24 hr 4% 4%
Mean INR at 12 hr 4.4 ± 1.1 3.8 ± 1.4
Mean INR at 24 hr 2.9 ± 0.8 2.6 ± 0.8
hr: hours, INR: international normalized ratio

Notes: IV Vitamin K works faster than PO with effects seen in 6 hours (IV), but similar degree of
reversal (IV and PO) at 24 hours.
• Approaches to reversing warfarin: Multiple factors should be incorporated into

any plan for reversing warfarin based on
{{ Measured level of anticoagulation (Table 9-17).
{{ Urgency of the situation (Table 9-18).
{{ Ability to sustain goals for bleeding and thrombosis management.
{{ Agents available.
Need for combined rapid onset and potential need for
prolonged duration of effect.

Warfarin
Examples of Pharmacologic Comment
Laboratory Assays Reversal Agents
to Consider
INR/PT Vitamin K (IV or • Large amounts of FFP may be required to get

PO), PCC (3 or 4 close to a normalized INR. INR of FFP is ≤1.3.
Options include factor), FFP • Vitamin K doses take 12–48 hours for full effect
Factor II or Factor X to be seen.
PCC4 (Kcentra™) dosing:
• Maximum dosing weight 100 kg
{{ INR <2: 12.5–25 units/kg (actual body
weight) (Note: Not included in prescribing
information)
{{ INR 2–4: 25 units/kg (actual body weight)
{{ INR 4.1–6: 35 units/kg (actual body weight)
{{ INR >6: 50 units/kg (actual body weight)
Option: Draw INR and immediately administer
500–1,000 units PCC up front. The balance of the
dose can be administered once the INR is back if the
clinical situation still warrants additional PCC. Some
products have heparin and are not recommended
in the setting of HIT or allergy to heparin. Repeat
INR 10–15 min post-dose and reassess bleeding
presentation as part of the assessment to determine
if additional doses are necessary.
• Some experience with low dose aPCC: (500–
1,000 units x 1).36,37 See Chapter 8, Table 8-2.
aPCC: activated prothrombin complex concentrates, FFP: fresh frozen plasma, HIT: heparin-
induced thrombocytopenia, INR: international normalized ratio, IV: intravenous, PCC:
prothrombin complex concentrates, PCC4: 4 factor prothrombin complex concentrates, PO: oral,
PT: prothrombin time
TABLE 9-18: Dose for Method of Reversala
Dose for Method of Reversal
Often Used in Combination Addition of Either rFVIIa or PCC (3 or 4) Can Be

Considered, Not Both
Clinical Scenario FFP Vitamin K rFVIIa PCC

b
Life-threatening bleeding 10–20 mL/kg IV Up to 10 mg IV administered slow 10–40 mcg/kg 25–50 International Units/kg
over 30 min ICH: Neurocritical Case Society
guidelines recommend 50 units/kg22
Acute situations requiring Up to 10–15 mL/kg IV Dose-determined by several factors: NR 8–50 International Units/kg
invasive procedure within (NR for fluid-overloaded heart failure • End target INR
6–24 hr patients) • Current INR
• Duration of reversal
• Dose of warfarin
For INR <3: 0.25–2 mg IV
INR <2: Depending on how fast this
is desired, a slightly higher dose IV or
PO may be considered.
Minor bleeding NR 1–5 mg PO; dose based on INR NR NR
(continued)
Dose for Method of Reversal
Often Used in Combination Addition of Either rFVIIa or PCC (3 or 4) Can Be

Considered, Not Both
Clinical Scenario FFP Vitamin K rFVIIa PCC
Elective procedure in NR 1–5 mg PO or 0.25 –1 mg IV; dose NR NR

greater than 24 hr Note: FFP given with vitamin K the based on INR (Caution: For patients
day prior to a procedure in general will with higher risk of thrombosis, i.e.,
have minimal effects on pre-procedure mechanical cardiac valve replacement
INR if any at all compared to vitamin patients.)
K alone.
a
The table provides modalities to reverse the effects of vitamin K antagonists. The modalities are not always complete in their reversal but provide strategies to decrease the
drug’s effects.7,38-42
b
The vitamin K dose of 10 mg IV assumes a goal for full reversal and limited concerns to reinitiate a vitamin K antagonist for a period of time (>1 week). Consider the risk
for thrombosis, timing of the procedure, and potential rebound with rFVIIa, FFP, or PCC. Doses for these agents just prior to the procedure may provide a higher period of
hemostasis over earlier administration. Vitamin K may be warranted to sustain reversal post procedure.
FFP: fresh frozen plasma, ICH: intracranial hemorrhage, IV: intravenous, PO: oral, rFVIIa: recombinant activated factor VII, NR: not reported, NRL: not recommended, PCC:
prothrombin complex concentrates
• A t lower INR values, a larger change in the

percent of activated clotting factors is necessary
to see a rise in the value (INR of 2–3 will be
~25–40% of normal). INR values >6 will be
<10% of normal activated clotting factors.
At this level, small changes in the number of
activated clotting factors will lead to larger
changes in the INR.
{{ Because it does not take much of a change in
clotting factors to lower very high INR values
(e.g. >6) back into the target range, a small
increase in the number (or percent of normal)
of clotting factors will lead to a larger drop in
the INR compared to the amount of clotting
factors needed to drop the INR <2, or back to
baseline. Thus, small doses of vitamin K may
drop a high INR into the therapeutic range,
but a larger dose may be necessary to drop
the INR <2.
• T
he dose of vitamin K to reverse warfarin will
depend on how high the INR is and the targeted
value after reversal. Only a small change in the
percent of activated clotting factors is required
to drop critical values into the target range (and
thus a small amount of vitamin K required)
compared to dropping the INR value below the
therapeutic range or back to baseline where a
larger dose of vitamin K may be considered.
• O
ne strategy to consider when a patient is not
bleeding—but after clinical assessment a decision
is made to expedite dropping the INR to a lower
value (for invasive procedure)—is to administer
a low dose vitamin K dose with a follow-up INR
later (e.g., 12 hours). If the INR has dropped
sufficiently, then no additional dose may be
needed. If not a sufficient drop, the dose can be
repeated. FFP/PCC can also be administered
shortly prior to the procedure.
Note: For a given INR, the value may drop faster
independent of vitamin K in individuals requiring a
higher maintenance dose of warfarin (Figure 9-2).3
Reversing an elevated INR with vitamin K may depend on the presence of

bleeding. In a recent analysis assessing bleeding and thrombotic–related
outcomes in clinically stable, nonbleeding patients with no plan for an invasive
procedure, use of vitamin K solely to drop the INR was not associated with
improving outcomes (see Table 9-14).35
• Vitamin K 2.5 mg PO appears to be an effective reversal strategy in nonbleeding
outpatients with INR values over 10.43
Using Concentrated Clotting Factors to Reverse

Warfarin47,48
• Details regarding the various concentrated clotting factors are described in Chapter 8.
• Lack of effect in the clinical trial for KCentra may be from delays with consent,
randomization, and administration of agent. In one post-marketing series in the
setting of ICH with warfarin, an INR <1.3 within 4 hours (PCC4 ~average 2,000
units given) was associated with improved long-term outcomes.49
Note: There may be a point of diminishing returns (which can vary between situa-
tions) for improved ICH related outcomes despite the reversal therapy given.
The longer the period of time post-initial bleeding event, the more limited the
benefits and greater the potential of creating additional management challenges.
• Concentrated clotting factors are associated with a higher risk for thrombosis
with effects potentially lasting several days.
{{ Symptomatic thrombosis may not occur for more than a week
post-administration.
{{ Because risk of thrombosis may be a concern, thromboprophylaxis
should be considered as soon as feasible once bleeding concerns
subside.
• Dose-ranging trials in bleeding patients are limited. Many earlier reports
included both PCC and surgical interventions, limiting clarity on what drove
the outcomes observed.
• Because these are blood-derived products, lot numbers need to be recorded.
• The variability of the INR range, dosing determined in clinical trials based on
the common vial size (e.g., 500 units) and not the actual anti-factor IX concen-
tration (e.g., 532 units) suggests that dosing should not be delayed for specific
unit calculations. The studies were not conducted in this manner, and any delay
created may impact outcomes.
• S everal PCC products are currently available.

Be familiar with the products available for
use (Table 8-6). Differences between products
do exist. Some products contain additional
substances including heparin, which may
be of concern for patients with a history of
HIT. The duration of effect and potential for
inducing thrombosis may be related to the dose
given. Generally, rFVIIa should be avoided in
individuals receiving a PCC.
RESTARTING ANTICOAGULATION THERAPY

• Assess risk for thrombosis and bleeding.
• In the setting of anticoagulation therapy, once issues relative to the bleeding
event or need to reverse the anticoagulants has diminished, it will be important
to assess the risk of bleeding to thrombosis treatment or prevention. Anti-
coagulation prophylaxis may need to be considered if sufficient risk for VTE
exists (see Chapter 12).
• In the setting of ICH with warfarin, warfarin therapy should be restarted at some
point in most (but not all) situations.
{{ Potential exceptions (CNS bleeds)
Cerebral amyloid angiopathy (lobar) bleeding
Microvascular risks
Microbleeds on gradient-ECHO magnetic resonance
imaging (MRI)
Primary prevention atrial fibrillation (AF) with low
CHADS2 <4 or CHADS-VASC <5 (Chapter 14)
Anticipated inability to adequately manage anticoagula-
tion therapy
Patient unable to safely use anticoagulation therapy
{{ Time to restart post an ICH may range from immediately to prefer-
ably 7–14 days in the setting of selected high-risk patients (mechani-
cal mitral valve) to 1–2 months in low-risk AF patients. Decisions
on this should carefully explore the risk involved on a continuous
basis (Figure 9-4).
• Time to restarting anticoagulation post a bleeding event will depend on the
clinical presentation and need for anticoagulation.
{{ For selected circuit patency goals (e.g., left ventricular devices),
continued anticoagulation may be necessary (but at times the target
goals may be lower until bleeding concerns diminish).
• F
alling is a frequent reason for stopping
anticoagulation therapy. Occasional falling may
not be a reason to stop anticoagulation therapy
as the risk of the consequences of the fall may
not be as high as the risk for a recurrent bleeding
event. Keep in mind other potential causes for
falling and removing them.
• Gastrointestinal bleeding (GIB)50

{{ Timing of resumption
Patients who never interrupted therapy or resumed
therapy within 14 days experienced no thrombosis.
Recurrent GIB: Significantly increased if warfarin
resumed within 7 days.
Death rate was lowest when warfarin resumed between
15 and 90 days (potential optimal time is approximately
14 days).
{{ Resumption less likely: Older patients if the source of the GIB was
not identified.
{{ Resumption more likely with:
Mechanical cardiac valve
Left ventricular assist devices
Bleeding confined to hemorrhoidal bleeding
THROMBOLYTICS
• No clear antidote exists; however, blood products and antifibrinolytics have
been used.39
• Blood product replacement and replacement of factors (e.g., FFP, cryoprecipi-
tate [if low fibrinogen] and/or packed red blood cells [PRBCs]), especially in
hemorrhage.
• Thromboelastograms (e.g. TEG or ROTEM – see Chapter 21) may help determine
the level of lysis present and if it is resolving (closing of the tail in the graph
[Chapter, Figure 21-13] would demonstrate cessation of effect).

1. Smythe MA, Dager WE, Patel NM. Managing complications of anticoagulant therapy. J
Pharm Pract. 2004;17:327-346.
*2. Nutescu E, Dager WE, Kalus JS, et al. Management of bleeding and reversal strategies
for oral anticoagulants: clinical practice considerations. Am J Health-Syst Pharm.
2013;70:1914-1929.
3. Hylek EM, Regan S, Go AS, et al. Clinical predictors of prolonged delay in return
of the international normalized ratio to within the therapeutic range after excessive
anticoagulation with warfarin. Ann Intern Med. 2001;135:393-400.
4. Watson HG, Baglin T, Laidlaw SL, et al. A comparison of the efficacy and rate of
response to oral and intravenous vitamin K in reversal of over-anticoagulation with
warfarin. Br J Haematol. 2001;115:145-149.
5. Smythe MA, Trujillo T, Fanikos J. Reversal agents for use with direct and indirect
anticoagulants. Am J Health-Syst Pharm. 2016;73(10 Suppl 2):S27-S48.
6. Dager W, Hellwig T. Current knowledge about measuring the anticoagulant effect
and managing bleeding with direct oral anticoagulants. Am J Health-Syst Pharm.
2016;73(10 Suppl 2):S14-S26.
7. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev.
2007;21:37-48.
8. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal - full
cohort analysis. N Engl J Med. 2017 [Epub ahead of print].
9. Koster A, Chew D, Gründel M, et al. An assessment of different filter systems
for extracorporeal elimination of bivalirudin: an in vitro study. Anesth Analg.
2003;96:1316-1319.
10. Awad NI, Brunetti L, Juurlink DN. Enhanced elimination of dabigatran through
extracorporeal methods. J Med Toxicol. 2015;11:85-95.
11. Galeone A, Rotunno C, Guida P, et al. Monitoring incomplete heparin reversal and
heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth. 2013;27:853-858.
12. Crowther MA, Berry LR, Monagle PT, et al. Mechanisms responsible for the failure of
protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116:178-
186.
13. Bijsterveld NR, Moons AH, Boekholdt M, et al. Ability of recombinant factor VIIa
to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy
volunteers. Circulation 2002;106:2550-2554.
14. Lisman T, Bijsterveld NR, Adelmeijer J, et al. Recombinant factor VIIa reverses the in
vitro and ex vivo anticoagulant and profibrinolytic effects of fondaparinux. J Thromb
Haemost. 2003;1:2368-2373.
15. Young G, Yonekawa KE, Nakagawa PA, et al. Recombinant activated factor VII
effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux,
argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood
Coagul Fibrinolysis. 2007;18:547-553.
*16. Desmurs.-Clavel H, Huchon C, Chatard B, et al. Reversal of the inhibitory effect
of fondaparinux on thrombin generation by rFVIIa, aPCC and PCC. Thromb Res.
2009;123:796-798.
17. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic
18. Stratmann G, deSilva AM, Tseng EE, et al. Reversal of direct thrombin inhibition after
cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth
Analg. 2004;98:1635-1639.
19. Nagle E, Tsu L, Dager WE. Bivalirudin for anticoagulation during hypothermic
cardiopulmonary bypass and recombinant factor VIIa for iatrogenic coagulopathy. Ann
Pharmacother 2011;45:e47.
20. Lessire S, Douxfils J, Baudar J, et al. Is thrombin time useful for the assessment of
dabigatran concentrations? An in vitro and ex vivo study. Thromb Res. 2015;136:693-
696.
21. Dager WE, Gosselin RC, Kitchen S, et al. Dabigatran effects on the international
normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen:
a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627-1636.
*22. Frontera JA, Lewin Iii JJ, Rabinstein AA, et al. Guideline for reversal of antithrombotics
in intracranial hemorrhage: a statement for healthcare professionals from the
Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care.
2016;24:6-46.
23. Dager WE, Banares L. Reversing the anticoagulation effects of dabigatran. Hosp Pract.
2017;45:29-38.
24. Steele AP, Lee JA, Dager WE. Incomplete dabigatran reversal with idarucizumab. Clin
Toxicol (Phila). 2017 [Epub ahead of print].
25. Dager W, Roberts A. DOAC reversal with low (<20 Units/kg) or moderate dose (≥20
Units/kg) FEIBA in urgent management of major bleeding. Res Pract Thromb Haemost.
2017;1(Suppl. 1) (Abstract 2016):977.
26. Yin EB, Tan B, Nguyen T, et al. Safety and effectiveness of factor VIII inhibitor
bypassing activity (FEIBA) and fresh frozen plasma in oral anticoagulant-associated
intracranial hemorrhage: a retrospective analysis. Neurocrit Care. 2017 [Epub ahead of
Print].
27. Khadzhynov D, Wagner F, Formella S, et al. Effective elimination of dabigatran by
haemodialysis. A phase I single-centre study in patients with end-stage renal disease.
Thromb Haemost. 2013;109:596-605.
28. Chiew AL, Khamoudes D, Chan BS. Use of continuous veno-venous haemodiafiltration
therapy in dabigatran overdose. Clin Toxicol (Phila). 2014;52:283-287.
29. Chang DN, Dager WE, Chin AI. Removal of dabigatran by hemodialysis. Am J Kidney
Dis. 2013;61:487-489.
30. Liesenfeld KH, Staab A, Härtter S, et al. Pharmacometric characterization of
dabigatran hemodialysis. Clin Pharmacokinet. 2013;52:453-462.
31. Lam WW, Reyes MA, Seger JJ. Plasma exchange for urgent apixaban reversal in a
case of hemorrhagic tamponade after pacemaker implantation. Tex Heart Inst J.
2015;42:377-380.
*32. Shetty HGM, Backhouse G, Bentley DP, et al. Effective reversal of warfarin-induced
excessive anticoagulation with low dose vitamin k1. Thromb Haemost. 1992;67:13-15.
*33. Tsu LV, Dienes JE, Dager WE. Vitamin K dosing to reverse warfarin based on INR,
route of administration, and home warfarin dose in the acute/critical care setting. Ann
Pharmacother. 2012;46:1617-1626.
34. White RH, McKittrick T, Hutchinson R, et al. Temporary discontinuation of warfarin
therapy: changes in the international normalized ratio. Ann Intern Med. 1995;122:40-
42.
35. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct
excessive anticoagulation in patients receiving warfarin: a randomized trial. Ann Intern
Med. 2009;150:293-300.
36. Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate
factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin induced
coagulopathy. Int J Emerg Med. 2009;2:217-225.
37. Rowe AS, Mahbubani PS, Bucklin MH, et al. Activated prothrombin complex
concentrate versus plasma for reversal of warfarin-associated hemorrhage.
*38. Leissinger CA, Blatt PM, Hoots K, et al. Role of prothrombin complex concentrates
in reversing warfarin anticoagulation: a review of the literature. Am J. Hematol.
2008;83:137-143.
39. Goldstein JN, Marrero M, Masrur S, et al. Management of thrombolysis-associated
symptomatic intracerebral hemorrhage. Arch Neurol. 2010;67:965-969.
40. Levy JH, Tanaka KA, Dietrich W. Perioperative hemostatic management of patients
treated with vitamin K antagonists. Anesthesiology. 2008;109:918-926.
41. Dager WE, Regalia R, Williamson D, et al. Reversal of elevated international normalized
ratios and bleeding with low-dose recombinant activated factor VIIa in patients
receiving warfarin. Pharmacotherapy. 2006;26:1091-1098.
42. Garcia D, Crowther MA, Ageno W. Practical management of coagulopathy associated
with warfarin. BMJ. 2010;340:c1813.
43. Whitling AM, Bussey HI, Lyons RM. Comparing different routes and doses of
phytonadione for reversing excessive anticoagulation. Arch Intern Med. 1998;158:2136-
2140.
44. Baker RI, Coughlin PB, Gallus AS, et al. Warfarin reversal consensus guidelines
on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust.
2004;181:492-497.
*45. Lubetsky A, Yonath H, Olchovsky D, et al. Comparison of oral vs intravenous
phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective
randomized controlled study. Arch Intern Med. 2003;163:2469-2473.
46. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international
normalized ratio more rapidly than subcutaneous vitamin K in the treatment of
warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med.
2002;137:251-254.
47. van Aart L, Eijkhout HW, Kamphuis JS, et al. Individualized dosing regimen for
prothrombin complex concentrate more effective than standard treatment in the
reversal of oral anticoagulant therapy: an open, prospective randomized controlled
trial. Thromb Res. 2006;118:313-320.
48. Preston FE, Laidlaw ST, Sampson B, et al. Rapid reversal of oral anticoagulation with
warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42
patients. Br J Haematol. 2002;116:619-624.
*49. Kuramatsu JB, Gerner ST, Schellinger PD et al. Reversal, blood pressure levels, and
anticoagulant resumption in patients with anticoagulation-related intracerebral
hemorrhage JAMA. 2015;313:824-836.
50. Qureshi W, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after
major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014;113:662-668.
10 Chapter
TRANSITIONS IN CARE—
PERIPROCEDURAL BRIDGING
AND TRANSITIONS BETWEEN
AGENTS
Jessica Rimsans, Katelyn W. Sylvester, and John Fanikos
INTRODUCTION
Patients receiving long-term antiplatelet (AP) therapy or oral anticoagulation (OAC)
with vitamin K antagonists (VKA) or a direct-acting oral anticoagulant (DOAC)
commonly transition from the ambulatory setting to the hospital and back again.
This clinical scenario often requires antithrombotic therapy changes. Each transition
point (hospital admission, procedure, unit transfer, discharge to home, or long-
term care) represents an opportunity to assess medication regimens for errors,
omissions, and treatment adjustments. Emphasis on abbreviating hospital stay
and reducing costs further magnifies the need for seamless conversion between
oral and parenteral antithrombotic therapies. As these patients transition, either
electively or urgently, the diagnosis and indications for anticoagulant therapy
should be evaluated. Surgical and invasive procedures add additional levels of
complexity where OAC and AP therapy may be continued, interrupted, or replaced
with short-term parenteral or bridge therapy. Since there is not a standardized
definition of bridging, most regimens have been developed from observational and
retrospective studies, registry data, and more recently a randomized controlled trial.
Physician and patient preference will play a role in determining whether therapy
is continued, stopped, or replaced with an alternative agent.
PERIPROCEDURAL BRIDGING PRINCIPLES

• Determine thromboembolism risk with interruption of anticoagulant (AC) and/or AP
therapy.
• Assess bleeding risk associated with:
{{ Parenteral AC/AP therapy
{{ Surgical or invasive procedure
{{ Continuation of AC/AP therapy
• Weigh risk versus benefits of bridging
• Consider patient and physician’s goals and preferences
223
PERIPROCEDURAL THROMBOEMBOLIC RISK

ASSESSMENT
• Patients should undergo a thorough assessment for thromboembolism using a
standardized risk stratification evaluation.1
• Identify level of thromboembolism risk based on underlying disease and comor-
bidities.
• Previous literature and current guidelines historically risk stratified patients using
Cardiac Failure, Hypertension, Age, Diabetes, and Stroke (doubled) (CHADS2);
however, CHA2DS2-VASc (vascular disease and sex category) has since been
validated and adopted into clinical practice.2-4
PERIPROCEDURAL BLEEDING RISK

ASSESSMENT5-9
• Patients should undergo a thorough assessment for bleeding risk.
• The procedure itself is one of the most important risk factors for bleeding.
• Consider patient risk factors and comorbidities that may impact oral or paren-
teral anticoagulation and increase procedural and postprocedural bleeding risk.
• Various prognostic and scoring indices for bleeding exist for initiating VKA
therapy, in-hospital risk, and postprocedural risk.10-13
• Consider using an appropriate bleeding index to identify patient’s risk level
for bleeding.
DETERMINING PROCEDURAL RISK OF

HEMORRHAGE
• Assess the risk of bleeding from the procedure.5,6
• Incidence of hemorrhage will depend on the procedure and occurs in as many
as 11.9% of patients during routine surgery. Published bleeding rates include
the following:
{{ Thoracic surgery 33.7%
{{ Abdominal surgery 11.4%
{{ Other major surgery 14.3%
• Two thirds of bleeding events will occur within 48 hours after the intervention.
• Procedures in closed areas or cavities carry a high risk for hemorrhagic compli-
cations (Table 10-1), including:
{{ Pericardial region (related to pacemaker/internal cardiac defibril-
lator [ICD] insertion)
{{ Spinal (related to trauma from lumbar puncture or epidural place-
ment)
{{ Urologic procedures (involving the retroperitoneum or bladder
lumen)
• Assess patient specific risk factors for bleeding (Table 10-2).4,7
TRANSITIONS IN CARE 225
TABLE 10-1: Procedural Risk of Hemorrhage in the Setting of

Perioprocedural Anticoagulation1,5-9
When assessing the risk of periprocedural bleeding in the setting of anticoagulation, it is im-
portant to evaluate the bleeding risk in relation to the dose of anticoagulation (i.e., therapeutic
anticoagulation vs. prophylactic doses of anticoagulation).1
High Bleeding Risk Invasive Procedure or Low Bleeding Risk Invasive Procedure or
Surgery Surgery
Cardiothoracic Abdominal hernia repair

• Thoracic aortic aneurysm repair, heart Abdominal hysterectomy
valve replacement/repair, coronary Axillary node dissection
artery bypass, cardiac biopsy, heart Arthrocentesis
transplantation, coronary angiography Ablation
+/- PCI Arthroscopy
• Lung surgery: lobectomy, wedge Biopsy if low vascularity of site (bladder,
resection, segmentectomy, thyroid, lymph node, pancreas)
pneumonectomy Bronchoscopy without biopsy
Cataract eye surgery
• Implantable cardiodefibrillator device
Central venous catheter removal
implantation or pacemaker insertion
Cutaneous surgeries
Urological Dental hygiene or extraction (uncomplicated)
• Transurethral prostate resection, Dermatologic procedures (minor)
prostectomy, prostate surgery/biopsy, Dilation and curettage
bladder resection or tumor ablation, Electrophysiologic testing
nephrectomy, kidney biopsy/surgery, Hemorrhoid surgery or hydrocele repair
urogynecological surgery Joint and soft tissue injections/aspirations
Gastrointestinal Non-coronary angiography
• Intra-abdominal surgery, appendectomy, Gastrointestinal endoscopy or colonoscopy
bowel resection, intestinal anastomosis, without biopsy
PEG tube placement, cholecystectomy, Skin cancer excision
polypectomy, colonoscopy with biopsy
>2 cm
Orthopedic
• Joint arthroplasty, hip/knee replacement,
other major orthopedic surgery
Vascular
• AAA repair, endarterectomy, carotid
bypass surgery, port placement, other
major vascular surgery
Cancer
• Urologic, gynecologic, head and neck,
colorectal, breast
Neurosurgical
• Intracranial or spinal surgery,
laminectomy, other major neurosurgery
(continued)

High Bleeding Risk Invasive Procedure or Low Bleeding Risk Invasive Procedure or
Surgery Surgery
Surgery and procedures/biopsies in highly

vascular organs
• Kidney, liver, spleen, breast
Reconstructive plastic surgery with
extensive tissue injury
Other
• Complicated dental surgery (multiple
tooth extractions)
• Sternotomy wire removal
• Endoscopy guided fine-needle aspira-
tion
• Any major surgery >45 min in duration
AAA: abdominal aortic aneurysm, PCI: percutaneous coronary intervention, PEG: percutaneous
endoscopic gastrostomy
PERIPROCEDURAL MANAGEMENT OF
ANTIPLATELET THERAPY
• Evidence supporting periprocedural management of AP therapy is limited.
TRANSITIONING FROM VKA TO PARENTERAL

THERAPY
• There are limited high quality data to guide clinicians on how to devise a bridge
strategy, if necessary, based on thromboembolism and bleeding risk (Table
10-3).1
• Optimal bridge therapy for temporary warfarin interruption for invasive proce-
dures has been shown to increase the risk of bleeding in atrial fibrillation patients
without a corresponding decrease in thromboembolism risk (BRIDGE trial); it
is also associated with an increased risk of bleeding, without a corresponding
decrease in thromboembolism risk in patients receiving VKA for prior venous
thromboembolism (VTE).14-19
• In patients on VKA, low dose vitamin K 1 mg orally can be given to normalize INR
the day before surgery without conferring warfarin resistance postoperative.20
BRIDGING WITH LOW MOLECULAR WEIGHT

HEPARIN
• Registry data suggests bridging may be unnecessary for the vast majority of
patients in an anticoagulation management service even with interruptions in
warfarin therapy (continued, lower-intensity, or interrupted).19-25
TABLE 10-2: Major Patient Risk Factors and Comorbidities

Increasing Bleeding Risk with Anticoagulation4–7
Risk Factor or Explanation
Comorbidity
Increasing age Risk increases as age increases >55 years
History of bleeding Higher risk with more recent bleeding event (e.g., gastrointestinal,
intraocular, hematuria)
Vascular disease Prior stroke or peripheral vascular disease
Renal dysfunction Creatinine clearancea <90 mL/min or serum creatinine >1.2 mg/dL
associated with higher risk
Hepatic dysfunction Associated with altered coagulation function and a higher risk of
bleeding with worsening liver function
Congestive heart Exacerbations may alter anticoagulant response and pharmacodynamics

failure
Anemia Hematocrit <30% or hemoglobin <13 g/dL males, <12 g/dL females is
associated with higher risk
Cancer Bleeding risk correlates with the type and extent of cancer
Hypotension Systolic blood pressure <100 mm of Hg
Hypertension Systolic blood pressure >200 mm of Hg
Female Predictor of higher risk; exact mechanism is unknown
Diabetes mellitus Impacts many risk factors that increase bleeding risk
Labile INRs Poorly controlled INR, <60% time in therapeutic range
Alcohol ≥8 units alcoholic consumption per week

consumption
Concomitant drugs Antiplatelet agents and nonsteroidal anti-inflammatory agents

a
Calculated using Cockcroft-Gault formula.
• Low molecular weight heparin (LMWH) prophylactic doses have never been
studied in the arena of preventing thromboembolism. Thus, when bridging
for atrial fibrillation and mechanical heart valves, therapeutic dosing is usually
preferred.
• There is no randomized controlled trial in patients with atrial fibrillation or heart
valves that shows therapeutic LMWH has any benefit in reduction in stroke risk.
• Standardized LMWH “bridge” regimens often result in significant residual
anticoagulant activity shortly before surgery.26
• Patients with impaired renal function are likely to have delayed LMWH clearance.
• Residual LMWH activity, as measured by anti-factor Xa testing, can last 24 hours
after a dose.
• Duration of LMWH bridging may be significantly longer (12 days) than is reported
in clinical trials.27
• In those patients undergoing pacemaker or ICD placement, a strategy of contin-
ued warfarin reduced the incidence of clinically significant pocket hematoma
compared with those being bridged with intravenous unfractionated heparin
(IV UFH).16
RE-INITIATION OF VKA
• Patients receiving higher weekly warfarin doses are likely to eliminate the drug
faster and return to baseline INR earlier than those patients on lower weekly
warfarin doses.
• Consider any events during the intraoperative and immediate postoperative
period (excessive bleeding or bleeding vessels which required intervention) that
may impact reinitiating anticoagulation.
• The decision to restart anticoagulation after a procedure must be made in
consultation with the surgeon or proceduralist, taking into account procedure,
presence of neuraxial anesthesia, and risk of bleeding/thromboembolism.
• When warfarin is restarted, often the maintenance dose is reinitiated. When there
is a desire for earlier “measured” INR response, another option is to start with
an increased dose for the initial 2 days (≈50-100% increase in the maintenance
dose), then follow with the usual maintenance dose.28,29
TRANSITIONING BETWEEN DIRECT-

ACTING ORAL ANTICOAGULATION OR TO
PARENTERAL THERAPY30-33
• DOACs have a fast onset and offset. The use of a pre-operative parenteral
bridging agent is not needed. Use of a parenteral bridging (generally IV UFH)
may be necessary after surgery in high bleeding risk situations due to its short
duration and ability to reverse.18
• For low bleeding risk procedures (i.e., dental, ophthalmology, superficial surger-
ies) in patients with normal renal function, the DOAC may be continued uninter-
rupted at the discretion of the interventionalist.30
• When a DOAC is restarted, renal function, procedure, presence of neuraxial
anesthesia, risk of bleeding/thromboembolism, and onset of the agent should
be taken into account.
• The effect of the DOAC on the UFH monitoring strategy (aPTT, anti-factor Xa
testing) must be considered; alternative monitoring strategies could be needed
to avoid lags in anticoagulation (Table 10-6).
• In some situations (high bleeding risk/low thrombosis risk, delayed DOAC clear-
ance due to acute kidney injury), heparin initiation may be delayed beyond
standard recommendations until the DOAC has largely cleared; appropriate
laboratory measures may help guide when to initiate UFH (Table 10-6).
TABLE 10-3: Summary of Evidence from Bridging Trials
Trial Study Design Population Intervention Outcome
BRIDGE trial Randomized AF patients (n = 1,884) Dalteparin 100 IU/kg SQ • Incidence of arterial thromboembolism was 0.4% in the no-
(Douketis et controlled trials Majority CHA2DS2-VASc 2–3, BID vs placebo 1-3 days bridging group and 0.3% in the bridging group (CI 0.6–0.8,
al.15) <10% with stroke/TIA before procedure to 24 hr P = 0.01 for noninferiority)
before then 5–10 days post • Incidence of major bleeding was 1.3% in the no-bridging
procedure group and 3.2% in the bridging group (CI 0.2 to 0.78, P =
0.005 for superiority)
BRUISE Randomized Pacemaker or ICD Warfarin continued through • Clinically significant device pocket hematoma occurred in
CONTROL controlled trial placement (n = 643), annual procedure vs. IV UFH or 12 of 343 patients (3.5%) in the continued warfarin group,
trial (Birnie et risk of TE >5% or more LMWH before and/or after compared with 54 out of 338 (16%) in the heparin-bridging
al.16) procedure group (RR 0.19 P <0.001)
• Major surgical and TE complications did not differ
significantly
Clark et al.14 Retrospective History of VTE (n = 1,178), Use of bridge vs. no bridge • 30 day rates of clinically relevant bleeding were 2.7% and
cohort majority >12 months prior, during warfarin interruption 0.2% in bridge vs. no bridge (CI 3.9–75.1)
low recurrent VTE risk • For therapeutic and prophylactic LMWH, there were 2.2%
category Therapeutic LMWH (89%) vs. 3.9% clinically relevant bleeding events
and heparin (11%)
• Of the 15 bleeding events in the bridge cohort, 52.9% were
procedural complications and 33.3% were directly related to
the bridging agent
• Recurrent VTE were not significantly different between
groups (P = 0.56)
(continued)
Substudy Pre-specified AF patients (n = 4,133), Evaluated bridging strategies • Bridging was used more during warfarin interruption than
of RELY sub study of the average CHA2DS2-VASc 3.6 in patients treated with dabigatran (27.5% vs 15.4% P<0.001)
(Douketis et RELY (randomized warfarin INR 2–3, dabigatran • Dabigatran interruption: bridged patients had more major
al.15) controlled trial) 110 mg BID, or 150 mg BID. bleeding than those not bridged (6.5% vs 1.8% P <0.001)
Bridging before and/or after and not bridged groups did not differ for TE (1.2% vs 0.6%
procedure: P = 0.16), and stroke or systemic embolism (0.5% vs. 0.3%
• IV UFH P = 0.007)
• Enoxaparin 1 mg/kg BID
• Warfarin interruption: bridged patients had more major

• Enoxaparin 40 mg BID bleeding (6.8% vs 1.6% P <0.001) and TE than those not
• Enoxaparin 40 mg/day bridged (1.8% vs 0.3 P = 0.007); and not bridged did not
differ for stroke or systemic embolism (0.5% vs 0.2% P =
• UFH SQ 5,000 units BID
0.321)
Siegal et al.18 Meta-analysis of 24 AF patients (44%), Warfarin INR 2–3 compared TE events occurred in 73 of 7,118 bridged patients (0.9%;
studies mechanical heart valve with bridging IV UFH or CI 0.0.0–3.4) and 32 of 5,160 nonbridged patients (0.6%;
(24%), previous VTE (22%), LMWH before and/or after CI, 0.0–1.2)
other (10%) procedure: • There was no difference in the risk of TE events in 8 studies
(n = 12,000) • Dalteparin 200 comparing bridged and nonbridged groups (OR 0.80;
IU/kg day or 100-120 CI, 0.42–1.54)
IU/kg BID
• Enoxaparin 1.5 mg/kg
day or 1 mg/kg BID
• Ardeparin 100–130
IU/kg BID
• Tinzaparin 175 IU/kg day
• Prophylactic doses were
included
(continued)
ORBIT-AF19 Registry data AF patients (n=10, 132), Primarily warfarin INR 2–3 Bridged patients were more likely to have cerebrovascular events
(Steinberg CHA2DS2-VASc ~4, CHADS2 with bridging before and/or (22% vs. 15%, P=0.0003), and mechanical valve replacements
BA, et al.) 2.3–2.5 after procedure: (9.6% vs. 2.4% P<0.0001); however, no difference in CHA2DS2-
• IV UFH (15%) VASc scores (P=0.5)
• LMWH (73%) • Bleeding events more common in bridged vs. nonbridged
patients (5% vs. 1.3% adjusted OR 3.84, P<0.0001)
• Fondaparinux (1.1%)
• Incidence of MI, stroke or systemic embolism, major
bleeding, hospitalization, or death within 30 days was also
significantly higher in patients receiving bridging (13% vs.
6.3%, adjusted OR 1.94, P=0.0001)
CHADS2: cardiac failure, hypertension, age, diabetes, and stroke (doubled); VAS: vascular disease; ICD: implantable cardioverter defibrillator; IV: intravenous; LMWH: low
molecular weight heparin; TE: thromboembolism; TIA: transient ischemic attack; UFH: unfractionated heparin; VTE: venous thromboembolism
• T
he use of DOACs as a bridge to therapeutic
warfarin is a controversial topic. While it should
be safe, in actual practice the lack of provider
recognition on how the DOACs affect INR and
knowledge of the correct timing of INRs (when
used in these patients) can lead to suboptimal
care. Due to this, using a parenteral agent with
warfarin for bridging may often still be the best
option. See Chapter 21 on DOAC effects on
coagulation laboratory tests for more information
(see Tables 10-4, 10-5, and 10-6).
TABLE 10-4: Periprocedural Management of Direct-Acting Oral

Anticoagulants1,9,39-43
Calculated Timing of Last Dose Before Surgery
CrCl (mL/min)
Dabigatran Low Risk of Bleeding High Risk of Bleeding
>50 24 hr 2 days
(PI: Discontinue 1–2 days (PI: Consider longer times if major surgery,
before) spinal puncture, spinal or epidural catheter,
patients in whom complete hemostasis may be
required)
31–50 2 days 5 days
(PI: Discontinue 3–5 days (PI: Discontinue 3–5 days before if CrCl
before if CrCl <50 mL/min) <50 mL/min)
<30 4 days 5–6 days
Rivaroxaban, Apixaban, Edoxaban
>50 1 day 2 days
31–50 1–2 days 3–4 days
<30 2 days 4 days
CrCl: creatinine clearance, PI: prescribing information

TABLE 10-5: Comparison of Pharmacodynamic Properties of

Direct-Acting Oral Anticoagulants40-43
Agent Target Clotting Reversible Binding tmax (hr) t½ (hr) Renal Excretion
Factor to Catalytic Site of Active Drug
Rivaroxaban Xa Yes 1.25–3 7–7.6 36%
Apixaban Xa Yes 1–3 8–15 25%
Dabigatran IIa Yes 1.25–3 12–17.2 80%
Edoxaban Xa Yes 1–2 10-14 35%
tmax: time to reach maximum plasma concentrations, t½: half-life
CONSIDERATIONS IN USING
ANTICOAGULANT THERAPY IN
CONJUNCTION WITH NEURAXIAL
ANESTHESIA
• Ensure safe transition with anticoagulation through neuraxial (spinal or epidural)
procedural anesthesia (Table 10-7).
• Avoid risks of spinal hematoma.
{{ Incidence with no anticoagulant; 1:220,000 with epidural anesthesia
and 1:2,320,000 with spinal anesthesia
{{ Incidence with heparin; 1:70,000 with epidural anesthesia and
1:100,000 with spinal anesthesia
• M
any health systems choose to avoid LMWH
prophylaxis in conjunction with indwelling
epidural catheters due to the complex
requirements needed to do it safely. Many health
systems consider delaying warfarin/DOAC
re-initiation until catheter is removed to avoid
complications in catheter removal.
TABLE 10-6: Practical Considerations for Transitioning Between Various Direct-Acting Oral Anticoagulants or to
Parenteral Agents32, 33, 39-43
Conversion from adjusted-dose IV Consider pharmacodynamics: IV UFH (t½ = 60 min).
UFH infusion to oral rivaroxaban, Consider tmax for oral agent.
dabigatran, edoxaban, or apixaban Stop IV UFH infusion.
Rivaroxaban, dabigatran, edoxaban, or apixaban:
1. Administer first oral dose of rivaroxaban, dabigatran, edoxaban, or apixaban at the time of UFH discontinuation.
2. Continue direct-acting oral anticoagulant per prescribed regimen.
Conversion from sub-Q LMWH (or Consider pharmacodynamics: LMWH (t½ = 6–7 hr), fondaparinux (t½ = 17–21 hr) sub-Q.
sub-Q fondaparinux) therapeutic Consider tmax for oral agent.

dosing to oral rivaroxaban, dabigatran, Rivaroxaban, dabigatran, edoxaban, or apixaban:
edoxaban, or apixaban 1. Give rivaroxaban, dabigatran, edoxaban, or apixaban when next LMWH (or fondaparinux) dose is due.
2. Stop all following parenteral doses.
3. Continue direct-acting oral anticoagulant per prescribed regimen.
Converting from prophylactic dose Stop current parenteral prophylaxis agent.

sub-Q UFH, LMWH (or fondaparinux) Rivaroxaban, dabigatran, edoxaban, or apixaban:
to oral rivaroxaban, dabigatran, 1. Administer rivaroxaban, dabigatran, edoxaban, or apixaban orally at the time of the next scheduled parenteral dose.
edoxaban, or apixaban prophylactic 2. Continue direct-acting oral anticoagulant per prescribed regimen.
dose
Converting from direct thrombin Consider pharmacodynamics: bivalirudin (t½ = 25 min) or argatroban (t½ = 45 min), IV.41
inhibitor (bivalirudin or argatroban) Consider tmax for oral agent.
IV infusion to oral therapeutic dose Aim for oral agent tmax to correspond to direct thrombin inhibitor elimination.
rivaroxaban, dabigatran, edoxaban, or Rivaroxaban, dabigatran, edoxaban, or apixaban:
apixaban 1. Administer first rivaroxaban, dabigatran, edoxaban, or apixaban oral dose immediately at cessation of bivalirudin/
argatroban infusion.
2. Evaluate patient’s renal and hepatic status; if impaired, extend initiation interval accordingly.
(continued)
Converting from warfarin to oral For all DOACs:
rivaroxaban, dabigatran, edoxaban, or 1. Give final warfarin dose.
apixaban 2. Wait 2–3 days.
3. When INR <2, give first dose of rivaroxaban, dabigatran, edoxaban, or apixaban:
{{ For atrial fibrillation patients taking rivaroxaban, consider starting when INR <3.
{{ For atrial fibrillation patients taking edoxaban, consider starting when INR <2.5.
Converting from oral rivaroxaban, Rivaroxaban:

dabigatran, edoxaban, or apixaban to 1. Discontinue rivaroxaban.
warfarin 2. Begin a parenteral agent with warfarin when the next scheduled dose of rivaroxaban would be due.
Dabigatran:
1. Discontinue dabigatran.
2. Begin warfarin based on creatinine clearance:
{{ For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran.
{{ For CrCl 30–50 mL/min, start warfarin 2 days before discontinuing dabigatran.
{{ For creatinine clearance 15–30 mL/min, start warfarin 1 day before discontinuing dabigatran.
{{ For creatinine clearance <15 mL/min, no recommendations can be made.
Apixaban:
1. Discontinue apixaban.
2. Begin a parenteral agent and warfarin when the next scheduled dose of apixaban would be due.
(continued)
Converting from oral rivaroxaban, Edoxaban
dabigatran, edoxaban, or apixaban to Oral option:
warfarin 1. For patients taking 60 mg of edoxaban, reduce dose to 30 mg and begin warfarin concomitantly. For patients taking 30 mg
of edoxaban, reduce the dose to 15 mg and begin warfarin concomitantly. Once INR ≥2 is achieved, edoxaban should be
discontinued and continue warfarin therapy.
2. All INRs done in this fashion must be immediately prior to an edoxaban dose.
3. Patient compliance to this regimen may be extremely difficult, and may lead to improper levels of anticoagulation.
Parenteral option:
1. Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the same time of the next scheduled dose
of edoxaban. Once the INR is ≥2, the parenteral agent should be discontinued and continue warfarin therapy.
Converting from oral therapeutic dose Oral anti-Xa inhibitors (rivaroxaban, apixaban, edoxaban):*
rivaroxaban, dabigatran, edoxaban, 1. Start when next dose of DOAC is scheduled.
or apixaban to adjusted-dose IV UFH 2. Calculate the appropriate IV infusion UFH dose based on indication for use and patient weight.
infusion
3. Omit bolus or loading dose.
4. Check aPTT or anti-factor Xa activity level at 6 hr after initiating the IV UFH infusion.
5. Adjust further UFH doses based on aPTT or anti-factor Xa activity level and dosing nomogram.
*As noted above, in patients with high thrombotic risk, alternative UFH anticoagulation monitoring for 48-72 hours may be
needed (e.g., Xa inhibitor transitioning to UFH in hospital using anti-factor Xa levels for monitoring and using aPTT to guide
titrations); in high bleeding risk/low thrombosis risk situations and/or delayed DOAC clearance due to acute kidney injury,
heparin initiation may need to be delayed beyond standard recommendations to avoid over anticoagulation until the DOAC has
largely cleared; appropriate laboratory measures may help guide when to initiate UFH (e.g., waiting until an apixaban patient’s
heparin correlated anti-factor Xa level is in the measurable range to start therapy).
(continued)
Dabigatran:
1. Wait 12 hr for patients with a creatinine clearance ≥30 mL/min; wait 24 hr for patients with a creatinine clearance
<30 mL/min
2. Calculate the appropriate IV infusion UFH dose based on indication for use and patient weight.
3. Omit bolus or loading dose.
4. Evaluate patient’s renal status; if impaired, the IV UFH dosing initiation interval needs to be extended accordingly.
5. Check aPTT or anti-factor Xa activity level at 6 hr after initiating the IV UFH infusion.
6. Adjust further UFH doses based on aPTT or anti-factor Xa activity level and dosing nomogram.
Converting oral rivaroxaban, Discontinue direct-acting oral anticoagulant.

dabigatran, edoxaban, or apixaban to Consider peak activity for LMWH (3–5 hr) or fondaparinux (3 hr).
LMWH (or fondaparinux) Calculate the appropriate LMWH (or fondaparinux) dose based on the specific indication for use and patient weight.
Oral anti-Xa inhibitors (rivaroxaban, apixaban, edoxaban):

1. Discontinue oral anti-Xa and start LMWH/fondaparinux at the next scheduled dose of DOAC.
2. Calculate the appropriate LMWH/fondaparinux dose based on indication for use and patient weight.
3. Evaluate patient’s renal status; if impaired, the LMWH dosing initiation interval needs to be extended accordingly.
Dabigatran:
1. Wait 12 hr for patients with a creatinine clearance ≥30 mL/min; wait 24 hr for patients with a creatinine clearance
<30 mL/min.
2. Calculate the appropriate LMWH/fondaparinux dose based on indication for use and patient weight.
aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, IV: intravenous, INR: international normalized ratio, LMWH: low molecular weight heparin, sub-Q:
subcutaneous, tmax: time to reach maximum plasma concentrations, t½: half-life, UFH: unfractionated heparin
TABLE 10-7: Guidelines for Regional Anesthesia with Anticoagulation or Antiplatelet Use33,39-43
Agent or Class
Neuraxial Fibrinolytic UFH Prophylaxis Intravenous LMWH Prophylaxis LMWH Oral Anticoagulation Antiplatelet
Anesthesia Therapy UFH Therapeutic Therapy
Technique
Epidural Avoid fibrinolytic 5,000 units sub-Q Delay heparin Presence of blood during needle and Warfarin: Stop warfarin at least Stop GP IIb/
or spinal administration BID dosing administration catheter placement delays initiation of 4–5 days prior to procedure. IIIa inhibitors 8
anesthesia for at least is considered until 1 hr LMWH 24 hr. INR should be checked prior to hr (eptifibatide,
needle or 10 days after acceptable. after needle insertion if warfarin given more tirofiban) to 48
catheter puncture. The safety of placement. than 24 hr earlier. hr (abciximab)
insertion If patients 5,000 units sub-Q Pre-op LMWH Pre-op INR must be normal prior to prior to needle
are to receive TID dosing prophylaxis dosing: LMWH needle placement. placement.
fibrinolytic has not been Delay needle therapeutic Patients receiving warfarin Stop ticagrelor
therapy, established. placement at least 12 doses: Delay therapy during epidural 5 days prior,
neuraxial hr after the LMWH needle analgesia should have INR clopidogrel 5–7
anesthesia dose. placement monitored daily. days prior, and
techniques Post-op LMWH daily by at least Dabigatran: Stop 4-6 days prior prasugrel 7 –10
should be dosing: Administer 24 hr after to insertion. days prior to
avoided. first LMWH dose 6–8 LMWH dose; Rivaroxaban: Stop at least 2–3 needle placement.
hr post-op; administer indwelling days prior to insertion. Can Minimum hold
second dose no catheters consider stopping at least 4 period for
sooner than 24 hr after should be days prior if the patient has vorapaxar has not
the first dose. removed impaired renal function or age been established.
Post-op LMWH BID prior to greater than 65. Avoid use.
dosing: First LMWH LMWH Apixaban: Stop at least 3–5 Stop cilostazol
dose no earlier than 24 initiation. days prior to insertion. 48–72 hr prior to
hr postop; indwelling Edoxaban: Stop at least 3–5 needle placement.
catheters should be days prior to insertion. Stop ticlopidine
removed prior to BID 14 days prior to
LMWH initiation. needle placement.
(continued)
Agent or Class
Neuraxial Fibrinolytic UFH Prophylaxis Intravenous LMWH Prophylaxis LMWH Oral Anticoagulation Antiplatelet
Anesthesia Therapy UFH Therapeutic Therapy
Technique
Epidural No No Remove Catheter removal a Catheter Check INR prior to catheter Catheters must
or spinal recommendation. contraindications. indwelling minimum of 12 hr after removal a removal. be removed
anesthesia If fibrinolytic catheter 2–4 last LMWH dose. minimum of Catheters should ideally be prior to initiating
catheter therapy is hr after the last Administer first dose 24 hr after removed when INR is below eptifibatide,
removal given, monitor heparin dose. 2 hr after catheter the last dose 1.5, but removal can be tirofiban,
fibrinogen level Reheparinize removal. of LMWH. cautiously considered if INR abciximab,
recovery as 1 hr after 1.5–3. clopidogrel,
guidance. catheter If a DOAC was started in the ticagrelor,
removal. event a catheter was placed: prasugrel,
• Dabigatran: Wait cilostazol, or
24–48 hr or longer before ticlopidine. May
removing. be considered if
• Rivaroxaban: Wait 18 hr or last dose 8–12 hr
longer before removing. previously.
• Apixaban: Wait 24 hr or
longer before removing.
• Edoxaban: Wait 24 hr or
longer before removing.
BID: twice daily, GP: glycoprotein, INR: international normalized ratio, LMWH: low molecular weight heparin, sub-Q: subcutaneous, TID: three times daily, UFH:
unfractionated heparin
TRANSITIONING BETWEEN PARENTERAL

ANTICOAGULANTS
• During hospitalization, patients may require transition between parenteral
therapies or as a bridge to VKA (Table 10-8).
• Consider differences in pharmacokinetic properties of UFH and LMWH (or
fondaparinux).
• Avoid concurrent use of parenteral anticoagulant agents to ensure safety.
• When transitioning from IV UFH to an alternative parenteral anticoagulant agent
with rapid onset of activity, it may be preferable to wait a selected period of time
before initiating the alternative therapy in patients at increased risk of bleeding.
• Because of potential distractions and logistic considerations, consider stopping
the UFH at the same time as initiating any new anticoagulant unless an atypical
clinical situation is present.
TRANSITIONING FROM PARENTERAL

ANTICOAGULATION TO ORAL VKA THERAPY
• For patients with active thrombosis, UFH or LMWH is administered concurrently
and overlapped with warfarin for at least 5 days and until the INR has reached
a therapeutic range for 24 hours.
• INR ranges will vary depending on indication for anticoagulation.
• For warfarin-naïve patients, initiation nomograms can avoid excessive anti-
coagulation and rapidly achieve target INR with a starting dose between 5 and
10 mg.36-38
• For previously treated warfarin patients, re-initiate therapy at prior chronic
maintenance dose. When there is a desire for earlier “measured” INR response,
another option is to start with an increased dose for the initial 2 days (≈50-100%
increase in the maintenance dose), then follow with the usual maintenance dose.28
• Elderly patients with comorbidities or recent surgery should initiate warfarin
with a dose <5 mg.
• For younger, healthier, heavier patients, may consider larger initial doses (7.5–10
mg).
• Consider clinically significant disease states and drug–drug interactions.
• INR monitoring starts, at the latest, after the initial 2–3 VKA doses. Unstable
patients in the hospital should have daily monitoring.
• Warfarin maintenance doses are adjusted based on the cumulative weekly
dosage with increases or decreases of no more than 10–20% of the weekly dose.
Any variation in doses from day-to-day should be spread evenly over the week.
TABLE 10-8: Practical Considerations for Transitioning Between

Various Parenteral Anticoagulants
Conversion from adjusted-dose • Calculate the 24-hr IV UFH dose requirement needed
IV UFH infusion to adjusted-dose to maintain therapeutic aPTT.
sub-Q UFH • Increase the total 24-hr UFH dose requirement by 10-
20% (sub-Q dosage requirements are higher than IV).
• Divide the dose calculated above by 2 to determine
the initial q12 hr sub-Q dosing requirement.
• Discontinue IV UFH and initiate the first sub-Q UFH
dose (as calculated above) within 1 hr.
• Check aPTT or anti-factor Xa activity level at 6 hr after
first sub-Q dose.
• Adjust further sub-Q UFH doses based on aPTT or
anti-factor Xa activity level.
• Ensure a heparin 10,000- or 20,000-unit/mL
concentration is available (ensure your dispensing
procedures guarantee the safe use of these agents
due to the well-known neonatal intensive care heparin
errors).
Conversion from IV UFH infusion • Calculate the appropriate LMWH (or fondaparinux)
to sub-Q LMWH (or sub-Q dose based on the specific indication for use and
fondaparinux) patient weight.
• Discontinue IV UFH.
• Initiate the first sub-Q LMWH (or fondaparinux) dose
within 1 hr.
• If aPTT drawn within the last 6 hr is >100 sec or an
anti-factor Xa activity level >1 International Unit/
mL, wait 2 hr before administering LMWH (or
fondaparinux).
Conversion from sub-Q LMWH • Calculate the appropriate IV UFH dose based on
(or fondaparinux) to IV UFH indication for use and patient weight.
infusion • Discontinue sub-Q LMWH (or fondaparinux).
• Omit bolus or loading dose.
• Initiate IV UFH 1–2 hr before the next scheduled
LMWH or fondaparinux dose administration:
a. When switching from sub-Q LMWH given q 12 hr,
initiate IV UFH at 10–11 hr after last LMWH dose.
b. When switching from sub-Q LMWH given q 24 hr,
initiate IV UFH at 22–23 hr after last LMWH dose.
c. When switching from sub-Q fondaparinux given
q 24 hr, initiate IV UFH at 22–23 hr after last
fondaparinux dose.
d. Evaluate patient’s renal status and if impaired, the
IV UFH dosing initiation intervals suggested in a–c
above need to be extended accordingly.
• Check aPTT or anti-factor Xa activity level at 6 hr after
initiating the IV UFH infusion.
• Adjust further UFH doses based on aPTT or anti-factor
Xa activity level and dosing nomogram.
(continued)

Conversion from sub-Q LMWH • Calculate the adjusted-dose sub-Q UFH dosing
(or fondaparinux) to adjusted- requirements: The recommended initial dose is
dose sub-Q UFH 250 units/kg sub-Q given q 12 hr.
• Ensure a heparin 10,000- or 20,000-unit/mL
concentration is available (see the above precaution on
these dosing forms).
• Discontinue sub-Q LMWH (or fondaparinux).
• Initiate sub-Q UFH at the time the next sub-Q
LMWH (or fondaparinux) dose is scheduled to be
administered:
a. When switching from sub-Q LMWH given q 12 hr,
initiate sub-Q UFH at 12 hr after last LMWH dose.
b. When switching from sub-Q LMWH given q 24 hr,
initiate sub-Q UFH at 24 hr after last LMWH dose.
c. When switching from sub-Q fondaparinux given
q 24 hr, initiate sub-Q UFH at 24 hr after last
fondaparinux dose.
d. Evaluate patient’s renal status; if impaired, the
sub-Q UFH dosing initiation intervals suggested in
a–c above need to be extended accordingly.
• aPTT or anti-factor Xa activity level should be drawn at
6 hr (mid-interval) after the first sub-Q UFH dose.
• Subsequent sub-Q UFH doses should be adjusted
based on aPTT or anti-factor Xa activity level and
dosing nomogram.
Conversion between For patients receiving prophylactic sub-Q UFH q 8 or 12 hr,

prophylactic fixed dose UFH discontinue UFH:
to LMWH (or fondaparinux) or • Evaluate patient’s renal status and determine
LMWH (or fondaparinux) to UFH appropriate LMWH (or fondaparinux) dose and
interval.
• Administer LMWH (or fondaparinux) at the next
scheduled dose administration time.
• Continue LMWH dosing per prescribed regimen.
For patients receiving prophylactic sub-Q LMWH (or
fondaparinux) q 12 or 24 hr, discontinue LMWH (or
fondaparinux):
• Administer UFH at the next scheduled dose
administration time.
• Continue UFH dosing q 8 or 12 hr per prescribed
regimen.
aPTT: activated partial thromboplastin time, BID: twice daily, IV: intravenous, LMWH: low
molecular weight heparin, sub-Q: subcutaneous, UFH; unfractionated heparin
BRIDGING CONSIDERATIONS AND

RECOMMENDATIONS
Determine if patient is a candidate for bridging therapy:
• Mechanical/bioprosthetic heart valves
• Atrial fibrillation
• Venous thromboembolism
Steps to consider in transitioning anticoagulation therapy for periprocedural
bleeding:
• Operationalize an individualized plan for the patient (Figure 10-1).34
Mechanical/Bioprosthetic Heart Valves

Considerations High Risk for Moderate Risk for Low Risk for
Thromboembolism Thromboembolism Thromboembolism
Patient characteristics • Any mitral valve • Bileaflet aortic • Bileaflet aortic

prosthesis valve prosthesis valve prosthesis
• Older aortic AND one of the without AF and
valves (caged- following: AF, no other risk
ball or tilting prior stroke, or factors for stroke
disc) TIA, HTN, DM, • Medtronic Hall
CHF, age >75 yr tilting disc valve
• Recent (within 3
months) stroke
or TIA
• Bioprosthetic
heart valve*
Peri-op bridging • IV UFH (should • Therapeutic No bridging**

options be used for LMWH
all mechanical • IV UFH
mitral valves)
• Therapeutic
LMWH
*When used within 3 months of surgery; not for patients with concurrent atrial fibrillation after this
period.
** Post-procedure DVT prophylaxis should still be considered in procedures that require routine
prophylaxis.
AF: atrial fibrillation, CHF: congestive heart failure, DM: diabetes mellitus, HTN: hypertension,
IV: intravenous, LMWH: low molecular weight heparin, TIA: transient ischemic attack, UFH:
Consider bridge
High TE risk
HOLD OAC
Immediate
Resume OAC 6–8
hemostasis, low
risk procedure hours postoperatively
Assess the
following:
Low bleeding
• Bleeding risk No bridge
and TE risk
• Thrombosis risk HOLD OAC
• Patient May continue VKA
preference uninterrupted or at
• Physician lower intensity Inadequate
Procedure
Delay OAC until
preference and hemostasis,
high risk hemostasis achieved
resources (48–72 hours)
procedure
No bridge
High bleeding risk
HOLD OAC
FIGURE 10-1. Individualized Periprocedural Plan35

Consider bridge with a
reversible anticoagulant
OAC: oral anticoagulant, TE: thromboembolism, VKA: vitamin K antagonist

such as heparin
if high TE risk
Atrial Fibrillation
• No randomized data are available that demonstrate a benefit of LMWH in
reducing risk of stroke, systemic embolism, and transient ischemic attack (TIA)
caused by atrial fibrillation.
• Summary of the BRIDGE trial:
{{ LMWH bridging therapy compared to placebo showed no differ-
ence in the reduction of stroke, systemic embolism, and TIA, but
did demonstrate nearly a 3 x higher major bleeding rate.
{{ Based on the results of the BRIDGE trial,15 the use of periprocedural
LMWH in patients with atrial fibrillation is discouraged. Individual
clinicians should evaluate groups that were not well represented
in the trial, such as recent stroke/TIA in previous 12 weeks, those
who are over 10% yearly risk (CHADS2VASc ≥7 or CHADS2 ≥5,
rheumatic valvular disease, and those who had a stroke with warfarin
interruption).
{{ In the rare cases where clinicians choose to use bridging, thera-
peutic doses of LMWH/heparin should be used.
{{ For many pacemaker (PPM) and implantable cardioverter-defibrilla-
tor (ICD) placement patients, warfarin should be continued based on
the BRUISE CONTROL study showing continued warfarin reduced
the risk of pocket hematomas with no difference in thrombotic
complications compared to bridging therapy with heparin.16
{{ Post-procedure DVT prophylaxis should still be considered in
procedures that require routine prophylaxis.
Venous Thromboembolism
Considerations High Risk for Moderate Risk for Low Risk for
Thromboembolism Thromboembolism Thromboembolism
Patient • Recent (within 3 • VTE within the past • Single VTE

characteristics months) VTE 3 to 12 months occurred >12
• Severe • Nonsevere months ago AND
thrombophilia thrombophilic no other risk
(deficiency of conditions factors
protein C, protein (heterozygous
S or antithrombin, factor V Leiden
antiphospholipid mutation,
antibodies, heterozgyous
or multiple factor II mutation)
abnormalities). • Recurrent VTE
• Active cancer
(treated within
6 months or
palliative)
Peri-op bridging • Therapeutic No bridging* No bridging*

options LMWH
• IV UFH
*Post-procedure DVT prophylaxis should still be considered in procedures that require routine
prophylaxis.
Determine which bridging therapy is appropriate:

• Therapeutic dosing of LMWH
• IV UFH
{{ Heparin infusion may be started targeting aPTT 1.5–2.5 x baseline,
while taking into account procedural and patient risk factors.
• Prophylactic LMWH
Determine when to stop bridging therapy prior to surgery:
Bridging Therapy Discontinuation of Therapy Peri-Operatively
Therapeutic LMWH Last dose to be administered 24 hr prior to surgery/procedure
Prophylactic LMWH Last dose to be administered 12–24 hr prior to surgery/procedure
IV UFH Discontinue infusion 6 hr prior to surgery/procedure
Determine when to re-initiate anticoagulation therapy post-op:

• In all cases, it is recommended to discuss re-initiation of anticoagulation therapy
with the surgeon/proceduralist.
• Based on anticipated bleeding risk, hemostasis must be achieved before any
parenteral therapy.
Surgery/Procedure Bleeding Anticoagulation Re-Initiation Recommendation

Risk1
Low risk • Approximately 24 hr after (following day)

• Warfarin may be initiated the evening of the procedure
at the patient’s previously determined maintenance
dose or a slightly increased dose about 50% higher than
previous dose.
High risk The following options may be considered:

• Therapeutic LMWH/IV UFH re-initiation may be delayed
48–72 hr (POD 2 or 3) after procedure.
• Prophylactic LMWH may be initiated until bleeding risk
subsides and then therapeutic LMWH can be started.
• All anticoagulant medications may be held.
• Warfarin may be initiated the evening of surgery
(orthopedic surgeries) or delayed until bleeding risk
subsides.


1. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of
antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis. 9th
Chest. 2012;141(suppl 2):e326S-e305S.
2. Olesen JB, Torp-Pedersen C, Hansen ML, et al. The value of the CHA2DS2-VASc score
for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2
score 0–1: a nationwide cohort study. Thromb Haemost. 2012;107:1172-1179.
*3. Ferrandis R, Castillo J, de Andres J, et al. The perioperative management of new direct
oral anticoagulants: a question without answers. Thromb Haemost. 2013; 110: 515-
522.
4. January CT, Wann S, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the
Management of Patients with Atrial Fibrillation: executive summary. J Am Coll Cardiol.
2014;64(21):2246-2280.
5. Douketis JD, Johnson JA, Turpie AG. Low-molecular-weight heparin as bridging
anticoagulation during interruption of warfarin. Assessment of a standardized
periprocedural anticoagulation regimen. Arch Intern Med. 2004;164:1319-1326.
6. Torn M, Rosendaal FR. Oral anticoagulation in surgical procedures: risks and
recommendations. Br J Surg. 2003;123:676-682.
7. Di Biase L, Burkhardt D, Santangeli P, et al. Periprocedural stroke and bleeding
complications in patients undergoing catheter ablation of atrial fibrillation with different
anticoagulation management. Circulation. 2014;129:2638-2644.
8. El Khoury Z, Miller JM. What is the optimal international normalized ratio for patients
undergoing catheter ablation of atrial fibrillation? Pick your poison (dose). Circ
Arrhythm Electrophysiol. 2013;6:239-240.
*9. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an
elective procedure or surgery. Blood. 2012;120(15):2954-2962.
10. Ruiz-Giménez N, Suárez C, González R, et al. Predictive variables for major bleeding
events in patients presenting with documented acute venous thromboembolism.
Findings from the RIETE Registry. Thromb Haemost. 2008;100:26-31.
11. Wells PS, Forgie MA, Simms M, et al. The outpatient bleeding risk index. Arch Intern
Med. 2003;163:917-920.
12. Subherwal S Bach RG, Chen AY, et al. Baseline risk of major bleeding in non–ST-
segment–elevation myocardial infarction. The CRUSADE (Can Rapid risk stratification
of Unstable angina patients Suppress ADverse outcomes with Early implementation of
the ACC/AHA guidelines) bleeding score. Circulation. 2009;119:1873-1882.
13. Nikolsky E, Mehran R, Dangas G, et al. Development and validation of a prognostic
risk score for major bleeding in patients undergoing percutaneous coronary intervention
via the femoral approach. Eur Heart J. 2007;28:1936-1945.
*14. Clark NP, Witt DM, Davies LE, et al. Bleeding, recurrent venous thromboembolism,
and mortality risks during warfarin interruption for invasive procedure. JAMA Intern
Med. Published online May 26, 2015.
*15. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in
patients with atrial fibrillation. N Engl J Med. 2015;373:823-833.
16. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without
interruption of anticoagulation. N Engl J Med. 2013;368:2084-2093.
17. Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation
during dabigatran or warfarin interruption among patients who had an elective surgery
or procedure. Substudy of the RE-LY trial. Thromb Haemost. 2015;113:625-632.
18, Siegal D, Yudin J, Kaatz S, et al. Periprocedural heparin bridging in patients
receiving vitamin K antagonists; systematic review and meta-analysis of bleeding and
thromboembolic rates. Circulation. 2012;126:1630-1639.
*19. Steinberg BA, Peterson ED, Kim S, et al. Use and outcomes associated with bridging
during anticoagulation interruptions in patients with atrial fibrillation (ORBIT-AF).
Circulation. 2015;131:488-494.
20. Woods K, Douketis JD, Kathirgamanathan K, et al. Low-dose oral vitamin k to
normalize the international normalized ratio prior to surgery in patients who require
temporary interruption of warfarin. J Thromb Thrombolysis. 2007;24:93-97.
21. Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term
interruption of warfarin therapy. Arch Intern Med. 2008;168:63-69.
22. Wanzi OM, Beheiry A, Fahmy T, et al. Atrial fibrillation in patients with therapeutic
international normalized ration. Comparison of strategies of anticoagulation
management in the periprocedural period. Circulation. 2007;116:2531-2534.
23. Beldi G, Beng L, Siegel G, et al. Prevention of perioperative thromboembolism in
patients with atrial fibrillation. Br J Surg. 2007;94:1351-1355.
24. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 Guidelines for the
management of patients with valvular heart disease: executive summary. A report of
Guidelines. Circulation. 2006;114:450-452.
25. Larson BJG, Zumberg MS, Kitchen CS. A feasibility study of continuing dose-reduced
warfarin for invasive procedures in patients with high thromboembolic risk. Chest.
2005;127:922-927.
26. O’Donnell MJ, Kearon C, Johnson J, et al. Brief communication: Preoperative
anticoagulant activity after bridging low-molecular-weight heparin for temporary
interruption of warfarin. Ann Intern Med. 2007;146:184-187.
27. Eerhake JP, Merz JC, Cooper JV. The duration of anticoagulation bridging therapy
in clinical practice may significantly exceed that observed in clinical trials. J Thromb
Thrombolysis. 2007;23:107-113.
28. Schulman A, Hwang HG, Eikelboom JW, et al. Loading dose vs. maintenance dose
of warfarin for reinitiation after invasive procedures: a randomized trial. J Thromb
Haemost. 2014;12:1254-1259.
29. Pengo V, Cucchini U, Denas G, et al. Standardized low-molecular-weight heparin
bridging regimen in outpatients on oral anticoagulants undergoing invasive procedure
or surgery. An inception cohort study. Circulation. 2009;119:2920-2927.
30. Kristensen SD, Knuuti J, Saraste A, et al. 2014 ESC/ESA Guidelines on non-cardiac
surgery: cardiovascular assessment and management. Eur Heart J. 2014;35:2383-
2431.
*31. Faraoni D, Levy JH, Albaladejo P, et al. Updates in the perioperative and emergency
management of non-vitamin K antagonist oral anticoagulants. Crit Care. 2015;19:203.
32. Faust AC, Kanyer D, Wittkowsky AK. Managing transitions from oral factor Xa
inhibitors to unfractionated heparin infusions. Am J Health-Syst Pharm. Dec 15
2016;73(24):2037-2041.
33. Macedo KA, Tatarian P, Eugenio KR. Influence of direct oral anticoagulants on anti-
factor Xa measurements utilized for monitoring heparin. Ann Pharmacother. Feb
2018;52(2):154-159.
*34. Bergmark B, Giugliano RP. Perioperative management of target-specific oral
anticoagulants. Hosp Pract. 2014;42;1:38-45.
35. Narouze S, Benzon HT, Provenzano DA, et al. Interventional spine and pain procedures
in patients on antiplatelet and anticoagulant medications. Reg Anesth Pain Med.
2015;40:182-212.
36. Harrison L, Johnston M, Massicotte MP, et al. Comparison of 5 mg and 10 mg loading
doses in initiation of warfarin therapy. Ann Intern Med. 1997;126:133-136.
37. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5 mg and 10
mg loading doses. Arch Intern Med. 1999;159:46-48.
38. Kovacs MJ, Roger M, Anderson DR, et al. Comparison of 10 mg and 5 mg warfarin
initiation nomograms together with low molecular weight heparin for outpatient
treatment of acute venous thromboembolism. Ann Intern Med. 2003;138:714-719.
39. Dabigatran [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals,
Inc; 2015.
40. Rivaroxaban [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2015.
41. Apixaban [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company; 2015.
42. Edoxaban [package insert]. Parsippany, NJ: Daiichi Sankyo Inc.; 2015.
43. Schulman S, Carrier M, Lee AYY, et al. Perioperative management of dabigatran:
A prospective cohort study. Circulation 2015;115.015688 published online before
print May 12, 2015.
11 Chapter
CONSIDERATIONS IN SPECIAL
POPULATIONS
Thaddaus Hellwig and William E. Dager
INTRODUCTION
It is widely known that giving various patient populations the same dose of the
same drug may lead to different treatment outcomes. Differences in dose and
response relationships of anticoagulants within various populations may lead to a
decreased thromboembolic effect or increased rates of bleeding. The “one dose
fits all” strategy may not be appropriate for all patient populations. Independently,
these special populations can have risks for bleeding or thrombosis. This chapter
will outline special patient populations in renal dysfunction, hepatic dysfunction,
elderly, obesity, low body weight, and malignancy.
RENAL IMPAIRMENT1-5
• The majority of anticoagulant agents are partially or fully eliminated by the kidneys.
• Patients with renal impairment may be at risk for drug accumulation and increased rates
of bleeding, and the clinician can play a significant role in recommending alternative
agents or recommend dose adjustments.
• The majority of data concerning anticoagulants in renal disease are in patients with
stable chronic kidney disease, and data are limited regarding the use of anticoagu-
lants in patients with altering degrees of renal impairment because this population
was frequently excluded.
• None of the agents has been formally studied in patients with end-stage renal disease
(ESRD) for their U.S. Food and Drug Administration (FDA)-approved indications, and
patients generally were excluded from clinical trials involving direct-acting oral anti-
coagulants (DOACs) with a creatinine clearance (CrCl) <25–30 mL/min.
• In general, as CrCl decreases, bleeding rates increase with anticoagulant therapy.
Renal failure is also associated with drivers for both thrombosis and bleeding (Table
11-1). Other factors less expressive in normal renal function can accumulate to exert
influence (e.g., plasminogen activator inhibitor [PAI-1]).
• CrCl should be calculated using the Cockcroft-Gault equation using actual body weight
in accordance with the majority of clinical trials; however, use caution in morbidly obese
patients since they weren’t commonly represented in clinical trials.
• Studies and recommendations for CrCl <30 mL/min may not have included patients
requiring renal replacement therapy, for which dosing should be separately considered.
• Anticoagulant dosing is specifically impacted by both indication and renal function
(Tables 11-2, 11-3, 11-4, 11-5, 11-6, and 11-7).
251
TABLE 11-1: Examples of Factors Influencing Hypercoagulable

or Hemorrhagic Risk in Renal Failure
Drivers for Thrombosis
• Increased
{{ PAI-1, vWF, homocysteine, fibrinogen, clotting factors, tissue factor expression,
antiphospholipid antibodies
• Decreased
{{ Antithrombin, protein C and S, p-selectin, phosphatidylserine
• High Hgb with ESA use
• Prothrombotic microparticles
• Hemodialysis-induced platelet aggregation
• Endothelial changes
• History of thrombotic event
• Factors associated with stroke in the setting of atrial arrhythmias
• Inadequate prophylaxis during acute risk periods (acute illness)
• Heparin-induced thrombocytopenia (HIT)
• Nephrotic syndrome
• Graft thrombosis
{{ Low albumin
{{ Shear stress
{{ Stenosis
{{ Blood stasis
Drivers for Bleeding

• Systemic anticoagulation
• Excessive anticoagulation (including excessing dosing as elimination declines, drug
interactions)
• Antiplatelet therapy
• Recent use of systemic thrombolytic agent
• Anemia (hereditary and acquired), frequent blood draws
• Impaired platelet function (uremia, oxidative, and mechanical stress)
• Vascular tone modulation (increased NO and prostacyclin, inflammation)
• Dialysis circuit (sheer wall stress by dialyzer on platelets)
• Severe hypocalcemia
• Increased fibrinogen fragments
• Defect in vWF
• Advanced age
• Poorly controlled high blood pressure
• History of bleeding events
• Trauma, increased risks for traumatic events
ESA: erythrocyte-stimulating agent, HgB: hemoglobin, NO: nitrous oxide, PAI-1: plasminogen
activator inhibitor – 1, vWF: von Willibrand factor
CONSIDERATIONS IN SPECIAL POPULATIONS 253
TABLE 11-2: Pharmacokinetic Changes of Anticoagulants in

Patients with Renal Impairment1-18
Drug Dosing Outcome Mild (CrCl Moderate Severe
50–80 mL/ (CrCl 30–50 (CrCl <30
min) mL/min) mL/min)
Dalteparin Treatment T1/2 (hr) NR NR ↑↑↑
Enoxaparin Prophylactic Anti-Xa levels ↔ ↑ ↑↑↑a
Enoxaparin Treatment Mean anti-Xa NR ↑↑↑ ↑↑↑

level
Tinzaparin Treatment T1/2 (hr) NR NR ↑↑
Fondaparinux Treatment T1/2 (hr) ↑ ↑ ↑↑
Argatroban Treatment Css (ng/mL) ↔ ↔ ↔

AUC (ng*h/ ↔ ↔ ↔
mL) ↔ ↔ ↑
T1/2 (min)
Bivalirudin Treatment T1/2 (min) NR ↑↑ ↑↑↑
Dabigatran Treatment Cmax (ng/mL) NR ↑ ↑↑↑

AUC (ng*h/ ↑↑ ↑↑↑
mL) ↔ ↑↑↑
T1/2 (hr)
Rivaroxaban Treatment Cmax (ng/mL) NR ↔ ↔

AUC (ng*h/ ↔ ↑b
mL) ↔ ↔
T1/2 (hr)
Apixaban Treatment Cmax (ng/mL) NR ↔ ↔

AUC (ng*h/ ↑ ↔c
mL) ↑ ↑
T1/2 (hr)
Edoxaban Treatment AUC (ng*h/ NR ↑↑↑ ↑↑↑

mL) ↑ ↑↑↑d
T1/2 (hr)
a
In patients on hemodialysis: AUC 2-fold higher compared to control.
b
A single pharmacokinetic study (n=16) in patients on hemodialysis demonstrated a 56% increase
in AUC.
c
A single pharmacokinetic study (n= 8) in patients on hemodialysis demonstrated a 36% increase
in AUC.
d
Peritoneal dialysis or hemodialysis: 93% increase in AUC and T1/2 of 12.2 hours.
↑ (20−40%), ↑↑ (41−60%), ↑↑↑ (>60%), *: multiplication sign, AUC: area under the curve,
Cmax: maximum drug concentration after a dose, CrCl: creatinine clearance, Css: plasma or serum
concentration on steady state, NR: not reported, T1/2: half-life of a drug in (units of time)
Caveats for Consideration

• All heparin products have different fragment sizes, and smaller fragments are
generally cleared renally and may accumulate with reduced renal function.
• In single-dose pharmacokinetic (PK) studies, the measured elimination in renal
failure tends to be much faster than observed if measured after several doses.
• Dalteparin may be a good low molecular weight heparin (LMWH) choice in
patients with reduced renal function.
• It is unknown how much of an increase in a drug’s AUC can occur before a clini-
cally significant increase in bleeding is observed.
• It is unknown how each drug’s PK is influenced in patients with rapidly changing
CrCl or patients with acute kidney injury, as most studies are primarily in patients
with chronic stable renal disease.
• Recent trials in prophylaxis have suggested no difference in bleeding between
enoxaparin and heparin for thromboprophylaxis; however, in lower-weight
individuals, the enoxaparin dose could be close to what has been used for
therapy to bridge to warfarin.
• Drug level monitoring should be considered in patients with rapidly changing
renal function, or anticoagulant choices may be changed to agents with lower
percentages of renal elimination.
• Often, traditional therapy of unfractionated heparin and/or warfarin are used
in patients with severe renal dysfunction/ESRD due to the ability to monitor
laboratory parameters; however, bleeding complications are still common with
these traditional therapies.
• Warfarin: Several studies have observed a 20–25% dosing reduction in mild-
to-severe renal impairment. This could potentially be driven by renal failure
diminishing hepatic metabolism of cytochrome P450 2C19 isoenzyme (CYP
2C19). In the setting of hemodialysis, international normalized ratio (INR) values
should be drawn prior to dialysis and peripheral blood draws avoided as access
can be difficult.
TABLE 11-3: Dosing for Venous Thromboembolism Prophylaxis Following Orthopedic Surgery2-4,15-17
Renal Function Dalteparin Enoxaparin Fondaparinux Dabigatran Rivaroxabana Apixaban Edoxaban
Standard dosing 5,000 units once 40 mg once daily 2.5 mg daily 150 mg BID to 10 mg every day 2.5 mg BID 30 mg every dayb
CrCl >30 mL/min daily if initiated 220 mg BIDb
pre-operatively
or 30 mg BID
CrCl <30 mL/min No dose 30 mg once dailyc Contraindicated Cannot be Avoid used No dose No dose
adjustment providedd adjustmentd adjustmentd
a
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4 inhibitors unless benefit outweighs bleeding risks.
b
Study dose, not FDA-approved.
c
Derived from pharmacokinetics studies.
d
Excluded patients with CrCl <30 mL/min in clinical trials.
BID: twice daily, CrCl: creatinine clearance
TABLE 11-4: Treatment Dosing for Venous Thromboembolism19-22
Renal Function Heparin Dalteparin Enoxaparin Fondaparinux Dabigatrana Rivaroxabanb Apixaban Edoxaban
Standard dosing 80 units/kg IV 200 units/kg 1 mg/kg BID or 5 mg (<50 kg), 150 mg BID 15 mg BID with 10 mg BID for 60 mg every
CrCl >50 bolus followed daily x 30 days 1.5 mg/kg once 7.5 mg (50−100 following food for 21 days 7 days followed day following
by 18 units/ followed by 150 daily kg), 10 mg 5–10 days of followed by 20 by 5 mg BID 5–10 days of
kg/hr units/kg daily (>100 kg) parenteral mg every day parenteral
for months 2–6 therapy Extended therapy
333 units/kg (patients with Extended treatment to
sub-Q followed malignancy) Extended treatment to prevent VTE Extended
by 250 units/kg treatment to prevent VTE recurrence: treatment to
sub-Q BID 100 units/kg prevent VTE recurrence: 20 2.5 mg BID after prevent VTE
BIDc recurrence: 150 mg once daily 6 months of recurrence: 60
mg BID therapy mg once daily
CrCl 30−50 No dose No dose No dose Use with caution No dose No dose No dose 30 mg every
adjustment adjustment adjustmentsf adjustment adjustment adjustment day
CrCl <30 No dose No dose 1 mg/kg once Contraindicated Avoid usee See Table 11-5 See Table 11-5 30 mg every
adjustment adjustment dailyd,g (See Chapter 18 daye
for use in renal
failure and HIT)
a
Avoid concomitant use with P-glycoprotein inhibitors.
b
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4 inhibitors unless benefit outweighs bleeding risks if CrCl <80 mL/min.
c
Non-FDA approved dose.
d
Dose for CrCl 20−30 mL/min. Anti-Xa monitoring has been a proposed measure of anticoagulant effect in patients.
e
Patients with CrCl <30 mL/min were excluded from the clinical trials.
f
Pharmacokinetic data demonstrate a possible 20-30% reduction in dose.
g
In one single center observation, enoxaparin doses of ~ 0.6–0.7 mg/kg in the setting of hemodialysis was a safe effective bridge to warfarin.
BID: twice daily, CrCl: creatinine clearance, HIT: heparin-induced thrombocytopenia, IV; intravenous, sub-Q: subcutaneous, VTE: venous thromboembolism

• Dabigatran, rivaroxaban, and apixaban are not renally dose-adjusted for treat-
ment of venous thromboembolism (VTE).
TABLE 11-5: DOAC Dosing for Stroke Prophylaxis in Atrial

Fibrillation23-27
Renal Function Dabigatran Rivaroxaban Apixaban Edoxaban
Standard dosing 150 mg BID 20 mg every day 5 mg BID or 2.5 60 mg every

CrCl >30 mg BIDa dayb
CrCl <30 75 mg BIDc,d 15 mg every No dose 30 mg every day

daye,d adjustmenta
(note critical
footnote)
ESRD Avoid usei 15 mg every 5 mg BIDf,g Not

dayf,i 2.5 mg BIDg,h recommended
a
Dose of 2.5 mg BID in patients with any two of the following: age >80 years old, body weight
<60 kg, or SCr >1.5 mg/dL.
b
Do not use if CrCl >95 mL/min, increased thromboembolic (TE) outcomes.
c
Avoid use in patients with concomitant P-glycoprotein inhibitors.
d
Dose has not been fully evaluated in clinical trials for patients with CrCl <30 mL/min.
e
Avoid concomitant use with drugs that are both P-glycoprotein inhibitors and moderate CYP3A4
inhibitors unless benefit outweighs bleeding risks.
f
Use if patient is maintained on hemodialysis based on a pharmacokinetic study. Clinical efficacy
nor safety studies have not been conducted on chronic therapy in ESRD.
g
Patients with CrCl <25 mL/min were not studied in clinical trials.
h
Use if patient is >80 years old or body weight <60 kg while maintained on hemodialysis.
Use in ESRD is associated with increased bleeding and bleeding-related-mortality.
i
BID: twice daily, CrCl: creatinine clearance, DOAC: direct-acting oral anticoagulant, ESRD: end-
stage renal disease

• Dabigatran 75 mg twice daily (BID) dosing has not been studied in clinical trials
and was derived from pharmacokinetic modeling studies.
• Dabigatran 150 mg BID dosing in patient with a CrCl between 30–50 mL/min
may be associated with increased extracranial bleeding events, especially in
elderly patients.
• Dabigatran 110 mg BID dosing (not FDA-approved) demonstrated lower rates of
bleeding in patients with a CrCl between 30–50 mL/min and might be beneficial
in this CrCl range.
• In patients with atrial fibrillation and a significant reduction in renal function,
apixaban maintained consistent benefit in lower bleeding rates compared to
warfarin.
• Edoxaban has demonstrated a significant increase in thromboembolism (TE)

events compared to warfarin in patients with atrial fibrillation and CrCl >95 mL/
min and, therefore, should be avoided in that patient population.
TABLE 11-6: Dosing in Acute Coronary Syndromes15-17,28-31

Renal Function Dalteparin Enoxaparin Fondaparinux Bivalirudin
Standard dosing Primary PCI: No Primary PCI in Primary PCI in Primary PCI in
recommendation STEMI: Single STEMI (with GP STEMI: 0.75
IV dose of 0.5 IIB/IIIa inhibitor): mg/kg IV bolus
mg/kg and 0.75 2.5 mg IVa followed by 1.75
mg/kg mg/kg/hr
Primary PCI in
STEMI (without
GP IIb/IIIa
inhibitor): 5
mg IVa
STEMI with STEMI with STEMI with STEMI with

fibrinolytics: No fibrinolytic: fibrinolytic: 2.5 fibrinolytics: no
recommendation (<75 y.o.): 30 mg IV followed recommendation
mg IV bolus by 2.5 mg sub-Q
followed by 1 daily
mg/kg sub-Q
q12 hr
(≥75 y.o.): 0.75
mg/kg sub-Q
q12 hr
(>100 kg and
<75 y.o.): Cap
first two doses at
100 mg
(>100 kg and
≥75 y.o.): Cap
first two doses at
75 mg
NSTEMI: 120 NSTEMI: 1 mg/ NSTEMI: 2.5 NSTEMI: 0.1

International kg sub-Q q12 hr mg/kg sub-Q mg/kg IV bolus
Units/kg dailyd followed by
sub-Q q12 hr 0.25 mg/kg/
(maximum dose hr; at time of
of 10,000 units) PCI, administer
additional IV
bolus of 0.5 mg/
kg and increase
infusion rate to
1.75 mg/kg/hr
(continued)

Renal Function Dalteparin Enoxaparin Fondaparinux Bivalirudin
CrCl <30 Likely no dose STEMI with Contraindicated Primary PCI:

adjustment fibrinolyic: 1 mg/ May consider
neededb kg sub-Q once reduction in
daily infusion to 1
mg/kg/hrc
NSTEMI 1 mg/
kg sub-Q once
daily
ESRD Unknown No available Contraindicated Primary PCI:

data May consider
reduction in
infusion to 0.25
mg/kg/hrc
a
At time of PCI, administer additional 50−60 units/kg of UFH.
b
Data for dalteparin in the setting of acute coronary syndrome has not been evaluated to the
extent of enoxaparin.
No dose reduction for renal dysfunction was used in clinical trials.
c
d
Additional 200 International Units of UFH may be used to minimize thrombosis formation on
guide wire.
CrCl: creatinine clearance, ESRD: end-stage renal disease, IV: intravenous, NSTEMI: non-ST-
elevation myocardial infarction, PCI: percutaneous coronary intervention, STEMI: ST-segment
elevation myocardial infarction, sub-Q: subcutaneous
TABLE 11-7: Dosing Considerations to Prevent Thrombosis of

the Hemodialysis Circuit33-43
Agent Intermittent Hemodialysis Continuous Renal
Replacement40-43
Heparin See Chapter 3 See Chapter 3
Dalteparin 5,000 units IV or 39 units/kg have CVVHDF:

been explored. Dose is given prior to Dalteparin 20 units/kg vs.
hemodialysis.33 10 units/kg/hr vs. UFH: No
difference in filter life
95 units/kg of dalteparin via the arterial CVVH:

line just prior to starting of 8 hr nocturnal Dalteparin 70 units/kg;
hemodialysis followed by a dose of 45 30–40 units/kg/hr vs. UFH: No
units/kg at 4 hr was able to prevent differences in filter life (~31 hr)
circuit thrombosis. Measured anti-factor
Xa activity was 0.34 at 4 hours and 0.49
at the end of an 8-hr dialysis session.34
Dalteparin given either 5,000 units IV or

≥7,000 units with an additional ≥1,000
units at 2 hr in a ~ 4-hr dialysis yielded
end of dialysis anti-factor Xa levels of
0.15 and 0.6, respectfully. No difference
in clot formation was noted in the
dialyzer or air trap.35
Dalteparin 60 units/kg (~5,000 units

arterial side) was safe and effective in
preventing circuit thrombosis in high-flux
HD and HDF. Measured anti-factor Xa
levels at 1 hr were 0.4–0.75 IU/mL and
<0.4 IU/mL (mean 0.26) at the end of the
session.
Dalteparin 7,500 units yielded the same
end of dialysis anti-factor Xa activity. No
accumulation was noted, and assessment
was done after dosing for 10 dialysis
sessions. The regimen was still indicating
success in 53 of the 55 patients at 4
months.36
Enoxaparin 0.4–0.8 mg/kg appears to be effective CVVHDF:

in protecting the dialysis circuit. Higher Enoxaparin sieving coefficienta:
doses may be considered if prolonged 0.31–0.67
duration of dialysis.37-39
High-flux dialyzers (larger pore sizes) may

be associated with increased removal
and lower measured anti-factor Xa
activity.
(continued)

Agent Intermittent Hemodialysis Continuous Renal
Replacement40-43
In one prospective, randomized, cross- CVVHDF:

over trial (n=36), pre-dialysis enoxaparin Enoxaparin 0.5 vs. 1 mg/kg/day
1 mg/kg vs. UFH 5,000 units resulted vs. UFH: No difference in filter
in increased minor bleeding with life (~24 hr)
enoxaparin. Reducing the enoxaparin
dose to 0.69 mg/kg resulted in a 44%
reduction in minor bleeding.
Thrombosis rates: 0.5% UFH vs. 0.1%
enoxaparin after adjusting the dose.
Minor bleeding: Enoxaparin 4.3% vs.
UFH: 2.8% (p<0.001).
CVVHD:
Enoxaparin ~3.5–4.4 mg/hr
(86 mg/day): Anti-Xa ~0.3
units/mL
Filter life 31 hr vs. 22 hr (UFH)
a
Sieving coefficient is calculated by dividing the concentration in the ultrafiltrate by the plasma
concentration.
HD: hemodialysis, HDF: high-flux dialysis, CVVH: continuous venovenous hemofiltration, CVVHD:
continuous venovenous hemodialysis, CVVHDF: continuous venovenous hemodiafiltration, UFH:

• Based primarily on small studies and experience. Anti-Xa activity of ~0.2 to
0.4 units/mL has been proposed as a target goal to prevent thrombosis of the
circuit. Lower level at the end of dialysis, however, has been observed in effec-
tive therapies. If a patient is receiving systemic anticoagulation with a parenteral
agent, additional parenteral anticoagulation for protection of the circuit may
not be necessary.
• The technology of the dialysis circuits and filters continues to evolve and may
impact observed outcomes. In general, as more efficient dialyzers are used,
elimination may increase.
• More convective approaches of hemodialysis may be associated with a higher
rate of thrombosis.
• In the setting of hemodialysis and requirement for systemic anticoagulation,
heparin (typically by continuous infusion) and warfarin are the established
therapies.
{{ One option explored in a single center study, matched for indication
compared adjusted dose heparin to enoxaparin 0.7 ± 0.2 mg/kg/
day (range 0.1–1 mg/kg/day) for 3.3 ± 4.2 doses while transition-
ing to warfarin. Enoxaparin was associated with a lower rate of
major bleeding (6.1% vs. 11%; p = 0.04), clinical thrombosis (0%
vs. 2.4%; p=0.5), and duration of hospital stay (20 ± 54 days vs.
29 ± 44 days; p = 0.02). This suggests that enoxaparin doses of
around 0.6–0.7 units/kg may be a feasible option to bridge when

continuous infusion heparin is not an option or able to transition
to warfarin as an outpatient.44
• L
aboratory monitoring of LMWH has
been proposed in patients with severe renal
impairment and those with moderate renal
impairment and prolonged use (>10 days) to
identify potential accumulation and need for
dose adjustment to prevent bleeding. However, no
guide or data exist on outcomes of thrombosis
and bleeding or how to adjust the dose. Notable
additional variables driving bleeding and
thrombosis independent of anti-factor Xa activity
are also present. Reported correlation with renal
function and measured anti-factor Xa activity
is poor. Use of other surrogate markers such as
D-dimer in ESRD, especially with convective
dialysis, has not correlated with measured anti-
factor Xa activity. Use of UFH may be preferred
in patients with severe renal impairment.
• T
rough anti-Xa monitoring has been suggested
to evaluate accumulation at the end of the dosing
interval in patients with renal impairment.
Notable assay errors, however, can also be
present and correlation to CrCl has been poor.
It is important to know the timing of anti-Xa
monitoring in relation to the previous dose.
• V arious doses of LMWH and DOACs are used for
VTE prophylaxis following orthopedic surgery,
treatment of VTE, and stroke prophylaxis
in atrial fibrillation. Caution is advised in
determining the appropriate dose for the specific
indication.
• B
ecause renal dosing adjustments can be different
secondary to different therapeutic indications,
it is critical for hospitals and health systems
to facilitate easy access to the indication so
pharmacists can ensure correct dosing.
• V enous line administration of enoxaparin (1

mg/kg) is associated with higher measured
anti-factor Xa levels at 4 hours than
arterial line administration for prevention of
thrombosis of the dialysis circuit (0.58 vs.
0.39 for hemodialysis and 0.82 vs. 0.39 for
hemodiafiltration; p< 0.001). Thus, lower
doses may be administered if considering venous
administration versus arterial administration.32
Hepatic Dysfunction45-48
• Patients with hepatic insufficiency may have intrinsic coagulation abnormalities
that may lead to both increased bleeding and thromboembolic events.
• Both clotting factors and natural anticoagulants produced in the liver can be
reduced.
• Clinical studies involving DOACs have largely excluded all patients with Child-
Pugh class B or C hepatic insufficiency (see Table 11-8). Note the INR is a
component of the scoring system and could create misleading assessments.
• Limited data are available regarding the use of DOACs in patients with hepatic
impairment.
TABLE 11-8: Child-Pugh Score for Liver Impairment

Child-Pugh Score 1 2 3
Bilirubin (mg/dL) 1–2 2–3 >3
Albumin (g/dL) >3.5 2.8–3.5 <2.8
Ascites None Mild Moderate
Encephalopathy (grade)a None 1 and 2 3 and 4
Prothrombin time (seconds prolonged) 1–4 4–-6 >6

a
Encephalopathy grades: Grade 1: disordered sleep, mild confusion; Grade 2: lethargic, moderate
confusion; Grade 3: somnolent but rousable, confused, disoriented; Grade 4: coma, unarousable.
Total the score from the 5 rows. Score interpretation: Class A (mild disease) <7; Class B (moderate
disease) 7–9; Class C (severe disease) 10–15.
TABLE 11-9: Use in Patients with Hepatic Dysfunction45-48

Agent Parameter Child- Use in Moderate Use in Severe
Pugh B Hepatic Failure Hepatic Failure
(Child Pugh B) (Child Pugh C)
Warfarin INR ↑ May need May need more

more frequent frequent monitoring
monitoring and and lower doses
lower doses
Argatroban Cmax (ng/mL) ↑↑ Initial dose of 0.5 Initial dose of 0.25

mcg/kg/min mcg/kg/min
AUC (ng*h/mL)
↑↑↑ May need
T1/2 (min) more frequent
monitoring and
↑↑↑ dose adjustments
Bivalirudin Cmax (ng/mL) ↔ Mild dosing

reductions may be
necessary
Dabigatran Cmax (ng/mL) ↔ Patients displayed Not recommended

large inter-subject
AUC (ng*h/mL) variability; no
↔ evidence of
T1/2 (min) consistent change
in exposure
↔
Rivaroxaban Cmax (ng/mL) ↑ Avoid use Avoid use
AUC (ng*h/mL)
↑↑↑
T1/2 (min)
Apixaban Cmax (ng/mL) ↔ No Not recommended

recommendation
AUC (ng*h/mL) can be provided
↔
T1/2 (min)
Edoxaban Cmax (ng/mL) ↔ Use not Use not

recommended recommended
AUC (ng*h/mL)
↔
T1/2 (min)
*: multiplication sign, AUC: area under the curve, Cmax: maximum drug concentration after a dose,
INR: international normalized ratio, T1/2: half-life of a drug in (units of time)
↑ (20-40%), ↑↑ (41-60%), ↑↑↑ (>60%)

• Argatroban dosing requirements are much lower in patients with hepatic
dysfunction.
• Rivaroxaban’s AUC significantly increases in patients with Child-Pugh Class B
hepatic dysfunction.
• None of the DOAC agents is recommended to use in hepatic dysfunction as
these patients were excluded in clinical trials.
Elderly Patients
• Elderly patients have an increased prevalence of atrial fibrillation, and rates of
VTE also increase with age.
• Risk of bleeding may increase in elderly patients receiving anticoagulation due
to low body weight, altered body composition of fatty tissue or muscle, and
higher frequency of renal insufficiency.
TABLE 11-10: Use of DOACs in Elderly Patients2-5

Category Dabigatran Rivaroxaban Apixaban Edoxaban
Patients >75 15% of patients 16% of patients

years old in orthopedic in orthopedic
prophylaxis prophylaxis
40% of patients 38% of patients 31% of patients 41% of patients

in atrial treated for atrial treated for atrial treated for atrial
fibrillation trial fibrillation fibrillation fibrillation
9.9% of patients 16% of patients 13% of patients 14% of patients

treated for VTE treated for VTE treated for VTE treated for VTE
and 5.3% >80
years old
Manufacturer The risk of stroke In clinical trials, No clinically In clinical trials,

recommendation and bleeding the efficacy of significant the efficacy and
increases with rivaroxaban in differences safety in elderly
age, but the elderly patients in safety or (>65 years) and
risk−benefit (>65 years) effectiveness younger patients
profile is was similar to were observed were similar.
favorable in all that in younger in different age
age groups. patients. groups.
Thrombotic and
bleeding rates
were higher in
older patients,
but the risk−
benefit profile
was favorable in
all age groups.
DOAC: direct-acting oral anticoagulant, VTE: venous thromboembolism


• Dabigatran 150 mg BID has demonstrated decreased intracranial bleeding but
increased extracranial bleeding rates; however, the increased extracranial bleed-
ing rates are largely due to gastrointestinal bleeding in patients >75 years old
with atrial fibrillation compared to warfarin.49
• Rivaroxaban has significantly less bleeding in elderly patients treated for VTE.
• Apixaban displayed significantly reduced bleeding rates in patients with VTE
and atrial fibrillation.21,27
• DOAC agents are associated with lower rates of intracranial hemorrhage
compared to vitamin K antagonists (VKA).
• Dabigatran, rivaroxaban, and edoxaban are associated with a significant
increased risk of gastrointestinal bleeding when used for atrial fibrillation stroke
prevention.
• C
ontroversy surrounds the benefit of
anticoagulation in patients with atrial
fibrillation who are at a perceived increased risk
of falling. It has been estimated that a patient
must fall 295 times a year on warfarin before
risks of subdural hematoma outweigh benefits of
stroke prevention.50
• I n patients prone to falling, modifying the
anticoagulation approach should not be the only
consideration. Other factors such as medications
that may have promoted balance issues, or use of
afternoon diuretics that will result in having to go
to the bathroom late at night unassisted, should
also be considered. Obstacles that can lead to
tripping should be addressed and walking aids
promoted.
• C
onsider once-daily dosing of anticoagulants,
especially sub-Q administered agents like
enoxaparin, in patients who may have trembling
hands and may not be able to administer doses
appropriately.
• P
ill boxes may be beneficial because this
patient population is prone to forgetting to take
medications.
Obesity and Low Body Weight51-56

• The prevalence of obesity (body mass index [BMI] >30 kg/m2) has increased
substantially over recent years and has now reached 35% of adults in 2010.
• An increased BMI is recognized as a major risk factor for thrombotic disorders
such as cardiovascular disease, stroke, and VTE (especially pulmonary embolism
[PE]).
• Little evidence exists on whether or not a particular medication dose needs to
be increased in obese patients to allow for adequate concentrations to prevent
or treat thromboembolic disease and whether or not the dose should be capped
to prevent any unwanted bleeding from occurring.
• Patients >150 kg and <50 kg are largely underrepresented in clinical trials. With
population extremes, very small numbers of patients may have been involved
making it difficult to draw solid conclusions on observations.
• Total body weight is recommended for dosing LMWH.
• Capping doses of LMWH is not recommended for treatment of VTE.
TABLE 11-11: Maximum and Minimum Weights Studied in

Anticoagulant Clinical Trials
Agent Highest Weight Lowest Weight
Enoxaparin 196 kg 45 kg
Dalteparin 190 kg Unknown
Fondaparinux 215 kg Unknown
Tinzaparin 165 kg Unknown
Dabigatran 222 kg 32 kg
Rivaroxaban 209 kg 33 kg
Apixaban 210 kg 28.9 kg
Edoxaban NA NA
NA: not available

TABLE 11-12: Pharmacokinetics of Patients with Obesity or Low

Body Weight1-5,15-17
Drug Outcome Weights
Dalteparin Anti-Xa trough <20% IBW >40% IBW

↔ ↔
Enoxaparin Mean anti-Xa level <23 kg/m2

↑↑
Tinzaparin Mean Cl (L/hr) >30 kg/m2

↑
Fondaparinux Mean Cl (L/hr) <50 kg

↓
Dabigatran Steady-state concentration <50 kg >100 kg

(ng/mL/mg) ↑ ↓↓
Rivaroxaban <50 kg >120 kg

Cmax (ng/mL) ↑↑ ↔
AUC (mcg*h/L) ↔ ↔
T1/2 (hr) ↑ ↔
Apixaban <50 kg >120 kg

Cmax (ng/mL) ↑ ↓↓
AUC (mcg*h/L) ↔ ↓
T1/2 (hr) ↑ ↓
Edoxaban Total exposure 13% increase total

exposure in 55 kg
weight vs. 85 kg
weight
↑ (20−40%), ↑↑ (41−60%), ↑↑↑ (>60%), AUC: area under the curve, Cmax: maximum drug
concentration after a dose, IBW: ideal body weight, T1/2: half-life of a drug in (units of time)

• Fondaparinux has a flat dose−response curve so dose adjustments due to
obesity aren’t likely.
• There is a 30% higher dabigatran concentration in low-weight compared to
high-weight patients.
• Rivaroxaban demonstrates no real change in pharmacokinetics between patients
with extremes of weight.
• Apixaban demonstrates roughly a 50% decrease in AUC and t ½ in obese patients
compared to patients of low body weight.
• Apixaban has displayed consistent, reduced rates of bleeding in obese patients
compared to non-obese patients.
• Apixaban dose should be reduced in patients weighing <60 kg (if SCr is >1.5
mg/dL or age >80) who have atrial fibrillation.
• A reduced dose of edoxaban of 30 mg is recommended in patients with body
weight <60 kg for treatment of VTE.
• The International Society on Thrombosis and Haemostasis (ISTH) has recently
published guidance statements on the use of DOACs in obesity.57
{{ Standard dosing in patients with BMI ≤40 kg/m2 and weight ≤120 kg.
{{ DOACs should not be used in patients with a BMI >40 kg/m2 or
weight >120 kg.
Check drug-specific peak and trough levels if DOACs are
used in this patient population and if the trough is below
the expected range change to a vitamin K antagonist.
• Bariatric surgery may alter absorption, distribution, metabolism, or elimina-
tion of drugs secondary to changes in the gastrointestinal tract anatomy, body
weight, and adipose tissue change.58 Clinical data on DOACs following bariatric
surgery are nonexistent.
{{ Recommend using a vitamin K antagonist rather than DOACs.
{{ Check drug-specific peak and trough levels if DOACs are used after
bariatric surgery, and change to a vitamin K antagonist if levels are
above or below recommended ranges.
TABLE 11-13: Potential Dosing of LMWH in Morbidly Obese

Patients
Indication Dalteparin Enoxaparin Tinzaparin Fondaparinux Heparin
VTE 7,500 units 40 mg BID Not 2.5 once daily 7,500 units 3 x
prophylaxis daily indicated daily
VTE 200 units/kg 1 mg/kg 175 units/ 10 mg once 80 units/kg

treatment daily q12 hr kg daily daily bolus followed
by 18 units/
kg/hr
BID: twice daily, LMWH: low molecular weight heparin, q: every, units: International Units, VTE:
venous thromboembolism, x: times

• Enoxaparin 40 mg BID was significantly better than 30 mg BID in patients weigh-
ing >50 kg/m2 for VTE prophylaxis after bariatric surgery.59
• Once-daily dosing strategies with enoxaparin should be avoided in obese
patients with VTE based on observations of a notably higher recurrent throm-
bosis rate.60
• Capping doses of LMWH is not needed for treatment of VTE. In morbidly obese
individuals, life-threatening thrombosis and PE associated with obesity typically
outweighs the risk for bleeding. Some data suggest that the dalteparin dose
can be split into twice daily as an option.
• I ncreasing the prophylactic doses of LMWH may

be appropriate in morbidly obese patients (body
mass index 40 kg/m2).
• L
aboratory monitoring of LMWH could be
considered in patients with morbid obesity
(weight >190 kg). Peak anti-Xa levels should
be drawn 4 hours after sub-Q injection of
LMWH; however, the efficacy and safety of dose
adjustments have not been established.
• B
e aware of syringe size of LMWH when
choosing a dose in obese patients. Using
once-daily enoxaparin may not be practical in
patients >100 kg due to available doses and
required number of syringes to use, and it did not
appear as efficacious as twice-daily dosing in the
Merli study that led to market approval.60
Patients with Malignancy61-67

• VTE in patients with malignancy is secondary to a hypercoagulable state, and
patients with cancer have an increased risk of VTE especially in the first few
months after diagnosis. Although not all malignancies are associated with throm-
bosis, the overall risk of VTE is increased 7-fold in patients with a malignancy
and up to 28-fold in certain malignancies.
• VTE is the second most common cause of mortality in patients with cancer.
• Treatment guidelines for VTE in patients with cancer are available through
multiple national organizations (National Comprehensive Cancer Network
[NCCN]/American Society of Clinical Oncology [ASCO]/American College of
Chest Physicians [ACCP]). The guidelines generally recommend LMWH for the
initial treatment of VTE in patients with cancer.
• Extended duration of therapies are generally preferred over shorter durations
of therapy at least until cancer is in remission or surgically removed.
TABLE 11-14: Treatment Guidelines for the Management of VTE

in Patients with Cancer63-65
Category NCCN ASCO ACCP
Initial treatment LMWH is preferred LMWH is preferred LMWH over

therapy. over UFH for the VKA therapy is
initial 5–10 days in recommended in
newly diagnosed patients with DVT
VTE in patients with or PE.
cancer.
Recommended No preference of
agents: Recommended VKA over DOACs in
• Dalteparin agents: patients not receiving
• Enoxaparin • UFH LMWH.
• Fondaparinux • Dalteparin
• UFH • Enoxaparin
• Tinzaparin
• Fondaparinux
Long-term treatment LMWH is preferred LMWH for at least 6 Extended

for the first 6 months months is preferred anticoagulation is
as monotherapy over VKAs. recommended if the
without VKA. risk of bleeding is not
VKAs are acceptable high in patients with
VKA therapy with INR alternatives if LMWH DVT or PE.
value targeted at 2–3. is not available.
Use of novel oral

anticoagulants is not
recommended at this
time.
Recommended
agents:
• Dalteparin
• Enoxaparin
• Tinzaparin
• VKA
Duration Minimum of 3 months At least 6 months Recommend

extended
Indefinite Therapy beyond 6 anticoagulant therapy
anticoagulation if months considered over 3 months of
active cancer or in patients with therapy in patients
persistent risk factors. metastatic disease with DVT or PE.
or receiving
chemotherapy.
ACCP: American College of Chest Physicians, ASCO: American Society of Clinical Oncology,
DOAC: direct-acting oral anticoagulant, DVT: deep vein thrombosis, LMWH: low molecular
weight heparin, NCCN: National Comprehensive Cancer Network, PE: pulmonary embolism,
UFH: unfractionated heparin, VKA: vitamin K antagonist
TABLE 11-15: Cancer-Related Thromboembolism68,69

Two-Year Cumulative Incidence Relative Risk (95% CI)
Prostate Uterus Noncancer in patients: (1)

• Localized (1%) • Localized (1.2%) patients without cancer
• Regional (1.3%) • Regional (2.2%) Head/Neck—0.29 (0.2– 0.4)
Bladder—0.42 (0.36– 0.49)
• Remote (1.2%) • Remote (4.8%)
Breast—0.44 (0.40– 0.48)
Breast Bladder Esophagus—0.76 (0.58–0.97)
• Localized (0.8%) • Localized (0.9%) Cervix—0.90 (0.68–1.18)
• Regional (1.3%) • Regional (2%) Liver—0.92 (0.076–1.10)
• Remote (2.6%) • Remote (4.3%) Prostate—0.98 (0.93–1.04)
Lung Pancreas
Rectum—1.11 (1–1.22)
• Localized (1.3%) • Localized (3.2%)
Lung—1.13 (1.07–1.19)
• Regional (2.2%) • Regional (3%) Colon—1.36 (1.29–1.44)
• Remote (2.6%) • Remote (5.4%) Renal—1.41 (1.25–1.59)
Colon/Rectum Stomach Stomach—1.49 (1.33–1.68)
• Localized (1%) • Localized (2.3%) Lymphomas—1.80 (1.65–1.96)
Pancreas—2.05 (1.87–2.4)
• Regional (2.4%) • Regional (3.4%) Ovary—2.16 (1.93–2.41)
• Remote (2.9%) • Remote (4.4%) Leukemia—2.18 (2.01–2.37)
Melanoma Ovary Brain—2.37 (2.04–2.74)
• Localized (0.3%) • Localized (2.3%) Uterus—3.4 (2.97–3.87)
• Regional (0.9%) • Regional (3.4%)
• Remote (2.9%) • Remote (4.4%)
Non-Hodgkin Lymphoma Kidney
• Localized (1.5%) • Localized (1.3%)
• Regional (3.2%) • Regional (3.8%)
• Remote (2.1%) • Remote (3.5%)
*Patients without cancers, but with other medical conditions, were assumed to have a risk of 1 for
venous thromboembolism.
TABLE 11-16: Khorana Scale (Predictive Model for

Chemotherapy-Associated VTE)70
Patient Characteristic Risk Score*
• Site of cancer
• Very high risk (stomach, pancreas) 2
1
• High risk (lung, lymphoma, gynecologic, bladder, testicular)
• Prechemotherapy platelet count ≥350 x 109/L 1
• Hemoglobin level <10 g/dL or use of red cell growth factors 1
• Prechemotherapy leukocyte count >11 x 10 /L 9

1
• BMI ≥35 kg/m2 1
*Low risk, score = 0; Intermediate risk, score = 1–2; High risk, score = ≥3
BMI: body mass index, VTE: venous thromboembolism, x: times

• Patients with malignancy are at high risk for developing VTE with a score of ≥3
based on collection of simple variables.
• Patients with malignancy should be assessed for VTE risk at the time of chemo-
therapy initiation and periodically thereafter.
TABLE 11-17: Dosing of LMWH in Patients with VTE and

Malignancy71-79
Agent Dalteparin Enoxaparin Tinzaparin Fondaparinux
Dose 200 units/kg x 1 1 mg/kg q12h x 1 175 units/kg once 5 mg (wt <50 kg)
month month daily 7.5 mg (wt 50–100
kg)
150 units/kg daily 1.5 mg/kg once 10 mg (wt >100
thereafter daily thereafter is kg) once daily
an option
LMWH: low molecular weight heparin, units: International Units, VTE: venous thromboembolism

• Dalteparin has demonstrated significant reductions in VTE.
• LMWH trials have showed varying results in bleeding rates and mortality.
• The trial for enoxaparin in cancer was stopped for enrollment reasons. Several
trials have demonstrated inferior performance of once-daily enoxaparin for
acute VTE treatment, so the dosing regimen above is extrapolated from the
dalteparin trials.
• Subset analysis of DOACs has demonstrated lower rates of VTE and bleeding
compared to VKA; however, these have been nonsignificant changes.
• The Hokusai VTE Cancer trial assessing edoxaban and dalteparin showed
non-inferiority in the composite outcome, but the edoxaban group failed to
show a significant reduction in VTE while leading to a significant increase in
bleeding, especially GI bleeding.80
• L
MWH are the recommended agents to treat
VTE in patients with malignancy, as they have
demonstrated reductions in VTE compared to VKA.
• P
atients who receive PEG asparaginase may
experience a severe drop in antithrombin. If
they develop a VTE, they may not respond to
an antithrombin dependent anticoagulant until
antithrombin recovers. In such situations, a
DOAC may need to be considered.
• I n patients with Trousseau syndrome
(spontaneous or recurrent venous thrombosis),
heparin is the preferred anticoagulant of choice

(not VKA or DOACs) and should be continued
indefinitely because stopping for even 1 day can
result in recurrence of thrombosis.
• T
he use of VKAs in patients with malignancy
may have several limitations including drug
interactions with chemotherapeutic medications,
altered absorption and pharmacokinetics,
inability to take secondary to nausea, and need
for increased monitoring in patients with liver
metastasis.
• P
ractical issues in the long-term use of LMWH
include cost of the medication, ability of the
patient to administer parenteral or subcutaneous
medications, possible need for monitoring of
medication in certain patients, and the patient’s
quality of life.
• D
OAC agents have not been directly compared
to LMWH or to VKA specifically in patients
with malignancy, however, subset analysis of
several DOAC trials have assessed their role in
this patient population. In general, DOACs have
demonstrated similar rates in VTE recurrence
and bleeding compared to VKA; however, many
clinicians feel cancer-specific studies are needed
and that comparisons to long-term LMWH are
needed. In addition, the effects of the DOACs
on the chemotherapy regimen should also be
considered.

*1. Nutescu EA, Wittkowsky A, Dager WE. Low-molecular weight heparins in renal
impairment and obesity: available evidence and clinical practice recommendations
across medical and surgical settings. Ann Pharmacother. 2009;43:1064-1083.
2. Pradaxa® (dabigatran etexilate) [package insert]. Ridgefield, CT: Boehringer Ingelheim
Pharmaceuticals Inc.; April 2014.
3. Xarelto® (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.;
August 2014.
4. Eliquis® (apixaban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company;
August 2014.
5. Savaysa® (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc.;

Updated January 2015.
6. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban:
effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy.
2000;20(3):318-329.
7. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy.
2002;22:105s-111s.
8. Stangier J, Rathgen K, Stahle H, et al. Influence of renal impairment on the
pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label,
parallel-group, single-centre study. Clin Pharmacokinet. 2010;49:259-268.
9. Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the
pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor
Xa inhibitor. Br J Clin Pharmacol. 2010;70:703-712.
*10. Nutescu EA. Oral anticoagulation therapies: balancing the risks. Am J Health-Syst
Pharm. 2013;70(Suppl 1):S3-11.
11. Wang X, Song Y, Tirucheraiet G, et al. Apixaban pharmacokinetics in subjects with
end-stage renal disease on hemodialysis. Poster presented at: 2012 American College of
Clinical Pharmacology Annual Meeting. September 23-25, 2012; San Diego, CA.
12. Ridout G, de la Motte S, Niemczyk S, et al. Effect of renal function on edoxaban
pharmacokinetics and on population PK/PK-PD model [abstract]. J Clin Pharmacol.
2009;49:1124.
13. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with
warfarin in relation to renal function in patients with atrial fibrillation—insights from
the ARISTOTLE trial. Eur Heart J. 2012;33:2821-2830.
14. FDA briefing information, dabigatran etexilate mesylate capsules, for the September
20, 2010 meeting of the Cardiovascular and Renal Drugs Advisory Committee;
available online at: http://www.fda.gov/downloads/advisorycommittees/
committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/
ucm226009.pdf. Accessed June 1, 2015.
15. Fragmin® (dalteparin) [package insert]. Kirkland, Quebec: Pfizer; August 2014.
16. Arixtra® (fondaparinux) [package insert]. Mississauga, Ontario: GlaxoSmithKline Inc.;
July 2013.
17. Lovenox® (enoxaparin) [package insert]. Bridgewater, NJ: Sanofi-Aventis; October
2013.
18. Chen KE, Thadhani RI, Maddux FW. No difference in bleeding risk between
subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal
disease. Kidney International. 2013;84:555-561.
19. Prins MH, Lensing AWA, Brighton TA, et al. Oral rivaroxaban versus enoxaparin with
vitamin K antagonist for the treatment of symptomatic venous thromboembolism
in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup
analysis of two randomized controlled trials. Lancet Haematol. 2014;1:e37-46.
20. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of
symptomatic venous thromboembolism [supplementary appendix]. N Engl J Med.
2013;369:1406-1415.
21. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous
thromboembolism (supplementary appendix). N Engl J Med. 2013;368:699-708.
22. Pon TK, Dager WE, Roberts AJ, et al. Subcutaneous enoxaparin for therapeutic
23. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
24. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
25. Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with
rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation
and moderate renal impairment. Eur Heart J. 2011;32:2387-2394.
26. Giugliano RT, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with
27. Halvorsen S, Atar D, Yang H, et al. Efficacy and safety of apixaban compared with
warfarin according to age for stroke prevention in atrial fibrillation: observations from
the ARISTOTLE trial. Eur Heart J. 2014. doi:10.1093/eurheartj/ehu046.
28. Angiomax® (bivalirudin) [package insert]. Parsippany, NJ: The Medicines Company;
May 2013.
29. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators.
Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J
Med. 2006;354:1464-1476.
30. Kuhsner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines
for the management of patients with ST-elevation myocardial infarction (updating
the 2004 Guidelines and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on
Percutaneous Coronary Interventions (updating the 2005 Guideline and 2007 Focused
Update): a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. Circulation. 2009;120:2271-2306.
31. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the
management of patients with unstable angina/non ST-elevation myocardial infarction:
a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines: developed in collaboration with the American College of
Emergency Physicians, the Society of Cardiovascular Angiography and Interventions,
and the Society of Thoracic Surgeons: endorsed by the American Association of
Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency
Medicine. Circulation. 2007;116:e148-e304.
32. Kurtkoti J, Bose B, Hiremagalur B, et al. Arterial line versus venous line administration
of low molecular weight heparin, enoxaparin for prevention of thrombosis in the
extracorporeal blood circuit of patients on heamodialysis or haemodiafiltration—a
randomized cross-over trial. Nephrology. 2015. doi: 10.1111/nep.12681
33. Sagedal S, Hartmann A, Sundrtrom K, et al. Anticoagulation intensity sufficient for
hemodialysis does not prevent activation of coagulation and platelets. Nephrol Dial
Transplant. 2001;16:987-993.
34. Verhave G, Weijmer MC, van Jaarsveld BC. Anticoagulation with dalteparin and
nadroparin in nocturnal haemodialysis. Neth J Med. 2015;73:270-275.
35. Nigten J, de Groot KA, Grootendorst DC, et al. Pharmacokinetics of dalteparin during
haemodialysis. Nephron Clin Pract. 2013;124:179-183.
36. Sridharan S, Berdeprado J, Sivalingam M, et al. Dalteparin dosing in high-flux
haemodialysis and haemodiafiltration. Nephron Clin Pract 2012;122:53-57.
37. Saltissi D, Morgan C, Westhuyzen J, et al. Comparison of low-molecular-weight

heparin (enoxaparin sodium) and standard unfractionated heparin for haemodialysis
anticoagulation. Nephrol Dial Transplant. 1999;14:2698-2703.
38. McMahon LP, Chester K, Walker RG. Effects of different dialysis membranes on serum
concentrations of epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose during
dialysis. Am J Kidney Dis. 2004;44:509-516.
39. Naumnik B, Pawlak K, Mysliwiec M. Different effects of enoxaparin and unfractionated
heparin on some thrombogenesis markers during hemodialysis: a cross-over study.
Thromb Res. 2009;123:631-636.
40. Reeves JH, Graan M. Randomized controlled trial enoxaparin versus heparin in
continuous renal replacement therapy. Blood Purif. 2003;21:207.
41. Joannidis M, Kountchev J, Rauchenzauner M, et al. Enoxaparin vs. unfractionated
heparin for anticoagulation during continuous veno-venous hemofiltration: a
randomized controlled crossover study. Intensive Care Med. 2007;33:1571-1579.
42. Isla A, Gascon AR, Maynar J, et al. In vitro and in vivo evaluation of enoxaparin
removal by continuous renal replacement therapies with acrylonitrile and polysulfone
membranes. Clin Ther. 2005;27:1444-1451.
*43. Reeves JH, Cumming AR, Gallagher L, et al. A controlled trial of low-molecular-weight
heparin (dalteparin) versus unfractionated heparin as anticoagulant during continuous
venovenous hemodialysis with filtration. Crit Care Med. 1999;27:2224-2228.
44. Pon TK, Dager WE, Roberts AJ, et al. Subcutaneous enoxaparin for therapeutic
45. Stangier J, Staehle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of
dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate
hepatic impairment. J Clin Pharmacol. 2008;48:1411-1419.
46. Kubitza D, Roth A, Becka M, et al. Effect of hepatic impairment on the
pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban-an oral, direct
Factor Xa inhibitor [poster]. Presented at the XXI Congress of the International Society
of Thrombosis and Haemostasis (ISTH). Geneva, Switzerland; July 6-12, 2007.
47. Frost C, Yu Z, Wang J, et al. Single-dose safety and pharmacokinetics of apixaban in
subjects with mild or moderate hepatic impairment. Presented at: The 2009 American
Society for Clinical Pharmacology and Therapeutics Annual Meeting. March 18-21,
2009. National Harbor, MD: poster PI-84.
48. Mendell J, Johnson L, Chen S. On open-label, phase 1 study to evaluate the effects
of hepatic impairment on edoxaban pharmacokinetics and pharmacodynamics. J
Pharmacol. 2015; epub ahead of print doi: 10.1002/jcph.550.
49. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of
dabigatran compared with warfarin in older and younger patients with atrial
fibrillation. An analysis of the Randomized Evaluation of Long-Term Anticoagulant
Therapy (RE-LY) Trial. Circulation. 2011;123:2363-2372.
50. Donze J, Clair C, Hug B, et al. Risk of falls and major bleeds in patients on oral
anticoagulation therapy. Am J Med. 2012;125:773-778.
51. Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol.
2013;20:437-444.
52. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the
safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-
7939) in healthy subjects. J Clin Pharmacol. 2007;47:218-226.
53. Turpie AGG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous
thromboembolism after hip or knee arthroplasty. Thromb Haemost. 2011;105:444-
453.
54. Upreti VV, Wang J, Barrett Y, et al. Effect of body weight on the single-dose
pharmacokinetics of apixaban. Presented at: The 39th Annual Meeting of the American
College of Clinical Pharmacology. September 12-14, 2010. Baltimore, MD: poster 016.
55. Pineo GF, Gallus AS, Raskob GE, et al. Apixaban after hip or knee arthroplasty
versus enoxaparin: efficacy and safety in key clinical subgroups. J Thromb Haemost.
2013;11:444-451.
56. Sandhu R, Ezekowitz J, Andersson U, et al. Body mass index and outcomes with
apixaban versus warfarin in patients with atrial fibrillation in the ARISTOTLE trial.
Presented at: The 64th American College of Cardiology Annual Scientific Session &
Expo; March 14-16, 2015; San Diego, CA.
*57. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants
in obese patients: guidance from the SSC of the ISTH. Journal of Thrombosis and
Haemostasis. 2016;14:1308-1313.
*58. Martin KA, Lee CR, Farrell TM, Moll S. Oral anticoagulant use after bariatric surgery:
a literature review and clinical guidance. The American Journal of Medicine. 2017;
http://dx.doi.org/:10.1016/j.amjmed.2016.12.033.
59. Rowan BO, Kuhl DA, Lee MD, et al. Anti-Xa levels in bariatric surgery patients
receiving prophylactic enoxaparin. Obes Surg. 2008;18:162-166.
60. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice
daily compared with intravenous unfractionated heparin for treatment of venous
thromboembolic disease. Ann Intern Med. 2001;134(3):191-202.
61. Blom JW, Doggen CJM, Osanto S, et al. Malignancies, prothrombotic mutations, and
the risk of venous thrombosis. JAMA. 2005;293:715-722.
62. Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br
J Cancer. 2010:102(suppl 1):S2-S9.
63. Bick RL. Cancer-associated thrombosis. N Engl J Med. 2003;349:109-111.
64. Devita VT, Lawrence TS, Rosenberg SA. Devita, Hellman & Rosenberg’s Cancer:
Principles & Practice of Oncology. 8th ed. Philadelphia, PA: Lippincott, Williams &
Wilkins; 2008.
65. National Comprehensive Cancer Network. Clinical practice guidelines in oncology
venous thromboembolic disease version 2.2014. Available at: http://www.nccn.org/
professionals/physician_gls/pdf/vte.pdf. Accessed May 31, 2015.
66. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis
and treatment in patients with cancer: American Society of Clinical Oncology clinical
practice guideline update. J Clin Oncol. 2013;31:2189-2204.
67. Kearon C, Akl EA, Omelas J, et al. Antithrombotic therapy for VTE disease. CHEST
68. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its
effect on survival among patients with common cancers. Arch Intern Med. 2006 Feb
27;166(4):458-464.
69. Thodiyil PA, Kakkar AK. Variation in relative risk of venous thromboembolism in
different cancers. Thromb Haemost 2002;87:1076-1077.
70. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a
predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-
4907.
71. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin
and warfarin for the secondary prevention of venous thromboembolism in patients with
cancer. Arch Intern Med. 2002;162:1729-1735.
*72. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin
for the prevention of recurrent venous thromboembolism in patients with cancer. N
Engl J Med. 2003;349:146-153.
73. Deitcher SR, Kessler CM, Merli G, et al. Secondary prevention of venous
thromboembolic events in patients with active cancer: enoxaparin alone versus
initial enoxaparin followed by warfarin for a 180-day period. Clinical and Applied
Thrombosis/Hemostasis. 2006;12:389-396.
74. Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin
versus usual care in proximal-vein thrombosis patients with cancer. Am J Med.
2006;119:1062-1072.
75. Van Doormal FF, Raskob GE, Davidson BL, et al. Treatment of venous
thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical
trials. Thromb Haemost. 2009;101:762-769.
76. Schulman S, Eriksson H, Goldhaver SZ, et al. Influence of cancer on the efficacy
and safety of dabigatran vs. warfarin for the acute and extended treatment of venous
thromboembolism. Presented at the International Conference on Thrombosis and
Hemostasis Issues in Cancer. May 11, 2014.
77. Raskob GE, Buller H, Angchaisuksiri P, et al. Edoxaban for the long-term treatment of
venous thromboembolism in cancer patients. Blood. 2013;122:211.
78. Wun T, White RH. Epidemiology of cancer-related venous thromboembolism. Best
Pract Res Clin Haematol. 2009;22(1):9-23.
79. Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs. warfarin for treatment
of acute venous thromboembolism in patients with active cancer. JAMA.
2015;314(7):677-686.
80. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-
associated venous thromboembolism. N Engl J Med. 2018;378(7):615-624.
PART II.
CONDITIONS REQUIRING
ANTICOAGULATION
THERAPY
12. Venous Thromboembolism Prevention
13. Venous Thromboembolism Treatment
14. Atrial Fibrillation
15. Acute Coronary Syndromes
16. Prosthetic Heart Valves
17. Mechanical Circulatory

Support Devices
18. Heparin-Induced
Thrombocytopenia
19. Pregnancy
20. Pediatrics
281
12 Chapter
VENOUS THROMBOEMBOLISM
PREVENTION
Paul P. Dobesh and Kelsey Aker
INTRODUCTION
Venous thromboembolism (VTE), which encompasses both deep vein thrombosis
(DVT) and pulmonary embolism (PE), is a significant healthcare problem produc-
ing considerable morbidity, mortality, and resource utilization. In the United
States alone, over a million DVT events and more than 100,000 deaths per year
are attributed to PE. These events occur in a wide range of both surgical and
medical patients. With appropriate prophylaxis, many of these VTE events can be
prevented. Despite more than 30 years of demonstrated efficacy and safety of VTE
prophylaxis, it is substantially underutilized. This underutilization has led to the
recent involvement of government and other regulatory agencies in an attempt to
improve VTE prophylaxis for both surgical and medical patients in U.S. hospitals.
Numerous pharmacologic agents, clinical trials, and nationally recognized clinical
guidelines (Table 12-1) as well as limited data in special populations can provide
challenges to understanding what constitutes appropriate VTE prophylaxis.1
283
TABLE 12-1: Venous Thromboembolism Prevention Guidelines

and Resources
Guideline/Resource Web Link
American College of http://journal.publications.chestnet.org/article.

Chest Physicians (CHEST aspx?articleid=1085923
Guidelines)2-4
Surgical Care Improvement http://www.jointcommission.org/specifications_manual_for_

Project (SCIP) national_hospital_inpatient_quality_measures.aspx
Agency for Healthcare http://www.ahrq.gov/qual/vtguide/

Research and Quality (AHRQ)
The Joint Commission http://www.jointcommission.org/venous_thromboembolism/
Deep Vein Thrombosis http://www.preventdvt.org/home.aspx

Coalition
American Academy of http://www.aaos.org/research/guidelines/VTE/VTE_full_

Orthopedic Surgeons (AAOS) guideline.pdf
American Society of Clinical http://jco.ascopubs.org/content/early/2015/01/20/

Oncology (ASCO)5 JCO.2014.59.7351.full
National Comprehensive http://www.jnccn.org/content/9/7/714.short

Cancer Network (NCCN) http://www.nccn.org/professionals/physician_gls/pdf/vte.pdf
VENOUS THROMBOEMBOLISM PREVENTION 285
Rates and Risk Factors for Venous Thromboembolism

See Tables 12-2–12-6.
TABLE 12-2: Approximate Risk of VTEa in Different Hospitalized

Patient Populations6
Patient Group DVT Prevalence without Prophylaxis
Medically ill patients 10–20%

• Heart failure
• Chronic obstructive pulmonary disease
• Infection
General surgery 15–40%
Major gynecologic surgery 15–40%
Major urologic surgery 15–40%
Neurosurgery 15–20%
Stroke 20–50%
Major orthopedic surgery 40–60%

• Total hip replacement surgery 57%
• Hip fracture surgery 60%
• Total knee replacement surgery 84%
Major trauma 40–80%
Spinal cord injury patients 60–80%
Critical care patients 10–80%
Rates of deep vein thrombosis (DVT) are determined by venography.

a
TABLE 12-3: Levels of Thromboembolic Risk as Classified by

ACCP6
Level of Risk Approximate DVT Risk
without Prophylaxis*
Low risk <10%

Minor surgery in mobile patients
Medical patients that are fully mobile
Moderate risk 10–40%

Most general, open gynecologic or urologic surgery patients
Medical patients, bed rest or sick
High risk 40–80%

Hip or knee replacement surgery, hip fracture surgery
Major trauma, spinal cord injury
*Many incidence rates with surgical procedures are classical data. With advances in technology
and a lack of randomized controlled trials, current rates are unknown but would likely decrease as
surgical techniques improve.
ACCP: American College of Chest Physicians
TABLE 12-4: Venous Thromboembolism Risk Factors

• Age >40 years
• Surgery
• Major trauma or lower-extremity injury
• Immobility, lower extremity paresis
• Cancer (active or occult)
• Cancer therapy
{{ Hormonal therapy
{{ Chemotherapy
{{ Angiogenesis inhibitors
{{ Radiation therapy
• Pregnancy and the postpartum period
• Paroxysmal nocturnal hemoglobinuria
• Myeloproliferative disorders
• Inflammatory bowel disease
• Acute medical illness
{{ Heart failure
{{ Respiratory disease
{{ Infection
{{ Stroke
• Central venous catheterization
• Smoking
• Varicose veins
• Medications
{{ Estrogen-containing oral contraceptives
{{ Hormone replacement therapy
{{ Selective estrogen receptor modulators
{{ Erythropoiesis-stimulating agents
{{ Recent concentrated clotting factors
• Inherited or acquired thrombophilia; see Chapter 22
• Obesity
• Previous/history of venous thromboembolism
• Venous compression (tumor, hematoma, arterial abnormality)
TABLE 12-5: Validated Risk Score for Prediction of Cancer-

Associated Thromboembolism7
Predictive Variables Risk Score
Site of Cancer Very high risk (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic) 1
Pre-chemotherapy platelet count 1

≥350,000/mm3
Hemoglobin <10 g/dL or use of 1

red cell growth factors
Pre-chemotherapy leukocyte count 1

>11,000/mm3
Body mass index ≥35 kg/m2 1
Risk Score Risk Level Estimated Rate of VTE

at 2.5 Months
0 Lower risk 0.5%
1–2 Intermediate risk 2%
>3 High risk 7%
• T
he incidence of VTE increases as the cancer
stage advances (local, regional, and remote).
• T
he incidence of VTE is higher within 3–6
months of the diagnosis of cancer.
TABLE 12-6: Venous Thromboembolism Systematic Prophylaxis

Strategies
Tool Description
Risk-scoring forms Match risk level with appropriate prophylactic strategy.
Electronic alerts Electronic medical record requires response to prophylactic

screening before proceeding; daily reports for high-risk
patients not on prophylaxis.
Default prophylaxis strategy All patients receive prophylaxis with efforts placed on
identifying contraindications rather than indications.
Opt-out approach May be considered in the following clinical scenarios:

• Healthy, fully ambulatory, <40 yr
• Immobility/length of stay estimated <2 days
• Warfarin with INR >1.4 or on therapeutic anticoagulation
• Imminent invasive procedure
• Recent intraocular or intracranial surgery
• Spinal tap or epidural anesthesia within 12 hr
• Thrombocytopenia
• History of HIT/hypersensitivity to UFH or LMWH
• Active bleeding
• Active or chronic severe liver disease
• Comfort care/hospice
HIT: heparin-induced thrombocytopenia, INR: international normalized ratio, LMWH: low

molecular weight heparin, UFH: unfractionated heparin
Nonpharmacological Prophylaxis Options

See Tables 12-7–12-9 and Figures 12-1–12-3.
TABLE 12-7: Nonpharmacological Prophylaxis Options

Option Description
TED hose Stocking without a compression gradient.
Graduated compression Stockings with a gradual decline in pressure from the distal to the
stocking proximal end.
Intermittent pneumatic A microprocessor directs pressurized air into segmental

compression device diaphragms secured around the leg for a fixed period of time.
The compression is delivered in a sequential manner up the leg,
producing a wavelike milking effect to evacuate leg veins.
IVC filter Medical device implanted into the inferior vena cava to catch
emboli.
IVC: inferior vena cava, TED: thromboembolic disease

SIZE ANKLE CALF THIGH HIP
S 7˝– 81/4 ˝ (18–21 cm) 11˝– 15˝ (28–38 cm) 15 3/4˝– 24 3/8˝ (40–62 cm) 28˝– 46˝ (71–117 cm)
M 8 3/8˝– 9 7/8˝ (21–25 cm) 117/8 ˝– 16 1/2˝ (30–42 cm) 181/8 ˝– 271/2 ˝ (46–70 cm) 30˝– 50˝ (76–127 cm)
L 10˝– 113/8 ˝ (25–29 cm) 12 1/2˝– 18 1/8˝ (32–46 cm) 211/4 ˝– 303/4 ˝ (54–78 cm) 32˝– 54˝ (81–137 cm)
XL 111/2 ˝– 13˝ (29–33 cm) 13 3/8˝– 195/8 ˝ (34–50 cm) 23 5/8˝– 32˝ (60–81 cm) 40˝– 65˝ (102–166 cm)
FIGURE 12-1. Custom Fit Graduated Stocking Measurements

Source: Figure is courtesy of JOBST, Inc. Used with permission.
• I t may be easier to wear the stockings if the

patient lies down and elevates each leg above the
heart for several minutes to reduce swelling.
• G
raduated stockings should be placed first thing
in the morning.
• R
ubber gloves may be used to help get a better
grip on the stocking fabric.
• C
ornstarch or grease-free talcum can be used in
patients with moist skin to pull stocking up.
• N
ever fold or roll the graduated stocking down—
the garment becomes a tourniquet.
• S tocking may not fit after (1) weight loss or
gain or (2) changes in leg swelling. A stocking
that falls or wrinkles on its own is too large and
should be refitted.
• S tockings should be replaced every 3–6 months as
the stocking may lose its elasticity over time.
• F
ollow-up is very important in patients
prescribed graduated stockings. Monitoring the
proper use of the stocking should occur daily for
the inpatient setting and at each office visit for
the outpatient setting.
Firm Support- 30–40 mm Hg
Moderate Support- 20–30 mm Hg
Mild Support- 15–20 mm Hg
Light Support- 8–15 mm Hg
Compression Guide
Light Support- 8–15 mm Hg
Recommended for minor ankle and leg swelling, minor

varicosities, pregnancy, and general leg fatigue. A
light energizing compression.
Mild Support- 15–20 mm Hg
Mild support is frequently recommended for minor ankle

and leg swelling, minor varicosities, and leg fatigue.
Great for traveling and those who sit or stand for long
periods of time.
Moderate Support- 20–30 mm Hg
Recommended for moderate ankle and leg swelling,

moderate varicosities, venous stasis ulcerations,
postschlerotherapy, and preventing DVT.
Firm Support- 30–40 mm Hg
Recommended for severe ankle and leg swelling,

severe varicosities, post-thrombotic syndrome, venous
stasis ulcerations, lymphadema, and preventing DVT.
FIGURE 12-2. Compression Guide

Figure is courtesy of JOBST, Inc. Used with permission.
TABLE 12-8: Inferior Vena Cava Filters

Indications Contraindications Complications
• PE when anticoagulant • Chronically thrombosed • Migration of the filter

therapy is inferior vena cava (slippage or fracture) to
contraindicated • Inaccessible inferior vena the heart
• Failure of anticoagulant cava • Penetration of vena cava
therapy in • Patients at risk for septic wall into vascular or
thromboembolic disease embolism gastrointestinal systems
• Emergency treatment • Caval occlusion
following massive PE • Puncture site bleeding
where anticipated
benefits of conventional
therapy are reduced
• Chronic, recurrent PE
where anticoagulant
therapy has failed or is
contraindicated
• Massive trauma
(including a GCS
score <8, incomplete
spinal cord injury
with paraplegia or
quadriplegia, complex
pelvic fractures
associated with long
bones, or multiple long
bone fractures)
The PREPIC trial, an 8-year follow-up study, was designed to assess the long-term safety and
efficacy of permanent vena cava filter insertion in patients with a diagnosis of acute proximal DVT
and considered high risk for the development of PE.8 Filter insertion resulted in a number needed
to treat of 12 to prevent one PE, but was offset by a number needed to harm of 10 for causing
one DVT (it increased the rate of DVT). No difference in post-thrombotic syndrome or mortality
was observed between patients with or without a permanent filter.
In the PREPIC 2 trial, a 3-month use of a retrievable vena cava filter with anticoagulation in
patients with acute symptomatic PE did not reduce recurrent PE at 3 or 6 months compared to
anticoagulation alone in patients presenting with acute PE (3% filter vs. 1.5% no filter; p=0.50).9
No differences were detected in the incidence in symptomatic DVT, major bleeding, or mortality
at 3 or 6 months.
DVT: deep vein thrombosis, GCS: graduated compression stockings, PE: pulmonary embolism
FIGURE 12-3. IVC Filter Placement

Source: Image courtesy of Amicus Visual Solutions, Used with permission.
TABLE 12-9: Inferior Vena Cava Filter Comparisons

Types Permanent (P) or Maximum IVC MRI Alloy
Retrievable (R) Diameter Compatible
Bird’s Nest Filter P 40 mm Yesa Stainless

(Cook Medical) steel
VenaTech Low Profile P 35 mm Yes Phynox

Filter
(B. Braun Vena Tech)
Nitinol TrapEase Filter P 30 mm Yes Nitinol

(Cordis Endovascular)
OptEase R 30 mm Yes Nitinol

(Cordis Endovascular)
Gunther Tulip Filter R 30mm Yes Conichrome

(Cook Medical)
Celect P 30 mm Yes Conichrome

(Cook Medical)
VenaTech LGM Filter P 28 mm Yes Phynox

(B. Braun Vena Tech)
Simon Nitinol Filter P 28 mm Yes Nitinol

(C. R. Bard)
Titanium Greenfield P 28 mm Yes Titanium

Filter
(Boston Scientific)
Stainless-Steel P 28 mm Yesa Stainless

Greenfield Filter steel
(Boston Scientific)
Denali Vena Cava R 28 mm Yes Nickel-

Filter (BARD Peripheral titanium
Vascular)
Eclipse Vena Cava R 28 mm Yes Nitinol

Filter (BARD Peripheral
Vascular)
Opton ELITE (Argon R 30 mm Yes Nitinol

Medical Devices, Inc)
a
No displacement due to the magnetic field has been demonstrated with MRI, but the metallic
component causes an imaging artifact.
• R
etrievable filters must be rotated or removed
within 2 weeks or they become permanently
affixed to the IVC wall.
• T
he presence of a clot within a temporary filter,
at the time of retrieval, may result in permanent
placement.
• O
nce the contraindication for anticoagulation has
been resolved, concomitant use of warfarin should
be considered in patients with permanent filters.
• F
ilter retrieval does not require interruption of
anticoagulation.
• M
RI procedures should be postponed for 6 weeks
following implantation to ensure incorporation
into vessel wall.
• P
atients with IVC filters requiring restraints who
are combative should not have restraints over
their abdomen in the region of the filter to prevent
dislodging.
• W
hen retrievable filters are used for temporary
primary or secondary VTE prevention, a system
of care should be in place to assure they are
removed in a timely manner.
VTE Prophylaxis in Medically Ill Patients

See Table 12-10.
TABLE 12-10: VTE Prophylaxis in Medically Ill Patients

UFH Enoxaparin Dalteparin Tinzaparin Fondaparinux Warfarin
5,000 units sub-Q 40 mg 5,000 units Insufficient 2.5 mg sub-Q Insufficient

q 8 hr or sub-Q q sub-Q q evidence q 24 hr* evidence
5,000 units sub-Q 24 hr 24 hr
q 12 hr
*Not approved by the U.S. FDA.

q: every, sub-Q: subcutaneous, UFH: unfractionated heparin, units: International Units, VTE:
venous thromboembolism
• N
umerous clinical trials have not demonstrated
efficacy with the use of UFH 5,000 units every
12 hours and, therefore, UFH 5,000 units every 8
hours would be the preferred UFH regimen.10
• A lthough not evidence-based, UFH 5,000 units
every 12 hours may be considered in individuals
of advanced age and low weight (i.e., TBW <50
kg) or elevated baseline aPTT (>1.3 or 1.4 x
baseline).
• E
noxaparin 20 mg once daily has been evaluated
and is not more effective compared to placebo.10
• E
noxaparin 20 mg once daily has demonstrated
equal efficacy compared to UFH 5,000 units every
12 hours.10
• I n head-to-head trials between UFH 5,000 units
every 8 hours and enoxaparin 40 mg daily, the
regimens have demonstrated similar efficacy,
except for higher-risk medically ill patients (heart
failure and ischemic stroke) in which enoxaparin
seems to demonstrate greater protection against
VTE. In these same trials, enoxaparin has
demonstrated significantly less hematoma (>5
cm) compared to UFH. Although some data
suggest a lower bleeding rate with the use of
LMWH in medically ill patients, these findings
are not consistent across trials.11
• B
oth apixaban (2.5 mg twice daily) and
rivaroxaban (10 mg once daily) have been
evaluated in medically ill patients.12,13 Both
trials evaluated 6–14 days of enoxaparin 40
mg once daily to about a month of apixaban
or rivaroxaban. Both trials demonstrated
significant increases in major bleeding with
nominal benefit. Betrixaban 80 mg once daily,
after a 160 mg loading dose, demonstrated
reductions in VTE without a significant increase
in major bleeding.14 Betrixaban was approved by
the FDA in June 2017. For more information on
betrixaban (Bevyxxa), please see Appendix N.
VTE Prophylaxis in Nonorthopedic Surgery Patients

See Table 12-11.
TABLE 12-11: VTE Prophylaxis in General Surgery

Surgical VTE Prophylaxis in General Surgery
Indication
UFH Enoxaparin Dalteparin Tinzaparin Fondaparinux
General surgery 5,000 units 40 mg 5,000 units 3,500 units 2.5 mg sub-Q
sub-Q q 8 hr or sub-Q sub-Q q sub-Q q 24 hr
5,000 unit q 24 hr 24 hr* q 24 hr
sub-Q q 12 hr
Neurosurgery 5,000 units 40 mg Insufficient Insufficient Insufficient

sub-Q q 8 hr sub-Q q evidence evidence evidence
24 hr
Vascular surgery 5,000 units 40 mg 5,000 units 3,500 units 2.5 mg sub-Q
sub-Q q 8 hr or sub-Q q sub-Q q sub-Q q q 24 hr
5,000 units 24 hr 24 hr* 24 hr
sub-Q q 12 hr
Gynecologic 5,000 units 40 mg 5,000 units 3,500 units 2.5 mg sub-Q

sub-Q q 8 hr or sub-Q sub-Q sub-Q q 24 hr
5,000 units q 24 hr q 24 hr* q 24 hr
sub-Q q 12 hr
Urologic 5,000 units 40 mg 5,000 units 3,500 units 2.5 mg sub-Q

5,000 units q 24 hr q 24 hr* q 24 hr
sub-Q q 12 hr
Laparoscopic Patients undergoing laparoscopic procedures without additional VTE risk

factors do not require prophylaxis beyond early ambulation.
Bariatric 5,000 units 40 mg 7,500 units Insufficient 2.5 mg sub-Q

sub-Q q 8 hr sub-Q sub-Q evidence q 24 hr
q 12 hr q 24 hr
Thoracic 5,000 units 40 mg 5,000 units 3,500 units 2.5 mg sub-Q

5,000 units q 24 hr q 24 hr q 24 hr
sub-Q q 12 hr
Coronary bypass 5,000 units 40 mg 5,000 units 3,500 units Not discussed
surgery sub-Q q 8 hr or sub-Q sub-Q sub-Q in current
5,000 units q 24 hr q 24 hr q 24 hr guidelines
sub-Q q 12 hr
*Different strategies on when to initiate dalteparin after surgery have been studied. Please see
the dalteparin package labeling for more details.
q: every, sub-Q: subcutaneous, units: International Units
• General surgery
{{ Meta-analysis comparisons between UFH
and LMWHs demonstrate comparative
efficacy in preventing DVT, but a greater
reduction in the incidence of PE when a
LMWH is used.15
{{ Mechanical prophylaxis is sometimes
inappropriately selected over pharmacologic
prophylaxis due to concerns of bleeding in
surgical patients. A meta-analysis of almost
34,000 surgical patients demonstrated that
the most common bleeding complications
are injection site bruising (6.9%) and
wound hematomas (5.7%). Major bleeding
complications in <1% of patients.16
Gastrointestinal bleeding: 0.2%
Retroperitoneal bleeding: 0.08%
Surgery needed for bleeding: 0.7%
• Neurosurgery
{{ Pharmacologic prophylaxis is typically
given with mechanical prophylaxis, and the
combination has been demonstrated to be
equally safe and more effective compared to
mechanical prophylaxis alone.
{{ Pharmacologic prophylaxis is typically
started 18-24 hours after neurosurgery.
• Vascular surgery
{{ Routine prophylaxis is recommended for
patients with additional risk factors such as
advanced age, limb ischemia, long duration
of surgery, and intra-operative local trauma.
{{ Due to the limited number of trials in
patients with vascular surgery, dosing
recommendations are based on evidence of
pharmacologic agents in general surgery.
• Gynecologic surgery
{{ Low-risk gynecologic surgery procedures
(laparoscopic procedures or procedures
lasting <30 minutes) do not require
prophylaxis beyond early ambulation.
{{ Major surgery without malignancy should
receive UFH or a LMWH.
• Gynecologic cancer surgery
{{ UFH three x daily is more effective than twice
daily. UFH three x daily and a LMWH seem
to have similar efficacy and safety.
{{ In a subgroup analysis of a general surgery
trial, fondaparinux was more effective than
dalteparin in patients undergoing surgery for
cancer.17
• Urologic surgery
{{ Patients undergoing transurethral or
laparoscopic urologic procedure do
not require prophylaxis beyond early
ambulation.
patients undergoing urologic surgery, dosing
• Bariatric surgery
{{ Higher than recommended doses of LMWH
and UFH are needed. UFH three x daily and
enoxaparin 40 mg twice daily have been
evaluated.18 Dalteparin 7,500 units daily has
been evaluated in a retrospective study using
anti-Xa levels.
• Thoracic surgery
patients undergoing thoracic surgery, dosing
• Coronary bypass surgery

patients undergoing coronary artery bypass
surgery, dosing recommendations are based
on evidence of pharmacologic agents in
general surgery.
{{ Due to concerns about higher incidence of
HIT in cardiac surgery patients, a LMWH
may be preferred over UFH for prophylaxis.
VTE Prophylaxis in Orthopedic Surgery

See Table 12-12.
• U
FH has consistently demonstrated insufficient
protection against VTE in patients undergoing
orthopedic surgery and, therefore, should not
be considered an acceptable alternative to the
options listed below.
• A lthough aspirin has a recommendation from
the ACCP and the American Association of
Orthopedic Surgeons (AAOS) guidelines, the
recommendation is based on a single study with
multiple limitations.4,19,20
• P
atients placed on mechanical prophylaxis after
surgery due to high risk of bleeding should have
their risk of bleeding consistently reassessed, with
pharmacologic prophylaxis started as soon as the
bleeding risk is decreased.
• P
atients undergoing knee arthroscopy typically
do not need VTE prophylaxis beyond early
mobilization, unless they have additional VTE
risk factors or have a complicated procedure.
In those cases, patients should receive VTE
prophylaxis with a LMWH.
• D
alteparin has not been evaluated in a published
prospective trial for VTE prophylaxis in knee
replacement surgery.
TABLE 12-12: VTE Prophylaxis in Orthopedic Surgery
Orthopedic VTE Prophylaxis in Orthopedic Surgery
Indication
Enoxaparin Dalteparin Tinzaparin Fondaparinux Warfarin Dabigatran Rivaroxaban Apixaban
Knee 30 mg sub-Q q 2,500 units sub-Q 75 units/kg sub-Q 2.5 mg sub-Q q Initiated pre- 110 mg initiated 10 mg once 2.5 mg
replacement 12 hr initiated given 6–8 hr after q 24 hr initiated 24 hr initiated operatively or the 1–4 hr after daily initiated twice daily,
surgery 12–24 hr after surgery, then 5,000 the evening 6–8 hr after evening of the surgery, then 6–10 hr after initiated
surgery units sub-Q q 24 hr* prior to surgery surgery surgical day with 220 mg once surgery 12–24 hr
or 12–24 after adjusted-dosing to daily* after surgery
surgery* achieve a target INR
of 2.5 ± 0.5
Hip 30 mg sub-Q q 2,500 units sub-Q 75 units/kg sub-Q 2.5 mg sub-Q q Initiated pre- 110 mg initiated 10 mg once 2.5 mg
replacement 12 hr initiated given 4–8 hr after q 24 hr initiated 24 hr initiated operatively or the 1–4 hr after daily initiated twice daily,
surgery 12–24 hr after surgery, then 5,000 the evening prior 6–8 hr after evening of the surgery, then 6–10 hr after initiated
surgery units sub-Q q 24 hr to surgery or 12– surgery surgical day with 220 mg once surgery 12–24 hr
or or 24 hr after surgery* adjusted-dosing to daily after surgery
40 mg sub-Q q 5,000 units sub-Q or achieve a target INR
24 hr initiated q 24 hr initiated the 4500 units sub-Q of 2.5 ± 0.5
10–12 hr prior evening prior to q 24 hr initiated 12
to surgery surgery hr prior to surgery*
Hip fracture 30 mg sub-Q q Insufficient evidence Insufficient 2.5 mg sub-Q q Initiated pre- Insufficient Insufficient Insufficient
surgery 12 hr initiated evidence 24 hr initiated operatively or the evidence evidence evidence
12–24 hr after 6–8 hr after evening of the
surgery* surgery surgical day with
adjusted-dosing to
achieve a target INR
of 2.5 ± 0.5
Orthopedic VTE Prophylaxis in Orthopedic Surgery
Indication
Enoxaparin Dalteparin Tinzaparin Fondaparinux Warfarin Dabigatran Rivaroxaban Apixaban
Spine Pharmacologic prophylaxis is generally not recommended unless patients have addition risk factors of advanced age, malignancy, neurologic deficit,
surgery previous VTE, or an anterior surgical approach. Based on the lack of clinical trials, pharmacologic prophylaxis recommendations are general and include
sub-Q UFH or a LMWH.
LMWH: low molecular weight heparin, q: every, sub-Q: subcutaneous, UFH: unfractionated heparin, units: International Units, VTE: venous thromboembolism
*Not approved by the U.S. FDA.
• D
abigatran is now available in the United States
for VTE prevention in patients undergoing hip
replacement surgery, but not for knee replacement
surgery. Dabigatran was found to be inferior
to enoxaparin 30 mg twice daily in patients
undergoing knee replacement surgery.21
• R
ivaroxaban has demonstrated a superior
reduction in VTE events compared to enoxaparin
40 mg once daily in hip replacement surgery and
enoxaparin 40 mg once daily and enoxaparin
30 mg twice daily in knee replacement surgery.
Although major bleeding was not significantly
increased in these studies, it should be noted that
the definition of major bleeding did not include
surgical site bleeding (considered non-major
bleeding).
• A pixaban has demonstrated a superior reduction
in VTE events compared to enoxaparin 40 mg
once daily in hip and knee replacement surgery
with no significant increase in major bleeding.
Apixaban was not non-inferior to enoxaparin
30 mg twice daily in knee replacement surgery,
although the event rates were similar (9%
apixaban vs. 8.8% enoxaparin).22 Although no
difference in major bleeding was observed, the
combination of major and clinically relevant
nonmajor bleeding was significantly reduced with
the use of apixaban.22
• T
iming of initiation of VTE prophylaxis after
surgery is an important and complicated issue.
The risk of thromboembolic events begins
immediately after surgery; therefore, VTE
prophylaxis is generally more effective when
started earlier rather than later. The challenge
comes in that early VTE prophylaxis is also
associated with increased bleeding compared to
VTE prophylaxis started later.
• I nitiation of VTE prophylaxis after elective spinal
surgery can typically start 12-24 hours post-
operatively. Prophylaxis may need to be delayed if
the surgical site remains open.
• T
he frequency and severity of complications
using non-neuraxial techniques (plexus or
peripheral delivery) are influenced by the size
of the catheter and degree of anticoagulation.
The most serious complication from excessive
anticoagulation using non-neuraxial techniques
appears to be blood loss rather than loss of
neural function.
VTE Prophylaxis in Critically Ill Patients

See Table 12-13.
TABLE 12-13: VTE Prophylaxis in Critically Ill Patients

Critical Care VTE Prophylaxis in Critically Ill Patients
Setting
UFH LMWH Fondaparinux
Trauma Insufficient evidence Dalteparin 5,000 units Insufficient evidence

sub-Q q 24 hr or
Enoxaparin 30 mg
sub-Q q 12 hr
Acute spinal 5,000 units sub-Q q 8 hr Enoxaparin 30 mg Insufficient evidence

cord injury23 sub-Q q 12 hr or
Enoxaparin 40 mg
sub-Q q 24 hr
Burns 5,000 units sub-Q q 8 Dalteparin 5,000 units Insufficient evidence

hr or sub-Q q 24 hr or
5,000 units sub-Q q Enoxaparin 40 mg
12 hr sub-Q q 24 hr
Critical care 5,000 units sub-Q q 8 Dalteparin 5,000 units Insufficient evidence
hr or sub-Q q 24 hr 2.5 mg sub-Q daily
5,000 units sub-Q q Enoxaparin 30 mg may be an option in
12 hr sub-Q q 12 hr or suspected HIT
Enoxaparin 40 mg
sub-Q q 24 hr
HIT: heparin-induced thrombocytopenia, sub-Q: subcutaneous, units: International Units, VTE:

venous thromboembolism
• Trauma
{{ Meta-analysis has demonstrated UFH to be
no more effective than control.24
{{ Enoxaparin 30 mg twice daily has
demonstrated better efficacy to UFH 5,000
units twice daily.25
{{ Evidence for dalteparin is based on
observational data.
{{ Pharmacologic prophylaxis can be safely
started within 24 to 36 hours. Patients with
acute spinal cord injury may need to be
delayed for 48 to 72 hours.
{{ Patients with severe trauma (injury severity
score >23) may present with antithrombin
deficiency; therefore, sub-Q prophylaxis may
be insufficient.26 Although not prospectively
evaluated, an option may be to use an UFH
infusion while the patient is in the intensive
care unit early in the course of events. Only
a slight bump in the aPTT (35–45 seconds)
would be targeted since VTE prevention is the
goal.
• Acute spinal cord injury
{{ UFH three times daily demonstrated similar
rates of DVT and bleeding compared
to enoxaparin twice daily, but there
was a significant reduction in PE with
enoxaparin.27
{{ While enoxaparin 30 mg twice daily should
be used during the acute injury period (about
2–3 weeks), either regimen could be used
during the rehabilitation period.
{{ In a retrospective case-control study,
dalteparin 5,000 units daily failed to
demonstrate non-inferiority to enoxaparin
30 mg twice daily in prevention of VTE
(9.7% vs. 1.6%).28 Further investigations of
dalteparin and tinzaparin are warranted.
• Burns
{{ The recent evidence in burn patients currently
comes from only observational studies with
UFH, enoxaparin, and dalteparin. The most
commonly used regimen is UFH 5,000 units
sub-Q every 12 hours.
• Critical care
{{ In medically ill or post-operative general
surgery patients, UFH or a LMWH can be
used. In orthopedic surgery or trauma, a
LMWH is preferred.
{{ If mechanical prophylaxis is selected due
to high risk of bleeding, the patient should
be frequently re-evaluated and switched
to pharmacologic prophylaxis when the
bleeding risk decreases.
{{ Some pharmacodynamic studies suggest that
critical care patients with significant edema
or receiving vasopressors may not achieve
detectable anti-Xa levels with LMWH.
{{ In the largest trial of VTE prevention in
critical care patients, dalteparin 5,000 units
sub-Q once daily provided similar protection
against proximal DVT, better protection
against PE, similar bleeding, and less HIT
compared to UFH 5,000 units twice daily.29
{{ Dalteparin has been shown to not have
significant accumulation in critical care
patients with renal insufficiency.30
{{ A retrievable IVC filter may be considered
for PE prophylaxis, but it should be noted
that this practice has limited evidence and is
controversial. See the IVC discussion earlier
in this chapter.
Travel Prophylaxis Strategies

See Table 12-14.
TABLE 12-14: Travel Prophylaxis Strategies

Indications Persons with previous VTE, thrombophilic disorders, severe obesity,
recently active cancer, pregnancy, estrogen use, advanced age, or
recent major surgery or trauma, who are traveling on flights >6 hr
Non-pharmacological Hydration
In-route exercises
• Foot lifts: Place your heels on the floor, and bring your toes up as
high as you can. Then put both feet back flat on the floor. Then
pull your heels up while keeping the balls of your feet on the
floor.
• Ankle turns: Lift your feet off the floor and move your toes in
a circle, one foot moving clockwise and the other foot moving
counterclockwise. Change direction and repeat direction.
Frequent travel breaks every 1–2 hr
Avoid restrictive clothing (tight clothes, belts, etc.)
Avoid or limit alcohol and caffeine prior to travel
Airline, bus, or train aisle seating
Graduated compression devices
Pharmacological LMWH before takeoff on the outgoing and return flights
LMWH: low molecular weight heparin, VTE: venous thromboembolism
• Below knee compression devices with ≥15–30

mmHg graduated pressure are recommended for
travel prophylaxis.
• C
ompression devices should be placed 3–4 hours
before departure and removed upon arrival.
• P
harmacological therapy should be administered
2–4 hours prior to departure.
• T
he ACCP provides a recommendation (Grade
2C) against the use of LMWH in this setting.
Contrary to this recommendation, some will give
a single prophylactic dose of LMWH. The only
trial mentioned in the ACCP guidelines that used
a LMWH gave sub-Q enoxaparin 1 mg/kg.
• A spirin has been shown to be ineffective in this
setting.
Duration of VTE Prophylaxis

See Table 12-15.
TABLE 12-15: Duration of VTE Prophylaxis

Indication Duration
General medically ill patients LMWH/UFH: 6–14 days as long as immobile during
acute illness; betrixaban: 35–42 days
Major general surgery Until hospital discharge
Major general surgery in patients with Beyond hospital discharge for up to 28 days
previous venous thromboembolism
Surgery for gastrointestinal, Beyond hospital discharge for up to 28 days

genitourinary, or gynecologic cancer
Total knee replacement surgery At least 10 days
Total hip replacement surgery 4 to 6 weeks*
Hip fracture surgery 4 to 6 weeks*
Critical care patients For the duration of the intensive care unit stay, with
re-evaluation when the patient is transferred to the
general medical ward
Major trauma Until hospital discharge and continued prophylaxis in

patients with impaired mobility who undergo inpatient
rehabilitation (up to 8 weeks)
Spinal cord injury patients Until hospital discharge in patients with incomplete
injuries
For 8 weeks in patients with uncomplicated complete
motor injury
For 12 weeks or discharge from rehabilitation in
patients with complete motor injury and other risk
factors
*While the average time from surgery to VTE in knee replacement surgery is 7 days, the average
time to VTE with hip procedures is delayed to 17 days.31
Pharmacological Prophylaxis in Special Populations

Severe Renal Insufficiency
• Patients with renal insufficiency are at higher risk of bleeding regardless of the
anticoagulant used.
• Patients with a serum creatinine >2.5 mg/dL have been excluded from most
clinical trials.
• Enoxaparin should be dosed at 30 mg sub-Q once daily regardless of the indica-
tion with CrCl <30 mL/min.
• Dalteparin and tinzaparin do not seem to significantly accumulate in patients
with severe renal insufficiency when prophylaxis doses are used.
• Fondaparinux, dabigatran, and rivaroxaban are contraindicated in patients with

a CrCl <30 mL/min. Apixaban should not be used in patients with a CrCl <25
mL/min.
• Patients on hemodialysis (renal failure) should receive sub-Q UFH.
Obesity
• ACCP guidelines recommend possible weight-adjusted dosing in obese patients,
but the guidelines provide no insight at what weight this should be considered,
or what the “adjusted” dosing should be. Obese patients are at considerable
risk of PE, but data from clinical trials on drug dosing are limited.
• Enoxaparin 40 mg sub-Q twice daily has demonstrated better efficacy than 30
mg sub-Q twice daily in bariatric surgery patients.18
• Injections of enoxaparin into the thigh in obese patients have a lower bioavail-
ability compared to injections into the abdomen.
• One study suggests that the typical dose of a LMWH may have to be higher in
patients with a body mass index ≥40.32
• Dalteparin 7,500 units daily has been evaluated in a retrospective study using
anti-Xa levels in patients undergoing bariatric surgery.33
• Efficacy and safety of direct oral anticoagulants in obese patients is similar to
non-obese patients with the heaviest patients studied ranges from 150 to 190 kg.
• Optimal dosing of any agent for VTE prophylaxis in the morbidly obese patient is
unclear; clinicians need to use discretion weighing thrombosis versus bleeding.
Pregnancy34 (see Chapter 19 for more information)
• Warfarin has been associated with congenital abnormalities when used during
the 1st trimester, and is therefore contraindicated. While warfarin could be used
during the 2nd trimester, it is typically avoided throughout pregnancy.
• A LMWH or UFH can be used throughout pregnancy.
• LMWHs (or fondaparinux) are not contraindicated in the 3rd trimester of
pregnancy and can be used in the early 3rd trimester. During the peripartum
period, many prefer to use UFH due to the shorter half-life and risk of bleeding
during delivery.
• DOACs have not been evaluated in pregnancy and should not be used.
HIT (see Chapter 18 for more information)
• Meta-analysis demonstrates a risk of HIT of 2.6% for UFH and 0.2% for LMWH
when prophylaxis doses are used.35
• Due to a cross-reactivity of 80-90%, a LMWH cannot be used as a substitute for
UFH in patients who develop HIT.
• Although fondaparinux may be an option in patients with a history of HIT due
to low cross reactivity, case reports of HIT with fondaparinux have been noted.
• DOACs have not been reported to cause HIT but have not been evaluated in
the management of HIT at this time.
For information on neuraxial anesthesia/analgesia, see Chapter 10.
Quality Improvement
See Table 12-16.
TABLE 12-16: Quality Improvement Strategies

Strategy Description
Educational initiatives Peer-led presentations and inservices

Mailings
Decision support tools Electronic alerts and reminders

Risk assessment models and prophylaxis reminders in
admission charts
Audit and feedback process Quality indicators and reports

Benchmarking against outcomes from highest performing
provider
Organizational changes Integrated care pathways

Changing from paper to computer-held patient records
Standardized dosing times Utilize pharmacologic prophylaxis options that require less
frequent dosing to avoid possible missed doses.
Utilize a standard dosing time in the evening (i.e., 2100) to
avoid missing morning dosing due to patients being off the
floor.
Regulations and policy Reimbursement schemes including fee-for-service

changes Required assessment policy

*1. Dobesh PP, Wittkowsky AK, Stacy ZA, et al. Key articles and guidelines for the
prevention of venous thromboembolism. Pharmacotherapy. 2009;29:410-458.
2. Kahn SR, Lim W, Dunn AD, et al. Prevention of VTE in nonsurgical patients. Chest.
2012;141(Suppl 2):e195S-e226S.
3. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical
patients. Chest. 2012;121(Suppl 2):e227S-e277S.
4. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery
patients. Chest. 2012;141(Suppl 2):e278S-e325S.
*5. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology
guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment
in Patients with Cancer. J Clin Oncol. 2007;25:5490-5505.
6. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism.
Chest. 2008;133:381S-453S.
7. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a
predictive model for chemotherapy-associated thrombosis. Blood. 2008;111(10):4902-
4907.
8. The PREPIC Study Group. Eight-year follow-up of patients with permanent vena
cava filters in the prevention of pulmonary embolism: the PREPIC (prevention du
risque d’embolie pulmonaire par interruption cave) randomized study. Circulation.
2005;112:416-422.
9. Mismetti P, Laporte S, Pellerin O, et al., for the PREPIC2 Study Group. Effect of a
retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk
of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313:1627-
1635.
10. Enders JM, Burke JM, Dobesh PP. Prevention of venous thromboembolism in acute
medical illness. Pharmacotherapy. 2002;22:1564-1578.
*11. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis
in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch
Intern Med. 2007;167:1476-1486.
12. Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for
thrombopropylaxis in medically ill patients. N Engl J Med. 2011:365:2167-2177.
13. Cohen AT, Spiro TE, Büller HR, et al., for the MEGELLAN Investigators. Rivaroxaban
for thromboprophylaxis in acutely ill medial patients. N Engl J Med. 2013;368:513-
523.
14. Cohen AT, Harrington RA, Goldhaber SZ, et al., for the APEX Investigators. Extended
thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med.
2016;375:534-544.
15. Mismetti P, Laporte S, Darmon JY, et al. Meta-analysis of low molecular weight
heparin in the prevention of venous thromboembolism in general surgery. Br J Surg.
2001;88:913-930.
*16. Leonardi MJ, McGory ML, Ko CY. The rate of bleeding complications after
pharmacologic deep venous thrombosis prophylaxis. A systematic review of 33
randomized controlled trials. Arch Surg. 2006;141:790-799.
17. Agnelli G, Bergqvist D, Cohen AT, et al. Randomized clinical trial of postoperative
fondaparinux versus periperative dalteparin for prevention of venous thromboembolism
in high-risk abdominal surgery. Br J Surg. 2005;92:1212-1220.
18. Scholten DJ, Hoedema RM, Scholten DE. A comparison of two different prophylactic
dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg.
2002;12:19-24.
19. American Academy of Orthopaedic Surgeons Clinical Guideline on Prevention of
Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee
Arthroplasty. Adopted by the American Academy of Orthopedic Surgeons Board of
Directors May 2007. Available at: http://www.aaos.org/research/guidelines/VTE/VTE_
full_guideline.pdf. Accessed April 26, 2017.
20. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of
pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary
Embolism Prevention (PEP) trial. Lancet. 2000;355:1295-1302 .
21. Ginsberg JS, Davidson BL, Comp PC, et al. Oral thrombin inhibitor dabigatran
etexilate vs North American enoxaparin regimen for prevention of venous
thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.
22. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for
thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.
23. Dhall SS, Hadley MN, Aarabi B, et al. Deep venous thrombosis and thromboembolism
in patients with cervical spinal cord injuries. In: Guidelines for the management of
acute cervical spine and spinal cord injuries. Neurosurgery. 2013;72(Suppl 2):244-254.
24. Upchurch GR, Demling RH, Davies J, et al. Efficacy of subcutaneous heparin
in prevention of venous thromboembolic events in trauma patients. Am Surg.
1995;61:749-755.
25. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-
molecular-weight heparin as prophylaxis against venous thromboembolism after major
trauma. N Engl J Med. 1996;335:701-707.
26. Owings J, Bagley M, Gosselin R, et al. Effect of critical injury on plasma antithrombin
activity: low antithrombin levels are associated with thromboembolic complications. J
Trauma. 1996;41:396-406.
27. Spinal Cord Injury Thromboprophylaxis Investigators. Prevention of venous
thromboembolism in the acute treatment phase after spinal cord injury: a randomized,
multicenter trial comparing low-dose heparin plus intermittent pneumatic compression
with enoxaparin. J Trauma. 2003;54:1116-1124.
28. Slavik RS, Chan E, Gorman SK, et al. Dalteparin versus enoxaparin for venous
thromboembolism prophylaxis in acute spinal cord injury and major orthopedic trauma
patients: DETECT trial. J Trauma. 2007;62:1075-1081.
29. The PROTECT Investigators. Dalteparin versus unfractionated heparin in critically ill
patients. N Engl J Med. 2011;364:1305-1314.
30. Prophylaxis of thromboembolism in critical care (PROTECT) trial: a pilot study. J Crit
Care. 2005;20:364-372.
31. White RH, Romano PS, Zhou H, et al. Incidence and time course of thromboembolic
outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158:1525-
1531.
32. Kucher N, Leizorovicz A, Vaikus PT, et al, for the PREVENT Medical
Thromboprophylaxis Study Group. Efficacy and safety of fixed low-dose dalteparin in
preventing venous thromboembolism among obese or elderly hospitalized patients. A
subgroup analysis of the PREVENT trial. Arch Intern Med. 2005;165:341-345.
33. Simoneau M-D, Vachon A, Picard F. Effect of prophylactic dalteparin on anti-factor Xa
levels in morbidly obese patients after bariatric surgery. Obes Surg. 2010;20:487-491.
34. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy,
and pregnancy: Chest. 2012;141(Suppl 2):e691S-e736S.
35. Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with
unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-
analysis. Blood. 2005;106:2710-2715.
13 Chapter
VENOUS THROMBOEMBOLISM
TREATMENT
Snehal H. Bhatt and Michael P. Gulseth
INTRODUCTION
Venous thromboembolism (VTE) is comprised of deep vein thrombosis (DVT) and
pulmonary embolism (PE) and affects between 350,000–600,000 patients each
year. In addition, it has been estimated that up to 100,000 patients directly or
indirectly die of this disease process annually.1 Optimal treatment of VTE is critical
to prevent death and future recurrence as well as minimize the risk of complications
such as post-thrombotic syndrome (PTS) and chronic thromboembolic pulmonary
hypertension (CTEPH).
VENOUS THROMBOEMBOLISM OVERVIEW

DVT, in the lower extremity, typically begins in a calf vein and can propagate
proximally to the popliteal vein and higher. Lower extremity DVT is 10 times more
common than upper extremity DVT. In the upper extremity, DVT typically has an
iatrogenic cause such as internal cardiac defibrillators, pacemakers, or in-dwelling
central venous catheters (e.g., peripherally inserted central catheter [PICC] line).
For DVT of the upper extremity, the risk increases with the diameter of inserted
catheters and number of lumens used.
PE occurs when a DVT embolizes to the lungs (see Figure 13-1). Patients
with signs and symptoms of shock, elevated cardiac biomarkers, and signs of
right ventricular (RV) dysfunction are classified as having massive PE. Massive
PE accounts for 5–10% of all PE cases and indicates extensive thrombus affect-
ing over half of the pulmonary vascular tree. Classic symptoms include syncope,
hypotension, dyspnea, and cyanosis. Patients with massive PE often present in
shock and can die. Patients who have cardiac manifestations (e.g., RV dysfunction,
release of cardiac enzymes) but who are hemodynamically stable are classified as
having submassive PE, which represents 20–25% of all PE cases. The remaining
70–75% of patients with PE are classified as having nonmassive PE and have a
good prognosis for recovery.
313
FIGURE 13-1. Pathophysiology of DVT and PE

Pulmonary emboli usually originate in the deep veins of the leg. The thrombus typically
originates around the venous valves and other areas of stasis. Thrombi that extend
above the knee or originate above the knee are at a higher risk of embolization.
Pulmonary emboli travel through the venous system, into the right side of the heart, to
the lungs.
Source: Image printed with permission from The Mayo Foundation for Medical
Education and Research. All rights reserved. http://healthletter.mayoclinic.com/
common/images/609/Deep_vein_thrombosis_lg.jpg
Common Areas for Venous Thrombosis2

• Lower extremity DVT.
• Lower extremity superficial vein thrombosis.
• Upper extremity DVT (UEDVT) represents approximately 10% of all DVT cases.
See Tables 13-1 and 13-2 for veins found in the upper and lower extremities.
See Figure 13-2 of lower extremity venous anatomy.
VENOUS THROMBOEMBOLISM TREATMENT 315
• D
VT can embolize; superficial vein thrombi do
not (unless they extend into a deep vein).
• I solated calf DVTs are less likely to embolize than
proximal DVTs.
• P
roximal DVTs are any DVTs that occur above
the level of the knee (popliteal vein) and higher.
• P
atients with DVT can often present with
nonspecific symptoms such as leg pain or
tenderness, warmth, discoloration, swelling, and
surface vein distention.
TABLE 13-1: Lower Extremity Venous Anatomy

Deep Veins of the Lower Leg Superficial Lower Limb Veins
Proximal veins Proximal veins

Deep femoral vein Anterior lateral thigh vein
External iliac vein External pudendal veins
Femoral vein Great saphenous vein
Gluteal vein Intra saphenous vein
Iliac vein Small saphenous vein
Medial and lateral circumflex femoral veins Superficial circumflex iliac vein
Mid-thigh perforator (Hunterian) vein Superficial epigastric vein
Popliteal vein Vein of Giacomini
Calf veins Calf veins

Anterior and posterior tibial veins Accessory saphenous vein
Dorsal and plantar metatarsal veins Dorsal venous arch
Fibular veins Dorsal venous network
Gastrocnemius vein Femoropopliteal vein
Genicular veins Great saphenous vein
Peroneal vein Plantar venous network
Plantar digital veins Plantar venous arch
Soleal vein Posterior arch vein
Sural veins
TABLE 13-2: Upper Extremity Venous Anatomy

Deep Veins of the Upper Extremity Superficial Upper Extremity Veins
Anterior interosseous veins Accessory cephalic vein

Axillary vein Basilic vein
Brachial veins Cephalic vein
Deep palmar venous arch Median antebrachial vein
Posterior interosseous veins Median basilica vein
Radial veins Median cephalic vein
Subclavian vein Median cubital vein
Ulnar veins Dorsal venous network of the hand
Palmar metacarpal veins Superficial palmar venous arch
Inguinal External
ligament iliac vein
Popliteal
vein
Short
Lateral Medial saphenous
circumflex circumflex vein
femoral veins veins
Anterior
Long tibial
Deep saphenous vein
femoral vein vein
Femoral vein Accessory Fibular
saphenous veins
vein
Adductor
canal Posterior
Short
tibial veins
saphenous
Popliteal vein vein
Adductor
hiatus
Genicular Lateral
veins malleolus
Long
saphenous
vein
Posterior view
Anterior
tibial veins
Short
saphenous
veins
Dorsal venous
network of
the foot
Anterior view
FIGURE 13-2. Lower Extremity Venous Anatomy

See Figure 13-3 of upper extremity venous anatomy.
• M
ost UEDVTs are associated with central venous
catheters.3
• U
EDVT is treated with anticoagulation therapy
similar to that of lower extremity DVT with
regard to initial therapy and duration of therapy,
although randomized controlled trials have not
been performed in patients with UEDVT.
• R
outine removal of the central venous catheter
is not recommended, but can be considered
when there is concern for infection or if there are
contraindications to anticoagulation therapy.
Subclavian vein
Axillary vein
Thoracoepigastric vein
Thoracodorsal vein
Brachial veins
Anterior interosseous
veins Ulnar veins
Radial veins
Deep palmar
venous arch
Palmar
metacarpal
veins
Palmar
Deep arm veins digital veins
FIGURE 13-3. Upper Extremity Venous Anatomy

PARADOXICAL EMBOLISM
In some patients with atrial septal defects (i.e., a patent foramen ovale [PFO]),
DVTs that embolize can cross over from the right atrium to the arterial system
via the left atrium and left ventricle (see Figure 13-4).
1. Embolus (blood clot) from a vein in leg or pelvis enters right atrium.
2. Embolus passes through defect in septum between right and left atria, and enters
left artrium.
3. Embolus enters left ventricle, and is then pumped into the aorta and hence into the
brain, causing a stroke.
* Narrowing of the pulmonary artery causes increased pressure differential between
right and left side of heart, expediting passage of embolus from right to left atrium.
FIGURE 13-4. Paroxysmal Embolism

Source: Image reprinted with permission from Medscape Drugs & Diseases (http://
emedicine.medscape.com/), 2016; available at: http://emedicine.medscape.com/
article/460607-overview.
PROVOKING RISK FACTORS FOR VTE

See Table 13-3.
TABLE 13-3: Common Provoking (Reversible) Risk Factors for

VTE4
Common Provoking Risk Factors
Major risk
• Hospitalization
• Plaster cast immobilization
• Surgery
Minor risk
• Estrogen therapy
• Flight >8 hours
• Leg injury
• Pregnancy
DIAGNOSIS OF DEEP VEIN THROMBOSIS

The diagnosis of DVT involves a thorough review of patient history and signs
and symptoms, recognizing that in some patients, these may be unremark-
able. Imaging of the leg veins by duplex ultrasonography with compression
is often performed to aid in the diagnosis of DVT. Venography is rarely used
due to invasive nature and dye exposure.
DVT Signs/Symptoms*
• Calf tenderness
• Erythema
• Increased leg warmth
• Leg swelling
• Pain in the back of the knee when the foot is dorsiflexed (Homans’ sign)
• Pain in the leg
• Palpable superficial veins
*Key point: These are very nonspecific signs/symptoms; objective testing is
needed to confirm the diagnosis.
DVT Diagnostic Testing

Role of D-Dimer Testing in Establishing the Diagnosis of DVT
• D-dimer is a degradation product that is produced from the breakdown of a
fibrin blood clot.
• D-dimer is elevated during acute VTE but conditions such as cancer, sepsis,
surgery, trauma, pregnancy, myocardial infarction, bleeding, inflammation, and
other systemic illnesses can also cause elevation.5
• D-dimer is an effective “rule out” of VTE in the setting of low clinical pretest
probability, but a positive result requires further diagnostic verification. Table
13-4 describes how to estimate pretest probability using Wells Pretest Probabil-
ity scoring.
• There are many different D-dimer assays, and the sensitivity of D-dimer is depen-
dent on the assay method; no universal cutoff level exists.
• Sensitivity of D-dimer may be reduced if the duration of signs and symptoms of
VTE exceed 2–3 days or if the patient has received heparin therapy.
Role of Duplex Ultrasonography (with Compression) in
Establishing the Diagnosis of DVT
• It is preferred to venography because it is noninvasive and does not carry the
side effects of venography (i.e., hypotension, cardiac arrhythmias, vessel wall
irritation, nephrotoxicity due to the contrast medium).
• Positive duplex ultrasound in combination with moderate-to-high pretest
probability scoring, or a positive D-dimer can be used to confirm the diagnosis
(see Table 13-4).
• Negative testing does not exclude DVT, particularly in calf veins.
• The ability to diagnose new DVT can be difficult in patients with previous history
of DVT.
Role of Pretest Probability Scoring
The Wells Score is a clinical prediction tool that can aid in the diagnosis of
DVT. This score, when used in combination with other clinical assessments,
can guide clinicians toward which patients require further testing to either
confirm or rule out DVT. However, like most prediction rules, this scoring
system performs variably in different patient populations and should not
replace clinical judgment (see Table 13-4).
See Figure 13-5 on how to use Wells Pretest Probability Scoring to aid
in DVT diagnosis.
• F
urther diagnostic testing is not necessary in
patients with low pretest probability score for
DVT and a negative D-dimer.
DVT Diagnostic Algorithms

See Figures 13-5A-C.
TABLE 13-4: Wells Pretest Probability Scoring for Deep Vein

Thrombosis6
Clinical Features Score
Tenderness along entire deep vein system 1
Swelling of the entire leg 1
Greater than 3-cm difference in calf circumference 1
Pitting edema 1
Collateral superficial veins 1
Risk factors:
• Active cancer 1
• Prolonged immobility or paralysis 1
1
• Recent surgery or major medical illness
Alternative diagnosis likely –2
Total
≥3: high probability, 1–2: moderate probability, ≤0: low probability

Source: Adapted from Wells PS, et al. Lancet. 1997.
High or moderate
sensitive D-dimer
Positive Negative
Proximal US No DVT
Negative Positive
No DVT Treat DVT
FIGURE 13-5A. Diagnosis Algorithms for DVT, Low Probability4

The following diagram summarizes the current recommendations for the diagnosis of
DVT based on a low pretest probability. In these patients, the initial diagnostic test is a
moderate or high sensitive D-dimer initially, followed by ultrasound testing only if the
result of the D-dimer test is positive.
High sensitive
D-dimer
Negative Positive
No DVT Proximal US
Negative Positive
Repeat
Proximal US in Treat DVT
1 week
Negative Positive
No DVT Treat DVT
FIGURE 13-5B. Diagnosis Algorithms for DVT, Moderate

Probability4
The following diagram summarizes the current recommendations for the diagnosis of
DVT based on a moderate pre-test probability. In these patients, using a high sensitive
D-dimer initially is recommended, followed by ultrasound only if the result of the
D-dimer test is positive. In the case of a negative initial ultrasound, the test should be
repeated in 1 week to confirm the absence of DVT.
DVT: deep vein thrombosis, US: ultrasound
Proximal US
Negative Positive
Repeat Highly
Proximal US in sensitive Treat DVT
1 week D-dimer
Negative Positive Negative Positive
Repeat
No DVT Treat DVT No DVT Proximal US in
1 week
Negative Positive
No DVT Treat DVT
FIGURE 13-5C. Diagnosis Algorithms for DVT, High Probability4

The following diagram summarizes the current recommendations for the diagnosis
of DVT based on a high pretest probability. In these patients, initial ultrasound is
recommended; however, the highly sensitive D-dimer test is recommended if the initial
ultrasound is negative.
DIAGNOSIS OF PULMONARY EMBOLISM
Signs and Symptoms of Pulmonary Embolism

Table 13-5 describes the many signs and symptoms associated with PE. Note
that most of these signs and symptoms are nonspecific to PE, which helps
explain why the diagnosis of PE is often challenging and requires careful
clinical judgment.
TABLE 13-5: Diagnosis of Pulmonary Embolism5

Three Most Common Signs/Symptoms
Dyspnea
Pleuritic chest pain with clear x-ray
Tachypnea
Additional Signs and Symptoms
Apprehension
Cough
Cyanosis
Diaphoresis
ECG findings: right bundle branch block, SIQIIITIII, and T wave inversions in leads V1-V4
Elevated neck veins
Fever
Hemoptysis
Hypotension
Increased pulmonic component (P2) of the second heart sound
Nonpleuritic chest pain
Pleural rub
Rales
Syncope
Systolic murmur (tricuspid regurgitation)
Tachycardia
Wheezing
Signs/Symptoms of Massive PE
Hemodynamic instability: The presence of shock or hypotension, specifically defined as a systolic

blood pressure <90 mm Hg or a >40 mm Hg drop in blood pressure for >15 minutes
Cardiac arrest
Cyanosis
Hypoxia
Oliguria
Cardiac and Imaging Signs/Symptoms of Massive PE
Greater than 50% or more absent perfusion of the lung on angiography or ventilation/perfusion
scanning
Echocardiography: Evidence of RV failure/strain (RV enlargement, hypokinesis, pulmonary
hypertension, intraventricular septal flattening or “bowing”)
Elevated pulmonary artery pressure
Elevated B-type natriuretic peptide (BNP)
Elevated troponin
• S imilar to patients with DVT, patients with PE

often present with atypical symptoms or may
also present with asymptomatic disease.
Pulmonary Embolism Diagnostic Testing

Computed Tomographic Pulmonary Angiography
• Considered first-line choice for use in diagnosis unless contraindications exist.
• Contrast dye is typically used, which can make the test unsuitable for patients
with poor renal function.
• Positive scan results for a PE have good specificity and generally confirm the
diagnosis.
• Negative scans lack sensitivity and may require further diagnostic studies if PE
seems likely due to pretest probability scoring and/or D-dimer results.
• Both sensitivity and specificity of the scan is improved with central clots as to
those that are more peripheral.
• Scan must be performed well technically including appropriate timing from
contrast injection, patient holding his or her breath for about 20 seconds, and
optimized spatial resolution parameter settings.
• False positives are more common for segmental/subsegmental embolism, and
follow-up testing may be needed.
A saddle PE is a large bilateral PE because anatomically the thrombi straddles
the bifurcation of the main pulmonary artery and often extends into the left
and right main pulmonary artery. Approximately 3–6% of patients with PE
will be diagnosed with saddle PE.
See Figure 13-6 for an example of a saddle PE on computed tomography
(CT).
Ventilation/Perfusion Lung Scan
• Highly positive scan results for a PE have good specificity and can help confirm
the diagnosis.
• Ventilation/perfusion (V/Q) scanning is often preferred in patients with pregnancy,
renal insufficiency, or allergies to contrast dye.
• Chronic obstructive pulmonary disease, asthma, and congestive heart failure
can impair the specificity of the scan.
• A negative scan has good specificity and generally rules out the diagnosis.
• A nondiagnostic (intermediate or low radiologic probability scan) result lacks
sensitivity and requires further diagnostic studies if PE seems likely.
See Figure 13-7 for sample V/Q scan.
Pulmonary Embolism Pretest Probability Scoring

Much like in DVT, a Wells Score is also available to estimate the probability
of PE. This score, when used in combination with other clinical assess-
ments, can guide clinicians toward which patients require further testing to
FIGURE 13-6. CT of a Saddle Pulmonary Embolism

Source: Used with permission from Wikicommons7 https://commons. (https://upload.
wikimedia.org/wikipedia/en/e/ea/SADDLE_PE.JPG)
FIGURE 13-7. Ventilation/Perfusion Lung Scan of a Pulmonary

Embolism8
Panel A shows good ventilation of the lung, while panel B shows poor blood perfusion
to the right upper lobe, right lower lobe, and left lower lobe. This patient had a PE.
Source: Used with permission from Wikimedia commons. https://commons.wikimedia.
org/wiki/File:Pulmonary_embolism_scintigraphy_PLoS.png
either confirm or rule out PE. Like most prediction rules, this scoring system
performs variably in different patient populations and should not replace
clinical judgment. It is most likely to be useful in situations of suspected PE
without hypotension/shock (see Table 13-6).
TABLE 13-6: Wells Pretest Probability Scoring for Pulmonary

Embolism9,10
Clinical Features Score Simplified Score
Clinical signs of DVT 3 1
PE as likely or more likely than alternative diagnosis 3 1
Heart rate >100 beats/min 1.5 1
Immobilization or surgery in the previous 4 weeks or surgery or 1.5 1

fracture within past month
Previous DVT or PE 1.5 1
Hemoptysis 1 1
Cancer 1 1
Total
Wells criteria: >6 = high probability, 2–6 = moderate probability, <2 = low probability.
Simplified Wells criteria: ≥ 2 = PE likely, 0–1 = PE unlikely
DVT: deep vein thrombosis, PE: pulmonary embolism
See Figures 13-8 A and B for use of pretest probability scoring in the
diagnosis of PE.
Pulmonary Embolism Diagnostic Algorithms

Assess clinical
probability of PE
Low/intermediate High clinical

clinical probability probability
D-dimer CT angiography
Negative Positive No PE PE confirmed
No treatment CT angiography No treatment Treat PE
No PE PE confirmed
No treatment Treat PE
FIGURE 13-8A. Diagram for the Diagnosis of Pulmonary

Embolism and No Shock*
*Shock is defined as a systolic blood pressure <90 mm Hg or a >40 mm Hg drop in
blood pressure for >15 minutes.
Source: Adapted with permission from European Heart Journal, from Konstantinides
SV, Torbicki A, Agnelli G, et al. ESC Guidelines on the diagnosis and management of
acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute
Pulmonary Embolism of the European Society of Cardiology (ESC). Endorsed by the
European Respiratory Society (ERS). Eur Heart J. 2014; 35:3033-3069, 3069a-3069k.
Copyright © 2014 by European Society of Cardiology. Reproduced with permission of
Oxford University; permission conveyed through Copyright Clearance Center, Inc.
CT angiography immediately
available
No Yes
Echocardiography†
RV overload
CT angiography
No Yes CT angiography
available and patient
is stabilized
No other test
available or Positive Negative
patient is unstable
Search for other causes of PE specific treatment: Search for other causes of
hemodynamic instability Primary reperfusion hemodynamic instability
FIGURE 13-8B. Diagram for the Diagnosis/Treatment of PE with

Hypotension/Shock*5
†
Direct sign of PE on an echocardiogram would include (1) thrombi in the right atrium,
right ventricle, or pulmonary artery; and (2) thrombi that protrude into the left atrium
through a patent foramen ovale. Indirect signs on an echocardiogram would include (1)
right ventricular dysfunction (see Figure 13-9); (2) a systolic pressure gradient between
the right ventricle and the right atrium of >30 mm Hg; and (3) pulmonary arterial flow
acceleration time of <80 msec.
*Shock is defined as a systolic blood pressure <90 mm Hg or a >40 mm Hg drop in
blood pressure for >15 minutes.
CT: computed tomography, PE: pulmonary embolism
Source: Adapted with permission from European Heart Journal, from Konstantinides
SV, Torbicki A, Agnelli G, et al. ESC Guidelines on the diagnosis and management of
acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute
Pulmonary Embolism of the European Society of Cardiology (ESC). Endorsed by the
European Respiratory Society (ERS). Eur Heart J. 2014; 35:3033-3069, 3069a-3069k.
Copyright © 2014 by European Society of Cardiology. Reproduced with permission of
Oxford University; permission conveyed through Copyright Clearance Center, Inc.
VENOUS THROMBOEMBOLISM TREATMENT

PRINCIPLES
Early and aggressive anticoagulation is the preferred treatment modality in
patients with PE. Fibrinolysis can be considered in selected high-risk cases,
as highlighted below.
When Should Systemic Fibrinolysis Be Considered for

PE?4 (see Chapter 6 on thrombolytic therapy)
• Sustained hypotension (SBP <90 mm Hg) in patients who do not have high risk
of bleeding.
• Select patients without hypotension who deteriorate clinically after starting
anticoagulation therapy and who are also at low risk of bleeding.
• Patients without hemodynamic compromise who:
{{ Are very ill in conjunction with severe dyspnea, anxiety, and poor
oxygen saturation (high or very high 30-day mortality risk, deter-
mined by the Pulmonary Embolism Severity Index [PESI] (Table
13-7).
{{ Have elevated troponin (indicative of right ventricular micro-
infarction).
{{ Have right ventricular dysfunction demonstrated by an echocar-
diogram.
{{ Have right ventricular enlargement on chest CT (Figure 13-9).
{{ Are at low risk of bleeding (see Table 6-4).
For administering systemic fibrinolysis for PE, see Chapter 6, Table 6-2.
• Note: The 2016 American College of Chest Physician (ACCP) and 2014 European
Society of Cardiology (ESC) Pulmonary Embolism guidelines4,5 recommend use
of accelerated regimens with short infusion times (e.g., a 2-hour infusion) over
those with prolonged infusion times (e.g., a 24-hour infusion).
For contraindications to thrombolytic therapy, see Chapter 6, Table 6-4.
Pulmonary Embolism Severity Index Scoring Systems

The PESI score is the most extensively validated prognostic clinical score
currently available, using clinical and patient characteristics to determine
which patients are at risk for adverse outcomes, including 30-day mortal-
ity from PE. The strength of the PESI is its ability to rule out negative PE
outcomes (e.g., mortality). Many institutions advocate using the PESI score
to determine which patients can be safely treated for PE at home (Class I–II),
versus which patients should be admitted to the hospital for management.
TABLE 13-7: Original and Simplified Pulmonary Embolism

Severity Index (PESI) Scoring Systems11,12
Parameter Original Scoring Version Simplified Scoring
(points) Version (points)
Age Points = age in years 1 (if age >80 years)
Male sex 10 -
Cancer 30 1
Chronic heart failure 10 1*
Chronic pulmonary disease 10 1*
Heart rate >110 BPM 20 1
Systolic blood pressure <100 30 1

mm Hg
Respiratory rate >30 breaths per 20 -

minute
Temperature <36ºC 20 -
Altered mental status 60 -
Arterial oxygen saturation <90% 20 1
30-day Mortality Risk
Very low: 0–1.6% Class I: <65 points 0 points: 1%
Low: 1.7–3.5% Class II: 66–85 points
Moderate: 3.2–7.1% Class III: 86–105 points
High: 4–11.4% Class IV: 106–125 points ≥1 point: 10.9%
Very high: 10–24.5% Class V: >125 points
*These variable were combined into a single category called chronic cardiopulmonary disease.
This depicts a normal cross section

of a heart. Note the normal size Right Left
of the right and left ventricle. ventricle ventricle
This depicts a heart that is in cor

pulmonale due to pulmonary
hypertension. Note how the
Right Left
increased pressure in the right
ventricle ventricle
ventricle has impaired the
appropriate filling and size of
the left ventricle, which can lead
to cardiovascular shock.
FIGURE 13-9. Right Ventricular Dysfunction in Acute

Pulmonary Embolism
• I ntravenous agents (e.g., labetalol, nicardipine,

nitroglycerin) can be used to lower blood pressure
to allow for fibrinolytic therapy administration.
• P
ercutaneous catheter-directed treatment
allows for localized delivery of lower doses of
fibrinolytics to the pulmonary thrombi (10–24
mg) and may be considered for PE patients with
hemodynamic instability or RV dysfunction when
systemic fibrinolysis has failed, if local expertise
is available.13
Heparins in Combination with Systemic Fibrinolysis

Heparin (or in some cases LMWH) typically accompanies the use of throm-
bolytic therapy for VTE. See Chapter 6 for dosing recommendations based
on setting and approach to therapy when thrombolytic agents are used.
Heparin Dosing Considerations When Given with

Catheter-Directed Fibrinolysis for DVT Treatment
• Catheter-directed fibrinolysis is often utilized for massive iliofemoral DVT to
help prevent the development of post-thrombotic syndrome.
• The heparin dosing is not standardized for this indication; often, lower intensities
were used in reported studies than standard DVT therapy (often ≤1,000 units/hr).
• C
aution must be exercised whenever using
anticoagulants with, or in close proximity to,
fibrinolytics. See Chapter 6 for more details and
dosing considerations.
Use of Inferior Vena Cava Filters

• Inferior vena cava (IVC) filters come in two types: permanent and retrievable.
• Retrievable filters can be removed when the need for the filter has dissipated.
{{ Removal can be difficult if the filter has become imbedded in the
wall of the IVC or if a large amount of clot is present in the filter.
In these cases, the filter then becomes permanent.
{{ To help prevent imbedding in the wall, filters can be rotated
periodically.
{{ In some cases, warfarin therapy may not be initiated until the filter
is removed.
• A randomized study assessing the efficacy and safety of IVC filters in patients
with proximal DVT found that while filters decrease PE rates, they also increase
DVT rates with no mortality benefit.14
• In a randomized study of patients with PE receiving anticoagulation therapy
deemed to be at high risk for recurrence, placement of an IVC filter did not
provide additional benefit in reducing recurrent symptomatic or fatal PE.15
• IVC filters may reduce in-hospital mortality in PE patients, but randomized data
are lacking.16,17
• In patients with acute VTE who are treated with anticoagulants, the 2016 ACCP
Treatment of VTE Disease Guidelines recommend against the use of an IVC
filter (Grade 1B).4
Standard Indications for IVC Filter Placement
• Known VTE with a contraindication to anticoagulation therapy.
• Known VTE with complications of anticoagulation therapy.
• Objectively confirmed recurrent PE despite adequate anticoagulation treatment
(anticoagulation failure).
• Chronic thromboembolic hypertension patients who will undergo thrombo-
endarterectomy.
Evolving Indications for IVC Filter Placement*
• Recurrent PE leading to pulmonary hypertension.
• DVT patients with limited cardiopulmonary reserve capacity or patients with
chronic obstructive pulmonary disease (COPD).
• Patients who have large, free-floating iliofemoral thrombus.
• Patients who have had thrombectomy, embolectomy, or fibrinolysis of DVT.
• High-risk trauma patients (spinal cord injury, pelvic or lower extremity fractures)
who cannot be safely anticoagulated.
• High-risk surgical patients who are contraindicated for anticoagulation.
• DVT patients with burns, cancer, or who are pregnant.

• Treatment of acute DVT organ transplant patients.
*Many of these indications are controversial with little high-quality evidence
to support their use.
See Table 13-8 for known IVC filter complications.
TABLE 13-8: Potential IVC Filter Use Complications

Filter Use Complications
• DVT recurrence
• Filter migration
• Filter thrombosis (can be on top of the filter)
• Guidewire entrapment
• IVC thrombosis
• Penetration of the IVC
• Post-thrombotic syndrome
• Thrombosis at the insertion site
• Tilting or fracture of the filter (filter fragments can embolize)
• Vena caval obstruction
DVT: deep vein thrombosis, IVC: inferior vena cava
• When IVC filters should be used is a very

controversial topic. Clinicians who routinely
work in anticoagulation should be familiar
with the data regarding their use. Systemic
anticoagulation generally should be used long
term in patients with permanent (including those
with retrievable filters that are not removed) IVC
filters provided they are appropriate candidates
for long-term anticoagulation.
Use of Anticoagulants to Treat VTE

General Principles of Therapy
• For patients with a high clinical suspicion of VTE, parenteral anticoagulation
therapy should be started even if diagnostic tests are pending.
• Parenteral anticoagulation therapy, when utilized with warfarin, should be
overlapped with warfarin for at least 5 days and until the INR is >2 and stable
to allow the vitamin K antagonist (VKA) enough time to reach its full anticoagu-
lant effect.
• Patients with either a DVT or PE who are otherwise stable and have no other
reason to be hospitalized may be considered for outpatient therapy (see Chapter
10).
{{ See key considerations below on home treatment.
• Alternatively, apixaban and rivaroxaban can be used without initial parenteral

therapy. If parenteral therapy has been used, patient can be transitioned to
apixaban/rivaroxaban. Simply shut off the heparin drip when the new agent is
given, or if LMWH/fondaparinux is used, give the new agent when the next dose
of parenteral therapy would be due.
• Warfarin can be started on the first day along with the parenteral anticoagulation.
• Upper extremity DVTs are generally treated in a similar fashion to lower extremity
DVTs, but this is based on limited data.
• Patients with isolated distal DVT without severe symptoms can be managed
with serial ultrasonography for 2 weeks with anticoagulation only provided if
extension occurs.
• In some select patients with subsegmental PE (no involvement of proximal
pulmonary arteries) and no proximal DVT of the legs (ultrasound imaging required
of lower extremities and other high-risk areas) who are at low risk of recurrent
VTE, clinical surveillance can be used over anticoagulation particularly in those
at high risk of bleeding with good pulmonary reserve.
Key Considerations for Use of Anticoagulants in VTE
Use of Unfractionated Heparin (UFH) for treatment of VTE (see Chapter 3):
• Preferred agent when fibrinolytics would be used (systemic fibrinolytic treatment
of PE, catheter-directed therapies, etc.).
• May also be preferred in patients with severe renal insufficiency.
• Both intravenous (IV) infusions and subcutaneous therapy are acceptable options
for VTE treatment.
• When IV infusions are utilized, achieving a therapeutic activated partial throm-
boplastin time (aPTT) in the first 24 hours may be associated with decreased
VTE recurrence rates.
• Targeted aPTTs should be regularly correlated to therapeutic heparin levels of
0.3–0.7 units/mL anti-factor Xa activity (see Chapter 21).
• IV route is the preferred option whenever there are concerns over subcutane-
ous absorption.
Use of LMWH/fondaparinux for treatment of VTE (see Chapter 4):
• Patients who were initially treated with IV UFH can have a single injection at
discharge to complete a full 5 days of heparin therapy. (Note: Documentation
will still be needed to fulfill core measure requirements.)
• Routine measurements of anti-factor Xa activity levels are not needed.
• Can be utilized long term, alone, for the treatment of VTE; recommended initial
approach to the treatment of VTE in the setting of cancer (see Treatment of
VTE in Cancer).
• When using enoxaparin for the treatment of VTE, 1 mg/kg sub-Q twice a day is
preferred over 1.5 mg/kg once daily, particularly in those with cancer or those
who are obese.
• When using enoxaparin, many clinicians round to the nearest syringe to simplify
the therapy for patients and to avoid expelling the air bubble, which may lead
to more bruising.
• Due to practicality reasons (e.g., lack of available syringe sizes, need for multiple
syringes per dose), along with lower efficacy in obese patients, many clinicians
avoid once daily enoxaparin in patients greater than 100 kg.
Treatment of VTE in cancer:18,19
• The ACCP guidelines, the National Comprehensive Cancer Network (NCCN), and
the American Society of Clinical Oncology (ASCO) recommend LMWH therapy
alone for the initial treatment of VTE in cancer patients.18,19
• LMWH is recommended for the first 3–6 months of therapy of the total duration
of therapy; longer-term therapy, if needed, should be continued with warfarin
or LMWH depending on the patient’s specific scenario.
• Dalteparin is U.S. Food and Drug Administration (FDA) indicated for this use,
but other agents are also used in practice despite weaker evidence.20
• Once-daily enoxaparin should be avoided in patients with acute thrombosis
with cancer.
• Data for use of direct-acting oral anticoagulants (DOACs) in patients with cancer
are limited. Although the definition of active cancer differed between each of
the DOAC studies and also did not quite match the definition for active cancer
used in the LMWH studies, the pooled results from over 1,000 patients showed
no difference in their safety or effectiveness compared to conventional VKA
treatment.21,22 See Chapter 11 for more details.
Use of LMWH/fondaparinux/DOACs at home:
• Ensure the patient/caregiver is fully educated on administering parenterals (if
used) and willing to comply.
• Ensure the follow-up appointments have been made for anticoagulation monitor-
ing.
• Ensure the outpatient provider clearly understands the treatment plan and the
importance of making sure the patient follows up.
• Ensure the patient can pay for the drug before a final decision on treatment
is made.
• Ensure that the patient’s pharmacy has the medication in stock.
• Ensure the patient has phone numbers to call if he or she has any questions/
concerns about therapy when at home and that the care providers have the
patient’s contact information if needed.
• At least one of the DOAC agents is available in a starter pack; this may be an
excellent option for many patients to help facilitate adherence.
• Patients who have low-risk PE (PESI <85, modified PESI of 0) whose support
structure is adequate can be treated at home or via early discharge from the
hospital (<5 days).
Use of DOACs for the treatment of VTE (see Chapter 7):
• Apixaban, dabigatran, edoxaban, and rivaroxaban are all FDA-approved for
the acute treatment of DVT and PE. Apixaban, dabigatran, and rivaroxaban are
approved for long-term, secondary prevention of DVT and PE.
• Rivaroxaban and apixaban can be used upon diagnosis of VTE without parenteral
anticoagulant therapy, whereas it is recommended that all patients receive at
least 5 days of parenteral therapy prior to initiation of dabigatran or edoxaban.
• All DOACs are recommended over warfarin therapy for the treatment of
non-cancer VTE in the 2016 ACCP Treatment of VTE Disease Guidelines (Grade
2B).4
• DOACs have demonstrated less or comparable rates of major bleeding in clinical
trials when compared with warfarin.23-27
• Pharmacokinetic studies of the DOACs have suggested that obesity does not
meaningfully impact drug exposure when compared to non-obese patients.
In clinical trials of direct factor Xa inhibitors for VTE treatment, 15–19% of all
patients enrolled had a body weight >100 kg, accounting for >1,000 patients.28-30
(See Chapter 11 for more information.)
• Low doses of both apixaban (2.5 mg twice daily) and rivaroxaban (10 mg daily)
have been shown to be effective at reducing the risk of recurrent VTE after initial
therapy. Rivaroxaban 10 mg daily was superior to low-dose aspirin (100 mg) at
reducing recurrent VTE without any difference in major bleeding, while apixaban
2.5 mg twice daily was effective at reducing recurrent VTE when compared with
placebo without increasing major bleeding.31
• Patients with hemodynamic instability or those with suspected need for invasive
management for PE were excluded from all DOAC clinical trials; UFH remains a
better choice for initial therapy in these patients.
• Clinical data are sparse on the safety of the DOACs in severe renal impairment,
because this was an exclusion from their major clinical trials for VTE. UFH remains
a better choice for initial therapy in these patients.
See Table 13-9 for a summary of the randomized data for DOACs in the
treatment and secondary prevention of VTE.
Use of warfarin for treatment of VTE (see Chapter 2):
• Typical warfarin initiation doses are between 5–10 mg; lower doses are needed
in some populations who are sensitive to warfarin (see Chapter 2).
• Higher initial treatment doses (e.g., 10 mg) have been associated with obtain-
ing a more rapid therapeutic international normalized ratio (INR) in outpatients
treated for DVT.
• Delay in obtaining therapeutic INRs has the potential to prolong costly hospi-
talization or LMWH therapy.
• Ensure that all transitional care issues are addressed if initial therapy is given in
the inpatient setting (follow-up INR scheduled, provider is aware of discharge
and transition plans, duration of therapy is communicated).
• Make sure the patient receives warfarin education and VTE education (Joint
Commission National Patient Safety Goal requirement and part of the VTE
Core Measures).
• Desired goal INR range is 2–3; higher INR targets have been linked to more
bleeding events, and lower INR targets (1.5–2) were not as effective with no
clear benefit on bleeding outcomes.32,33
• A lower INR range of 1.5–2 has been found to be superior to placebo after an
initial 6 months of conventional goal therapy (2–3 target INR) and may be an
option to help decrease the number of needed INR tests (INR measurements
were 8 weeks apart if INR 1.3–3).34
TABLE 13-9: Summary of Phase 3 Clinical Trials/Dosing of

DOACs versus Standard of Care for Acute VTE Treatment
DOAC Acute Treatment Dose Long-Term Comments
Secondary
Prevention Dose
Dabigatran Parenteral AC >5 days, 150 mg po twice Similar rate of recurrent

then 150 mg po BID x 6 daily VTE, less major bleeding in
months dabigatran-treated patients.
Rivaroxaban 15 mg po BID x 21 20 mg po daily or Similar rate of recurrent

days, then 20 mg po 10 mg po daily VTE, less major bleeding
daily x 3–12 months in patients treated with
rivaroxaban 20 mg daily.
For long-term secondary
prevention, 10 mg was no
different than 20 mg daily in
recurrent VTE or bleeding,
and was superior to aspirin
100 mg daily in preventing
recurrent VTE.
Apixaban 10 mg po BID x 7 days, 2.5 mg po twice Similar rate of recurrent

then 5 mg po BID x 6 daily (after VTE, less major bleeding in
months 6 months) apixaban-treated patients.
Edoxaban Parenteral AC >5 Not studied Similar rates of recurrent VTE,

days, then 60 mg po similar rate major bleeding in
daily x 3–12 months edoxaban-treated patients.
(30-mg dose was used
for CrCl 30–50 mL/
min, weight <60 kg, or
potent p-glycoprotein
inhibitors)
AC: anticoagulation, BID: twice daily, CrCl: creatinine clearance, PO: by mouth, VTE: venous
thromboembolism, x: times
Duration of Use of Anticoagulants in VTE

See Table 13-10 for therapy duration recommendations.
TABLE 13-10: ACCP Recommended Duration of Anticoagulation

Therapy4
Indication* Length of Therapy ACCP Evidence Grade
Provoked proximal DVT or PE 3 months 1B

Provoked isolated distal DVT† 2C
First unprovoked proximal DVT or PE with 1B
high bleeding risk 2B
Second unprovoked VTE, high bleeding risk
First unprovoked isolated distal†, proximal At least 3 months 1B

DVT, or PE 1B
Evaluate for risk–benefit of extended
therapy at 3 months
First unprovoked proximal DVT or PE Extended therapy 2B (low bleeding risk)

2B (moderate bleeding
risk)
Second unprovoked VTE Extended therapy 1B (low bleeding risk)

2B (moderate bleeding
risk)
DVT of leg or PE with active cancer Extended therapy 1B (low bleeding risk)
2B (high bleeding risk)
*See Table 13-3 provoking risk factors and Table 13-11 for bleeding risk stratification; see Table
13-12 for risk factors helpful in determining length of therapy in patient with unprovoked VTE.
†
Isolated DVT without severe symptoms can be managed by serial imaging for 2 weeks;
anticoagulate if clot extends proximally.
TABLE 13-11: ACCP Bleeding Risk Stratification for VTE4

Risk factors for Age >65, previous bleeding, active malignancy, renal failure, liver
bleeding on failure, thrombocytopenia, previous stroke, diabetes mellitus, anemia,
anticoagulation antiplatelet therapy, poor warfarin control, reduced functional capacity,
therapy recent surgery/intervention, frequent falls, alcohol abuse, nonsteroidal
anti-inflammatory medications
Low risk 0 risk factors
Moderate risk 1 risk factor
High risk ≥2 risk factors
Source: Adapted from the 2016 Antithrombotic Therapy for VTE Disease CHEST Guideline and
Expert Panel Report.
• Determining the duration of therapy:

{{ The length and duration of anticoagulation
should be regularly reassessed at least
annually, considering that the risk for overall
VTE recurrence is 7% within the first year
and 40% within 5 years.35
{{ In general, the long-term risks of
anticoagulant use (bleeding) must be weighed
against the risk of repeat thrombosis when
deciding the optimal length of therapy.
{{ The role of thrombophilia assessment to
help guide the length of therapy decision is
controversial.
{{ A positive d-dimer at the time of warfarin
discontinuation or shortly thereafter has been
shown in clinical trials to identify patients
at higher risk for developing recurrent VTE,
particularly in women.36
{{ The risk for recurrence is not the same
between men and women, with women
having a 45% lower risk of recurrent VTE
than men.37
{{ Patients that stop anticoagulation after
a provoked VTE should consider aspirin
therapy; aspirin does help prevent recurrent
VTE (less effective than anticoagulation),
and secondary prevention therapies for
arterial disease may have been stopped
because the patient was placed on
anticoagulation.
Risk Factors to Determine Length of Anticoagulation

Therapy
The patient characteristics and comorbidities in Table 13-12 are important
to recognize when determining the length of anticoagulation therapy. For
example, patients with known antiphospholipid antibody syndrome are high
risk for recurrent VTE and may benefit from a longer course of therapy.
TABLE 13-12: Positive and Negative Risk Factors for Recurrent

VTE to Help Determine Length of Therapy to Prevent
Recurrent VTE34,35
Risk Factor Relative Risk
Antiphospholipid antibody syndrome 2
Male gender 1.6
Hereditary thrombophilia 1.5
Residual thrombosis in proximal veins 1.5
Two or more prior VTE 1.5
Asian descent 0.8
Isolated calf thrombosis (vs. proximal DVT) 0.5
Negative D-dimer 1 month after VKA 0.4

discontinuation
THROMBOPHILIA TESTING
Patients diagnosed with VTE, accompanied with the characteristics below,
may be referred for thrombophilia testing as it could be helpful in determin-
ing length of therapy.
Indications When Hereditary Hypercoagulability Tests

May Be Useful to Guide Therapy*
• VTE before the age of 40
• Strong family history of VTE
• Thrombosis at an atypical anatomical site
• Large PE
• Neonatal purpura fulminans or warfarin skin necrosis
• Multiple VTEs
• Recurrent pregnancy losses, stillbirth
*These tests can be deferred until after a 3–6 month anticoagulant course
of therapy, as initial anticoagulation management is unlikely to change with
regard to the results of testing.
See Figure 13-10 for proposed treatment duration when thrombophilia
testing information is available.
Thromboembolism
Treatment duration
algorithm in inherited
hypercoaguable states
Indefinite Anticoagulation Variable Anticoagulation Indeterminate Anticoagulation 3–6 mo Anticoagulation
Protein C deficiency Prothrombin G20210A Malignancy Homocycystinemia

Protein S deficiency Factor V Leiden heterozygote (anticoagulate until (consider indefinite
Antithrombin deficiency Elevated factor VIII levels malignancy eradicated) vitamin
sticky platelet syndrome Uncommon hypercoaguable supplementation)
Greater than one abnormality disorder Antiphospholipid antibody syndrome
(indefinite anticoagulation unless 6 mo
of persistent negative antibodies)
Spontaneous or
recurrent thrombosis
Yes
Lifelong anticoagulation
No 3–6 mo anticoagulation
Use prophylaxis in high-risk scenarios
FIGURE 13-10. Proposed Treatment Algorithm When Thrombophilia Information Is Known

Source: Adapted with permission from Thomas RH. Hypercoagulability syndromes. Arch Intern Med. 2001;161(20):2433–2439.
SUMMARY
The management of VTE continues to evolve. Since the last edition of this
text, DOACs have supplanted VKA therapy as the preferred first-line therapy
for initial and secondary treatment for most patients, although their use in
special patient populations (e.g., patients with cancer and genetic throm-
bophilia) requires further study. Ongoing clinical trials in cancer-associated
VTE patients will help clarify the role of DOACs in this important patient
population. The data on the use of fibrinolytics continue to evolve yet remain
unclear in patients without massive PE. Careful consideration is needed on
the use of fibrinolytics in patients with submassive PE, where the risk–benefit
needs to be thoroughly reviewed in each patient. The duration of VTE treat-
ment also continues to evolve. When determining the medication choice and
duration of treatment, you should consider patient-specific characteristics
that influence both recurrent VTE risk and major bleeding along with patient
preference. All clinicians should closely monitor this quickly changing litera-
ture and be sure to individualize all patient treatment decisions.

1. Centers for Disease Control and Prevention. National Vital Statistics Reports. Deaths:
Final Data for 2012. http://www.cdc.gov/nchs/data/nvsr/nvsr63/nvsr63_09.pdf.
Accessed August 3, 2017.
2. Goldhaber SZ. Deep Venous thrombosis and pulmonary thromboembolism. In: Kasper
D, Fauci A, Hauser S, et al., eds. Harrison’s Principles of Internal Medicine. 19th ed.
New York, NY: McGraw-Hill; 2014.
3. Kucher N. Deep-vein thrombosis of the upper extremity. N Engl J Med. 2011;364:861-
869.
*4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST
Guideline. Chest. 2016;149:315-352.
*5. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis
and management of acute pulmonary embolism: The Task Force for the Diagnosis
and Management of Acute Pulmonary Embolism of the European Society of
Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). Eur Heart J.
2014;35:3033-3069, 3069a-3069k.
6. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of
deep-vein thrombosis in clinical management. Lancet. 1997;350(9094):1795-1798.
7. Wikimedia. https://upload.wikimedia.org/wikipedia/en/e/ea/SADDLE_PE.JPG.
8. Wikicommons. https://commons.wikimedia.org/wiki/File:Pulmonary_embolism_
scintigraphy_PLoS.png).
9. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to
categorize patients probability of pulmonary embolism: increasing the models utility
with the SimpliRED D-dimer. Thromb Haemost. 2000;83(3):416-420.
10. Gibson NS, Sohne M, Kruip MJ, et al. Further validation and simplification of the Wells
clinical decision rule in pulmonary embolism. Thromb Haemost. 2008;99:229-234.
11. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic
model for pulmonary embolism. Am J Respir Crit Care Med. 2005;172:1041-1046.
12. Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism
severity index for prognostication in patients with acute symptomatic pulmonary
embolism. Arch Intern Med. 2010;170:1383-1389.
*13. Vedantham S, Piazza G, Sista AK, Goldenburg NA. Guidance on the use of thrombolytic
therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis.
2016;41:68-80.
14. Eight-year follow-up of patients with permanent vena cava filters in the prevention of
pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par
Interruption Cave) randomized study. Circulation. 2005;112(3):416-422.
15. Mismetti P, Laporte S, Pellerin O, et al. Effect of retrievable inferior vena cava filter
plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism.
A randomized clinical trial. JAMA. 2015;313(16):1627-1635.
16. Stein PD, Matta F, Keyes DC, et al. Impact of vena cava filters on in-hospital case
fatality rate from pulmonary embolism. Am J Med. 2012;125(5):478-484.
17. Isogai T, Yasunaga H, Matsui H, et al. Effectiveness of inferior vena cava filters on
mortality as an adjuvant to antithrombotic therapy. Am J Med. 2015;128(3):312.e23-
321.e31.
18. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis
and treatment in patients with cancer: American Society of Clinical Oncology clinical
practice guideline update. J Clin Oncol. 2013;31(17):2189.
19. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology. Cancer-Associated Venous Thromboembolic Disease. Version 2.2014. http://
www.nccn.org. Published August 11, 2015; accessed August 3, 2017.
20. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin
for the prevention of recurrent venous thromboembolism in patients with cancer. N
Engl J Med. 2003;349(2):146-153.
21. Wu C, Lee AYY. Novel or non-vitamin k antagonist oral anticoagulants and the
treatment of cancer-associated thrombosis. Semin Thromb Hemost. 2015;41:237-243.
22. Vedovati MC, Germini F, Agnelli G, et al. Direct oral anticoagulants in patients with
VTE and cancer: a systematic review and meta-analysis. Chest. 2015; 147:475-483.
*23. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators.
Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled
analysis. Circulation. 2014;129:764-772.
*24. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral
rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med.
2012;366:1287-1297.
*25. Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy
for the treatment of symptomatic venous thromboembolism: a pooled analysis of the
EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.
*26. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the
treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
*27. Büller HR, Décousus H, Grosso MA, et al.; Hokusai-VTE Investigators. Edoxaban
versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J
Med. 2013;9:1406-1415.
28. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited influence on the
safety, tolerability, pharmacokinetics or pharmacodynamics of rivaroxaban (bay 59-
7939) in healthy subjects. J Clin Pharmacol. 2007;47:218-226.
29. Upreti VV, Wang J, Barrett YC, et al. Effect of extreme body weight on the
pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy
subjects. Br J Clin Pharmacol. 2013;76:908-916.
30. Lisenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of
the oral thrombin inhibitor dabigatran etexilate in patients with non valvular atrial
fibrillation from the RE-LY trial. J Thromb Haemost. 2011;11:2168-2175.
*31. Weitz JI, Lensing WA, Prins MH, et al.; EINSTEIN-CHOICE Investigators.
Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J
Med. 2017;376:1211-1222.
32. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy
with conventional-intensity warfarin therapy for long-term prevention of recurrent
venous thromboembolism. N Engl J Med. 2003;349(7):631-639.
33. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin
therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. Apr
10 2003;348(15):1425-1434.
34. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease:
Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.: American College
of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012
Feb;141(suppl 2):e419S-494S.
35. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous
thromboembolism after discontinuing anticoagulation in patients with acute proximal
deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626
patients. Haematologica. 2007;92(2):199-205.
36. Baglin T, Palmer CR, Luddington R, et al. Unprovoked recurrent venous thrombosis:
prediction by D-dimer and clinical risk factors. J Thromb Haemost. 2008;6:577-582.
37. McRae S, Tran H, Schulman S, et al. Effect of patient’s sex on risk of recurrent venous
thromboembolism: a metaanalysis. Lancet. 2006;368:371-378.
38. Thomas RH. Hypercoagulability syndromes. Arch Intern Med. 2001;161(20):2433-
2439.
14 Chapter
ATRIAL FIBRILLATION
Daniel M. Witt
INTRODUCTION
Atrial fibrillation (AF) is a common cardiac rhythm disorder. Although AF rarely
causes life-threatening hemodynamic compromise, it is an important independent
risk factor for cardiogenic embolic stroke and systemic arterial thromboembolism.1
Approximately 90% of AF thromboembolic complications are stroke related, while
the remaining 10% are systemic embolism (see Table 14-1 for more information on
classifications). The following contribute to thromboembolic risk associated with AF:
• Stasis or turbulence of blood flow within the left atrial appendage leads to thrombus
formation.
• Dysfunction of vascular endothelium predisposes to local or systemic hypercoagulability.
• Conversion to normal sinus rhythm (NSR)—spontaneous or intentional—may dislodge
any existing left atrial thrombi.
MORBIDITY AND MORTALITY ASSOCIATED

WITH AF1,2
• Nonvalvular AF is associated with a 5-fold increased risk of stroke.
• The annual risk for nonfatal stroke in untreated AF patients varies between 0.8% and
9.6% (average ~5%) depending on concurrent individual risk factors.
• Attributable stroke risk in AF increases with age:3
{{ 1.5% for patients 50–59 years
{{ 23% for patients 80–89 years
• AF-related strokes tend to be more severe than non-AF-related strokes.
Data from high-quality, randomized controlled clinical trials overwhelmingly
demonstrates that long-term, adjusted-dose anticoagulation therapy with vitamin
K-antagonists (e.g., warfarin) or direct-acting oral anticoagulants (DOACs) (e.g.,
dabigatran, rivaroxaban, apixaban, edoxaban) virtually eliminates the stroke risk
associated with AF.1 Despite the proven efficacy of anticoagulation therapy in
preventing AF-related stroke, only about half of patients who could benefit receive
anticoagulation therapy.3 Increasing age, perceived bleeding risk, and the innate
complexity of managing anticoagulation therapy are some reasons underlying why
clinicians and patients with AF opt against anticoagulation therapy.
347
TABLE 14-1: Classification of Atrial Fibrillation1

Paroxysmal AF Terminates spontaneously or with intervention within 7 days (may
recur)
Persistent AF Continuously sustained for >7 days
Long-standing Continuously sustained for >12 months

persistent AF
Permanent AF When patient and clinician jointly decide to stop further attempts to
restore/maintain sinus rhythm (a therapeutic attitude not related to
inherent pathophysiologic attributes of AF)a
Nonvalvular AF AF in the absence of rheumatic mitral stenosis, a mechanical or

bioprosthetic heart valve, or mitral valve repair
a
Attitude may change as symptoms, efficacy of therapeutic interventions, and patient–clinician
preferences evolve over time.
AF: atrial fibrillation
TREATMENT OVERVIEW
Rate versus Rhythm Control

• Evidence from randomized clinical trials indicates that cardioversion of AF to
normal sinus rhythm (rhythm control) is not necessary nor preferable to allowing
AF to continue while controlling ventricular response rate with AV node blockade
(rate control) with concurrent anticoagulation in those with high enough risk to
justify therapy.4,5
{{ The AFFIRM trial found no difference in mortality or stroke rate
between patients assigned to one strategy or the other.4
{{ The RACE trial (patients had persistent AF post failed cardioversion)
found rate control not inferior to rhythm control for prevention of
death and morbidity.5
{{ Rate- or rhythm-control strategies do not seem to affect quality of
life significantly or differently.
{{ Ischemic events occurred with similar frequency with either a rhythm
or rate control strategy, especially when warfarin was discontinued
or when anticoagulation was subtherapeutic.
{{ In younger individuals, a combined rate and rhythm approach may
minimize the risk of related heart failure.
{{ Whether a rate or rhythm control strategy is employed, AF patients
with thromboembolic risk factors should probably receive chronic
anticoagulation.1
ATRIAL FIBRILLATION 349
Antithrombotic Therapy for Stroke Prevention in

Nonvalvular AF
See Figure 14-1.
• Patients with valvular AF are at high stroke risk and should receive anticoagula-
tion therapy.
• Decisions regarding antithrombotic therapy for patients with nonvalvular AF
should be based on shared decision making, discussion of risks of stroke and
bleeding (including risk for falls), and patient’s preferences.1
• Aspirin provides little protection against stroke in AF and is markedly inferior to
warfarin (International Normalized Ratio [INR] 2–3) or DOAC therapy.1,2
• Adjusted-dose warfarin for stroke prevention is significantly better than clopi-
dogrel plus aspirin, and clopidogrel plus aspirin is superior to aspirin alone.1
• Apixaban for stroke prevention is significantly better than aspirin without
increased bleeding risk.6
• For patients with stable coronary artery disease, adding aspirin to warfarin
therapy increases the risk of major bleeding and does not provide further protec-
tion against ischemic stroke in patients with AF.2
• Patients with AF and mechanical heart valve replacement should be treated with
warfarin with the target INR determined by the location (mitral vs. aortic) and
type of valve (bi-leaflet versus older valve types).1
{{ Adding low-dose aspirin (50–100 mg/day) to warfarin therapy has
been suggested for patients with mechanical valves who are at
low risk for bleeding.7
{{ Dabigatran is contraindicated for use in patients with mechanical
heart valves (safety and efficacy information is lacking for rivar-
oxaban, apixaban, and edoxaban and mechanical heart valves).1
{{ Data examining DOAC use in patients with bioprosthetic heart
valves are limited, and use is not currently recommended.
• The need for ongoing anticoagulation therapy should be reevaluated at periodic
intervals.5
• The key decision in AF stroke risk reduction is whether to use oral antico-
agulation (warfarin or DOAC therapy)—Antiplatelet therapy with aspirin or
clopidogrel plus aspirin should be considered only when oral anticoagulation
is not an option due to either very low stroke risk or contraindications to oral
anticoagulation therapy (e.g., bleeding risk, inability to comply with the require-
ments of therapy).1,2
Nonvalvular AF Stroke Risk Stratification Tools and

Consensus Panel Treatment Guidelines
• Warfarin or DOAC therapy is highly effective at reducing the risk for stroke
associated with nonvalvular AF.
{{ However, anticoagulation therapy is associated with increased
bleeding risk—most importantly the risk for intracranial hemorrhage.
Cardioversion without prolonged anticoagulation No AF present for more
(therapeutic IV UFH, LMWH or DOAC suggested at
than 48 hours
presentation if no contraindication to anticoagulation)
Yes
Severe (angina, heart

failure, hypotension, Symptoms? Minimal
Algorithm
syncope)
Emergency electrical cardioversion (therapeutic IV UFH, LMWH or Control ventricular rate with
DOAC suggested as soon as possible) CCB, BB, or digoxin
Follow with at least 4 weeks of therapeutic anticoagulation if NSR
maintained
Rhythm control
Rate control
(reasonable for younger patients with paroxysmal AF or who remain
(reasonable for older patients with persistent AF and stroke risk factors)
symptomatic despite adequate rate control)
Screening TEE plus

immediate therapeutic Warfarin (INR 2-3) or DOAC
anticoagulation with IV UFH, Stroke risk?
for at least 3 weeks
LMWH or DOAC
No Prior stroke/TIA/systemic
Thrombus Electric or pharmacologic
No embolism or mitral stenosis CHA2DS2VASc=1 CHA2DS2VASc=0
seen? cardioversion
or CHA2DS2VASc >1
Yes
Chronic warfarin (INR Chronic warfarin (INR Omitting

Postpone cardioversion NSR? 2-3) or DOAC 2-3) or DOAC antithrombotic
(repeat TEE prior to
therapy is reasonable
attempting later Or
cardioversion) Yes
ASA + clopidogrel or
ASA alone
Stroke risk
factors?
Warfarin (INR 2-3) or DOAC
Omitting
No Yes antithrombotic
therapy is reasonable
Warfarin (INR 2-3) or Chronic warfarin (INR IV=intravenous; UFH=unfractionated heparin; LMWH=low-molecular weight heparin;
DOAC for at least 4 weeks 2-3) or DOAC NSR=normal sinus rhythm; CCB=calcium channel blocker (non-dihydropyridine); BB=beta
blocker; TEE=transesophageal echocardiogram; INR=international normalized ratio;
FIGURE 14-1. Stroke Prevention in Atrial Fibrillation Treatment

TIA=transient ischemic attack; ASA=aspirin; DOAC=direct oral anticoagulant
Therefore, various risk stratification schemes have evolved with the

following goals:
{{ Identifying AF patients at such low risk of stroke that anticoagulation
therapy-associated bleeding risk may outweigh stroke prevention
benefit.
{{ Encouraging anticoagulation therapy use in AF patients at high risk
for stroke where benefit has been clearly demonstrated.
• The CHADS2 score, which is well validated and easy to use, is the nonvalvular AF
stroke risk stratification tool used for recommendations of the 9th ed., American
College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9). 2
Risk Factor Points
Congestive heart failurea =1
Hypertensionb =1
Age ≥75 years of age =1
Diabetesc =1
Prior stroke/TIA/systemic embolusd =2

a
Signs/symptoms of heart failure confirmed with objective evidence of cardiac dysfunction.
b
Resting BP >140/90 mmHg on at least 2 occasions or current antihypertensive pharmacologic
treatment.
Fasting glucose >125 mg/dL or treatment with oral hypoglycemic agent and/or insulin.
c
d
Includes any history of cerebral ischemia.
Example: An 82-year-old male with hypertension and prior stroke would

have a CHADS2 score = 4.
Higher CHADS2 score = higher AF stroke risk8
CHADS2 Score Stroke AT9 Recommendations for Antithrombotic Therapy2

Rate (%/
year)
0 1.9 No therapy is suggested rather than antithrombotic therapy

(Grade 2B)
For patients choosing antithrombotic therapy, aspirin (75
mg–325 mg once daily) is suggested rather than warfarin (INR
2–3) or DOAC (Grade 2B) or combination therapy with aspirin
and clopidogrel (Grade 2B)
1 2.8 Warfarin (INR 2–3) or DOAC is recommended rather than

no therapy (Grade 1B) or aspirin (75 mg–325 mg once daily)
(Grade 2B) or combination therapy with aspirin and clopidogrel
(Grade 2B)
For patients unsuitable for or choosing not to take warfarin or
DOAC (for reasons other than concerns about major bleeding),
combination therapy with aspirin and clopidogrel is suggested
rather than aspirin (75 mg–325 mg once daily) (Grade 2B)
2 4 Warfarin (INR 2–3) or DOAC is recommended rather than no

therapy (Grade 1A), aspirin (75 mg– 325 mg once daily) (Grade
3 5.9 1B), or combination therapy with aspirin and clopidogrel
(Grade 1B)
4 8.5 For patients unsuitable for or choosing not to take warfarin
or DOAC (for reasons other than concerns about major
5 12.5
bleeding), combination therapy with aspirin and clopidogrel
6 18.2 is recommended rather than aspirin (75–325 mg once daily)
(Grade 1B)
Grade 1A: strong recommendation, high-quality evidence; Grade 1B: strong recommendation,
moderate-quality evidence; Grade 2B: weak recommendation, moderate-quality evidence; Grade
2C: weak recommendation, low- or very low-quality evidence
• A revised scoring approach (CHA2DS2-VASc) is the nonvalvular AF stroke risk

stratification tool used in recommendations from 2014 AHA/ACC/HRS Guideline
for the Management of Patients with Atrial Fibrillation: A Report of the Ameri-
can College of Cardiology/American Heart Association Task Force on Practice
Guidelines and the Heart Rhythm Society.1
Stroke Risk Factor Points
Congestive heart failurea =1
Hypertension b
=1
Age ≥75 years of age =2
Diabetesc =1
Prior stroke/TIA/systemic embolus d

=2
Vascular diseasee =1
Age 65–74 =1
Sex category (female) =1

a
Signs/symptoms of heart failure confirmed with objective evidence of cardiac dysfunction.
b
Resting BP >140/90 mmHg on at least 2 occasions or current antihypertensive pharmacologic
treatment.
Fasting glucose >125 mg/dL or treatment with oral hypoglycemic agent and/or insulin.
c
d
Includes any history of cerebral ischemia, peripheral arterial embolism, or pulmonary embolism.
e
Prior myocardial infarction, peripheral artery disease, or aortic plaque.
The CHA2DS2-VASc identifies a lower risk population; the impact of the

approach over the CHADS2 has not been determined.
CHA2DS2-VASc Stroke Rate AT9 Recommendations for Antithrombotic Therapy2

Score (%/year)
0 0 Reasonable to omit antithrombotic therapy (Class IIa: B)
1 1.3 No antithrombotic therapy or treatment with warfarin (INR

2–3), or DOAC or aspirin may be considered (Class IIb: C)
2 2.2 Warfarin (INR 2–3) (Class I:A) or DOAC (Class I:B)
3 3.2
4 4
5 6.7
6 9.8
7 9.6
8 6.7
9 15.2
Class I: A = recommendation that treatment is useful/effective, evidence from multiple

randomized trials; Class I: B = recommendation that treatment is useful/effective, evidence from
single randomized trial; Class IIa: B = recommendation in favor of treatment, some conflicting
evidence from single randomized trial or nonrandomized studies; Class IIb: C = recommendation’s
usefulness/efficacy less well established, only diverging expert opinion, case studies, or standard
of care.
• Echocardiography is often used in treatment decision-making but has limited

proven value in determining the need for chronic oral anticoagulation therapy.
{{ Echocardiography can detect the presence of features associ-
ated with thromboembolism. Anticoagulation therapy in patients
with these features has been shown to reduce stroke risk (e.g.,
impaired left ventricular systolic function, left atrial thrombus,
dense spontaneous echo contrast, “smoke,” or reduced velocity of
blood flow in the left atrial appendage); however, the absence of
these echocardiographic abnormalities has not been established as
identifying a low-risk group of AF patients who could safely forgo
warfarin therapy.1
{{ Echocardiography is valuable for detecting rheumatic mitral valve
disease (there is universal agreement that these patients should
receive warfarin therapy).1
{{ Detection of left atrial thrombus is a contraindication for cardiover-
sion of AF (see below).
{{ Transesophageal echocardiography (TEE) is the most sensitive and
specific technique to detect left atrial (LA) thrombi as a potential
source of systemic embolism in AF and can be used to guide the
timing of cardioversion or catheter ablation procedures.1
• Risk stratification caveats
{{ CHADS2 and CHA2DS2-VASc are appropriate only for patients with
nonvalvular AF.
{{ No published risk stratification tool is ideal, and all can frequently
underestimate stroke risk.9
{{ Although risk stratification tools identify AF patients who will likely
benefit most and least from warfarin therapy, the stroke versus
bleeding risk tipping point for anticoagulation therapy use is
controversial, especially for those at intermediate risk for stroke.
{{ Use of CHADS 2 and CHA 2DS2-VASc for patients with end-stage
renal disease on dialysis is controversial.
{{ No tool can incorporate all potential AF stroke risk factors. Risk
stratification tools can, therefore, best be described as “rough
guides” to help inform clinicians.9
{{ Although bleeding risk stratification tools exist (e.g., HAS-BLED),
they are rarely used in clinical practice because many clinicians
error toward preventing cardioembolic stroke at the expense of
bleeding as it is more often fatal or severely debilitating compared
to most types of bleeding, with the exception of intracranial hemor-

rhage (ICH).10
{{ Patient perspectives and preferences should also factor into clinical
decision making.1
Optimal Intensity of Warfarin Anticoagulation for AF

• Optimal warfarin therapy intensity involves a careful balancing between maximiz-
ing protection against thromboembolism while minimizing bleeding risk (ICH in
particular rivals ischemic stroke in terms of clinical importance).
{{ The risk of ischemic stroke is low at INR levels ≥2.10
{{ An INR >3.5 at ICH presentation doubles the risk for fatal ICH.11
{{ An INR of <2 at admission for a new stroke substantially increases
the likelihood of death and severe disability from AF-related
stroke.12
{{ There is virtually no evidence supporting a decreased risk of ICH
at INR levels <2.10
• Strong evidence supports the recommended INR target of 2.5 (range 2–3).
{{ Narrower target ranges have been suggested in certain situations
(e.g., INR 2–2.5 has been recommended in patients requiring
warfarin, aspirin, and clopidogrel following percutaneous coronary
intervention).13 Such narrow ranges are not supported by good
evidence, which makes achieving therapeutic INRs more difficult
and usually results in the need for more frequent INR testing.
{{ Target INR range 2–3 should be used for most patients with AF.10
Stroke Prevention Considerations During Cardioversion

• Systemic embolism can complicate cardioversion whether NSR is reestablished
by electrical, pharmacologic, or spontaneous means (see Figure 14-2).
• Conversion of AF to NSR, regardless of method, results in transient mechanical
dysfunction of the left atrium (“stunning”).1
{{ Recovery of mechanical function occurs over a period of days to
weeks (depending in part on duration of AF prior to conversion).
{{ Thromboembolism after cardioversion can be due to migration
of thrombi formed prior to cardioversion or to the formation and
subsequent migration of thrombi formed while atrial function is still
depressed in the period following cardioversion.1
• Although at least 4 weeks of warfarin (INR 2–3) or DOAC therapy is recommended
following successful cardioversion, patients with risk factors for thromboembo-
lism should continue anticoagulation beyond 4 weeks unless there is convincing
evidence that NSR is maintained.1
• DOACs have been shown to be effective and safe to use prior to cardiover-
sion—shocks can be delivered at any time during the dosing interval.
• There are no randomized clinical trials to guide anticoagulation for emergency
cardioversion. Expert opinion suggests that hemodynamically unstable patients
requiring emergency cardioversion should receive therapeutic anticoagulation
Elective IV=intravenous; UFH=unfractionated heparin; LMWH=low-molecular weight heparin;
cardioversion NSR=normal sinus rhythm; TEE=transesophageal echocardiogram; INR=international normalized
planned ratio; DOAC=direct oral anticoagulant
TEE guided Conventional Conventional Warfarin

vs. TEE vs.
guided? DOAC?
Warfarin (INR 2-3) DOAC

Perform TEE
No No
INR ≥2.0 No missed

for 3 doses for 3
weeks? weeks?
Cardioversion Treatment Algorithm

Thrombus No Attempt Yes
seen? cardioversion
Yes
Postpone cardioversion, continue No

Cardioversion
warfarin (INR 2-3) or DOAC , repeat TTE Warfarin (INR 2-3) or DOAC indefinitely
successful?
before attempting later cardioversion
FIGURE 14-2. Anticoagulation Therapy for Elective

Yes
No Yes Chronic warfarin (INR 2-3) or DOAC unless

Warfarin (INR 2-3) or DOAC for at least 4 Stroke risk
convincing evidence that NSR is
weeks factors?
maintained
with either intravenous (IV) unfractionated heparin (UFH), low molecular weight
heparin (LMWH), or DOAC therapy started as soon as possible, followed by at
least 4 weeks of warfarin (INR 2–3) or DOAC therapy.1
{{ The optimal strategy for initiating warfarin once patients are
hemodynamically stable is not known.
{{ Bridging with UFH or LMWH during initiation of warfarin in patients
with AF has been shown to increase the risk of bleeding without
the benefit of preventing stroke.14
{{ The optimal intensity for heparin or dose of a LMWH has not been
assessed in clinical trials. Higher doses (e.g., similar to doses used
for venous thromboembolism [VTE] treatment or acute coronary
syndrome [ACS] treatment) have evolved out of the high concern
for a stroke, yet evidence supporting this strategy as a bridge to
warfarin therapy is currently limited.
{{ Most stable patients do not require cross-coverage with parenteral
anticoagulants (bridge therapy).
Electrical versus Pharmacologic Cardioversion,

Implications for Anticoagulation Therapy
• Anticoagulation therapy recommendations are similar for electrical and pharma-
cologic cardioversion.
• Amiodarone is commonly used to maintain NSR in AF patients following
successful cardioversion and presents unique challenges for patients on warfarin
therapy.15
{{ Amiodarone inhibits the metabolism of warfarin leading to the
potential for excessive anticoagulation and increased bleeding risk.
{{ Amiodarone may take hundreds of days to reach steady state due
to its very long half-life.
{{ Co-administration of warfarin and amiodarone requires vigilant
INR monitoring (at least weekly for several weeks and as needed
thereafter). Some have advocated empiric warfarin dose reductions
(35–65%) when amiodarone is added to ongoing warfarin there-
apy; 15 however, optimal timing of empiric dose reductions are
challenging since the clinical onset of the interaction is often
delayed and becomes more significant over time
NONPHARMACOLOGIC PREVENTION OF AF
STROKE
• Obliteration of the left atrial appendage (LAA) by direct surgical truncation,
amputation, or closure devices inserted into the LAA (e.g., WATCHMAN device)
are emerging second-line options for patients who are not suitable candidates
for chronic anticoagulation therapy.1
{{ After 3.8 years of follow-up, percutaneous LAA closure with the
WATCHMAN device met criteria for both noninferiority and superi-
ority, compared with warfarin alone (INR 2–3), for preventing the
combined outcome of stroke, systemic embolism, and cardiovas-

cular death, as well as superiority for cardiovascular and mortality
from all causes.16
{{ Following implantation of the WATCHMAN device, antithrombotic
medication is required to allow endothelialization of the device
surface.
Continue warfarin for at least 45 days.
If device stability, flow leaks around the margins of the
filter, and thrombus formation are deemed satisfactory,
discontinue warfarin and substitute clopidogrel 75 mg/
day plus aspirin 81–325 mg/day until 6 months after
device implantation.
After 6 months, discontinue clopidogrel and continue
with aspirin alone.
FDA approved the WATCHMAN device in 2015.
{{ Surgical-based procedures to exclude the LAA during cardiac
surgery are controversial because of the inconsistency of surgical
techniques, the highly variable rates of successful LAA occlusion/
closure, and the unknown impact of LAA occlusion/closure on
future, thromboembolic events. 1 Because of the risk for incom-
plete LAA occlusion/closure and subsequent thrombus formation,
anticoagulation therapy should probably be continued following
surgical LAA ligation unless contraindicated and occlusion/closure
of the LAA is confirmed via TEE.1
{{ The Lariat snare device has also been used for the exclusion of the
LAA but has not been evaluated in clinical trials specifically for this
indication, so there is no way to know if the device is safe or if it
prevents stroke.17
• Other nonpharmacologic measures aimed at restoring NSR, including the surgi-
cal Maze procedure and various catheter ablation techniques, are playing an
increasing role in AF management.
{{ The current version of the Maze procedure involves cryotherapy
or bipolar radiofrequency ablation in the atria along with the
amputation of both atrial appendages to prevent the occurrence
of AF and restores NSR in over 90% of patients. The procedure
can be done in conjunction with other surgical procedures, such
as cardiac valve replacement or independently through a small
incision to access the atria.1
{{ The VATS/MAZE procedure is a video-assisted approach similar
to catheter-directed ablation; however, lines are drawn instead
of pinpoints
{{ The primary indication for catheter AF ablation is the presence
of symptomatic AF refractory to or intolerant of antiarrhythmic
medication.1
{{ Ablation involves placing a catheter into the left atrium and either
using a heating or freezing technique to tissues surrounding the
pulmonary veins to disrupt their electrical conduction by blocking

or destroying abnormal electrical pathways and/or ectopic foci.
AF recurrence rates with catheter ablation are high and
may be asymptomatic, even among previously symptom-
atic patients.18 The procedure may need to be repeated
to fully ablate conduction.
{{ AF patients with stroke risk factors should continue warfarin therapy
for a prolonged period after surgery or ablation procedures.18
{{ The Heart Rhythm Society/European Hearth Rhythm Association/
European Cardiac Arrhythmia Society Expert Consensus Statement
on Catheter and Surgical Ablation of Atrial Fibrillation makes the
following recommendations regarding anticoagulation therapy
during ablation procedures:18
Recommendations regarding anticoagulation at the time
of cardioversion apply to patients who are in AF at the
time of the ablation procedure.
If adequate systemic anticoagulation has not been
maintained for at least 3 weeks prior to the AF ablation
procedure, a pre-ablation TEE should be performed
in all patients with AF >48 hours in duration or of an
unknown duration.
The presence of a left atrial thrombus is a contraindica-
tion to AF catheter ablation.
Performance of a TEE in patients in NSR or who have
been in AF for 48 hours or less prior to AF ablation may
be considered but is not mandatory.
Continuing therapeutic anticoagulation with warfarin
during performance of catheter ablation of AF should
be considered. Because of concerns for procedure-
related bleeding, including transeptal perforations, use
of DOACs has not been widely considered.
During AF ablation, UFH adjusted to achieve and
maintain an activated clotting time (ACT – low range)
of 300–400 seconds should be administered prior to or
immediately following transseptal puncture regardless
of whether the patient is anticoagulated with warfarin.
Administration of protamine following ablation to reverse
heparin should be considered.
Patients who are not therapeutically anticoagulated with
warfarin at the time of AF ablation should be bridged
with LMWH (a reduction of the dose to 0.5 mg/kg should
be considered to reduce bleeding risk) or IV UFH during
resumption of warfarin. Alternatively DOAC initiation
may be considered as a post-ablation anticoagulation
strategy.
Warfarin (INR 2–3) or DOAC is recommended for at least
2 months following an AF ablation procedure (consider
prolonged therapy for patients who are at high risk of

stroke based on CHADS2 of CHA2DS2-VASc).
Continuous ECG monitoring to screen for asymptomatic
AF should be considered prior to discontinuing system-
atic anticoagulation.

*1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the
management of patients with atrial fibrillation: executive summary: a report of the
American College of Cardiology/American Heart Association Task Force on practice
guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-2104.
*2. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation:
Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141:e531S-
575S.
3. Lopes RD, Crowley MJ, Shah BR, et al. Stroke Prevention in Atrial Fibrillation.
Rockville, MD: Agency for Healthcare Research and Quality; 2013.
4. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm
control in patients with recurrent persistent atrial fibrillation. New Engl J Med.
2002;347:1834-1840.
5. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control
in patients with atrial fibrillation. New Engl J Med. 2002;347:1825-1833.
6. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation.
New Engl J Med. 2011;364:806-817.
7. Whitlock RP, Sun JC, Fremes SE, et al., American College of Chest Physicians.
Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy
and Prevention of Thrombosis. 9th ed. American College of Chest Physicians Evidence-
based Clinical Practice Guidelines. Chest. 2012;141:e576S-600S.
8. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes
for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA.
2001;285:2864-2870.
9. Lip GY. The balance between stroke prevention and bleeding risk in atrial fibrillation: a
delicate balance revisited. Stroke. 2008;39:1406-1408.
10. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of
anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis. 9th
Chest. 2012;141:e152S-184S.
11. Witt DM, Delate T, Hylek EM, et al. Effect of warfarin on intracranial hemorrhage
incidence and fatal outcomes. Thromb Res. 2013;132:770-775.
12. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke
severity and mortality in atrial fibrillation. New Engl J Med. 2003;349:1019-1026.
13. King SB, III, Smith SC, Jr., Hirshfeld JW, Jr., et al. 2007 Focused Update of the ACC/
AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention: a report of
Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/
SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf
of the 2005 Writing Committee. Circulation. 2008;117:261-295.
14. Kim TH, Kim JY, Mun HS, et al. Heparin bridging in warfarin anticoagulation
therapy initiation could increase bleeding in non-valvular atrial fibrillation patients: a
multicenter propensity-matched analysis. J Thromb Haemost. 2015;13:182-190.
15. Lu Y, Won KA, Nelson BJ, et al. Characteristics of the amiodarone-warfarin interaction
during long-term follow-up. Am J Health-Syst Pharm. 2008;65:947-952.
16. Reddy VY, Sievert H, Halperin J, et al. Percutaneous left atrial appendage closure vs
warfarin for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988-1998.
17. Varosy PD. Lariat-Small Step or Giant Leap? JAMA Intern Med. 2015;175(7):1110-
1111.
*18. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus
statement on catheter and surgical ablation of atrial fibrillation: recommendations
for patient selection, procedural techniques, patient management and follow-up,
definitions, endpoints, and research trial design. J Interv Card Electrophysiol.
2012;33:171-257.
15 Chapter
ACUTE CORONARY SYNDROMES

Sarah A. Spinler
EPIDEMIOLOGY OF ACS
It is estimated that more than 1.1 million patients experience an acute coronary
syndrome (ACS) each year, with 813,000 diagnosed with myocardial infarction (MI).1
Of patients presenting with suspected ACS, international registry data indicate
that approximately 31% have ST segment elevation (STE) MI, 32% non-ST segment
elevation (NSTE) MI, 26% unstable angina, 8% another cardiac diagnosis, and 4%
noncardiac final diagnosis (see Table 15-1).2
TABLE 15-1: In-Hospital Outcomes of ACS with MI2

Estimated In-Hospital Outcomes STEMI NSTEMI Unstable Angina
Death (%) 6.2 2.9 1.7
Reinfarction (%) 12 10 1.2
Heart failure (%) 15 10 6
Stroke (%) 1 0.5 0.2
Major bleeding (%) 1.4 1.2 0.5
PATHOPHYSIOLOGY AND EPIDEMIOLOGY OF

ACS
ACSs, (MI, or myocardial ischemia) are caused by partial or complete thrombotic
occlusion of a coronary artery due to plaque rupture, erosion, fissuring, or dissec-
tion (Figure 15-1).
SIGNS AND SYMPTOMS OF ACS
Signs
• Electrocardiogram (ECG) changes: ST-segment elevation, ST-segment depression,
T-wave inversion, new left bundle branch block, Q waves (Figures 15-2A and B).
363
Cross Section of a Coronary Artery
Arterial wall
Arterial blood
Clot
Myocardial infarction: Unstable angina:

complete occlusion partial occlusion
FIGURE 15-1. Pathophysiology of ACS
FIGURE 15-2. Electrocardiographic Findings in ACS

A. ST-segment elevation; B. ST-segment depression.
ACUTE CORONARY SYNDROMES 365
• Elevated biochemical markers: elevated troponin T or I,* elevated creatine

kinase MB.
• Acute heart failure or cardiogenic shock: rales, S3, hypoxia, hypotension, pulmo-
nary edema on chest x-ray.
• Ventricular arrhythmias.
*Negative biomarkers measured within 6 hours of symptom onset should be
remeasured 8–12 hours after symptom onset; positive biomarkers may be
remeasured at 6–8-hour intervals until a peak is observed.
Symptoms
• Anterior medial chest pain, pressure, tightness, or squeezing occurring at rest.
• Radiation of chest discomfort to left arm, shoulder, back, or jaw.
• Increasing frequency, severity, or duration of angina.
• Nausea, vomiting.
DIAGNOSTIC CRITERIA FOR ACS
Universal Criteria for Acute Myocardial Infarction3

Diagnosis of MI is made by any one of the following criteria:
• Detection of a rise or fall in biochemical markers (troponin preferred) with at least
one value above the 99th percentile of a normal reference population (upper
reference limit) together with at least one of the following:
{{ Symptoms of ischemia
{{ New or presumed new electrocardiography (ECG) changes
(ST-segment, T-wave changes, or new left bundle branch block)
{{ Development of pathological Q waves on the ECG
{{ Imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality (akinesis, dyskinesis) on echocardiogram
{{ Identification of intracoronary thrombus by angiography or on
autopsy
• Sudden, unexplained cardiac death involving cardiac arrest with symptoms
suggestive of ischemia.
• For patients undergoing percutaneous coronary intervention (PCI):
{{ If preprocedure troponin negative—elevated troponin level >5 x
above the 99th percentile of the upper reference limit.
{{ If preprocedure positive—elevated troponin level that rises >20%.
{{ With symptoms suggestive of myocardial ischemic, new ischemic
ECG changes, or angiographic evidence consistent with a proce-
dural complication or imaging suggestive of new loss of viable
myocardial or a new regional wall motion abnormality.
Myocardial infarction is classified as:

• Type 1: Spontaneous MI related to atherosclerotic plaque rupture, fissuring,
erosion, or dissection with resulting thrombus leading to decreased myocardial
blood flow and necrosis.
• Type 2: Demand ischemia with an imbalance between myocardial oxygen supply
and demand.
• Type 3: Cardiac death with symptoms suggestive of myocardial ischemia and
presumed new ECG changes, but death occurred before biomarkers could be
obtained.
• Type 4a: MI related to PCI.
• Type 4b: MI related to stent thrombosis.
RISK STRATIFICATION FOR NSTE ACS

An early invasive approach with coronary angiography and revascularization
with either PCI or coronary artery bypass graft (CABG) is recommended for
high-risk patients with NSTE ACS defined as either TIMI risk score of ≥5
(Table 15-2) or GRACE risk score >140 (Figure 15-3).4-8
On-line risk calculators:

{{ On-line risk calculators are available for
NSTE ACS.
{{ TIMI Risk Score5: http://www.mdcalc.com/
timi-risk-score-for-uanstemi/
{{ Grace Risk Score8: http://gracescore.org/
WebSite/default.aspx?ReturnUrl=%2f
ANTICOAGULATION CONSIDERATIONS IN
PATIENTS WITH ACS
Bleeding Definitions
Bleeding in ACS clinical trials is typically classified using either the TIMI,
GUSTO, or BARC bleeding definitions (see Table 15-3).9
Relationship Between aPTT and anti-Factor Xa for

Unfractionated Heparin and Outcomes
• Recent clinical trials have targeted a therapeutic range of 50–70 seconds without
calibration to anti-factor Xa activity to account for reagent variability.
• Data evaluating bleeding and thrombotic risk with unfractionated heparin (UFH)
in ACS are sparse and consist of post-hoc analysis of large, randomized trials.
TABLE 15-2: TIMI Risk Score for NSTE ACS4,5

One point is assigned for each of the seven medical history and clinical presentation findings.
The point total is calculated, and the patient is assigned a risk for experiencing the composite
endpoint of death, myocardial infarction, or urgent need for revascularization as follows:
• Age ≥65 years
• Three or more CHD risk factors: smoking, hypercholesterolemia, hypertension, diabetes

mellitus, family history of premature CHD death/events
• Known CAD (≥50% stenosis of at least one major coronary artery on coronary angiogram)
• Aspirin use within the past 7 days
• Two or more episodes of chest discomfort within the past 24 hr
• ST-segment depression ≥0.5 mm
• Positive biochemical marker for infarction
High Risk Medium Risk Low Risk
TIMI risk score TIMI risk score TIMI risk score
5–7 points 3–4 points 0–2 points
TIMI Risk Score Mortality, MI, or Severe Recurrent Ischemic Requiring Urgent Target
Vessel Revascularization
0/1 4.7%
2 8.3%
3 13.2%
4 19.9%
5 26.2%
6/7 40.9%
• Data supporting the therapeutic range of 50–70 seconds are strongest from
early fibrinolytic trials.10–13
{{ GUSTO-1 trial of patients with STEMI treated with fibrinolytics,
an aPTT of 50–70 seconds was associated with the lowest rates of
30-day mortality, stroke, and bleeding.10
{{ No evidence of increased thrombotic risk with aPTTs <50 seconds.10
{{ Increased mortality and reinfarction risk, as well as bleeding, was
found in patients with aPTTs >70 seconds.10
{{ In GUSTO-IIb, another STEMI fibrinolytic trial, weight was the
strongest predictor of a therapeutic aPTT and a simulated bolus
dose of 60 units/kg and initial infusion of 12 units/kg/hr resulted in
the highest proportion of therapeutic aPTTs. An aPTT of approxi-
mately 70 seconds and an initial infusion dose of 12 units/kg/hr
were associated with the lowest mortality rate.11
FIGURE 15-3. GRACE Risk Score

Source: Reprinted with permission from Pieper KS, Gore JM, FitzGerald G, et al. Validity
of a risk-prediction tool for hospital mortality: the Global Registry of Acute Coronary
Events. Am Heart J. 2009;157:1097-1105; copyright © 2009 with permission from
Elsevier.
{{ aPTT target range of 50–70 seconds using weight-based heparin

dosing nomograms was tested prospectively in the GUSTO-V trial.12
{{ Patients with STEMI treated with reteplase and heparin with or
without abciximab.12
{{ Higher aPTTs >70 seconds were associated with bleeding, but there
was no association between peak aPTT and mortality.12
{{ Lower aPTTs <50 seconds were also associated with worse
outcomes.12
TABLE 15-3: Bleeding Definitions9

TIMI Non-CABG–Related Bleeding
Major Any intracranial bleeding (excluding microhemorrhages <10 mm evident

only on gradient-echo MRI)
Clinically overt signs of hemorrhage associated with a drop in hemoglobin
of ≥5 g/dL
Fatal bleeding (bleeding that directly results in death within 7 days)
Minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to

<5 g/dL
Requiring medical Any overt sign of hemorrhage that meets one of the following criteria and
attention does not meet criteria for a major or minor bleeding event, as defined
above
Requiring intervention (medical practitioner-guided medical or surgical
treatment to stop or treat bleeding, including temporarily or permanently
discontinuing or changing the dose of a medication or study drug)
Leading to or prolonging hospitalization
Prompting evaluation (leading to an unscheduled visit to a healthcare
professional and diagnostic testing, either laboratory or imaging)
Minimal Any overt bleeding event that does not meet the criteria above
GUSTO Bleeding
Severe or life- Intracerebral hemorrhage

threatening Resulting in substantial hemodynamic compromise requiring treatment
Moderate Requiring blood transfusion but not resulting in hemodynamic

compromise
Mild Bleeding that does not meet above criteria
Bleeding Academic Research Consortium (BARC) Bleeding
Type 0 No bleeding
Type 1 Bleeding that is not actionable and does not cause the patient to seek
consultation or treatment
Type 2 Any clinically overt sign of hemorrhage that “is actionable” and
requires diagnostic studies, treatment by a healthcare professional, or
hospitalization and does not fit the criteria for Type 3, 4, or 5 bleeding
Type 3 a. Overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided

hemoglobin drop is related to bleed); transfusion with overt bleeding
b. Overt bleeding plus hemoglobin drop <5 g/dL (provided
hemoglobin drop is related to bleed); cardiac tamponade; bleeding
requiring surgical intervention for control; bleeding requiring IV
vasoactive agents
c. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar
puncture; intraocular bleed compromising vision
Type 4 CABG-related bleeding within 48 hr
Type 5 a. Probable fatal bleeding

b. Definite fatal bleeding (overt or autopsy or imaging confirmation)
{{ In the EXTRACT-TIMI 25 trial, markedly high aPTTs ≥2.75 x control

were associated with increased bleeding risk while low aPTTs
<1.25 x control tended to be associated with increased risk of MI
at 48 hours.13
• The data supporting a heparin therapeutic range in patients with NSTE ACS
are less robust.14-17
{{ In the OASIS-2 trial, a target aPTT of 60–100 seconds was suggested
for investigators. Patients with aPTTs <60 seconds had higher rates
of recurrent ischemic events, while those with aPTTs ≥100 seconds
had an increased risk of bleeding.14
{{ In PARAGON-A, there was no statistically significant association
between aPTT and death, reinfarction, or bleeding.15
{{ In TIMI-IIIB, a large randomized trial in patients with NSTE ACS
treated with fibrinolytics or placebo, neither heparin anti-factor
Xa activity levels nor aPTT were predictive of recurrent ischemia,
reinfarction, or death.16
{{ In SYNERGY, a large randomized trial in patients with NSTE ACS
treated with enoxaparin or UFH (target aPTT 1.5-2 x the upper limit
of normal, approximately 50–70 seconds), the aPTT on heparin was
not associated with either ischemic or bleeding events.17
• aPTT calibration to a heparin anti-factor Xa activity level of 0.3–0.7 International
Units/mL, from which to develop a weight-based heparin nomogram, is still
recommended by both the American College of Chest Physicians (ACCP) and
the American College of Pathologists.18,19 However,
{{ No data from ACS clinical trials support this target heparin anti-
factor Xa activity range, which was originally developed from a
single study of venous thromboembolism treatment.
{{ The 2012 ACCP guidelines acknowledge that the true therapeutic
range for coronary indications is unknown, but is likely associated
with heparin anti-factor Xa levels “that are about 10% lower than
those used for treatment of patients with VTE.”18
Relationship Between anti-Factor Xa Activity with Low

Molecular Weight Heparin and Outcomes
The best predictor of bleeding in patients treated with low molecular weight
heparins (LMWHs) is dose (mg) per kg.
• A desired therapeutic range for anti-Factor Xa activity with LMWHs in patients
with ACS has not been determined.20
• In TIMI-11A trial of patients with NSTE ACS, enoxaparin doses of 1.25 mg/kg
every 12 hours had a higher rate of major hemorrhage than patients receiving
a dose of 1 mg/kg every 12 hours.21
{{ In subgroup analysis of patients treated with the higher doses of
enoxaparin, patients who experienced a major bleeding event had
peak anti-factor Xa levels of 1.8 International Units/mL compared
to 1.4 International Units/mL in patients without major bleeding.
{{ Peak levels in patients treated with the 1 mg/kg dose were 1 Inter-
national Units/mL, and only two patients experienced bleeding.
• The STEEPLE trial randomized patients undergoing elective PCI for stable
coronary heart disease (CAD) to a single IV dose of either enoxaparin 0.5 mg/kg
or 0.75 mg/kg.22
{{ Patients with anti-factor Xa levels >0.9 International Units/mL had
increased non-CABG combined major/minor bleeding.
• A third smaller prospective study in patients with NSTE ACS suggested that
anti-factor Xa levels <0.5 International Units/mL were an independent predic-
tor of 30-day mortality. However, the mean dose of enoxaparin administered to
patients with low anti-factor Xa levels was only 0.66 mg/kg.23
• Overall, no strong data suggest routine monitoring of anti-factor Xa levels
achieve a target anti-factor Xa therapeutic range with LMWHs if dosed accord-
ing to body weight.
RISK FACTORS FOR MAJOR BLEEDING

Although validated risk prediction scores for predicting in-hospital major
bleeding, such as the CRUSADE Bleeding Risk Score and the ACTION
Registry®-GWTG™ Bleeding Risk Score, are available (see below), they are
seldom utilized clinically to alter anticoagulant or antiplatelet therapy and
no professional association guidelines recommend their use in practice at
this time.
• Important bleeding risk predictors are renal dysfunction (low estimated creati-
nine clearance), anemia, low body weight, and presence of acute heart failure/
shock.24-26
• Use of transradial rather than transfemoral access reduces bleeding.27
{{ The results from MATRIX radial versus femoral access study
demonstrated a significant 17% relative risk reduction in net clini-
cal adverse events (defined as major adverse CV events or major
bleeding) with radial versus femoral access, primarily due to a 33%
reduction in major bleeding. Mortality was also improved with the
radial approach (1.6% vs. 2.2%, p=0.045).28
{{ Transradial access is preferred access site for patients with ACS. 27,28
On-line calculator:
{{ CRUSADE Bleeding Risk Score29: http://
crusadebleedingscore.org/index.html
GUIDELINE-BASED SELECTION OF
ANTICOAGULANT THERAPY
Guideline-recommended anticoagulants for ACS and monitoring are
described in Tables 15-4 through 15-8 and guideline-recommended
antiplatelets for ACS are described in Tables 15-9 through 15-11.
TABLE 15-4: Primary PCI for STEMI30
Agent 2013 ACC/AHA STEMI Contraindications Dose (Class Recommendation) Duration Comments (Class Recommendation)
Guidelines Class
Recommendations
UFH IC Active bleeding, Primary PCI (without GP IIb/IIIa) Discontinue at end of Primary PCI without GP IIb/IIIa inhibitor:
HIT inhibitor): 70–100 units/kg to achieve procedure ACT 250–300 sec with HemoTec and
a therapeutic ACT 300–350 sec with Hemochron
Primary PCI (with GP IIb/IIIa inhibitor): Primary PCI with GP IIb/IIIa inhibitor:
50–70 units/kg IV bolus to achieve a ACT of 200–250 sec
therapeutic ACT
Bivalirudin IB Active bleeding 0.75-mg/kg IV bolus followed by Until end of PCI No dose reduction for renal
Preferred over UFH with 1.75 mg/kg/hr with or without prior procedure (preferred); dysfunction used in clinical trials; may
GP IIb/IIIa inhibitor in UFH treatment (for patients receiving option to continue at consider reduction in infusion to 1
patients with high risk of UFH; discontinue UFH and wait 30 same IV infusion dose mg/kg/hr for patients with CrCl <30
bleeding (IIA) min prior to starting bivalirudin) for 4 hr post-procedure; mL/min and to 0.25 mg/kg/hr for
An additional 0.3 mg/kg IV bolus option to continue patients receiving dialysis; may also
may be given lower dose 0.2 mg/kg/ be used in patients previously treated
hr for an additional 20 with UFH; preferred for patients with
hr post-procedure history of HIT; pretreatment with
P2Y12 inhibitor preferred; lower rate
of bleeding and mortality reduction
compared to UFH
ACT: activated clotting time, CrCl: creatinine clearance, GP: glycoprotein, PCI: percutaneous coronary intervention, UFH: unfractionated heparin
TABLE 15-5: STEMI with Fibrinolytics30
Agent 2013 ACC/ Contraindications Dose Duration Comments
AHA STEMI
Guidelines Class
Recommendations
UFH IC Active bleeding, HIT 60 units/kg (max 4,000 units) IV 48 hr aPTT 1.5–2 x control (50–70 sec); for secondary PCI
bolus followed by 12 units/kg/hr IV following administration of fibrinolytics, administer
infusion (max 1,000 units/hr) additional IV bolus doses to PCI ACT targets
Enoxaparin IA Active bleeding, HIT; For patients <75 yr old: 30-mg IV Minimum Avoid in patients previously treated with UFH; for
serum creatinine ≥2.5 bolus followed by 1 mg/kg sub-Q of 48 hr secondary PCI during hospitalization following
mg/dL in men or ≥2 q 12 hr and up to fibrinolytics, if the last sub-Q dose was administered
mg/dL in women For patients ≥75 yr old: 0.75 mg/kg 8 days at least 8–12 hr earlier, administer an IV dose of
sub-Q q 12 hr (omit IV bolus) 0.3 mg/kg; if the last sub-Q dose was administered
For patients weighing >100 kg and within the prior 8 hr, no additional enoxaparin should
<75 yr old: Cap first two doses at be given; lower rate of death or MI but higher
100 mg bleeding rate compared to UFH
For patients weighing ≥100 kg and
≥75 yr old: Cap first two doses at
75 mg
If during therapy CrCl <30 mL/min:
Decrease dose to 1 mg/kg sub-Q
once daily
Fondaparinuxa IB Active bleeding, 2.5 mg IV followed by 2.5 mg sub-Q Minimum Similar death or MI rate and similar bleeding
creatinine clearance daily starting day 2 of 48 hr rate compared to UFH; for secondary PCI during
< 30 mL/min and up to hospitalization, administer with additional UFH as for
8 days primary PCI
a
Not FDA-approved.
CrCl: creatinine clearance, HIT: heparin-induced thrombocytopenia, MI: myocardial infarction, PCI: percutaneous coronary intervention, sub-Q: subcutaneous, UFH:
TABLE 15-6: NSTE ACS31
Agent 2014 AHA/ Contraindications Dose Duration Comments
ACC NSTEMI
ACS Guideline
Recommendation
UFH IA Active bleeding, 60-units/kg (max 4,000 At least 48 hr or until aPTT 1.5–2 x control (50–70 sec)
HIT units) IV bolus followed by hospital discharge,
12 units/kg/hr IV infusion discontinue after PCI
(max 1,000 units/hr)
Enoxaparin IA Active bleeding, 1 mg/kg sub-Q q 12 hr; Continue for the duration For PCI, if the last sub-Q dose was administered at
HIT reduce dose to 1 mg/kg of hospitalization (up to 8 least 8–12 hr earlier, administer an IV dose of 0.3
q 24 hr if CrCl <30 mL/ days); discontinued after mg/kg; if the last sub-Q dose was administered
min; consider dose cap PCI within the prior 8 hr, no additional enoxaparin
of 120 mg (higher doses should be given; not studied in patients receiving
associated with bleeding dialysis; similar death or MI rate and higher
risk in CRUSADE registry) bleeding risk compared to bivalirudin for high-
risk patients treated with an early interventional
strategy; lower death, MI or urgent revascularization
and higher bleeding risk compared to UFH for
patients undergoing an early conservative strategy;
similar death or MI risk and higher bleeding risk
compared to fondaparinux for patients undergoing
an early conservative strategy
(continued)
Agent 2014 AHA/ Contraindications Dose Duration Comments
ACC NSTEMI
ACS Guideline
Recommendation
Fondaparinuxa IB Active bleeding, 2.5 mg/kg sub-Q daily Continue for the duration Increased risk of catheter thrombosis during PCI
CrCl <30 mL/min of hospitalization (up to 8 if used as sole anticoagulant; administer 50–60
days); discontinued after units/kg IV heparin bolus during PCI; similar death
PCI or MI risk and lower bleeding risk compared to
fondaparinux for patients undergoing an early
conservative strategy
Bivalirudinb IB Active bleeding 0.1-mg/kg IV bolus Until end of PCI procedure Not studied for initial conservative strategy;
followed by 0.25 mg/kg/ (preferred); option to preferred for patients with PCI and initial invasive
hr infusion until diagnostic continue at same IV strategy; similar efficacy and lower bleeding rate
angiography performed; infusion dose for 4 hr compared to UFH or enoxaparin for early invasive
at time of PCI, administer postprocedure; option to strategy; no dose reduction for renal dysfunction
additional IV bolus of continue lower dose 0.2 used in clinical trials; may consider reduction in
0.5 mg/kg and increase mg/kg/hr for an additional infusion to 1 mg/kg/hr for patients with CrCl <30
infusion rate to 1.75 mg/ 20 hr postprocedure mL/min and to 0.25 mg/kg/hr for patients receiving
kg/hr dialysis; preferred for patients with history of HIT;
pretreatment with a P2Y12 inhibitor (clopidogrel or
ticagrelor pre-PCI) preferred
a
Not FDA-approved.
b
Not FDA-approved for initial conservative strategy.
ACC: American College of Cardiology, AHA: American Heart Association, aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, IV: intravenous, PCI:
percutaneous coronary intervention, sub-Q: subcutaneous, UA/NSTEMI: unstable angina/non-ST-segment elevation myocardial infarction, UFH: unfractionated heparin
TABLE 15-7: Injectable Anticoagulant Monitoring

Agent Monitoring
UFH Daily weight, clinical signs and symptoms of bleeding, aPTT or heparin anti-
factor Xa activity levels at baseline and q 4–6 hr until in desired range then
daily thereafter, ACT during PCI; baseline and daily platelet count, baseline
INR
Enoxaparin Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline platelet count, baseline and daily CBC, baseline INR
Fondaparinux Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline and daily CBC, baseline platelet count, baseline INR
Bivalirudin Daily weight, clinical signs and symptoms of bleeding, baseline and daily
CrCl, baseline and daily CBC, baseline platelet count, baseline INR
ACT: activated clotting time, aPTT: activated partial thromboplastin time, CBC: complete blood
count, INR: international normalized ratio, PCI: percutaneous coronary intervention
TABLE 15-8: Interventional Issues: Arterial Femoral Sheath

Management Following Cardiac Catheterization32-35
Agent Recommended Sheath Management
UFH ACT <180 seca
Enoxaparin 1. 4 hr after last IV dose or 6–8 hr after last

sub-Q dosea
2. Can consider immediate removal with
arterial closure device if single 0.5 mg/
kg IV dose used
If continuing treatment, give next scheduled
dose no sooner than 6 hr after sheath
removed.
Bivalirudin 1. Immediate removal using an arterial

closure device, or
2. Remove 2 hr after discontinuation
without ACT monitoringa
a
Follow with direct manual groin compression (preferred over mechanical compression device).
ACT: activated clotting time, IV: intravenous, UFH: unfractionated heparin
TABLE 15-9: Concomitant Aspirin Therapy30,31

ACS Initial Dose Subsequent Doses Starting
Day 2 and Duration of
Therapy
NSTE ACS31 162–325 mg nonenteric 81–162 mg/day indefinitely

coated formulation either oral 81 mg/day preferreda
or chewed With ticagrelor 81 mg/day
STEMI with fibrinolysis)30 162–325 mg nonenteric 75–100 mg/day indefinitely

STEMI primary PCI30 162–325 mg nonenteric 81–325 mg/day indefinitely

a
Higher doses are not associated with improved efficacy and are associated with increased
bleeding risk (Grade IIaB recommendation).30
TABLE 15-10: Concomitant P2Y12 Inhibitor30,31,36

ACS Initial Dose Subsequent Doses Starting Day
2 and Duration of Therapy (Class
Recommendation)
NSTE ACS (initial Clopidogrel 300 mg or Clopidogrel 75 mg daily in addition to

ischemia guided 600 mg aspirin for up to 12 monthsa,b
strategy)31 Ticagrelor 180 mg 90 mg bid in addition to aspirin for up to
12 monthsa-c
Ticagrelor preferred over clopidogrel (Grade
IIaB recommendation)
NSTE ACS PCI stent31 Clopidogrel 300 mg or Clopidogrel 75 mg daily in addition to

600 mg aspirin for up to 12 monthsa,b
Ticagrelor 180 mg 90 mg bid in addition to aspirin for up to
12 monthsa-c
Ticagrelor preferred over clopidogrel
(Grade IIaB recommendation)
Prasugrel 60 mg Prasugrel 10 mg daily in addition to aspirin
for up to 12 monthsa; dose reduction to
5 mg daily for patients weighing <60 kg;
contraindicated in patients with prior
stroke/TIA
Prasugrel preferred over clopidogrel in
patients who are not at high risk for bleeding
(Grade IIaB recommendation)
STEMI fibrinolysis30 For patients age >75 yr: Clopidogrel 75 mg daily for at least 14 days
Clopidogrel 75 mg and up to 1 year
For patients age ≥75 yr:
Clopidogrel 300 mg
(continued)

ACS Initial Dose Subsequent Doses Starting Day
2 and Duration of Therapy (Class
Recommendation)
STEMI primary PCI30 Clopidogrel 600 mg Clopidogrel 75 mg daily in addition to

aspirin for up to 12 monthsa,b,d
Ticagrelor 180 mg 90 mg bid in addition to aspirin for up to
12 monthsa-d
Prasugrel 60 mg Prasugrel 10 mg daily in addition to aspirin
for up to 12 months,a,d dose reduction to
5 mg daily for patients weighing <60 kg;
contraindicated in patients with prior
stroke/TIA
For patients Clopidogrel Discontinue at least 5 days before surgery

undergoing elective Ticagrelor Discontinue at least 5 days before surgery
CABG surgery31 Prasugrel Discontinue at least 7 days before surgery
For patients Clopidogrel Ideally discontinue at least 24 hours before

undergoing urgent Ticagrelor surgery
CABG surgery31 Prasugrel Ideally discontinue at least 24 hours before
surgery
No recommendation given (unlikely to be
used as only given following angiography/
PCI)
a
Earlier discontinuation (i.e. <12 months) is reasonable if morbidity from bleeding outweighs
anticipated benefit (Grade IIaC recommendation).31
b
Continuation of dual antiplatelet therapy may be considered for >12 months (Grade IIbC
recommendation).
c
Also FDA-approved for a dose reduction to 60 mg bid after 12 months based on the results of
the PEGASUS trial, which demonstrated a 15% reduction in the composited endpoint of death,
MI or stroke at 3 years with a higher rate of bleeding.
d
Continue beyond 1 year for drug-eluting stent (Grade IIbC recommendation).
CABG: coronary artery bypass graft, NSTE: non-ST-segment elevation, PCI: percutaneous
coronary intervention, STEMI: ST-segment elevation myocardial infarction
TABLE 15-11: Glycoprotein IIb/IIIA Inhibitors for PCI in ACS30,31,37
Agent ACC/AHA Guideline Contraindications Dose (started at time of PCI, i.e., Comments
Recommendations30,31 downstream)
Abciximab NSTE ACS in patients with high-risk Active bleeding, 0.25-mg/kg IV or intracoronary bolus Agent with most data for STEMI
features not pretreated with clopidogrel thrombocytopenia, history of followed by 0.125 mcg/kg/min primary PCI; intracoronary
or ticagrelor prior to PCI (IA). stroke. (maximum 10 mcg/min) started at administration not an FDA-approved
STEMI primary PCI (IIaA) time of angiography. dose.
Eptifibatide NSTE ACS in patients treated with DAPT Active bleeding, 180-mcg/kg IV bolus x 2, 10 min Early routine use prior to coronary
(Class IIbB initial therapy, IIaB at time of thrombocytopenia, history of apart with an infusion of 2 mcg/kg/ angiography increases bleeding
PCI). stroke, kidney dialysis. min and not efficacy in high-risk patients
NSTE ACS in patients with high-risk with NSTE ACS37; dose adjusted to
features not pretreated with clopidogrel 1 mcg/kg/min in patients with CrCl
or ticagrelor prior to PCI (IA). <50 mL/min.
STEMI primary PCI (IIaB) Contraindicated in patients with prior
stroke.
Avoid in patients on dialysis.
Tirofiban NSTE ACS in patients treated with DAPT Active bleeding, High-dose bolus regimen: 25 mcg/ If CrCl ≤60 mL/min, give 25 mcg/kg
(Class IIbB initial therapy, IIaB at time of thrombocytopenia, history of kg within 5 min, then 0.15 mcg/kg/ within 5 min and then 0.075 mcg/
PCI). stroke. min kg/min.
NSTE ACS in patients with high-risk High-dose bolus regimen now FDA-
features not pretreated with clopidogrel approved for NSTEMI ACS, but not
or ticagrelor prior to PCI (IA). for STEMI.
STEMI primary PCI (IIaB)
In patients scheduled for CABG surgery, discontinue eptifibatide and tirofiban for at least 2–4 hr and abciximab at least 12 hours prior to surgery.
ACC/AHA: American College of Cardiology/American Heart Association, CABG: coronary artery bypass graft, CrCl: creatinine clearance, FDA: U.S. Food and Drug
Administration, IANSTE: non-ST-segment elevation, PCI: percutaneous coronary intervention, STEMI: ST-segment elevation myocardial infarction
In practice, infusions often omitted or duration of infusion brief <12 hours (no guideline recommendation on infusion duration).
Controversy: Triple Antithrombotic Therapy in Patients

with PCI/Coronary Artery Stents Requiring Long-Term
Anticoagulation
• Patients with ACS are indicated for dual antiplatelet therapy (DAPT) with aspirin
and a P2Y12 inhibitor for up to 1 year to prevent recurrent cardiovascular death,
MI, or stroke as well as stent thrombosis.30,31
• Data from well-designed clinical trials evaluating triple antithrombotic therapy
following PCI are scarce and limited to just two randomized trials, WOEST and
ISAR-TRIPLE.38-42
{{ In WOEST, 573 patients receiving a VKA and undergoing PCI were
randomized to dual therapy (DT) with VKA plus clopidogrel or triple
therapy with VKA, clopidogrel, and low-dose aspirin. At 1 year, the
DT group had lower:
Rates of all TIMI bleeding
Rates of BARC serious bleeding
Major adverse cardiac events40
{{ A recent meta-analysis confirmed similar thromboembolic but lower
bleeding risk with clopidogrel plus VKA versus triple therapy.42
{{ In ISAR-TRIPLE, patients receiving VKA therapy and aspirin (75–200
mg daily) and undergoing PCI (most had second- and third-genera-
tion DES) were randomized to 6 weeks vs. 6 months of clopidogrel
therapy with INR targets around 2.41
No difference in net clinical adverse effects (composite
of death, MI, definite stent thrombosis, stroke, or TIMI
major bleeding) at 9 months and no major difference in
TIMI major bleeding.
{{ Only about one-third of patients in WOEST and ISAR TRIPLE had
ACS; therefore, little information is available to base a recommen-
dation on dual versus triple therapy in this patient population.40,41
{{ Results from three small, observational studies reported a higher
bleeding rate with prasugrel and similar bleeding rates with ticagre-
lor as part of triple therapy.43-45
{{ Limitations with the registries and sparse data with randomized
clinical trials have resulted in variability in professional association
guideline recommendations (Table 15-12).30,31,46-48
{{ European guidelines recommend focus on patients with AF and
recommend a radial approach and newer generation DES. DAPT
without oral anticoagulation may be used in patients with AF
and low risk of stroke (CHA2DS2-Vasc score of 1 in males and 2 in
females). Either a DOAC or a VKA may be selected (Figure 15-4).47,48
{{ U.S. guidelines state:
Duration of triple therapy should be minimized.
Clopidogrel is preferred as the P2Y12 inhibitor.
Low-dose aspirin should be used as part of the triple
therapy regimen.
Use of DOAC compared to VKA is not discussed.30,31

PIONEER AF-PCI was released late in the publication
process of this book. For a short discussion of this trial,
see Appendix M.
TABLE 15-12: Triple Therapy30,31,46-48

Guideline Triple Antithrombotic Therapy Recommendation
2014 ACC/AHA NSTE Minimize the duration of triple therapy (IC).

ACS31 Use a lower intensity INR (2–2.5) (IIbC).
Add a proton pump inhibitor to minimize bleeding risk (IC for a
patient with prior GI bleeding, IIaC for all patients).
2013 ACC/AHA STEMI Minimize the duration of triple therapy (IC).

primary PCI30 Use a lower intensity INR (2–2.5) (IIbC).
Avoidance of a DES (no recommendation grade).
2014 ESC NSTE In patients with low bleeding risk (HAS-BLED score ≤2) triple therapy
ACS46,47 (Section 5.4) with either VKA or DOAC, clopidogrel and low-dose aspirin (75–100
mg/day) for up to 6 months, then oral anticoagulant plus single
antiplatelet therapy from 6 months to 1 year, then anticoagulant alone
after 1 year (IIaC).
In patients with high bleeding risk (HAS-BLED score ≥3) triple therapy
with either VKA or DOAC, clopidogrel and low-dose aspirin (75–100
mg/day) for 1 month, then oral anticoagulant plus single antiplatelet
therapy from 1 month to 1 year (regardless of stent type), then
anticoagulant alone after 1 year (IIaC).
Consider DAPT rather than triple therapy if high bleeding risk (HAS-
BLED score ≥3) and low stent thrombosis risk (IIbB).
In a patient with AF taking chronic anticoagulation and having a low
CHA2DS2-Vasc score of 1 in males and 2 in females (especially in normal
sinus rhythm with normal LV function), discontinue the DOAC and use
DAPT with low-dose aspirin and either prasugrel or ticagrelor (IIaC).
In a patient with AF on a DOAC, prefer radial access for coronary
angiography (section 5.4.1).
In a patient with AF requiring triple therapy, a DOAC may be used
in addition to aspirin and clopidogrel but use the lowest dose of the
DOAC tested in clinical trials of AF (dabigatran 110 mg bid, apixaban
2.5 mg bid, and rivaroxaban 15 daily).
Do not use prasugrel or ticagrelor as part of triple therapy with a
DOAC.
If DES, may use triple therapy (clopidogrel in regimen) for 1 month
then discontinue clopidogrel at 1 month, continue DT with aspirin
and oral anticoagulant from 1 month to 1 year, then anticoagulation
alone at 1 year.
Add a proton pump inhibitor for gastric protection.
Use radial access for PCI (IA).
For patients at low bleeding risk, new generation DES preferred over
BMS (IIaB).
For patients at high bleeding risk, individualize the choice of stent
type.
For medically managed patients (no PCI), consider 1 antiplatelet
agent plus oral anticoagulant for up to 1 year, then oral anticoagulant
alone (IIaC).
(continued)

Guideline Triple Antithrombotic Therapy Recommendation
2015 EHRA practical Low-dose aspirin 75–100 mg/day as part of DT or triple therapy.
guideline on the use Clopidogrel rather than prasugrel or ticagrelor as part of triple
of DOACs in patients therapy.
with AF48 Factors that shorten recommended durations of triple therapy:
Uncorrectable high bleeding risk (HAS-BLED score), low
atherothrombotic risk (ACS GRACE score <118).
Factors that may lengthen triple therapy: First-generation DES, ACS,
high GRACE risk score ≥118, left main coronary artery stent, left
anterior descending artery stent, proximal bifurcating stent, recurrent
MI, AND low bleeding risk (HAS-BLED).
Scenario 1: AF patients already taking DOAC undergoing PCI

Discontinue DOAC at least 24 hr prior to elective PCI and at least 12
hr for NSTE ACS PCI if possible; restart same DOAC post-PCI at a
lower dose (dabigatran 110 mg bid, apixaban 2.5 mg bid, rivaroxaban
15 mg daily, edoxaban 30 mg daily) with at least one antiplatelet
agent; consider proton pump inhibitor for gastric protection.
Elective PCI: 1 month triple therapy for a BMS or newer generation
DES, DOAC plus clopidogrel from 1 month to 1 year, then DOAC
alone.
ACS: 6 months triple therapy unless high bleeding risk then 1 month;
followed by DT with NOAC plus either clopidogrel or low-dose
aspirin.
Scenario 2: Recent (<1 year ACS) who develops AF requiring

anticoagulation
Follow above recommendation depending on month’s post-ACS.
Scenario 3: ACS ≥1 year ago (stable CVD) who develops AF requiring

anticoagulation
Follow above recommendation for DOAC alone (i.e., discontinue all
antiplatelet agents).
ACC/AHA: American College of Cardiology/American Heart Association, ACS: acute coronary

syndrome, CABG: coronary artery bypass graft, CrCl: creatinine clearance, CVD: cardiovascular
disease, DAPT: dual antiplatelet therapy, DOAC: direct-acting oral anticoagulants, EHRA:
European Heart Rhythm Association, ESC: European Society of Cardiology, FDA: U.S. Food and
Drug Administration, NSTE: non-ST-segment elevation, PCI: percutaneous coronary intervention,
STEMI: ST-segment elevation myocardial infarction
*European guidelines suggest lower dose DOAC (apixaban 2.5 mg PO bid, dabigatran
110 mg PO bid, rivaroxaban 15 mg PO daily, edoxaban 30 mg PO daily);b low-dose aspirin
81 mg PO daily, PCI = percutaneous coronary intervention; DES = drug-eluting stent; BMS
= bare metal stent; VKA = vitamin K antagonist; DOAC = direct-acting oral anticoagulant;
DAPT = dual antiplatelet therapy
FIGURE 15-4. Triple Antithrombotic Therapy in Patients

Undergoing PCI46,47
Source: Adapted with permission from Heidbuchel H, Verhamme P, Alings M, et al.
Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin
K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2015;17(10):1467-1507.
Controversy: Duration of Dual Antiplatelet Therapy

(DAPT) for Patients with Second- and Third-Generation
Drug-Eluting Stents
• The duration of DAPT with aspirin and a P2Y12 inhibitor following PCI with a
DES is evolving.
• Stent platforms of newer generation DES are becoming less thrombogenic than
older DES (Table 15-13).
TABLE 15-13: Drug-Eluting Stent Types

• First-generation (older generation): paclitaxel, sirolimus
• Second-generation: zotarolimus, everolimus
• Third-generation: biodegradable polymer (e.g., biolimus)
• Fourth-generation: bioresorbable (e.g., everolimus)
• First-generation DES were clearly associated with a four- to five-fold increased

risk of stent thrombosis, necessitating DAPT for at least 1 year after placement.49
• More recent trials with newer generation DES have suggested similar major
adverse cardiac event rates and bleeding with 6 months, compared to 9 months
of DAPT where patients were randomized to discontinue clopidogrel at 6 months
as well as at 24 months in another trial where clopidogrel or prasugrel were
discontinued at 6 months.50,51
In the recent DAPT study where the majority, but not all patients, received a
newer generation DES:49
{{ Rates of stent thrombosis (0.4% vs. 1.4%) and major cardiovascular
and cerebrovascular (4.3% vs. 5.9%) events at 24 months post-PCI
were reduced.
{{ Moderate or severe bleeding increased when DAPT with clopidogrel
or prasugrel was continued beyond 12 months (2.5% vs. 1.6%).
• When a duration of <12 months versus ≥12 months are compared, there is no
difference in major adverse cardiac events and an increased risk of bleeding.52,53
• There is no difference in CV, noncardiovascular, and total mortality with a duration
of longer than 6 months compared to a shorter duration.54
• In higher-risk patients with a history of MI at the time of PCI, DAPT for a median
of 33 months decreased ischemia events but increased major but not fatal bleed-
ing. There was no difference in CV mortality.55
• On November 6, 2015, the U.S. Food and Drug Administration (FDA) issued
a drug safety communication stating that it had conducted a meta-analysis of
available data and found that ≥12 months of DAPT does not increase or decrease
mortality compared to less than 12 months of therapy.56
• As of April 2018, the most contemporary practice guidelines incorporating this
recent data are the European Society of Cardiology guidelines for patients with
NSTE ACS.47
{{ Ideally, all patients, whether PCI or medically managed, should
continue DAPT for at least 12 months (IA recommendation). Newer
generation DES is recommended over BMS for PCI (IA recommenda-
tion) unless bleeding risk is increased and then a newer generation
BMS is recommended with 30-day duration of DAPT (IIbB recom-
mendation). For patients with NSTE ACS and a DES who develop
bleeding or an increased bleed risk, a shorter course of DAPT 3–6
months is recommended.
• P
atients with stable CAD receiving newer
generation DES likely derive little benefit from
extended duration of DAPT beyond 6 months.
• W
hereas in patients with ACS, the decision on
duration of DAPT should be individualized,
evaluating patient characteristics for recurrent
stent thrombosis or major adverse cardiac events
but is likely >12 months.
• A DAPT risk score has been developed to identify
patients at low risk of ischemic CV and major
bleeding events likely to derive little benefit from
continuing DAPT beyond 12 months.57,58 If
validated in other studies, this risk score would
be a valuable clinical tool to determine a plan for
DAPT duration.
Step-Down Therapy of P2Y12 Inhibitors Following

Myocardial Infarction: Ticagrelor for Secondary
Prevention
• Ticagrelor added to low-dose aspirin is now FDA-approved in a reduced dose
of 90 mg PO bid to reduce the risk of cardiovascular death, MI, or stroke for
patients who are at least 1 year post-MI without a history of prior stroke.
• In PEGASUS TIMI-54 patients who were 1–3 years post-MI (median time 1.7
years) to either ticagrelor 90 mg PO bid or 180 mg PO bid and placebo found.59
{{ Both ticagrelor groups significantly reduced ischemic risk by about
15%.
{{ Increased TIMI major bleeding (but not fatal or intracranial hemor-
rhage) more than two-fold.
{{ No mortality benefit observed in ticagrelor-treated patients
compared to placebo.
Controversy: Bivalirudin Efficacy and Safety Compared to

Unfractionated Heparin for PCI
• There have been conflicting data regarding the comparative efficacy and safety
of bivalirudin and UFH (with or without a glycoprotein IIb/IIIa inhibitor) in ACS
and PCI clinical trials.60-64 In general, the results suggest that bivalirudin reduces
major bleeding but increases the frequency of stent thrombosis with similar net
clinical benefit.62
• There has been no substantive biological plausibility as to why bivalirudin has
been found to reduce mortality in some trials but not others.65
• Until additional data are available, either anticoagulant is an acceptable choice
(as per ACC/AHA practice guidelines) and practitioners should review utilization
and patient in-hospital bleeding risk and rates.30,31
CURRENT DOAC DATA FOR SECONDARY ACS

PREVENTION
• Rivaroxaban and apixaban added to aspirin and clopidogrel have been studied
in secondary prevention following ACS.66
{{ In ATLAS ACS2 TIMI 51, rivaroxaban 2.5 mg twice daily and 5 mg
twice daily started were compared to placebo in 15,526 patients
with ACS.
{{ Both doses of rivaroxaban reduced the primary composite endpoint
of cardiovascular death, MI, or stroke as well as stent thrombosis
compared to placebo.
{{ Patients enrolled in COMPASS did not have ACS and did not have
a current indication for DAPT.
{{ Most patients discontinued clopidogrel at 12 months per practice
standards, and much of the benefit was seen during dual therapy
of rivaroxaban and aspirin alone.
{{ The lower dose of 2.5 mg twice daily also reduced the rate of
cardiovascular death.
{{ Frequency of non-CABG major bleeding was significantly increased
with both doses of rivaroxaban (1.8% and 2.4%) compared to
placebo (0.6%) as was the frequency of intracranial hemorrhage
(0.4% and 0.7% compared to 0.2%).
{{ Rivaroxaban has failed to achieve FDA approval for this indication.
• APPRAISE-2 was a trial of patients on apixaban 5 mg twice daily or placebo
for ACS.67
{{ Trial was terminated due to increased risk of TIMI major bleeding
with apixaban (2.4% vs. 0.9%) as well as increased intracranial
hemorrhage (0.6% vs. 0.2%).
Rivaroxaban with and without aspirin was more effective than aspirin alone
for secondary cardiovascular prevention in patients with stable cardiovascular
disease in the COMPASS trial.68
• 27,395 patients were randomized to rivaroxaban (2.5 mg twice daily) plus aspirin
(100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once
daily). To be eligible for the trial, patients had to have history of coronary artery
disease, peripheral arterial disease, or both.
• The group assigned to combined rivaroxaban and aspirin had a lower incidence
of the primary outcome (composite of cardiovascular death, stroke, or myocardial
infarction) than those assigned to aspirin alone. It also lowered all-cause mortal-
ity. However, the benefit came at the cost of more major bleeding, including
increased ICH, but not fatal bleeding.
• Rivaroxaban alone did not reduce the primary endpoint when compared to
aspirin alone, but did lead to more major bleeding.

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics—20169
update: a report from the American Heart Association Statistics Committee and Stroke
Statistics Subcommittee. Circulation. 2015 Dec 16 (Epub ahead of print).
2. Rich JD, Cannon CP, Murphy SA, et al. Prior aspirin use and outcomes in acute
coronary syndromes. J Am Coll Cardiol. 2010;56:1376-1385.
3. Thygesen K, Alpert JS, White HD, et al. Third universal definition of myocardial
infarction. Circulation. 2012;126:2020-2035.
*4. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-
ST elevation MI: A method for prognostication and therapeutic decision making. JAMA.
2000;284:835-842.
5. TIMI Risk Score for UA/NSTEMI. Available at: http://www.mdcalc.com/timi-risk-
score-for-uanstemi/. Accessed October 21, 2015.
6. Simms AD, Reynolds S, Pieper K, et al. Evaluation of the NICE mini-GRACE risk
scores for acute myocardial infarction using the Myocardial Ischaemia National Audit
Project (MINAP) 2003–2009: National Institute for Cardiovascular Outcomes Research
(NICOR). Heart. 2013;99:35-40.
7. Pieper KS, Gore JM, Fitzgerald G, et al. Validity of a risk-prediction tool for hospital
mortality: the Global Registry of Acute Coronary Events. Am Heart J. 2009;157:1097-
1105.
8. GRACE 2.0 Risk Calculator. Available at: http://gracescore.org/WebSite/default.
aspx?ReturnUrl=%2f. Accessed October 21, 2015.
9. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular
clinical trials: a consensus report from the Bleeding Academic Research Consortium.
Circulation. 2011;123(23):2736-2747.
10. Granger CB, Hirsch J, Califf RM, et al. Activated partial thromboplastin time and
outcome after thrombolytic therapy for acute myocardial infarction: results from the
GUSTO-I trial. Circulation.1996;93:870-878.
11. Gilchrist IC, Berkowitz SD, Thompson TD, et al. Heparin dosing and outcome in acute
coronary syndromes: the GUSTO-IIb experience. Global use of strategies to open
occluded coronary arteries. Am Heart J. 2002;144:73-80.
12. Nallamothu BK, Bates ER, Hochman JS, et al. Prognostic implication of activated
partial thromboplastin time after reteplase or half-dose reteplase plus abciximab:
results from the GUSTO-V trial. Eur Heart J. 2005;26:1506-1512.
13. Cheng S, Morrow DA, Sloan S, et al. Predictors of initial nontherapeutic anticoagulation
with unfractionated heparin in ST-segment elevation myocardial infarction.
Circulation. 2009;119:1195-1202.
14. Anand SS, Yusuf S, Pogue J, et al. Relationship of activated partial thromboplastin time
to coronary events and bleeding in patients with acute coronary syndromes who receive
heparin. Circulation. 2003;107:2884-2888.
15. Newby LK, Harrington RA, Bhapkar MV, et al. An automated strategy for bedside
aPTT determination and unfractionated heparin infusion adjustment in acute coronary
syndromes: insights from PARAGON A. J Thromb Thrombolysis. 2002;14:33-42.
16. Becker RC, Cannon CP, Tracy RP, et al. Relation between systemic anticoagulation as
determined by activated partial thromboplastin time and heparin measurements and
in-hospital clinical events in unstable angina and non-Q wave myocardial infarction.
Thrombolysis in Myocardial Ischemia III B Investigators. Am Heart J. 1996;131:421-
433.
17. Thomas MP, Mahaffey KW, Chiswell K, et al. Activated partial thromboplastin time
measurement is not associated with clinical outcomes in patients with high-risk non-
ST-segment elevation acute coronary syndromes treated with unfractionated heparin. J
Thromb Thrombolysis. 2012;34(1):114-119.
*18. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic
Evidence-based Clinical Practice Guidelines (8th ed.). Chest. 2012;141(suppl 2):e24S-
e43S.
19. Olson JD, Arkin CF, Brandt JT, et al. College of American Pathologists Conference
XXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of
unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122(9):782-798.
20. Harrington RA, Becker RC, Cannon CP, et al. Antithrombotic therapy for non-ST-
segment elevation acute coronary syndromes: Antithrombotic Therapy and Prevention
of Thrombosis. 9th ed. American College of Chest Physicians Evidence-based Clinical
Practice Guidelines. Chest. 2008;133(suppl 6):670S-707S.
21. TIMI 11A Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of
TIMI 11A. The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. J
Am Coll Cardiol. 1997;29:1474-1482.
22. Montalescot G, Cohen M, Salette G, et al. Impact of anticoagulation levels on outcomes
in patients undergoing elective percutaneous coronary intervention: insights from the
STEEPLE trial. Eur Heart J. 2008;29:462-471.
23. Montalescot G, Collet JP, Tanguy A, et al. Anti-Xa activity related to survival and
efficacy in unselected acute coronary syndrome patients treated with enoxaparin.
Circulation. 2004;110:392-398.
*24. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in non-ST-
segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification
of Unstable angina patients Suppress ADverse outcomes with Early implementation of
the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009;119(14):1873-1882.
25. Mathews R, Peterson ED, Chen AY, et al. In-hospital major bleeding during ST-
elevation and non-ST-elevation myocardial infarction care: derivation and validation
of a model from the ACTION Registry®-GWTG™. Am J Cardiol. 2011;107(8):1136-
1143.
26. Flores-Rios X, Couto-Mallon D, Rodriuez-Garrido J, et al. Comparison of the
performance of the CRUSADE, ACUITY-HORIZONS, and ACTION bleeding risk score
in STEMI undergoing primary PCI: insights from a cohort of 1391 patients. Eur Heart
J Acute Cardiovasc Care. 2012;2(2):19-26.
27. Routledge H, Sastry S. Radial versus fmoral access for acute coronary syndromes. Curr
Cardiol Rep. 2015;17:117.
28. Valgimigli M, Gagnor A, Calabo P, et al. Radial versus femoral access in patients with
acute coronary syndromes undergoing invasive management: a randomized multicenter
trial. Lancet. 2015;385(9986):2465-2476.
29. CRUSADE Bleeding Score Calculator. Available at: http://www.crusadebleedingscore.
org/. Accessed October 22, 2015.
*30. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the
management of ST-elevation myocardial infarction: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J
Am Coll Cardiol. 2013;61(4):e78-e140.
*31. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the
Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report
of the American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
32. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update
for percutaneous coronary intervention: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing
Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J
Am Coll Cardiol. 2006;47(1):e1-e121.
33. Gallo R, Steinhubl SR, White HD, et al. Impact of anticoagulation regimens on sheath
management and bleeding in patients undergoing elective percutaneous coronary
intervention in the STEEPLE trial. Catheter Cardiovasc Interv. 2009;73:319-325.
34. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute
coronary syndrome undergoing early invasive management can be reduced with radial
access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv.
2007;69:73-83.
35. Angiomax (bivalirudin) for injection. Removal of the femoral artery catheter. Available
at: http://www.angiomax.com/Catheter/Default.aspx. Accessed October 20, 2009.
36. Bonaca MP, Bhatt DL, Cohen M, Long-term use of ticagrelor in patient with prior
myocardial infarction. N Engl J Med. 2015;372:1791-1800.
37. Giugliano RP, White JA, Bode C. Early versus delayed, provisional eptifibatide in acute
coronary syndromes. N Engl J Med. 2009;360:2176–2190.
38. Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple
therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch
Intern Med. 2010;170(16):1433-1441.
39. Lamberts M, Gislason GH, Oleson JB, et al. Oral anticoagulation and antiplatelets in
atrial fibrillation patients after myocardial infarction and coronary intervention. J Am
Coll Cardiol. 2013;62(11):981-989.
40. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without
aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous
coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;
381(9872):1107-1115.
41. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring
oral anticoagulation after drug-eluting stent implantation: The ISAR-TRIPLE Trial. J
Am Coll Cardiol. 2015;65(16):1619-1625.
42. D’Ascenzo F, Taha S, Moretti C, et al. Meta-analysis of randomized controlled trials
and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants
in patients undergoing percutaneous coronary intervention. Am J Cardiol.
2015;115(9):1185-1193.
43. Sarafoff N, Martischnig A, Wealer J, et al. Triple therapy with aspirin, prasugrel,
and vitamin K antagonists in patients with drug-eluting stent implantation and an
indication for oral anticoagulation. J Am Coll Cardiol. 2013;61:2060-2066.
44. Braun OÖ, Bico B, Chaudhry U, et al. Concomitant use of warfarin and ticagrelor as an
alternative to triple antithrombotic therapy after an acute coronary syndrome. Thromb
Res. 2015;135(1):26-30.
45. Fu A, Singh K, Abunassar J, et al. Ticagrelor in triple antithrombotic therapy: predictors
of ischemic and bleeding complications. Clin Cardiol. 2016;39:19-23.
46. Collet JP, Roffi M, Mueller C, et al. Questions and answers on antithrombotic therapy:
a companion document of the 2015 ESC Guidelines for the management of acute
coronary syndromes in patients presenting without persistent ST-segment elevation.
Eur Heart J. 2016;37:e1-e7.
*47. Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute
coronary syndromes in patients presenting without persistent ST-segment elevation:
Task Force for the Management of Acute Coronary Syndromes in Patients Presenting
without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC).
Eur Heart J. 2016;37(3):267-315.
*48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm
Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in
patients with non-valvular atrial fibrillation. Europace. 2015;17(10):1467-1507.
49. Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy
after drug-eluting stents. N Engl J Med. 2014;371(23):2155-2166.
50. Schulz-Schupke S, Byrne RA, ten Berg JM, et al. ISAR-SAFE: a randomized, double-
blind, placebo-controlled trial of 6 vs. 12 months of clopidogrel therapy after drug
eluting stenting. Eur Heart J. 2015;36:1252-1263.
51. Gilard M, Barragan P, Noryani AAL, et al. 6- versus 24-month dual antiplatelet therapy
after implant of drug-eluting stents in patients nonresistant to aspirin: the randomized
multicenter ITALIC trial. J Am Coll Cardiol. 2015;(65):777-786.
52. Valgimigli M, Ariotti S, Costa F. Duration of dual antiplatelet therapy after drug-eluting
stent placement: will we ever reach a consensus? Eur Heart J. 2015;36:1219-1222.
53. Navarese EP, Andreotti F, Kołodziejczak M, et al. Optimal duration of dual antiplatelet
therapy after percutaneous coronary intervention with drug eluting stents: meta-
analysis of randomised controlled trials. BMJ. 2015;350:h1618.
54. Elmariah S, Mauri L, Doros G, et al. Extended duration dual antiplatelet therapy and
mortality: a systematic review and meta-analysis. Lancet. 2015;385:792-798.
55. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for
secondary prevention of cardiovascular events in the subgroup of patients with previous
myocardial infarction: a collaborative analysis of randomized trials. Eur Heart J.
2016;37(4):390-399.
56. Plavix (clopidogrel): FDA Drug Safety Communication - Long-term Treatment Does
Not Change Risk of Death. Available from: http://www.fda.gov/Safety/MedWatch/
SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm471531.htm. Accessed
November 10, 2015.
57. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Individualizing Treatment Duration of Dual
Antiplatelet Therapy after Percutaneous Coronary Intervention: An Analysis from the
DAPT Study. Presented at the American Heart Association Meeting Scientific Sessions;
November 10, 2015.
58. DAPT Study. DAPT Score Calculator. Available from: http://www.daptstudy.org/for-
clinicians/score_calculator.htm. Accessed November 10, 2015.
59. Bonaca, MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with
prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800.
60. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa
inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-
metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results
from a multicentre, randomised controlled trial. Lancet. 2011;377:2193-2204.
61. Steg PG, van ‘t Hog A, Hamm CW, et al. Bivalirudin started during emergency
transport for primary PCI. N Engl J Med. 2013;369:2207-2217.
62. Valgimigli M, Frigoli E, Leonardi S, et al. Bivalirudin or unfractionated heparin in acute
coronary syndromes. N Engl J Med. 2015 Sep 10;373(11):997-1009.
63. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary
percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre,
randomised controlled trial. Lancet. 2014;384:1849-1858.
64. Navarese EP, Andreotti F, Kolodziejczak M, et al. Comparative efficacy and safety of
anticoagulant strategies for acute coronary syndromes: comprehensive network meta-
analysis of 42 randomomised trials involving 117,353 patients. Thromb Haemost.
2015;114:933-944.
65. Alexander W. Bivalirudin versus heparin: a fight far from finished: efficacy, safety,
and cost remain battlegrounds for the treatment of ST-segment elevation myocardial
infarction. P&T. 2015;40:209-217.
66. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with recent acute
coronary syndromes. N Engl J Med. 2012;366(1):9-19.
67. Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy in acute
coronary syndromes. N Engl J Med. 2011;365(8):699-708.
68. Eikelboom JW, Connolly SJ, Bosch J, et. al. Rivaroxaban with or without aspirin in
stable cardiovascular disease. N Engl J Med. 2017;377:1319-1330.
16 Chapter
PROSTHETIC HEART VALVES

Douglas C. Anderson
INTRODUCTION
Patients with mechanical valve prosthesis (MVP) are at high risk for thromboem-
bolic complications (e.g., cerebrovascular accident [CVA]), and all MVPs require
antithrombotic prophylaxis. Bioprosthetic valves are less thrombogenic but not as
durable as MVP and are, thus, more prone to failure requiring replacement. An ideal
valve, which would be infinitely durable and non-thrombogenic, does not exist.
• Prosthetic valves are made of a broad range of materials that differ in their thrombo-
genicity.1
{{ Newer materials reduce the thrombogenicity, and future materials such
as polymerics may reduce thrombogenicity even more.2
• Valve prosthetics alter cardiac hemodynamics causing turbulence and other flow
anomalies.3
{{ MVPs in particular create high sheer stresses, which destroy blood
elements leading to activation of platelets, endothelial cells, and some
coagulation proteins, thus resulting in a very high level of thrombogenicity.
• Since valve position, type, and materials affect

thrombogenicity, it is important to determine exactly
which valve has been repaired and which prosthesis
was used to avoid mistakes in anticoagulation.
• Thromboembolic events include valve thrombosis, which may necessitate treatment
with fibrinolytics or valve replacement, systemic embolism, and stroke.
• There are a finite number of times a valve can be

replaced. After two replacements, careful oversight
of anticoagulation is critical to avoid any future
replacements.
393
RISK FACTORS FOR THROMBOSIS

• Annual risk for thromboembolism for MVP ranges 4−23% without prophylaxis. 4,5
• With prophylaxis, the relative risk of thromboembolic events (TEs) in patients
with MVP is reduced to 0.21, or 1–2 per 100 patient years.5,6
• Risk of TE is highest in the early post-surgical period (approximately 3 months)
until the valve is fully endothelialized.7
• Transesophageal echocardiography (TEE) is

the gold standard for imaging heart valves for
thrombosis, and preferred over transthoracic
echocardiograms (TTEs) because of higher
sensitivity of TEE in detecting thrombi.8
TYPES OF VALVES
Mechanical Prostheses
• Three basic types of mechanical valves: caged ball/disk, tilting disk, and bileaflet
(Table 16-1).
• Older caged ball and tilting disk valves are more thrombogenic than bileaflet
valves.
• Annual TE event rate in patients who are anticoagulated to an international
normalized ratio (INR) 2.5−4.9.9
{{ Bileaflet 0.5% per year.
{{ Tilting disk 0.7% per year.
{{ Caged ball 2.5% per year.
TABLE 16-1: Types and Models of Mechanical Valves

Type Models Example
Caged-ball Starr-Edwards Starr-Edwards ball mitral heart

valve (see Figure 16-1)
Tilting disc Björk-Shiley Medtronic-Hall valve

Monostrut (see Figure 16-2)
Medtronic Hall
Omniscience
Omnicarbon
Ultracor
Bileaflet St. Jude On-X -ConformX-Aortic valve

Carbomedics (see Figure 16-3]
Baxter TEKNA
Duromedics
Sorin Bicarbon Baxter TEKNA
Duromedics
Sorin Bicarbon
PROSTHETIC HEART VALVES 395
FIGURE 16-1. Starr-Edwards Ball Mitral Heart Valve

Source: Photo used with permission of Edwards Lifesciences LLC, Irvine, CA. Edwards,
Edwards Lifesciences, and Starr-Edwards are trademarks of Edwards Lifesciences
Corporation.
FIGURE 16-2. Medtronic-Hall Tilting Disc Valve

Source: Used with permission. Copyright © 2016 Medtronic, Inc.
Bioprostheses
• Bioprosthetic valves (Table 16-2) use a ring of material attached to valves from
an animal source (e.g. porcine, bovine).
• Bioprosthetics are less thrombogenic than MVPs.
{{ Fewer disturbances in hemodynamics.
{{ Less damage to cellular components of blood.
• Bioprosthetics are less durable than MVPs and are more likely to require replace-
ment for valve failure.
• Homografts involve replacing aortic or pulmonary valves with donated human
valves.
FIGURE 16-3. On-X ConformX Bileaflet Aortic Valve

Source: Photo reproduced with permission from Austin, TX: On-X Life Technologies.
TABLE 16-2: Types and Models of Bioprosthetic Valves

Type Models Example
Porcine Hancock I Hancock II valve

Hancock II (see Figure 16-4)
Intact
Carpentier-Edwards
Freestyle
Bicor
Transcatheter aortic valve SAPIEN 3 Transcatheter Heart SAPIEN 3 valve

replacement (TAVI, TAVR) Valve with Novaflex+ Delivery (see Figure 16-5)
System
CoreValve Evolut R TAVI

System
FIGURE 16-4. Hancock II Porcine Bioprosthetic Valve

Source: Used with permission. Copyright © 2016 Medtronic, Inc.
FIGURE 16-5. SAPIEN 3 Transcatheter Heart Valve with

Novaflex+ Delivery System
Source: Used with permission from Edwards Lifesciences LLC, Irvine, CA. Edwards,
Edwards Lifesciences. Edwards SAPIEN, SAPIEN, SAPIEN XT, and SAPIEN 3 are
trademarks of Edwards Lifesciences Corporation.
• Transcatheter aortic valve replacement (TAVR) utilizes a bioprosthetic tissue

valve compressed onto an expandable balloon that is inserted into the aortic
valve via catheter.
{{ It may be preferable to open-heart procedures for patients who
are poor surgical risks.
{{ It has been described as “valve-in-valve” because the TAVR is
inserted into the diseased valve, which is left in place.
It may be used to “replace” a diseased native valve, or
it may also be used for patients with a failed biopros-
thetic valve.
{{ Proprietary delivery systems are used to put the valve in place.
VALVE POSITION
• Valve position influences thrombogenicity.
{{ MVPs in mitral position appear to be more thrombogenic than
MVPs in the aortic position.
Annual TE rate with St. Jude Medical bileaflet valves
without antithrombotic prophylaxis10:
Aortic position: 12%
Mitral position: 22%
5-year TE event rate with Starr-Edwards valves11:
Aortic 35%
Mitral 70%
{{ Tricuspid valves are rarely replaced; however, they are the highest
risk valves when they are replaced.
• Other factors such as multiple valve replacement and co-morbidities also influ-
ence thrombogenicity (Table 16-3).
TABLE 16-3: Other Risk Factors for Thrombosis and/or Total

Morbidity/Mortality
Co-Morbid Effect(s) on Morbidity/Mortality
Condition
Aortic + mitral TE rate 2.4 x higher than AVR alone and 1.33 x higher than MVR alone.9,12
valve replacement Early mortality rate 3 x higher than AVR alone and 1.4 x higher than MVR
alone.
Atrial fibrillation TE rate 1.6 x higher than patients with AVR in sinus rhythm, and long-term
mortality rate 2.2 x higher.13
Poor LV function/ Patients with NYHA IV heart failure were 10.7 x more likely to die within
heart failure 5 years of aortic valve replacement with MVP compared with NYHA I-II.13
Left atrial 3 x higher incidence of systemic embolism in patients with left atrial
enlargement dimension ≥4 cm compared with patients with left atrial dimension
<4 cm.14
Age >70 years 1.9 x higher incidence of stroke compared to patients <70 years.15-17
Higher risk of perioperative mortality.17,18
Higher incidence of valve-related reoperation.19
History of prior TE Patients with history of pre-operative TE had 3.2 x risk for TE and 5.4 x risk
for repeated TE after AVR.13
AVR: aortic valve replacement, LV: left ventricle, MVP: mechanical valve prosthesis, MVR: mitral
valve replacement, NYHA: New York Heart Association, TE: thromboembolic event
ANTITHROMBOTIC PROPHYLAXIS
Mechanical Valve Prostheses

• Bridging for initiation of anticoagulation post-mechanical valve replacement:
{{ American College of Cardiology (ACC)/American Heart Associa-
tion (AHA): unfractionated heparin (UFH) or low molecular weight
heparin (LMWH)18,19
{{ American College of Chest Physicians (ACCP): prophylactic dose
UFH, or prophylactic or therapeutic dose LMWH6
• Choice of anticoagulant influenced by position, number of valves, and type of
valves:
{{ Vitamin K antagonist (VKA) currently recommended (Table 16-4)
over antiplatelet agents alone or DOACs.
{{ Target INR influenced by position(s) and number of valve replace-
ments.
{{ Two studies (Table 16-5) suggest that certain specific valves or valve
types may be treated with a lower INR than current guidelines.
TABLE 16-4: Summary of ACC/AHA and ACCP

Recommendations
Condition ACC/AHA18,19 ACCP6
AVR
Agent(s)
VKA Preferred over antiplatelet Preferred over no VKA or

agents alone antiplatelet agents alone
Target INR 2.5 (range 2–3) for bileaflet 2.5 (range 2–3) for all valves
or current-generation single
tilting disc and no risk factors
3 (range 2–3) if additional risk
factors* or older generation
valves (e.g., caged-ball)
Aspirin Added to VKA Added to VKA, if low risk of

bleeding**
Aspirin Dose 75–100 mg/day 50–100 mg/day
MVR
Agent(s)
VKA Preferred over no VKA or Preferred over no VKA or

antiplatelet agents alone antiplatelet agents
Target INR 3 (range 2.5–3.5) 3 (range 2.5–3.5)

bleeding**
AVR and MVR
Agent(s)
VKA Preferred over no VKA or Preferred over no VKA or

antiplatelet agents antiplatelet agents
Target INR 3 (range 2.5–3.5) 3 (range 2.5–3.5)

bleeding**
*See Table 16-3. Patients should be considered high risk if they have one or more risk factors.
**ACCP: “Caution should be used in patients at increased bleeding risk, such as history of GI
bleeding.”
ACC: American College of Cardiology, ACCP: American College of Chest Physicians, AHA:
American Heart Association, AVR: aortic valve replacement, INR: international normalized ratio,
MVR: mitral valve replacement, VKA: Vitamin K antagonist
TABLE 16-5: Evidence Supporting Lower INR Ranges for Specific Valves or Valve Types
PROACT20 LOWERING-IT21
Study patients AVR with On-X valve AVR with:

Sorin Bicarbon
St Jude Medical
Edwards Mira
Carbomedics
Design Multicenter, prospective, randomized, unblinded, controlled Single-center, open-label, prospective, randomized, controlled
Total N 375 396
Groups Treatment: First 3 months, warfarin target INR 2–3 + ASA 81 Treatment: INR 1.5–2.5
mg/day; then INR target 1.5–2 + ASA 81 mg/day. Control: INR 2–3
Control: Warfarin target INR 2–3 + ASA 81 mg/day No ASA was added
Duration (mean) 3.82 years 5.6 years
Results Treatment Control p-Value Treatment Control p-Value
Mean INR 1.89 ± 0.49 2.50 ± 0.63 <.0001 1.94 ± 0.21 2.61 ± 0.25 <.001
Thromboembolic 2.67%/pt-yr 1.59%/pt-yr 0.164 0.91 per 1000 pt/yr 2.73 per 1000 pt/yr p =.62, OR 0.33, 95% CI 0.006–4.20
events
Stroke-TIA 2.07%/pt-yr 1.46%/pt-yr 0.380 1 event 3 events
Minor bleeding 1.18%/pt-yr 3.31%/pt-yr 0.011 6 events 16 events
Major bleeding 1.48%/pt-yr 3.31%/pt-yr 0.032 0 events 3 events
Total bleeding 2.67%/pt-yr 6.62%/pt-yr <.001 5.62 per 1000 pt/yr 15.69 per 1000 pt/yr p =.04, OR 0.36, 95% CI 0.11–0.99
ASA: acetylsalicylic acid, AVR: aortic valve replacement, INR: international normalized ratio, pt: patient, yr: year, TIA : transient ischemic attack
• Direct-acting oral anticoagulants (DOACs)

{{ DOACs require more data before their use for thromboprophylaxis
in patients with mechanical valve replacement can be recom-
mended.
{{ RE-ALIGN trial22:
Design: Open-label, prospective, randomized, multi-
center, phase 2 trial.
Study patients: 252 patients with mechanical bi-leaflet
in aortic, mitral, or both, and implantation ≤7 days, or
>3 months.
Study groups:
Dabigatran adjusted for CrCl
<70 mL/min: 150 mg BID
70–109 mL/min: 220 mg BID
≥110 mL/min: 300 mg BID
Warfarin INR
“Low risk” 2–3
“High risk” 2.5–3.5
Duration: 12 weeks, terminated early by safety monitors
Results (dabigatran vs warfarin, respectively):
Thromboembolic events: 9% vs. 5%, p = 0.24
Any bleeding: 27% vs. 12%, p = 0.01
Major bleeding: 4% vs. 2%, p = 0.48
{{ The data on DOACs for atrial fibrillation patients with concurrent
bioprosthetic valves is limited as very few patients were included
in phase III clinical trials.
• Bridging for diagnostic or therapeutic procedures (see Chapter 10: Transitions
in Care—Periprocedural Bridging and Transitions Between Agents).
• Patients who have systemic embolism despite a therapeutic INR (Table 16-6).
{{ If patient was not previously on acetylsalicylic acid (ASA), then add
ASA 50–100 mg daily, and
{{ Titrate VKA to a higher INR range.
TABLE 16-6: INR Adjustments for Patients Who Have Systemic

Embolism Despite Therapeutic INR
Previous INR Target (Range) Post-Systemic Embolism INR Target (Range)
ACC/AHA ACCP
2.5 (2–3) 3 (2.5–3.5) 3 (2.5–3.5)
3 (2.5–3.5) 3.5 (3–4.5) 3.5 (3–4)
American Heart Association, INR: international normalized ratio
• Example: If a patient with a prior TE event were having an aortic valve replaced
with a bileaflet MVR, then the VKA should be adjusted to an INR of 2.5–3.5 and
low dose ASA added.
Bioprosthetic Valves
• Because of the lower thrombogenicity, many patients will not need lifelong
anticoagulation with bioprosthetic replacement (Table 16-7).
• However, recent updated guidelines indicate that stroke risk and mortality are
lower if patients receive anticoagulation for up to 6 months.19 Anticoagulation
may also reduce risk of thrombosis of bioprosthetic valves.
TABLE 16-7: Summary of Recommendations for Prophylactic

Antithrombotics for Bioprosthetics Valve Replacements
Condition ACC/AHA18-19 ACCP6
AVR
Agent(s)
VKA At least 3 months*
Target INR 2.5 (range 2−3)
Aspirin Preferred Preferred over VKA for

patients in sinus rhythm with
no other indication for VKA
MVR
Agent(s)
VKA At least 3 months* First 3 months
Target INR 2.5 (range 2–3) 2.5 (range 2–3)
Aspirin After first 3–6 months** After first 3 months**
*As long as 6 months in patients at low risk of bleeding.

**Presence of AF, previous TE, hypercoagulable condition, or other indication for VKA requires
long-term VKA therapy.
American Heart Association, AVR: aortic valve replacement, INR: international normalized ratio,
MVR: mitral valve replacement, VKA, vitamin K antagonist
Transcatheter Aortic Valve Replacements

• Limited data comparing antithrombotic strategies
• ACCP: ASA 50–100 mg/day + clopidogrel 75 mg/day for first 3 months, then
long-term ASA6
• ACC/AHA: ASA 75–100 mg/day + clopidogrel 75 mg/day for first 6 months,
then lifelong ASA18

1. Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med.
1996;335(6):407-416.
2. Ghanbari H, Viatge H, Kidane AG, et al. Polymeric heart valves: New materials,
emerging hopes. Trends Biotechnol. 2009;27(6):359-367.
3. Schoen FJ. Evolving concepts of cardiac valve dynamics: The continuum of
development, functional structure, pathobiology, and tissue engineering. Circulation.
2008;118(18):1864-1880.
4. Björk VO, Henze A. Management of thrombo-embolism after aortic valve replacement
with the björk-shiley tilting disc valve. Medicamental prevention with dicumarol in
comparison with dipyridamole - acetylsalicylic acid. Surgical treatment of prosthetic
thrombosis. Scand J Thorac Cardiovasc Surg. 1975;9(3):183-191.
5. Cannegieter S, Rosendaal F, Briet E. Thromboembolic and bleeding complications in
patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635-641.
*6. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for
valvular disease. Chest. 2012;141(2 suppl):e576S-e600S.
7. Benussi S, Verzini A, Alfieri O. Mitral valve replacement and thromboembolic risk. J
Heart Valve Dis. 2004;13(Suppl 1):S81-S83.
8. Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: Diagnosis and
therapeutic considerations. Heart. 2007;93(1):137-142.
9. Baudet EM, Puel V, McBride JT, et al. Long-term results of valve replacement with the
St. Jude medical prosthesis. J Thorac Cardiovasc Surg. 1995;109(5):858-870.
10. Macmanus Q, Grunkemeier G, Thomas D, et al. The Starr-Edwards model 6000
valve. A fifteen-year follow-up of the first successful mitral prosthesis. Circulation.
1977;56(4):623-625.
11. Horstkotte D, Schulte H, Bircks W, et al. Unexpected findings concerning
thromboembolic complications and anticoagulation after complete 10 year follow up of
patients with St. Jude medical prostheses. J Heart Valve Dis. 1993;2(3):291-301.
*12. Kvidal P, Bergström R, Malm T, et al. Long-term follow-up of morbidity and mortality
after aortic valve replacement with a mechanical valve prosthesis. Eur Heart J.
2000;21(13):1099-1111.
*13. Burchfiel C, Hammermeister K, Krause-Steinrauf H, et al. Left atrial dimension
and risk of systemic embolism in patients with a prosthetic heart valve. Department
of Veterans Affairs Cooperative Study on valvular heart disease. J Am Coll Cardiol.
1990;15(1):32-41.
14. Arom K, Nicoloff D, Lindsay W, et al. Should valve replacement and related procedures
be performed in elderly patients? Ann Thorac Surg. 1984;38(5):466-472.
15. Lawrie GM, Earle EA, Earle NR. Abstract 2308: Conventional aortic valve replacement
in very elderly patients. Circulation. 2008;118(18_MeetingAbstracts):S_703-c.
16. Jebara VA, Dervanian P, Acar C, et al. Mitral valve repair using Carpentier techniques
in patients more than 70 years old. Early and late results. Circulation. 1992;86(5
Suppl):II53-9.
17. Chan V, Jamieson WRE, Germann E, et al. Performance of bioprostheses and
mechanical prostheses assessed by composites of valve-related complications to 15 years
after aortic valve replacement. J Thorac Cardiovasc Surg. 2006;131(6):1267-1273.
*18. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the
management of patients with valvular heart disease: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll
Cardiol. 2014;63(22):e57-e185.
*19. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the
2014 AHA/ACC Guideline for the management of patients with valvular heart disease:
a report of the American College of Cardiology/American Heart Association Task Force
on Clinical Practice Guidelines. Circulation. 2017;135:e1159-e1195. DOI: 10.1161/
CIR.0000000000000503
*20. Puskas J, Gerdisch M, Nichols D, et al. Reduced anticoagulation after mechanical
aortic valve replacement: Interim results from the prospective randomized on-X valve
anticoagulation clinical trial randomized food and drug administration investigational
device exemption trial. J Thorac Cardiovasc Surg. 2014;147(4):1202-1211.e2.
*21. Torella M, Torella D, Chiodini P, et al. LOWERing the INtensity of oral anticoaGulant
therapy in patients with bileaflet mechanical aortic valve replacement: Results from the
“LOWERING-IT” trial. Am Heart J. 2010;160(1):171-178.
*22. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in
patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214.
17 Chapter
MECHANICAL CIRCULATORY
SUPPORT DEVICES
Christopher Paciullo, Laura Baumgartner, and Lauren Roller
INTRODUCTION
The advancement of mechanical circulatory support (MCS) technology has allowed
for improved survival among patients with end-stage heart failure and acute cardio-
genic shock. Many different devices exist, but all share a common purpose—to
increase the delivery of oxygenated blood and improve end-organ function. They
also require anticoagulation to prevent thrombosis, either systemically or in the
device itself. Improvements in device design have reduced, but not completely
alleviated, the need for anticoagulation. In addition, the devices themselves alter
the patient’s coagulation system, further complicating the prescribed anticoagula-
tion regimen. Many patients on MCS will develop bleeding or thrombosis events
despite careful monitoring and recommended treatments.
MECHANICAL SUPPORT DEVICES1-5
Diagnoses Requiring Mechanical Circulatory Support

Mechanical circulatory support may be utilized either temporarily for acute manage-
ment issues, or long term that may include permanent for life (see Table 17-1).
Anticoagulation in many cases is required when these devices are in use.
405
TABLE 17-1: Diagnoses Requiring Mechanical Circulatory

Support
Temporary (Nondurable) Mechanical Long-Term (Durable) Mechanical Circulatory
Circulatory Support Support
• Acute cardiac failure • Class IV heart failure with severe

• Acute myocardial infarction, high-risk symptoms or refractory to optimal
coronary intervention therapy
• Acute myocarditis with shock • Dependence on intravenous inotropic
support
• Acute rejection post-cardiac transplant
with hemodynamic compromise
• Bridge to decision in a patient with a
relative contraindication to transplant or
durable mechanical circulatory support
• Cardiogenic shock
• High-risk electrophysiologic ablations
• Inability to wean from cardiopulmonary
bypass
• Need for right-sided failure refractory to
maximal medical therapy following LVAD
placement
• Valvular failure such as acute mitral
regurgitation
LVAD: left ventricular assist device
Indications for Mechanical Circulatory Support

See Table 17-2.
• Bridge to recovery (BTR): Patients who need short-term or temporary MCS and
are expected to recover cardiac function.
• Bridge to decision (BTD): Provide temporary circulatory support when a patient’s
neurologic status is unknown or they have undetermined durable VAD or trans-
plant candidacy, allowing for time to potentially reverse organ dysfunction to
appropriately assess the risks and benefits of durable options.
• Destination therapy (DT): Patients who need long-term MCS and are not candi-
dates for transplant.
• Bridge to transplant (BTT): Patients awaiting transplantation who need MC to
survive to transplant or to keep end-organ dysfunction from occurring while
waiting for a donor organ to become available.
• Bridge to transplant candidacy (BTC): Provide support to patients who have
reversible risk factors for transplant. The goal is to eventually transition to bridge
to transplant once the risk factors have been corrected.
ANTITHROMBOTIC MANAGEMENT
CONSIDERATIONS
Although guidelines for some devices exist, local practice varies widely.1 Each
hospital or health system should develop local protocols to guide therapy
MECHANICAL CIRCULATORY SUPPORT DEVICES 407
Example of a VV ECLS Circuit Example of a VA ECLS Circuit*
Oxygenator Oxygenator
RA LA RA LA
RV RV
LV LV
IVC IVC
A. A.
Pump Pump
FIGURE 17-1. Examples of the VV and VA ECLS Circuit and

Common Areas for Cannulation in to the Large Vessels
*In VA ECLS, arterial access can be via the femoral artery and venous access by the
femoral vein.
for each device and possible complications. Evidence is limited, and their
use is in a very diverse population. Interaction of blood cells with the device
surface leads to activation of the coagulation system. Thrombotic events in
MCS are a major contributor to morbidity and mortality. MCS devices may
be broadly divided into two categories:
1. Temporary support devices: Indicated for short-term (days to weeks) support
of cardiac function.
{{ Typically act as a bridge to something else—recovery, a durable
support device; heart transplant, or death.
2. Durable support devices: Indicated for long-term (months to years) support of
cardiac function.
{{ These devices may also act as a bridge, typically to a heart trans-
plant, or as destination therapy for permanent support in patients
who are not candidates for a heart transplant.
• Anticoagulants utilized for patients on MCS range from short-acting parenteral
medications to warfarin:
{{ Heparin may be utilized in the early postoperative period in
durable support devices; however, this practice is increasingly
less common.14,15
{{ Intravenous heparin is the most utilized parenteral agent for tempo-
rary support devices.
TABLE 17-2: Mechanical Circulatory Support Devices4-13

Device Implantation Duration of Flow Type Indication
Support
Cardiac Support
Intraaortic
Percutaneous Days Pulsatile Bridge to recovery
balloon pump
Bridge to recovery
Percutaneous
Impella Days Axial (Impella RP for right
or surgical
heart)
VA-ECMO Percutaneous Bridge to recovery,

Days to weeks Centrifugal
Temporary Devices
(Figure 17-1) or surgical decision, transplant
Bridge to recovery,
TandemHeart Percutaneous Days to weeks Centrifugal
decision
Bridge to recovery,
Thoratec PVAD Surgical Days to weeks Pulsatile
decision, transplant
Bridge to recovery,
BVS 5000 Surgical Days to weeks Pulsatile
Bridge to recovery,
AB 5000 Surgical Days to weeks Pulsatile
Percutaneous Bridge to recovery,

Centrimag VAD Days to weeks Centrifugal
or surgical decision
Cardiac Support
Syncardia TAH Implanted Weeks to Pulsatile Bridge to transplant

Durable Devices
months destination therapy
Heartware Implanted Weeks to years Centrifugal Bridge to transplant

HVAD destination therapy
Heartmate II Implanted Weeks to years Axial Bridge to transplant

destination therapy
VA-ECMO: veno-arterial extracorporeal membrane oxygenation

{{ Bivalirudin or argatroban may be substituted for heparin in tempo-

rary support devices if there is a history or suspicion of heparin-
induced thrombocytopenia (HIT), hypersensitivity, or resistance to
heparin.16-18
{{ Warfarin is initiated in durable support patients when they are able
to tolerate oral medications.
The international normalized ratio (INR) goal is device-
specific and discussed in Table 17-3.
{{ Direct-acting oral anticoagulants (DOACs) have not been studied
in this patient population, and are not recommended.
• Anticoagulation goals should be individualized based on patient-specific risks
for thrombosis and bleeding. Goals may need to be modified during therapy if
the patient experiences a bleeding or thrombotic complication.
• The use of antiplatelet agents in temporary support devices is not well studied,
but may be indicated for the patient’s underlying condition (i.e. acute coronary
syndromes, coronary artery bypass surgery, coronary stent placement).
• Acquired Von Willebrand disease has been observed in most devices, leading
to decreased platelet function.
TABLE 17-3: Anticoagulation Strategies by Device4,9,13,19-23
Indication For Anticoagulation or Antiplatelet Therapy
Device Antiplatelet Anticoagulant Therapy Specific Considerations

Therapy
Temporary Support Devices
VA ECMO None Heparin ACT is the most commonly utilized monitoring parameter.
Titrated to institution-
specific ACT goals
Impella (several None Heparin—purge solution The Purge solution of heparin with dextrose can vary between 5% and 40% dextrose, but
types) and commonly initiated at 5% dextrose and modified based on device-specific parameters. It
Systemic heparin—high is important to note that the device controls the rate of solution into the device, thereby
dose changing the rate of heparin administration. Typically, additional heparin will need to be
Titrated to institution- administered systemically to achieve therapeutic goals.
specific ACT (low range), Impella RP: This is placed on the right side of the heart, and goals will be different. Heparin
APTT, or anti-Xa goals 50 units/mL may be recommended, and it is important to avoid compounding different
heparin concentrations. The type of Impella catheter should be clearly identified and
potential confusion on the heparin concentrations and type of Impella identified with
management.
TandemHeart None Heparin— high dose No anticoagulation recommendations provided by manufacturer, although a localized
Titrated to institution- heparinized infusate (45,000 units/500 mL NS) is infused into the device at 10 mL/hr for
specific ACT (low range), local anticoagulation in the pump housing. Additional heparin will need to be administered
APTT, or anti-Xa goals systemically to achieve therapeutic goals.
Thoratec PVAD None Heparin—high dose Anticoagulation started after hemostasis achieved following implant.
specific ACT (low range),
APTT, or anti-Xa goals
(continued)
Indication for Anticoagulation or Antiplatelet Therapy

Therapy
BVS 5000 None Heparin—high dose Anticoagulation started after hemostasis achieved following implant.
AB 5000 None Heparin—high dose Higher thrombotic risk than other devices due to pulsatile flow.
Intra-aortic balloon None Heparin— low dose (if Choice to anticoagulate is institution-specific. Thrombosis risk increases with decrease in
pump needed, see special frequency of counterpulsation (1:1 vs 1:2 vs 1:3, etc.) where the balloon is immobile for
considerations) longer periods of time.
Also causes platelet destruction and thrombocytopenia, which will contribute to
coagulopathy during therapy.
Centrimag None Heparin—high dose Anticoagulation started after hemostasis achieved following implant
Durable Support Devices
Heartware HVAD Aspirin 325 mg PO Warfarin The decision to use heparin in the early postoperative period is institution-specific and may
daily INR Goal 2–3 lead to more bleeding events. Patients who are unable to take oral medications for more
than a few days postoperatively may need parenteral anticoagulation therapy.
(continued)
Indication for Anticoagulation or Antiplatelet Therapy

Therapy
Heartmate II Aspirin 81 mg PO Warfarin The decision to use heparin in the early postoperative period is institution-specific and may
daily INR Goal 2–3 lead to more bleeding events. Patients who are unable to take oral medications for more
than a few days postoperatively may need parenteral anticoagulation therapy.
SynCardia TAH Aspirin 81 mg PO Heparin—very low dose Many centers will have other monitoring goals other than INR (i.e., TEG parameters).
daily (early post op)

Dipyridamole 100 Warfarin (INR goal 2.5–3.5)
mg PO q 6–8hr
Pentoxifylline 400 mg
PO q 8hr
ACT: activated clotting time, APTT: activated partial thromboplastin time, hr: hour, INR: international normalized ratio, PO: by mouth, TAH: total artificial heart, TEG:
thromboelastography, VA ECMO: veno-arterial extracorporeal membrane oxygenation
MONITORING PARAMETERS
• Choice of monitoring should depend on local availability and provider experi-
ence with different parameters.
• Frequency of monitoring is institution-specific, but should be at least daily in
temporary support devices.
• Some parameters are not routinely checked unless a clinical situation (i.e., suspi-
cion of pump thrombosis) is suspected. Alternatively, for patients on temporary
support devices where thrombus formation may not be easily recognized, routine
surveillance may be warranted (Table 17-4).
TABLE 17-4: Antithrombotic Monitoring Parameters Used in

Mechanical Circulatory Support Devices9,21,22,24
Test Device Type Utility
PT/INR Temporary and Warfarin monitoring

durable Monitoring of extrinsic pathway and hepatic
function
aPTT* Temporary and Heparin or DTI monitoring

durable
ACT* Temporary POC test most commonly used in ECLS since the
value is rapidly available.
Anti-Xa activity* Temporary and Pharmacodynamic marker of heparin activity

durable
Fibrinogen Temporary Protein used in clot formation, level indicates

availability of protein for clot formation
Evaluation for DIC
Antithrombin activity Temporary Used to determine the availability of antithrombin.

A low antithrombin may be a cause of heparin
resistance.
Note: In ECLS, AT replacement may not change
heparin dosing.
Platelet function Durable When patients have device-related thrombosis

testing despite optimal anticoagulation parameters,
testing for aspirin resistance may be indicated
to optimize antiplatelet therapy (i.e., increasing
dosage or adding a second agent such as
dipyridamole).
Platelet mapping is another option.
Thromboelastography Temporary and Requires specialized equipment and personnel

durable trained on interpretation.
May be used when patient has bleeding or
thrombotic events despite adequate levels of
anticoagulation as determined by standard tests.
(continued)

Test Device Type Utility
Lactate Durable Marker of hemolysis and possible thrombosis

dehydrogenase formation in durable support devices.
Levels >600 units/L are associated with higher risk
of thrombus formation.
Plasma free Temporary Marker of hemolysis and possible thrombosis

hemoglobin formation in temporary support devices.
High bilirubin levels may interfere with test
accuracy.
Levels >30 mg/dL are associated with hemolysis
and possible thrombus formation.
CBC Temporary and Evaluate platelet quantity and early detector of

durable anemia.
*The preferential test between ACT, aPTT, or anti-Xa activity for managing heparin in ECLS is
institution specific. Correlation between the tests is poor and outcome data on which may be
optimal is limited. See Chapters 3 and 21.
ACT: activated clotting time, aPPT: activated partial thromboplastin time, CBC: complete
blood count, DIC: disseminated intravascular coagulation, DTI: direct thrombin inhibitor, ECLS:
extracorporeal life support, ECMO: extracorporeal membrane oxygenation, INR: international
normalized ratio, POC: point of care, PT: prothrombin time
MANAGEMENT OF COMPLICATIONS
• Complications following device implant are common.25,26
• The most common complications during the first 60 days are bleeding, infec-
tion, and arrhythmia.26
• Signs and symptoms are numerous and vary by device (Table 17-5).
TABLE 17-5: Signs and Symptoms of Device Complications20,34,35

Temporary Devices Durable Devices
Visualization of clot in device Signs of heart failure:

Sudden decrease in oxygen saturation • Pulmonary edema
(ECMO) • Low cardiac output
Plasma free hemoglobin >30 mg/dL
• Hypoperfusion (jaundice, decreased UOP,
Acute decrease in cardiac output
mental status changes)
Signs of pump thrombosis:
• Amber colored urine
• Low hemoglobin/hematocrit
• LDH >3 x upper limit of normal
• Increased pulsatility from frequent aortic
valve opening
• Power elevations (spikes)
ECMO: extracorporeal membrane oxygenation, LDH: lactate dehydrogenase, UOP: urine output
Bleeding
• Bleeding is the most common complication following LVAD placement.
• Arteriovenous malformations and acquired von Willebrand syndrome are thought
to be contributing factors to the increase in bleeding in continuous flow devices.
• Bleeding types (percentages specific to Heartmate II [HMII]) in one report27
{{ Thoracic and mediastinal (42.1%)
{{ Anemia of undetermined source (20%)
{{ Lower gastrointestinal tract (12.4%)
{{ Central nervous system (CNS) (6.9%)
{{ Epistaxis (3.4%)
• Patients who have a gastrointestinal (GI) bleed are more likely to have recur-
rent bleeds.
• Nonpulsatile devices experience more bleeding events than do pulsatile
devices.28,29
Interventions
• Hold all anticoagulation and antiplatelet therapy until bleed resolves.
{{ Therapeutic options:
Medical intervention
Surgical intervention
Lower target goals or reduce the number of agents
Proton pump inhibitors should be started and continued
indefinitely for upper gastrointestinal bleeds
• Transfusion of packed red blood cells (PRBCs) is based on variables such as
hemoglobin, platelet, INR, and mixed venous oxygen saturation (SvO2) thresh-
olds; they are determined by the surgeon.30
• Vitamin K, recombinant fact VII activated (rVIIa), and prothrombin complex
concentrate (PCC) use are controversial due to the risk of pump thrombosis.20
{{ If utilized, consider low doses and titrate to goals to limit prolonged
effects.
• Octreotide may be used to control GI bleeds.29,31,32
• Restart anticoagulation when bleed is controlled or resolved.
{{ Holding anticoagulation for short periods of time does not put the
patient at higher risk for thrombosis.33
{{ When to restart warfarin depends on severity of bleed and patient
status.
{{ Lower INR target may be considered and then revised as necessary.
Hemolysis and Thrombosis

See Table 17-6.
• Hemolysis refers to the destruction of red blood cells, which can occur with or
without thrombosis; however, during MCS it is more likely an early marker of
thrombosis.
TABLE 17-6: Interventions for Device Thrombosis
Strategy Intervention Regimen Considerations
Increase Increased aspirin Aspirin 325 mg PO Aspirin should be up titrated to 325 mg upon findings of thrombosis
antiplatelet34-38 (hemolysis, power spikes, and/or heart failure symptoms).
Addition of second Dipyridamole 75 mg PO TID Consideration can be given to the addition of second antiplatelet
antiplatelet medication medication.
Clopidogrel 75 mg daily
Glycoprotein IIb/IIIa Eptifibiatide 180 mcg/kg IV bolus Not routinely recommended; conflicting data regarding benefit with
inhibitor infusion over 1-2 minutes followed by increased risk of bleeding.

0.1–2 mcg/kg/min (dose adjust in
renal dysfunction)
Increased Increased INR goal Warfarin titrated to goal INR of 2.5 INR goal should be increased upon resolution of findings of hemolysis,
anticoagulant34,35,39-41 ± 0.5 power spikes, and/or heart failure symptoms.
Intravenous heparin Heparin drip titrated to goal aPTT Consider initiation in patients with early markers of thrombosis (hemolysis,
depending on MCS device power spikes, and/or heart failure symptoms). Heparin alone is typically not
effective; combination with increased aspirin doses of 325 mg PO daily or
add-on therapy with clopidogrel 75 mg daily may be reasonable.
In selected situations, anti-Xa activity or ACT may be alternatives to the
aPTT.
Intravenous direct thrombin Bivalrudin titrated to goal aPTT of Consider in patients with persistent hemolysis, power spikes, and/or heart
inhibitors 1.5–2.5 x normal level (dose adjust failure symptoms.
in renal dysfunction) Direct thrombin inhibitors may be more effective than heparin as they bind
both free and clot-bound thrombin.
Aragtroban titrated to 1.5–3 x Direct thrombin inhibitors may be an effective alternative to heparin when
normal level (dose adjust in hepatic antithrombin deficiency or other sources of heparin resistance are present
dysfunction) (if not a laboratory testing method issue). See Chapters 3 and 5.
(continued)
Strategy Intervention Regimen Considerations
Thrombolysis42-44 Thrombolytic Multiple published regimens: May be given systemically or intraventricularly depending on patient risk
for bleed.
Alteplase 1 mg/min
intraventricularly over 20–50 min For nonsurgical candidates who have failed medical management.
under direct visualization or 1 mg/
hr until normalization of hemolysis TEG may be one means to assess the level of thrombolysis.
or pump parameters
Consider following fibrinogen levels with prolonged infusions.
Systemic: Alteplase 10-100 mg IV
bolus For Left Ventricular Device thrombosis, follow the Power and trend lactate
dehydrogenase if elevated.
See Chapter 6
Pump modification Correct malpositioning NA

45
Pump exchange Replace thrombosed pump NA Four approaches:
• Isolated subxiphoid
• Subxiphoid approach with right anterior thoracotomy
• Subxihoid approach with small left anterior thoracotomy
• Full redo sternotomy
ACT: activated clotting time, aPTT: activated partial thromboplastin time, INR: international normalized ratio, IV: intravenous, MCS: mechanical circulatory support, NA: not
applicable, PO: by mouth, TEG: thromboelastography , x: times
• Thrombosis of a MCS device may result in device malfunction and/or systemic

embolism (Figures 17-2 and 17-3).
• VA-ECMO carries the additional risks of intra-cardiac or aortic root thrombus
due to stagnant blood flow during support.
{{ Elevation of the lactate dehydrogenase (LDH) over a period of time
has been associated with increased incidence of LVAD thrombosis.
• General treatment principles of thrombosis typically include intensification of the
antiplatelet/anticoagulant regimen. This may or may not include antifibrinolytic
therapy (Figure 17-4).
• When pharmacologic treatments are ineffective or when device thrombosis has
caused device failure, device exchange or removal is indicated.
FIGURE 17-2. Pump Thrombosis in the Outflow Bearing of a

Heartmate II LVAD
FIGURE 17-3. ECMO Oxygenator with Clot Formation

1 Isolated LDH Rise2 Evidence of Hemolysis3 New CHF Symptoms
Late • •Admit to Hospital

Early or Late?
• Check Serum Indices of Hemolysis •Consider IV Heparin
Early •CXR
Yes •Echocardiogram (± Pump Speed Changes), Consider RHC
• Consider Hemolysis?
•Monitor LDH, pfHgb, indirect bili
Echocardiogram (± Pump No
Speed Changes) • Consider Echocardiogram (± Pump Yes
Pump Thrombosis
LV Unloading?
Speed Changes)
LV Unloading?
No
No • Chest CT Angiogram • Evaluate Other Causes
Lung Transplant. 2013;32:667-670.

Yes LV Unloading?
of CHF and Hemolysis
Yes No
Close Follow Up
• Increase INR
Inflow Cannula Consider Surgical
• ASA 325 mg Yes
•
platelet Agent No
Yes • ICU – Add Inotropes,
Resolved4?
Diuresis as Needed
No
:
• Sustained (>24hrs) Power > 10W; or Yes Consider:
Resolved?
• Sustained (> 24hrs) Power Increase > 2W from Baseline
•Direct Thrombin Inhibitors
Isolated LDH Rise: No
•LDH > 3x Upper Limit of Normal (ULN)
Hemolysis: Surgical No
•Clinical Diagnosis; or Candidate?
•LDH > 3x ULN and pfHgb > 40
Resolved: Normal Powers, Normal LDHs, Sufficient LV Yes
Source: Reprinted with permission from Goldstein DJ, John R, Salerno C, et al.
Unloading, and No Clinical Evidence of Hemolysis
Pump Exchange or Urgent
Dehydrogenase; pfHgb, Plasma-free Hemoglobin; RHC,
Algorithm for the diagnosis and management of suspected pump thrombus. J Heart
FIGURE 17-4. Algorithm for the Diagnosis and Management of
Right Heart Cath; CXR, Chest X ray Recovery Compromise

1. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 International Society for
Heart and Lung Transplantation Guidelines for mechanical circulatory support:
executive summary. J Heart Lung Transplant. Feb 2013;32(2):157-187.
2. Helman DN, Oz MC. Developing a comprehensive mechanical support program. J
Card Surg. 2001;16(3):203-208.
3. Velez M, Johnson MR. Management of allosensitized cardiac transplant candidates.
Transplant Rev (Orlando). 2009;23(4):235-247.
*4. Ensor CR, Paciullo CA, Cahoon WD, Jr., et al. Pharmacotherapy for mechanical
circulatory support: a comprehensive review. Ann Pharmacother. Jan 2011;45(1):60-
77.
5. Kirkpatrick JN, Wieselthaler G, Strueber M, et al. Ventricular assist devices for
treatment of acute heart failure and chronic heart failure. Heart. 2015;101(14):1091-
1096.
*6. ELSO. General Guidelines for all ECLS Cases. https://www.elso.org/Resources/
Guidelines.aspx. Accessed September 22, 2017.
7. Torregrossa G, Anyanwu A, Zucchetta F, et al. SynCardia: the total artificial heart. Ann
Cardiothorac Surg. 2014;(6):612-620.
8. Pagani FD, Miller LW, Russell SD, et al. Extended mechanical circulatory support
with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol.
2009;54(4):312-321.
9. Burzotta F, Trani C, Doshi SN, et al. Impella ventricular support in clinical
practice: Collaborative viewpoint from a European expert user group. Int J Cardiol.
2015;201:684-691.
10. Aaronson KD, Slaughter MS, Miller LW. Use of an intrapericardial, continuous-
flow, centrifugal pump in patients awaiting heart transplantation. Circulation.
2012;125(25):3191-3200.
11. Desai NR, Bhatt DL. Evaluating percutaneous support for cardiogenic shock: data
shock and sticker shock. Eur Heart J. 2009;30(17):2073-2075.
12. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients
awaiting heart transplantation. N Engl J Med. 2007;357(9):885-896.
13. Lad V, Elhenawy A, Harwood S, et al. Mechanical circulatory support with the
ABIOMED BVS 5000: the Toronto General Hospital experience. Can J Cardiol.
2010;26(9):467-470.
14. John R, Kamdar F, Liao K, et al. Low thromboembolic risk for patients with
the Heartmate II left ventricular assist device. J Thorac Cardiovasc Surg.
2008;136(5):1318-1323.
15. Slaughter MS, Naka Y, John R, et al. Post-operative heparin may not be required for
transitioning patients with a HeartMate II left ventricular assist system to long-term
warfarin therapy. J Heart Lung Transplant. 2010;29(6):616-624.
16. Beiderlinden M, Treschan T, Gorlinger K, et al. Argatroban in extracorporeal membrane
oxygenation. Artif Organs. 2007;31(6):461-465.
17. Pieri M, Agracheva N, Bonaveglio E, et al. Bivalirudin versus heparin as an
anticoagulant during extracorporeal membrane oxygenation: a case-control study. J
Cardiothorac Vasc Anesth.. Feb 2013;27(1):30-34.
18. Bembea MM, Schwartz JM, Shah N, et al. Anticoagulation monitoring during pediatric
extracorporeal membrane oxygenation. ASAIO J. 2013;59(1):63-68.
19. Lee Y, Weeks PA. Effectiveness of protocol guided heparin anticoagulation in
patients with the TandemHeart percutaneous ventricular assist device. ASAIO J.
2015;61(2):207-208.
*20. Susen S, Rauch A, Van Belle E, et al. Circulatory support devices: fundamental
aspects and clinical management of bleeding and thrombosis. J Thromb Haemost..
2015;13(10):1757-1767.
*21. Extracorporeal Life Support Organization Anticoagulation Guidelines. 2014. Available
online at https://www.elso.org/resources/guidelines.aspx. Accessed July 2016.
22. Copeland J, Copeland H, Nolan P, et al. Results with an anticoagulation protocol in 99
SynCardia total artificial heart recipients. ASAIO J. 2013;59(3):216-220.
23. John R, Liao K, Lietz K, et al. Experience with the Levitronix CentriMag circulatory
support system as a bridge to decision in patients with refractory acute cardiogenic
shock and multisystem organ failure. J Thorac Cardiovasc Surg. 2007;134(2):351-
358.
24. Kirklin JK, Naftel DC, Kormos RL, et al. Interagency Registry for Mechanically Assisted
Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II
left ventricular assist device. J Heart Lung Transplant. 2014;33(1):12-22.
25. Dembitsky WP, Tector AJ, Park S, et al. Left ventricular assist device performance with
long-term circulatory support: lessons from the REMATCH trial. Ann Thorac Surg.
2004;78(6):2123-2129; discussion 2129-2130.
26. Genovese EA, Dew MA, Teuteberg JJ, et al. Incidence and patterns of adverse event
onset during the first 60 days after ventricular assist device implantation. Ann Thorac
Surg. 2009;88(4):1162-1170.
27. Bunte MC, Blackstone EH, Thuita L, et al. Major bleeding during HeartMate II
support. J Am Coll Cardiol. 2013;62(23):2188-2196.
28. Crow S, John R, Boyle A, et al. Gastrointestinal bleeding rates in recipients of
nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg.
2009;137(1):208-215.
29. Suarez J, Patel CB, Felker GM, et al. Mechanisms of bleeding and approach to patients
with axial-flow left ventricular assist devices. Circ Heart Fail. 2011;4(6):779-784.
30. Schaffer JM, Arnaoutakis GJ, Allen JG, et al. Bleeding complications and blood
product utilization with left ventricular assist device implantation. Ann Thorac Surg.
2011;91(3):740-747; discussion 747-749.
31. Demirozu ZT, Radovancevic R, Hochman LF, et al. Arteriovenous malformation and
gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.
J Heart Lung Transplant. 2011;30(8):849-853.
32. Hayes HM, Dembo LG, Larbalestier R, et al. Management options to treat
gastrointestinal bleeding in patients supported on rotary left ventricular assist devices: a
single-center experience. Artif Organs. 2010;34(9):703-706.
33. Kamdar F, Eckman P, John R. Safety of discontinuation of anti-coagulation in patients
with continuous-flow left ventricular assist devices. J Heart Lung Transplant. Mar
2014;33(3):316-318.
34. Goldstein DJ, John R, Salerno C, et al. Algorithm for the diagnosis and management of
suspected pump thrombus. J Heart Lung Transplant. 2013;32(7):667-670.
*35. Hohner E, Crow J, Moranville MP. Medication management for left ventricular assist
device thrombosis. Am J Health-Syst Pharm. 2015;72(13):1104-1113.
36. Bellumkonda L, Subrahmanyan L, Jacoby D, et al. Left ventricular assist device
pump thrombosis: is there a role for glycoprotein IIb/IIIa inhibitors? ASAIO J.
2014;60(1):134-136.
37. Al-Quthami AH, Jumean M, Kociol R, et al. Eptifibatide for the Treatment
of HeartMate II left ventricular assist device thrombosis. Circ Heart Fail.
2012;5(4):e68-e70.
38. Tellor BR, Smith JR, Prasad SM, et al. The use of eptifibatide for suspected pump
thrombus or thrombosis in patients with left ventricular assist devices. J Heart Lung
Transplant. 2014;33(1):94-101.
39. Najjar SS, Slaughter MS, Pagani FD, et al. An analysis of pump thrombus events
in patients in the HeartWare ADVANCE bridge to transplant and continued access
protocol trial. J Heart Lung Transplant. 2014;33(1):23-34.
40. Sylvia LM, Ordway L, Pham DT, et al. Bivalirudin for treatment of LVAD thrombosis:
a case series. ASAIO J. 2014;60(6):744-747.
41. Berry CN, Girardot C, Lecoffre C, et al. Effects of the synthetic thrombin inhibitor
argatroban on fibrin- or clot-incorporated thrombin: comparison with heparin and
recombinant Hirudin. Thromb Haemost. 1994;72(3):381-386.
42. Jabbar AA, Yau R, Frazier OH, et al. Direct thrombolytic therapy for thrombosis of a
centrifugal flow left ventricular assist device. ASAIO J. 2013;59(5):530-532.
43. Muthiah K, Robson D, Macdonald PS, et al. Thrombolysis for suspected intrapump
thrombosis in patients with continuous flow centrifugal left ventricular assist device.
Artif Organs. 2013;37(3):313-318.
44. Schlendorf K, Patel CB, Gehrig T, et al. Thrombolytic therapy for thrombosis of
continuous flow ventricular assist devices. J Card Fail. 2014;20(2):91-97.
45. Tchantchaleishvili V, Sagebin F, Ross RE, et al. Evaluation and treatment of pump
thrombosis and hemolysis. Ann Cardiothorac Surg. 2014;3(5):490-495.
18 Chapter
HEPARIN-INDUCED
THROMBOCYTOPENIA
William E. Dager
INTRODUCTION
Heparin-induced thrombocytopenia (HIT) is an immune-mediated process triggered
by exposure to unfractionated heparin (UFH) or low molecular weight heparin
(LMWH) that can create the paradox of increased thrombosis risk with concurrent
thrombocytopenia. It is important to recognize and promptly initiate appropriate
management when present. No gold standard test currently exists; thus, diagnosis
typically combines signs and symptoms with laboratory observations. Stopping
the heparin agent alone will not prevent the potential risk for thrombosis, limb
ischemia (which can lead to amputation), or death.
Identification of HIT1
See Table 18-1.
TABLE 18-1: Characteristics of Heparin-Related Nonimmune- and

Immune-Mediated Thrombocytopenia
Observation Nonimmune-Mediated Immune-Mediated Heparin-Induced
Heparin-Associated Thrombocytopenia (HIT)
Thrombocytopenia (HAT)
Frequency 10–30% <1–3%
Timing of onset 1–4 days Typical 5–10 days

Acute: Immediate if recent exposure
Delayed: Up to 40 days after last exposure
to the heparin compound
Decrease in platelets Slight Moderate/large
Antibody mediated No Yes
Thrombosis No 30–75%
Hemorrhage None Rare
Management Observe Discontinue all heparin/LMWH products,

flushes, coated lines, and rinses.
Start alternate parenteral anticoagulant.
423
Immune-mediated HIT is transient with the risk for recurrence highest from
re-exposure to heparin products lasting approximately 100 days.
HIT Terminology
See Table 18-2.
TABLE 18-2: HIT Terminology2

Term Description Treatment Duration
Acute HIT Period of thrombocytopenia Continue anticoagulation until

associated with current or recent recovery of platelet counts to a
exposure to heparin prior to stable plateau if no thrombosis.
platelet count recovery.
Isolated HIT Presence of HIT without Continue anticoagulation until

thrombosis related to heparin. recovery of platelet counts to a
Includes pre-existing thrombosis stable plateau if no thrombosis.
and subsequent HIT.
HIT-related thrombosis Presence of thrombosis that 3–6 months unless other factors
syndrome (HITTS) formed as a result of HIT. require longer anticoagulation.
History of HIT Previous history of HIT, NA—may receive anticoagulation

but not acute, or related for other reasons (i.e., DVT
thrombocytopenia. prophylaxis); consider using
fondaparinux.
HIT: heparin-induced thrombocytopenia
HIT-Related Disorders (Not Common)2

• Adrenal infarct
• Cardiovascular/anaphylactoid reactions on reexposure
• Skin lesions at heparin injection sites
• Venous limb gangrene (VLG) with excessive initial warfarin exposure
• Warfarin-induced skin necrosis
Phases of HIT
See Table 18-3.
TABLE 18-3: Phases of HIT3
Suspected HIT Acute HIT Subacute HIT Recent HIT History of HIT
Definition Timing: HIT diagnosis made HIT with clear platelet count HIT with platelet count Patient with history of HIT no
Immediate: Hours Timing: Hours to days recovery recovery longer on treatment for HIT
Typical: 5–10 days Timing: Days/weeks Timing: Week/months Timing: Over 100 days out from
Delayed: Typically up to HIT onset
~40 days
Platelet count Declining or declined Decreased Rising or recovered Recovered/baseline Baseline
Thrombotic Use pre-test probability Increased—highest risk Decreasing to normal after Normal Normal
risk score to estimate risk; see in first 5–7 days ~30 days
Table 18-7
Functional NA Positive Positive Negative (after ~50 days) Negative

assay
Immunoassay NA Positive Positive −/+ (often negative after Negative

~85 days)
Consideration Assess risk, evaluate need Remove all heparin- Consider transition to Reassess anticoagulation Evaluate assay date and if true
for alternative management; related triggers. longer-term anticoagulant if need unless secondary HIT occurred vs. documentation
laboratory testing and Initiate alternative on a parenteral continuous reason to continue of suspicion only. Evaluate
alternative management anticoagulant if not infusion DTI; if warfarin anticoagulation; for anticoagulation needs based on
typically instituted in those already done. used, see considerations in treatment durations, see risk and if >100 days since initial
considered intermediate-to- Table 18-19. Table 18-2. HIT event. For VTE prophylaxis,
high risk of HIT, including fondaparinux 2.5 mg/day may
removing heparin sources. be an easy option.
DTI: direct thrombin inhibitor, HIT: heparin-induced thrombocytopenia, VTE: venous thromboembolism
HEPARIN-INDUCED THROMBOCYTOPENIA 425
• I nitiating warfarin monotherapy, especially in

higher doses potentially leading to international
normalized ratio (INR) values >4, can increase
the risk for venous limb gangrene due to protein
C depletion.
Disorders That Can Mimic HIT

See Table 18-4.
TABLE 18-4: Pseudo-HIT Disorders That Can Mimic HIT,

Including Thrombocytopenia and Thrombosis4
Early Onset Late Onset
Antiphospholipid disorder Adenocarcinoma

Diabetic ketoacidosis Drug-induced thrombocytopenia (other than
GP IIb/IIIa inhibitors HIT)
Infective endocarditis Postsurgical thrombotic thrombocytopenic
Paroxysmal nocturnal hemoglobinuria purpura
Postsurgical thrombotic thrombocytopenic Post-transfusion purpura
purpura Pulmonary embolism
Pulmonary embolism
Septicemia-related purpura fulminans
Thrombolytic therapy
GP: glycoprotein, HIT: heparin-induced thrombocytopenia
Factors Associated with the Development of HIT

See Table 18-5.
TABLE 18-5: Factors Associated with the Development of HIT5–7

Factor Importance Hierarchy
Type of heparin Major UFH >LMWH >fondaparinux

Higher risk with more recent exposure
Duration of heparin Major 11–14 daysa >5–10 days >4 (or fewer) days
Type of patient Moderate Postsurgery >medical >pregnancy or neonate
Dose of heparin Moderate Therapeutic ≥prophylaxis >“flushes”
Gender of patient Minor Female >male
Minimal additional risk if heparin continued beyond 14 days.

a
>: greater than, ≥ : greater than or similar to, HIT: heparin-induced thrombocytopenia, LMWH:
low molecular weight heparin, UFH: unfractionated heparin
Recommended Platelet Count Monitoring

See Table 18-6.
TABLE 18-6: ACCP Recommendations for Platelet Count

Monitoring to Recognize HIT5
Situation Platelet Count Monitoring ACCP Recommendation
Grade
Heparin or LMWH administered Every 2–3 days (days 4–14 2C

with risk of HIT >1% or until D/C)
Heparin or LMWH administered No platelet monitoring 2C

with risk of HIT <1%
UFH or LMWH administered when Baseline, repeat within 24 hr NA

patient had UFH exposure within if feasible
100 days
UFH bolus given and acute Immediate and compare to NA

inflammatory reaction within 30 prior count
minutes of UFH bolus
ACCP: American College of Chest Physicians, D/C: discontinued, HIT: heparin-induced

thrombocytopenia, hr: hours, LMWH: low molecular weight heparin, NA: not applicable, UFH:
Note: Daily platelet count monitoring for the first 10 days may be a consideration in the setting of
recent (or history of HIT) and re-exposure to UFH, LMWH, or fondaparinux.
Estimating the Probability a Patient Has HIT

See Tables 18-7, 18-8, and 18-9.
TABLE 18-7: Proposed Modified Pretest Probability Scoring (4Ts) for HIT2,5
Indicator 2 Points 1 Point No Points
Thrombocytopenia • >50% platelet fall and nadir • 50% platelet fall but surgery • <30% fall
Compare the highest platelet count ≥20 K/mm2 AND no surgery within preceding 3 days or • platelet nadir <10 K/mm2
within the sequence of declining within preceding 3 days • Any combination of platelet
platelet counts with the lowest fall and nadir that does not fit
count to determine the percent of criteria for Score 2 or Score 0
platelet fall. (e.g., 30–50% fall, or platelet
(Select only 1 option) nadir 10–19 K/mm2)
Timing of platelet count fall or other • Clear onset 5–10 days after • Consistent with platelet fall • Platelet count fall within 4 days of initiation
sequelae* exposure to heparin day 5–10 but not clear (e.g., without exposure to heparin past 100 days
Day 0 = first day of most recent • Platelet fall within 1 day of missing counts)
heparin exposure. (Select only 1 start of heparin and exposure • Platelet fall within 1 day of
option) to heparin within past 5–30 start of heparin and exposure
days to heparin in past 31–100 days
• Platelet fall after 10 days
Thrombosis or other sequelae • Confirmed new thromboses • Recurrent venous thrombosis in • No related thrombosis suspected
(Select only 1 option) (venous or arterial) a patient receiving therapeutic
• Skin necrosis at injection site anticoagulants
• Anaphylactic reaction to IV • Suspected thrombosis (awaiting
heparin bolus confirmation with imaging)
• Adrenal hemorrhage • Erythematous skin lesions at
heparin injection sites
(continued)
Indicator 2 Points 1 Point No Points
Other causes of • No other cause for platelet • Possible causes evident. Sepsis • Definite other causes present
thrombocytopenia** count fall evident without proved microbial • Within 72 hours of surgery
(Select only 1 option) source
• Confirmed bacteremia/fungemia
• Thrombocytopenia associated
• Chemotherapy or radiation within past 20 days
with initiation of ventilator
• DIC due to non-HIT cause
• Posttransfusion purpura (PTP)
• Thrombotic thrombocytopenic purpura (TTP)
• Platelet count <20 AND given a drug implicated
in causing D-ITP (see list)
• Non-necrotizing skin lesions at LMWH injection
sites (presumed DTH)
Pretest Probability
6–8 High
4–5 Intermediate
0–3b Low
a
4 Ts: Thrombocytopenia, Timing, Thrombosis, Other
b
Some facilities classify patients with a score of 3 as an intermediate risk.
*In some circumstances, it may be appropriate to judge timing based on clinical sequelae, such as onset of heparin-induced skin lesions.
**Usually, “oTher” scores “0 points” if thrombocytopenia is not present. However, it may be appropriate to judge oTher based on clinical sequelae, such as whether
heparin-induced skin lesions are necrotizing (2 points, i.e., a non-HIT explanation is unlikely) or non-necrotizing (0 points, i.e., a non-HIT explanation is likely [see text]).
DIC: disseminated intravascular coagulation, DTH: delayed-type hypersensitivity, HIT: heparin-induced thrombocytopenia, IV: intravenous, LMWH: low molecular weight
heparin
Note: This is a more recent version of the 4Ts scoring system proposed in the 2012 CHEST Guidelines.
See Appendix J for drug-related causes of thrombocytopenia.

TABLE 18-8: Post-HIT Probability Assessment Tool Proposed by

Chong8
Indicator
Onset:
1 point—onset of thrombocytopenia is <4 days or >14 days
3 points—onset of thrombocytopeniaa (or a substantial decrease in platelet by >50% between
4–14 days after exposure)
2 points—other causes of thrombocytopenia excluded
2 points—thrombocytopenia resolves after stopping agent
1 point—thrombocytopenia recurs on heparin reexposure
1 point—thrombosis associated with thrombocytopenia
Laboratory tests:
• Immunoassay positive (2 points)
• Functional assay: two-point system positiveb (3 points)
• Functional assay: non-two-point systemb (3 points)
Score and Probability: >7 = definite; 5–6 = probable; 3–4 = possible; and <3 = unlikely.
Thrombocytopenia defined as platelet count <150 K/mm3 or drop >50%.
a
b
In the two-point system, there is the addition of a control using a high heparin concentration
(100 units/mL), which characterizes the heparin antibody (suppresses the antibody reaction).
TABLE 18-9: HIT Evaluation in the Setting of Cardiopulmonary

Bypass (CPB) Surgery9
Variable
Platelet count time course:

• 2 points if initial platelet count drop and full recovery >5 days with a notable subsequent
drop in the next few days
• 1 point if initial platelet count drop and small recovery in ~2 days followed by a
subsequent decline over the next few days
Note: Platelet count drops are very common post-cardiopulmonary bypass and why scoring is
based on some recovery prior to a secondary drop.
Time from CPB to assessment day: 2 points if ≥5 days
CPB duration: 1 point if ≥118 minutes
Classification:
≥ 2 = High probability of HIT
< 2 = Low probability of HIT
CPB: cardiopulmonary bypass, HIT: heparin-induced thrombocytopenia

• A ssessment tools (e.g., 4Ts) can assist in

determining the risk for HIT and potential
diagnosis to determine the management strategy.
However, after adoption into clinical practice,
neither tool has been prospectively validated to
improve the treatment outcomes of patients who
may or may not have HIT.
Laboratory Considerations in Evaluation of HIT

See Tables 18-10 and 18-11.
TABLE 18-10: Assays for Potential Presence of HIT5

• Platelet activation or functional assays detect platelet activation when the patient’s serum is
incubated with normal platelets and heparin.
• Antigen or immunoassays detect presence of antiplatelet factor 4/heparin antibodies;
these antibodies may or may not be pathogenic.
• Combination of a positive antigen assay OD >1 and pre-test intermediate probability score
to high provides the similar accuracy as a SRA assay.
• In the presence of a OD of 0.4–1 and a low-to-moderate pre-test probability, can consider
a SRA assay to confirm the diagnosis.
• For patients receiving heparin agents, routine use of HIT antibody screens in the absence
of thrombocytopenia, thrombosis, heparin-induced skin lesions, or other signs of HIT
should be generally avoided. Over-testing can lead to excessive costs and exposure to
more costly anticoagulants as well as bleeding risks because false positives are common
with immunoassays.
Assay Approach Assay Examples
Platelet activation: lack standardized controls Serotonin release assay (SRA)

Platelet aggregation test (PAT)
Washed platelet assays Heparin-induced platelet activation (HIPA)

ATP release using lumiaggregometry
Platelet microparticle assay using flow cytometry
Flow cytometry Annexin V-binding assay

Serotonin release using flow cytometry
PF-4 immunoassays Enzyme-linked immunosorbent assay (ELISA)

Rapid assays (particle gel immunoassay (PaGIA)
Lateral flow immunoassay Particle immuno-filtration assay (PIFA)
Chemiluminescent immunoassay
Latex immunoassay
ATP: adenosine triphosphate, OD: optical density

TABLE 18-11: Differences Between Common Assays Used to

Detect HIT4,10,11
Considerations Serotonin Release PF4 Immunoassays Platelet Aggregation
Assay Assay
Measures Radiolabeled serotonin Heparin-dependent Platelet activation

release for aggregated antibodies. Can
platelets in presence of either be polyclonal
low-dose heparin. or monoclonal (IgG
only) depending on
manufacturer.
Presence of PF4
antibodies.
Advantages High sensitivity (99%); Fast turnaround; low Easy to perform

high specificity (95%) false-negative rate. >90% specificity
Sensitive and specific;
rapid turnaround time.
Disadvantages Lack of standardization, Low specificity; high Very low sensitivity

donor platelet (~25%) false-positive (40%) leading to
sensitivity dependent, rate. high false-negative
requires special No controls and rates. Requires
equipment. Expensive; limited experience with aggregometer. Other
radio isotopes involved. outcomes. causes of platelet
activation can
influence test.
Comment Consideration for long- ELISA: Commonly used; Not routinely

term decisions where one product (GTI ELISA) recommended given
re-exposure to heparin has conformation step. availability of SRA and
anticipated and clinical Impact of this step ELISA.
diagnosis unclear. clinically unclear.
ELISA: enzyme-linked immunosorbent assay, PF4: platelet factor 4, SRA: serotonin release assay
Note:
• With the exception of the SRA, all the other assays have a lower positive predictive value.
• Available immunoassays may be polyspecific or IgG-specific with differences in optical density
thresholds. Because pathogenic HIT antibodies are IgG, a monoclonal IgG specific test should
be more specific for HIT, but false positives remain a concern.
• M
any clinicians get very confused with HIT
testing concepts. In addition to assessing
pre-test probability, when ordering laboratory
assessments, remember the basic concepts.
Platelet factor 4 (PF4) antibody enzyme-linked
immunosorbent assay (ELISA) assays are often
useful as an initial screen and, in general, a
negative value helps rule out a diagnosis of HIT.
The serotonin release assay (SRA) has a high
positive predictive value and may be helpful in

the diagnosis of HIT in situations where it is
otherwise unclear (lower pre-test probability with
an indeterminate PF4 antibody, etc.).
PRINCIPLES OF PHARMACOTHERAPY
MANAGEMENT
Initial Management of Suspected HIT

See Table 18-12 and Figure 18-1.
TABLE 18-12: Initial Management of Suspected HIT5,6,12

Intervention Comment
Remove all exposure Avoid heparin or LMWH; consider all heparin-related sources
to heparin-related including flushes, coated lines, dialysis rinses; LMWH should be
agents where possible avoided (ACCP grade 1C).
Reverse concurrent Vitamin K should be considered to reverse the effects of a VKA in

warfarin therapy acute HIT (ACCP grade 2C).
Initiate alternative Stopping heparin agent alone does not stop the progression of HIT
anticoagulant and may increase risk for thrombosis from loss of anticoagulant effects;
an alternative non-heparin agent needs to be started (ACCP grade
1C) (see Tables 18-13 through 18-17 for agent options). If significant
bleeding concerns are present and alternative anticoagulant therapy
poses a notable risk, consider frequent assessment for thrombosis
(i.e., duplex ultrasonography with compression) and initiate alternative
therapy as soon as possible.
Platelet transfusions Prophylactic transfusions of platelets in the absence of bleeding

should be avoided. Platelet transfusions should be given only if
bleeding or during a procedure with high risk of bleeding (ACCP
grade 2C).
ACCP: American College of Chest Physicians, HIT: heparin-induced thrombocytopenia, LMWH:

low molecular weight heparin, VKA: vitamin K antagonist
Suspected HIT; Evaluate probability of HIT

using “4Ts” risk score
High probability of HIT High or intermediate Low probability of HIT

(4T ≥ 6) probability of HIT (4T ≤ 3)*
(4T = 4–5)
Heparin, LMWH, or fondaparinux
Discontinue any heparin or LMWH Discontinue any heparin or LMWH, initiate may be continued, or therapy may
an alternative anticoagulant e.g., direct be withheld at clinicians’ discretion.
thrombin inhibitor (DTI) therapy***
Further testing may Consider alternative diagnosis.
not be necessary. Proceed Watch and repeat HIT evaluation
Consider HIT ELISA assay if other causes not apparent.
with treatment using an
alternative anticoagulant (DTI). Monitor for thrombosis
Weakly positive or Strongly positive (OD > 1), Negative PF4 test Negative PF4 test
Strongly positive PF4 test
indeterminate PF4 test weakly positive or AND High probability AND Intermediate
AND High probability of HIT
(OD <1) AND High indeterminate PF4 test of HIT probability of HIT
probability 4T score for HIT AND Intermediate
probability of HIT
HIT probability high enough

to warrant continued Consider functional platelet assay (Serotonin Consider alternative Consider alternative
alternative management. If Release Assay) if the result will change the diagnosis; HIT diagnosis; can consider
there is strong desire to avoid management approach, or continue alternative indeterminate. Assess restarting heparin/LMWH or
alternative anticoagulation, a anticoagulation if warranted.** risk and benefit of using consider fondaparinux.
SRA test can be considered a DTI or fondaparinux. Another option is to continue
Can repeat the PF4 assay DTI/Fondaparinux and
in a few days repeat the PF4 assay.
Negative Serotonin Release Positive Serotonin Release
Monitor platelet count and
Assay Assay
signs of thrombosis
Consider a SRA if the

HIT unlikely, appropriate traditional HIT probable, continue result will alter
therapy can be reconsidered alternative anticoagulation management
*A 4T score of 3 has been considered as a cutoff for low probability of HIT in some settings, and there is no need to initiate a
DTI. A PF4 test can be considered if the result alters management.
Definitions of “positivity” quantifications vary.
** SRA assay may be considered if the patient is anticipated to require procedures preferring the use of heparin
(i.e., cardiopulmonary bypass).
***If the risk of major bleeding exceeds the risk of thrombosis, surveillance for thomboembolism should be considered and the
DTI started when feasible.
Probability of positive SRA high if 4T score high probability and OD >1.4.
Probability of negative SRA high if 4T score low probability and OD < 0.4.
HIT: heparin-induced thrombocytopenia, DTI: direct thrombin inhibitor, LMWH: low molecular weight heparin,
ELISA: enzyme-linked immunosorbent assay, OD: optical density, PF4: platelet factor 4, SRA: serotonin release assay
FIGURE 18-1. Flow Diagram

Diagram describes a generalized approach to decisions incorporating the use of the 4T
scoring system, functional and immunoassays, and anticoagulation therapy decisions
when HIT is suspected.
General treatment of HIT depends on the phase (Tables 18-2, 18-6, and
18-12). In general, an initial non-heparin anticoagulant should be initiated
(not warfarin alone); once the platelet count is recovering, other longer term
agents such as warfarin can be started. In the trials assessing argatroban and
lepirudin, the majority of patients were transitioned to warfarin. Transitioning
to warfarin is described in Table 18-19. Despite limited published experi-
ences, fondaparinux is another option commonly used—even with initial
management of HIT (Table 18-18).
Treatment of HIT
See Tables 18-13 through 18-18.
TABLE 18-13: Agents Used in the Management of HIT4,5,12-14
Agent (ACCP Chemistry Route of Half-lifea Assay (usual target Comments
grade) Elimination range)b
Argatroban (2C) DTI: L-arginine Hepato-biliary 40–50 min aPTT: 1.5–3 × baseline FDA-approved for HIT prophylaxis or treatment, including PCI;
derivative prolongs INR. Alternative assay options: dTT or ECA.
Bivalirudin (2C) DTI: 20-aa Enzymatic 25 min aPTT: 1.5–2.5 x baseline Not approved for HIT (except during PCI) but commonly used.
hirudin analogue (80%); renal Alternative assay options: dTT or ECA.
(20%)
Danaparoid (2C) Mixture of Renal; other 25 hr Anti-Xa activity level Not marketed in U.S. (approved for HIT in EU, Canada); no effect
GAGs with (0.5–0.8 units/mL) on INR; IV, or sub-Q.
predominant Peak effect post-sub-Q
anti-Xa activity injection at 4–5 hr
Fondaparinux Sulfated penta- Renal; other 17 hr NA Not approved for HIT; use has become more common; however,
(Grade 2C) saccharide with case reports of HIT from fondaparinux have been reported.
anti-Xa activity
Warfarin (Grade Inhibits hepatic Hepatic 35–45 hr INR 2–3 Potential for microvascular thrombosis when given during acute
2C) production HIT without alternative anticoagulant agent in place or early
of vitamin K occurrence of INR values over the target range (see Table 18-19
dependent for more details).
clotting factors
Dabigatran Direct thrombin Renal (80%); gut 14–17 hr ECA Case reports only; effect on PF4 or PF4/heparin antibody not
inhibitor esterases and demonstrated; place in therapy unclear.
non-CYP liver
metabolism
(continued)
Agent (ACCP Chemistry Route of Half-lifea Assay (usual target Comments
grade) Elimination range)b
Rivaroxaban Xa inhibitor Renal (66%); 5–9 hr Chromogenic anti-Xa Case reports only; effect on PF4 or PF4/heparin antibody not
hepatic assay adjusted for demonstrated; place in therapy unclear.
rivaroxaban
Apixaban Xa inhibitor Renal (25%); 9–14 hr Chromogenic anti-Xa Case reports only; effect on PF4 or PF4/heparin antibody not
hepatic assay adjusted for demonstrated; place in therapy unclear.
apixaban
Edoxaban Xa inhibitor Renal (50%); 8–10 hr NA No case reports yet; place in therapy unclear.
hepatic
a
Half-life determined in normal subjects and may be longer in many patients with HIT.
b
Baseline is the patient’s baseline aPTT off heparin or the laboratory mean if the patient’s baseline value is notably elevated.
aa: amino acid, anti-Xa: anti-factor Xa activity, aPTT: activated partial thromboplastin time, DTI: direct thrombin inhibitor, dTT: dilute thrombin time, ECA: ecarin chromogenic
assay, EU: European Union, FDA: U.S. Food and Drug Administration, hr: hour, INR: international normalized ratio, IV: intravenous, min: minutes, NA: not applicable, PCI:
percutaneous coronary intervention, PF4: platelet factor 4, sub-Q: subcutaneous, x: times, Xa: factor Xa
Note: Lepirudin has been removed from the international market and is no longer available.
In the setting of acute PE, the combination of thrombolysis with a DTI has been reported in a case report.15
TABLE 18-14: Argatroban in HIT16,17

Evidence supporting In two multicenter, nonrandomized, historical-controlled trials, patients
argatroban with HIT or HITT treated with argatroban had significantly decreased
composite all-cause death, all-cause amputation, or new thrombosis
and new thrombosis and death caused by thrombosis compared to
historical controls. Patients treated with argatroban also had more
rapid rises in platelet count.
Dosing Initiate at 2 mcg/kg/min IV with titrations (max 10 mcg/kg/min) to

target an aPTT of 1.5 to 3 x the baseline aPTT (max 100 sec) (see
Chapter 5).
Note: The mean dose used in the clinical trials was lower at 1.5-1.6
mcg/kg/min. Notably lower doses are common depending on the
patient’s presentation. See Chapter 5.
Monitoring Typically aPTT 2–6 hr after each titration. Note: In patients at lower
doses (e.g., rate <1 mcg/kg/min), elimination may be slower and
steady-state may not be achieved within 6 hr.
Common adverse Diarrhea, pain, rash, unspecified hemorrhage, purpura,

events thrombophlebitis
aPTT: activated partial thromboplastin time, HIT: heparin-induced thrombocytopenia, HITT:

heparin-induced thrombocytopenia-related thrombosis syndrome, hr: hours, IV: intravenous, sec:
seconds, x: times
Note: For more detailed information, see Chapter 5.
TABLE 18-15: Bivalirudin in HIT5,18-20

Evidence supporting Several case series in over 800 patients with HIT initially treated
bivalirudin with bivalirudin have demonstrated similar rates of new thrombosis,
mortality, death related to thrombosis, major bleeding, and a
decreased rate of HIT-related amputation as argatroban. The largest
study to date included 461 patients with suspected, confirmed, or
previous history of HIT.
Clinical trials have been conducted on the use of bivalirudin in patients
with HIT concerns undergoing cardiac bypass graft surgery.
Dosing Initiate at 0.15–0.20 mg/kg/hr IV and titrate to target aPTT of 1.5–2.5

x the baseline aPTT. Patients with renal dysfunction require dose
reductions. Based on case studies, suggested initial doses are:
Clearance creatinine (CrCl 30–60 mL/min): 0.08–0.1 mg/kg/hr
CrCl <30 mL/min or receiving RRT: 0.03–0.05 mg/kg/hr
For more dosing insights, see Chapter 5 on Direct Thrombin Inhibitors.
Monitoring aPTT 2–6 hr after each titration.
Common adverse Bleeding, injection site reaction, headache, anxiety, insomnia, pelvic or
events back pain
aPTT: activated partial thromboplastin time, CrCl: creatinine clearance, hr: hours, HIT: heparin-
induced thrombocytopenia, IV: intravenous, min: minute, RRT: renal replacement therapy, x: times
Note: For more detailed information, see Chapter 5.
TABLE 18-16: Danaparoid in HIT*21

Chemistry Danaparoid is a mixture of depolymerized glycosaminoglycans:
heparan sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate
(4%); a lower degree of sulfation and charge density compared to
LMWH limits its binding to plasma proteins and platelets.
Pharmacology Indirect inhibition through antithrombin on factor Xa; anti-factor Xa:

anti-factor Ila ratio >22:1; no effect unless at high doses on the aPTT,
INR, or ACT.
Cross-reactivity with 10% cross reactivity but not of any noted clinical significance in HIT.
heparin antibodies
Observations in HIT In an assessment of 62 patients treated with danaparoid and

management transitioned to warfarin, compared to ancrod plus warfarin or warfarin
alone; a new thrombosis, death or limb amputations and bleeding
rates were significantly lower with danaparoid.
In a retrospective analysis of 1,478 cases of HIT receiving danaparoid,
a survival rate of 84% with new thrombosis during treatment of 9.7%
and 16.4% having an inadequate treatment response (new/extended
thrombosis, platelet count reduction, or unplanned amputation during
treatment); major bleeding occurred in 8.1%.
Similar efficacy (80%) to lepirudin if at therapeutic doses with a lower
bleeding rate (2.5% vs. 10.4%) in one analysis.
*Currently not available in the United States.

ACT: activated clotting time, aPTT: activated partial thromboplastin time, HIT: heparin-induced
thrombocytopenia, INR: international normalized ratio, LMWH: low molecular weight heparin
TABLE 18-17: Danaparoid Dosing and Monitoring3-5

Indication Danaparoid Dose Anti-Factor Xa
Targets
Acute HIT management Bolus: 0.5–0.8 units/mL

< 60 kg: 1,500 units
60–75 kg: 2,250 units
>75–90 kg: 3,000 units
>90 kg: 3,750 units
Accelerated post bolus initial infusion:
400 units/hr × 4 hr then 300 units/hr × 4 hr
then 200 units/hr (subsequently adjusted
by anti-factor Xa activity levels calibrated to
danaproid of 0.5 to 0.8 units/L)
Maintenance infusion:
• Normal renal function: 200 units/hr
• Renal dysfunction (Scr >220 micromils/L
or 2.5 mg/dL): 150 units/hr
VTE prophylaxis (history 750 units sub-Q q 8–12 hr

of HIT)
VTE treatment 2,250 units IV bolus followed by 400 units/hr 0.5–0.8 units/mL
× 4 hr then 150–200 units/hr
Option: 1,500–2,250 units sub-Q q 12 hr
Intermittent hemodialysis 3,750 IV prior to first two dialysis sessions, Predialysis:

(for preventing 3,000 units for third dialysis, then reduce to <0.3 units/mL
thrombosis of the circuit) 2,250 units During dialysis:
0.5–0.8 units/mL
Continuous renal 2,250 units IV bolus followed by 400 units/hr During

replacement therapy × 4 hr then 300 units/hr × 4 hr, then 150–400 hemodialysis:
units/hr 0.5–0.8 units/mL
Cardiac catheterization ≤75 kg: 2,250 units IV preprocedure

75–90 kg: 3,000 units
>90 kg: 3,750 units
PCI/balloon pump Cardiac cath-preprocedure then 150–200

units/hr for 1–2 days
Post-PCI until balloon pump removed
Cardiopulmonary bypass 125 units/kg IV bolus

Post-thoracotomy
Prime circuit: 3 units/mL, 7 units/kg/hr IV
infusion after bypass initiated, and stopping
45 min prior to going off circuit
Embolectomy/vascular 2,250 units IV preoperatively, 750 units in

surgery 250 mL 0.9% saline up to 50 mL uses as
intraoperative flushes
Postoperative:
Low risk: 750 units sub-Q q 8 hr
High risk:150–200 units/hr starting 6 hr or
more after procedure
Cardiac cath: cardiac catheterization, HIT: heparin-induced thrombocytopenia, hr: hour, IV:
intravenous, PCI: percutaneous coronary intervention, sub-Q: subcutaneous, VTE: venous
thromboembolism, x: times
TABLE 18-18: Fondaparinux in HIT22-27

Evidence Several cohort studies with historical controls suggest that fondaparinux
supporting is as effective as lepirudin or argatroban in the treatment of patients with
fondaparinux HIT or HITT. Case series studies have demonstrated that fondaparinux
may be a treatment option for suspected HIT, confirmed HIT, and post-
operative cardiac or vascular surgery. A multi-center review revealed that
fondaparinux was used in 40% of suspected HIT cases.
Dosing Treatment of acute/recent thromboembolism: Dose may need to be

modified in renal insufficiency.
• For patients who weigh <50 kg: 5 mg sub-Q daily
• For patients who weigh 50–100 kg: 7.5 mg sub-Q daily
• For patients who weigh >100 kg: 10 mg sub-Q daily
• Prophylaxis: (No need for full anticoagulation) 2.5 mg/day. In severe
renal impairment, 2.5 mg every other day has been used.
• Fondaparinux 2.5 mg/day was effective if no indication for full
anticoagulation in one analysis.24
Monitoring anti- The use of anti-factor Xa activity to monitor fondaparinux in HIT has not
factor Xa activity been validated. Dose response was not observed in Phase II trials for DVT
or ACS.
Evidence Several cases suggesting fondaparinux as the cause of HIT have been
suggesting reported.
caution
ACS: acute coronary syndrome, DVT: deep vein thrombosis, HIT: heparin-induced
thrombocytopenia, HITT: heparin-induced thrombocytopenia-related thrombosis syndrome,
sub-Q: subcutaneous
Note: See Chapter 4 for details on fondaparinux and use outside HIT.
• I t is unclear if the platelet count must be over

150 × 109/L prior to starting warfarin. In the
presence of other causes of thrombocytopenia
or patients with low baseline platelet counts,
alternative anticoagulant therapy can go for very
long periods of time and be very costly.
{{ Options once platelet count has begun
recovery and the patient can tolerate longer
acting anticoagulants: Fondaparinux or
starting warfarin at conservative doses can be
considered.
TABLE 18-19: Use of Warfarin in HIT4,5,12,28-30

Initial recognition of Use of warfarin is not recommended, and if present at the time of HIT
HIT (acute HIT) recognition, it should be reversed (ACCP grade 2C); monotherapy with
warfarin as the initial means to manage HIT is not recommended; if
possible, 5 days of overlapping therapy with a DTI until platelet count
has recovered and the INR is >2 (or higher if on some DTI therapies);
evidence supporting this is weak. ACCP defines platelet recovery
as 150 x 109/L, but a single center study suggests that it is safe and
effective to initiate warfarin after two consecutive platelet count
increases regardless of the absolute platelet count.
Place in therapy A majority of patients in the lepirudin and argatroban trials were
converted to warfarin for extended anticoagulation; duration for
isolated HIT has been until stable recovery of platelets and reduced
risk for thrombosis; in some settings, clinicians may complete 30 days
of alternative anticoagulation; longer therapy may be considered in
the presence of thrombosis or when other indications for continued
anticoagulation are present; based on case reports, initial dosing should
be conservative to decrease the risk for venous limb gangrene.
Monitoring INR, targeting a value of 2–3 if not an a DTI causing false INR elevation
(see Chapter 5); in the setting of false INR elevations with concurrent
DTI therapy; chromogenic factor X levels of 11–42% (similar to an INR
of 2–3.5) can be used (see Chapter 5).
Transitioning from a It is important to note that the assay for the INR and aPTT separately
DTI to warfarin when may be unique to each institution; further, other variables could
a DTI is present be affecting the INR at a given DTI dose; these reasons can make
the standard nomogram for argatroban provided in the prescribing
information packet difficult to use.
One alternative approach is the following:
1. Draw a baseline INR with an aPTT on DTI therapy alone.
2. Initiate warfarin and identify a desired 1.5–2 point increase in the
INR or a preselected INR, which considers the DTI-induced INR
prolongation (with minimal change in the aPTT).
3. Once the desired number of overlap days and desired platelet
recovery has occurred and the desired INR target is reached, hold
the DTI for 4–8 hr and recheck the INR and aPTT; if the INR is
between 2–3 with an aPTT value close to baseline (INR is being
elevated by warfarin alone since aPTT close to baseline), then the
DTI can be discontinued; it may take longer for the effects of a DTI
to diminish if a very low infusion rate with aPTT values in the target
range.
ACCP: American College of CHEST Physicians, aPTT: activated partial thromboplastin time, DTI:
direct thrombin inhibitor, HIT: heparin-induced thrombocytopenia, INR: international normalized
ratio
Recommendations on When to Begin Therapy

See Figure 18-1 for recommendations on when to begin therapy for HIT.
American College of Chest Physicians’ recommendation regarding patients
with a confirmed history of HIT to avoid a recurrence of HIT5:
• To avoid re-exposure to heparin and LMWH, in patients with history of HIT or
heparin allergy needing venous thromboembolism prophylaxis:
{{ Consider warfarin, danaparoid, fondaparinux, apixaban, dabigatran,
and rivaroxaban for pharmacologic prophylaxis.
{{ Consider nonpharmacologic deep venous thromboembolism
prophylaxis.
{{ May consider cautiously using a heparin product if:
Unable to avoid UFH or LMWH options
More than 100 days since HIT diagnosis
Duration of heparin therapy is limited
• Patients with history of HIT and acute thrombosis not related to HIT:
{{ Use fondaparinux at therapeutic doses until transition to warfarin
can be achieved (Grade 2C)
{{ Do not use warfarin alone
• Patients with history of HIT requiring ongoing renal replacement therapy (RRT):
{{ Use regional citrate (Grade 2C)
SPECIAL POPULATION
CONSIDERATIONS5,12,31-35
Acute Coronary Syndromes

• Alternative anticoagulant considerations
{{ Antiplatelet inhibitor or direct thrombin inhibitor or combination.
{{ Enoxaparin is preferred over heparin for anticoagulation >48 hours
to minimize the risk of developing HIT.
{{ Ability of glycoprotein IIb-IIIa inhibitors to block platelet response
in HIT during PCI or acute HIT is unknown.
• Percutaneous coronary intervention (PCI) dosing under HIT conditions
{{ Fondaparinux should not be given as the sole anticoagulant and
is contraindicated in CrCl <30 mL/min.
{{ Bivalirudin (Grade 2B) or argatroban (Grade 2C) are preferred over
other treatment options.
The dosing regimen used may depend on the ACS
setting and a history of HIT versus active HIT. During
PCI, a higher dose per the prescribing indication may
be used. In selected situations, a lower dose (e.g.,
0.2 mg/kg/hr) may be done for a short period of time
immediately after catheterization. Otherwise, the typical
regimen for HIT management if an alternate anticoagu-

lant is necessary can be considered.
Cardiac Surgery5,31,35,36
• History of HIT
{{ Antibody negative: Use of UFH intraoperatively is preferred (Grade
2C).
{{ Antibody positive: Check washed platelet aggregation assay, if
negative, use UFH intraoperatively; if positive, use nonheparin
anticoagulants (Grade 2C).
{{ Consider using a nonheparin agent postoperatively if possible.
In one case series (n=11), plasmapheresis using fresh frozen plasma for
replacement with heparin re-exposure during cardiopulmonary bypass was
used successfully.31 Separately, eponesesterol or tirofiban concurrent with
heparin have been used during surgery.
• Acute or subacute HIT
{{ If possible, delay surgery until HIT resolved and antibody negative
or weak positive (Grade 2C).
{{ Antibody positive: Bivalirudin is preferred over other treatment
options (Grade 2C).
{{ If heparin antibodies are absent, heparin use intraoperatively is
preferred (Grade 2C); avoid perioperative heparin use.
{{ UFH infusion combined with a parenteral antiplatelet agent infusion
(e.g., tirofiban) (Grade 2C—see Table 18-21).
{{ Danaparoid (off-pump procedures) (Grade 2C).
• I f bivalirudin is used intraoperatively,

ultrafiltration can be performed via the
cardiopulmonary bypass circuit prior to chest
closure to remove bivalirudin and decrease
perioperative bleeding.
Pregnancy, Pediatrics, and Other (i.e., ECLS, Impella

Devices)
• Pregnancy
{{ HIT in this population is rare.
{{ Special considerations: HIT antibodies cross the placenta.
{{ Pregnancy-induced increases in cardiac output, renal clearance,
blood volume, and weight may require doses different to that of
the general population.
{{ Danaparoid is preferred (Grade 2C); fondaparinux can be used if
danaparoid is not available (Grade 2C).
{{ Fondaparinux/danaparoid have the most supportive data for this

population and condition.
{{ Special consideration: fondaparinux crosses the placenta.
{{ Long-term anticoagulation: subcutaneous danaparoid, lepirudin,
or fondaparinux.
{{ Target: not established, but consider monitoring aPTT (parenteral
DTI); anti-factor Xa (danaparoid).
• Pediatrics (Table 18-20)
{{ Pathophysiology and frequency similar to that of adult population.
{{ Most pediatric cases reported in critically ill or cardiac surgery
patients.
{{ Use of LMWH may decrease likelihood of HIT.
{{ Body weight may be correlated with DTI clearance.
• For patients with HIT on extracorporeal life support (ECLS, ECMO): See Chapter
5 on dosing.
• For patients with HIT with Impella Devices: It is not clear how an alternate anti-
coagulant should be used and if that includes systemic anticoagulation, or additional
to the purge solution.
TABLE 18-20: Suggested Alternative Anticoagulant Dosing in

Pediatric Patients Under HIT Conditions (See Table 5-10)34
Agent Dose Comments
Argatroban In normal hepatic function, doses Higher doses may be necessary in the
similar to observations in adults may setting of ECLS.
apply; younger patients <6 months
old may have lower clearance and
require a lower dose.
Bivalirudin Infusion of 0.05–0.31 mg/kg/hour The higher doses may occur in ECLS.
If deemed necessary in selected Can be removed by hemofiltration.
settings (e.g., ECLS), a bolus dose Elimination may be blunted in
0.1–0.25 mg/kg has been used. hypothermia.
Danaparoid VTE prevention: Renal dialysis:

10 units/kg sub-Q BID <10 yr: 30 units/kg IV + 1,000 units
VTE treatment: before each of first two dialysis sessions
Bolus: 30 units/kg IV ≥10–17 yr: 30 units/kg IV + 1,500 units
Infusion: 1.2–2 units/kg/hr before each of first two dialysis sessions
Anti-factor Xa target on day 3:
0.4–0.6 units/mL (0.5–0.8 units/mL for
high dose)
BID: twice daily, ECLS: extracorporeal life support, HIT: heparin-induced thrombocytopenia, IV:
intravenous, sub-Q: subcutaneous, VTE: venous thromboembolism, yr: year
Maintaining Lines in HIT Patients

See Table 18-21.
TABLE 18-21: Considerations for Maintaining Lines in the

Setting of HIT
Agent Comments
0.9% saline None
Citrate 4% has been studied; volume depends on the line; flush drawn from
the Abbott ACD-A solution has been used
Bivalirudin Not recommended as a flush because of enzymatic degradation by

thrombin
HIT: heparin-induced thrombocytopenia
See Table 18-22.
TABLE 18-22: Dosing of Alternative Agents in Bypass Graft

Surgery Procedures35-37
Agent Dosing
DTI See Chapter 5 for DTI dosing insights.
Tirofiban Of the parenteral GP IIb/IIIa inhibitors, tirofiban has a shorter duration of

effect and complete binding to the PG IIB/IIIa receptor
Regimen: Stop DTI if being infused prior to cannulation; initiate tirofiban
(bolus 10 mcg/kg followed by a continuous infusion of 0.15 mcg/kg/
min) 10 min prior to cannulation for cardiopulmonary bypass and prior
to starting heparin; initiate UFH at 400 units/kg targeting an ACT of 480
sec; bolus UFH as necessary to maintain ACT of 480 sec; stop tirofiban
infusion 1 hr before conclusion of cardiopulmonary bypass; reverse
UFH with protamine as necessary; begin thromboprophylaxis with DTI
targeting a aPTT of 40–60 sec or 1.5–2.5 x control.36
Epoprostenol Prior to starting heparin, initiate infusion at 5 ng/kg/min, increasing as

tolerated until target of 30 ng/kg/min is reached; standard heparin during
surgery; norepinephrine may need to be used to manage hypotension;
delay heparinization as long as possible (just prior to aortic canalization).
Plasmapheresis One case series studied the use of plasmapheresis for HIT management
in cardiac surgery patients with history of HIT and positive heparin
antibodies at the time of surgery. Plasmapheresis decreased heparin
antibody titers by 50–85%, and all complications were deemed to be
unrelated to HIT.
Immunomodulation One case series suggested that IVIG, with plasmapheresis if needed,
could be given to patients with general immune dysfunction who
developed profound thrombocytopenia after cardiac surgery. Platelet
counts started recovering within 5 days of IVIG administration and 95% of
patients recovered to survive hospitalization.
ACT: activated clotting time, aPTT: activated partial thromboplastin time, DTI: direct thrombin
inhibitor, GP: glycoprotein, HIT: heparin-induced thrombocytopenia, IVIG: intravenous
immunoglobulin, sec: seconds, UFH: unfractionated heparin, x: times

1. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N
Engl J Med. 2001;344(17):1286-1292.
*2. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br
J Haematol. 2003;121(4):535-555.
*3. Cuker A. Management of the multiple phases of heparin-induced thrombocytopenia.
Thromb Haemost. 2016;116:835-842.
*4. Warkentin TE, Greinacher A, eds. Heparin-Induced Thrombocytopenia. 4th ed. New
York, NY: Informa Healthcare USA, Inc; 2008.
*5. Linkins LA, Dans AL, Moores LK et al. Treatment and prevention of heparin-induced
Chest. 2012;141:e495s-e530s.
*6. Greinacher A, Warkentin TE. Recognition, treatment, and prevention of heparin-
induced thrombocytopenia: review and update. Thromb Res. 2006;118:165-176.
7. Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J
Med. 2006;355:809-817.
8. Chong BH, Chong JH. Heparin-induced thrombocytopenia. Expert Rev Cardiovasc
Ther. 2004;2:547-559.
9. Lillo-Le Louet A, Boutouyrie P, Alhenc-Gelas M, et al. Diagnostic score for heparin-
induced thrombocytopenia after cardiopulmonary bypass. J Thromb Haemost.
2004;2:1882-1888.
10. Warkentin TE. Laboratory testing for heparin-induced thrombocytopenia. J Thromb
Thrombolysis. 2001;10(Suppl 1):35-45.
*11. Warkentin TE. New approaches to the diagnosis of heparin-induced thrombocytopenia.
Chest. 2005;127(2 Suppl):35S-45S.
*12. Dager WE, Dougherty JA, Nguyen PH, et al. Heparin-induced thrombocytopenia:
a review of treatment options and special considerations. Pharmacotherapy.
2007;27:564-587.
13. Huhle G, Hoffmann U, Hoffmann I, et al. A new therapeutic option by subcutaneous
recombinant hirudin in patients with heparin-induced thrombocytopenia type II: a
pilot study. Thromb Res. 2000;99:325-334.
14. Miyares MA, Davis KA. Direct-acting oral anticoagulants as emerging treatment options
for heparin-induced thrombocytopenia. Ann Pharmacotherapy. 2015;49:735-739.
15. Hourmouzis Z, Bhalla MC, Frey JA, et al. Pulmonary embolism and heparin-
induced thrombocytopenia successfully treated with tissue plasminogen activator and
argatroban. Am J Emerg Med. 2015;33:739.e5-6.
16. Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients
with heparin-induced thrombocytopenia. Circulation. 2001;103:1838-1843.
17. Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with
heparin-induced thrombocytopenia. Arch Intern Med. 2003;163:1849-1856.
18. Francis JL, Drexler A, Gwyn G, et al. Successful use of bivalirudin in the treatment
of patients suspected or at risk of, heparin-induced thrombocytopenia. Blood.
2004;104:Abstract 4077.
19. Joseph L, Casanegra AI, Dhariwal M, et al. Bivalirudin for the treatment of patients
with confirmed or suspected heparin-induced thrombocytopenia. J Thromb Haemost.
2014;12:1044-1053.
20. Tsu LV, Dager WE. Bivalirudin dosing adjustments for reduced renal function with or
without hemodialysis in the management of heparin-induced thrombocytopenia. Ann
Pharmacother. 2011;45:1185-1192.
21. Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of 1478
clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-
2004. Thromb Haemost. 2006;95:967-981.
22. Grouzi E, Kyriakou E, Panagou I, et al. Fondaparinux for the treatment of acute
heparin-induced thrombocytopenia: a single center experience. Clin Appl Thromb
Hemost. 2009 Oct 13. [Epub ahead of print]
23. Lobo B, Finch C, Howard A. Fondaparinux for the treatment of patients with acute
heparin-induced thrombocytopenia. Thromb Haemost. 2008;99:208-214.
24. Kang M, Alahmadi M, Sawh S, et al. Fondaparinux for the treatment of suspected
heparin-induced thrombocytopenia: a propensity score-matched study. Blood.
2015;125:924-929.
25. Warkentin TE, Pai M, Sheppard JI, et al. Fondaparinux treatment of acute heparin-
induced thrombocytopenia confirmed by the serotonin-release assay: a 30 month,
16-patient case series. J Thromb Haemost. 2011;9:2389-2396.
26. Schindewolf M, Steindl J, Beyer-Westendorf J, et al. Frequent off-label use of
fondaparinux in patients with suspected acute heparin-induced thrombocytopenia
(HIT)—findings from the GerHIT multi-centre registry study. Thromb Res.
2014;134:29-35.
27. Burch M, Cooper B. Fondaparinux-associated heparin-induced thrombocytopenia. Proc
(Bayl Univ Med Cent). 2012;25:13-15.
28. Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict
the international normalized ratio in patients transitioning from argatroban to warfarin.
29. Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin-inhibitors:
bivalirudin, lepirudin and argatroban, on prothrombin time and INR measurements.
Am J Clin Path. 2004;121:593-599.
30. Chen L, Dager WE, Roberts AJ. Safety and efficacy of starting warfarin after two
consecutive platelet rises in patients with heparin-induced thrombocytopenia
[abstract]. Abstracts of the XXI Congress of the International Society of Thrombosis and
Haemostasis 2015. J Thromb Haemost. 2015;13:S2-866. Abstract #PO312-WED.
31. Welsby IJ, Um J, Milano CA, et al. Plasmapheresis and heparin reexposure as
a management strategy for cardiac surgical patients with heparin-induced
thrombocytopenia. Anesth Analg. 2010;110:30-35.
management of patients with non-ST-elevation acute coronary syndromes. Circulation.
2014;130:e344-e426.
33. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for
the management of ST-elevation myocardial infarction. J Am Coll Cardiol.
2013;61:e78-e140.
34. Risch L, Fisher JE, Herklotz R, et al. Heparin-induced thrombocytopenia in

paediatrics: clinical characteristics, therapy and outcomes. Intensive Care Med.
2004;30:1615-1624.
35. Greinacher A. The use of direct thrombin inhibitors in cardiovascular surgery in patients
with heparin-induced thrombocytopenia. Semin Thromb Hemost. 2004;30:315-327.
36. Koster A, Meyer O, Fisher T, et al. One-year experience with the platelet glycoprotein
IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients
with heparin-induced thrombocytopenia type II. J Thorac Cardiovasc Surg.
2001;122:1254-1255.
37. Rankin JS, Stratton CW. Efficacy of immunomodulation in the treatment of
profound thrombocytopenia after adult cardiac surgery. J Thorac Cardiovasc Surg.
2014;147;808-815.
19 Chapter
PREGNANCY
Nancy L. Shapiro
INTRODUCTION
Pregnancy is considered an acquired hypercoagulable state due to increased
concentrations of several clotting factors, increased fibrinogen, and reductions in
the natural anticoagulants free protein S and antithrombin.1,2 The increase in hyper-
coagulability during pregnancy predisposes the mother to deep vein thrombosis
(DVT) and pulmonary embolism (PE), and the fetus to gestational complications
of recurrent pregnancy loss, intrauterine growth restriction, preeclampsia, and
placental abruption. These complications affect up to 15% of pregnancies, and
they are a major cause of fetal morbidity and mortality.3 The risk of venous throm-
boembolism (VTE), composed of DVT and PE, is 2- to 5-fold higher in pregnancy
compared to nonpregnant women of child-bearing age.1,2,4-6 The incidence of
VTE ranges between 0.5 to 2 women per 1,000 pregnancies. Most symptomatic
cases are DVT, with two-thirds of cases occurring antepartum, and half of these
events occurring before the third trimester.7,8 PE is the leading cause of mortality
in pregnant women but occurs more often in the postpartum period than during
pregnancy. In the postpartum period, the risk of VTE has been estimated to be
increased 20-fold. VTE accounts for 1.1 deaths per 100,000 deliveries or 10% of
all maternal deaths.9 Areas of controversy include management of anticoagulation
in pregnant patients with mechanical heart valves, selection of a safe anticoagu-
lant, management of a patient on a direct-acting oral anticoagulant (DOAC) who
becomes pregnant, and peripartum anticoagulation management.
USE OF ANTICOAGULANTS DURING

PREGNANCY AND LACTATION
Anticoagulation is used in pregnancy for the prevention and treatment of throm-
bosis, as well as for the prevention of pregnancy loss. A summary of indications
for anticoagulation use in pregnancy can be found in Table 19-1. The definitions
used by the American College of Chest Physicians (ACCP), the American College of
Obstetrics and Gynecology (ACOG), and the American Heart Association (AHA) for
their grades of recommendations are provided in Table 19-2 and will be referred
to throughout the chapter.
449
TABLE 19-1: Indications for Anticoagulation During Pregnancy

• Prevention of thrombosis during pregnancy
{{ Prophylaxis against VTE
{{ Prophylaxis against arterial thrombosis
Stroke prevention in patients with mechanical heart valves
Stroke prevention in atrial fibrillation
• Treatment of thrombosis during pregnancy
{{ Treatment of VTE during pregnancy
{{ Treatment of arterial events during pregnancy
• Prevention of pregnancy loss
TABLE 19-2: Definitions for Grading Recommendations10-12

ACCP Grade 1A: Strong recommendation, high-quality evidence
Grade 1B: Strong recommendation, moderate-quality evidence
Grade 1C: Strong recommendation, low or very low-quality evidence
Grade 2A: Weak recommendation, high-quality evidence
Grade 2B: Weak recommendation, moderate-quality evidence
Grade 2C: Weak recommendation, low or very low-quality evidence
ACOG Level A: Based on good and consistent scientific evidence

Level B: Based on limited or inconsistent scientific evidence
Level C: Based primarily on consensus and expert opinion
AHA Size of treatment effect:

Class 1: Procedure/treatment should be performed/administered
Class IIa: It is reasonable to perform procedure/administer treatment
Class IIb: Procedure/treatment may be considered
Class III: No benefit or harmful
Estimate of certainty:
Level A: Multiple populations evaluated, multiple RCT or meta-analyses
Level B: Limited populations evaluated, single RCT or nonrandomized
studies
Level C: Very limited populations evaluated, only consensus opinion of
experts, case studies, or standard of care
ACCP: American College of Chest Physicians, ACOG: American College of Obstetrics and
Gynecology, AHA: American Heart Association, RCT: randomized controlled trial
Safety of Anticoagulants During Pregnancy

Use of anticoagulants in pregnancy must consider the safety to the fetus
(Table 19-3) and the mother (Table 19-4). Use of anticoagulants for breast-
feeding mothers must consider drug and metabolite transmission into breast
milk and safety to the infant (Table 19-5).
PREGNANCY 451
TABLE 19-3: Safety to the Fetus13-32

Drug Supporting Evidence
Apixaban • In an ex vivo study using human placenta, apixaban was

shown to rapidly cross from the maternal to the fetal
circulation. Total apixaban concentrations in cord blood
in vivo are predicted at 35–90% of the maternal levels.
Apixaban may adversely affect fetal coagulation.
• Treatment of pregnant rats from implantation (gestation day
7) to weaning (lactation day 21) with apixaban at a dose
of 1,000 mg/kg (about 5 times the human exposure based
on unbound apixaban) did not result in death of offspring
or death of mother rats during labor in association with
uterine bleeding. However, increased incidence of maternal
bleeding, primarily during gestation, occurred at apixaban
doses of ≥25 mg/kg, corresponding to ≥1.3 x the human
exposure.
• ACCP: Recommends avoiding use (Grade 1C).
• ISTH: Recommends avoiding use.
Argatroban • Unknown if it crosses placenta.

• Limited case report data exist. In animal studies, there was
no evidence of impaired fertility or harm to the fetus in rats
given argatroban IV doses up to 27 mg/kg/day (0.3 times
the MRHD based on body surface area) and rabbits given
10.8 mg/kg/day (0.2 x the MRHD).
• Clinicians should avoid use during pregnancy whenever
possible and reserve its use for those pregnant women
with HIT or a history of HIT who cannot receive danaparoid
(ACCP Grade 2C).
Aspirin • Crosses placenta.

• Due to reported teratogenic and other effects, use of aspirin
and other salicylates is not recommended during pregnancy,
particularly in the third trimester.
• First trimester: Safety remains uncertain. There is no clear
evidence of harm to the fetus, and, if fetal anomalies
are caused by early aspirin exposure, they are very rare.
Clinicians should offer first-trimester patients aspirin if the
indication for aspirin is clear, and there is no satisfactory
alternative agent.
• Second and third trimester: Low-dose (50–150 mg/day)
aspirin therapy given to women at risk for preeclampsia
is safe for the mother and fetus. Aspirin is associated with
increased risk of intracranial hemorrhage in premature
infants when used in the last week of pregnancy.
(continued)

Bivalirudin • Unknown if it crosses placenta.

• Studies in rats receiving 1.6 x the recommended maximum
human dose and in rabbits at 3.2 x the MRHD showed no
evidence of harm to the fetus or impaired fertility.
(ACCP Grade 2C).
Clopidogrel • Unknown if it crosses the placenta.

• Animal studies in rats and rabbits demonstrated no evidence
of impaired fertility or fetotoxicity.
Dabigatran • Crosses the human placenta.

• In rats given 2.6–6 x the MRHD of 300 mg/day, decreased
implantations occurred and treatment given after
implantation increased the number of dead offspring and
caused increased bleeding. Delayed or irregular ossification
of fetal skull bones and vertebrae occurred in some animal
studies.
Danaparoida • Unknown if it crosses placenta.

• Most case reports show successful pregnancy outcomes;
however, the quality of the evidence is low.
Edoxaban • Unknown if it crosses placenta.

• In Hokusai-VTE Investigators, 10 human cases of first trimester
exposure up to 6 weeks of use resulted in live births (4 full-
term, 2 pre-term), 1 first-trimester spontaneous abortion, and
3 cases of elective termination of pregnancy.
• Rats experienced post-implantation loss, perhaps secondary
to maternal vaginal hemorrhage, at a dose of 300 mg/kg/day.
In rabbits, at maternally toxic doses, embryo-fetal toxicities
occurred at 600 mg/kg/day, as well as increased implantation
loss, increased spontaneous abortion, and decreased live
fetuses and fetal weight at doses ≥200 mg/kg/day (≥20 x the
human exposure). When rats were administered oral doses
up to 30 mg/kg/day (up to 3 x the human exposure based on
AUC) during the period of organogenesis through lactation
day 20, vaginal bleeding in pregnant rats and delayed
avoidance response in female offspring were seen.
(continued)
PREGNANCY 453

Fondaparinux • Unknown if it crosses placenta.

• Results from 65 human cases reported no major bleeding,
and 1 case of recurrent VTE, likely due to inadequate
anticoagulation. Obstetric complications occurred in 18
cases, with spontaneous abortions in 13 cases, 1 case of
ectopic pregnancy, 1 case of preterm rupture of membranes,
1 case of early preeclampsia, and 2 cases of intrauterine fetal
growth retardation.
• Animal studies conducted in rats and rabbits using doses
up to 10 mg/kg/day (32 and 65 x the MRHD based on body
surface area, respectively) revealed no evidence of impaired
fertility or fetal harm.
• Anti-factor Xa activity (at approximately 1/10 the
concentration of maternal plasma) has been found in
the umbilical cord plasma in newborns treated with
fondaparinux.
(ACCP Grade 2C).
LMWH (dalteparin, • Does not cross placenta.

enoxaparin, tinzaparin) • ACCP: Recommends LMWH over UFH (Grade 1B).
Prasugrel • Unknown if it crosses the placenta.

• Reproductive and developmental studies in rats and rabbits
given doses up to 30 x the recommended human exposure
found no evidence of fetal harm.
Rivaroxaban • Rivaroxaban crosses the placenta in animal studies.

• Increased post-implantation loss has been seen in rabbits,
and pronounced maternal hemorrhagic complication in rats.
Increased fetal toxicity (increased resorptions, decreased
number of live fetuses, decreased fetal body weight)
occurred in rabbits given oral rivaroxaban doses of ≥10 mg/
kg or greater (approximately 4 x the MRHD of 20 mg/day)
during organogenesis. Decreased fetal body weight was
reported with rivaroxaban doses of 120 mg/kg (about 14
x the human exposure of unbound drug) administered to
pregnant rats.
• There are limited human case reports of 64 patients that
used rivaroxaban during the first trimester.
Ticagrelor • Unknown if it crosses the placenta.

• In animal studies, structural abnormalities were reported at
maternal ticagrelor doses 5–7 x the MRHD on an mg/m2 basis.
Use during pregnancy is recommended only if the potential
benefit justifies the potential risk to the fetus.
(continued)

UFH • Does not cross placenta.
Warfarin • Crosses placenta. Use is contraindicated in pregnancy

except in women with mechanical heart valves and high
risk for TE. Doses >5 mg daily may be at higher risk of
complications than lower doses.
• Any time: There is a risk of fetal hemorrhage, particularly
when given close to time of delivery.
• Weeks 6–12 of pregnancy: Nasal hypoplasia, stippled
epiphyses, respiratory deficiency, CNS abnormalities have
been reported.
• 2nd and 3rd trimesters: CNS toxicities include mental
retardation, optic atrophy, spasticity, and seizures. Fetal
death, neonatal hemorrhage, and increased risk of maternal
hemorrhage have been reported.
a
Not available in the U.S. market at this time.
ACCP: American College of Chest Physicians, CNS: central nervous system, HIT: heparin-induced
thrombocytopenia, ISTH: International Society of Thrombosis and Haemostasis, LMWH: low
molecular weight heparin, MRHD: maximum recommended human dose, UFH: unfractionated
heparin, VTE: venous thromboembolism, x: times
• M
ultidose vials of unfractionated heparin (UFH)
and low molecular weight heparin (LMWH)
contain benzyl alcohol, which has been reported
to cause cases of fetal gasping syndrome in
neonates. Use of preservative-free vials or single-
dose syringes is advised.
• I nternational Society of Thrombosis and
Haemostasis (ISTH) recommends against the use
of DOACs in pregnancy and switching to LMWH
if an unintentional pregnancy occurs. However,
at this time, inadvertent exposure is not in itself
medical grounds for termination of pregnancy.
Women who do decide to continue with pregnancy
while on a DOAC are recommended to have early
obstetric review and fetal monitoring.16
• I STH recommends clinicians collect data on
the course and outcomes after DOAC exposure
and report findings to the manufacturers and
PREGNANCY 455
regulatory authorities, as well as to the ISTH

registry: https://www.isth.org/news/308993/
Participate-Registry-of-Pregnancy-in-
Patients-Exposed-to-DOACs.htm to ensure
consistency of data collection.16
TABLE 19-4: Maternal Safety1,2,33-35

Adverse Effect Supporting Evidence
Bleeding • Reported risk of major bleeding with therapeutic anticoagulants is

comparable in pregnant and nonpregnant women.
• PPH (blood loss >500 mL within 24 hr of delivery) is seen in up to
5% of women receiving anticoagulant therapy; the frequency of this
complication is dependent on a number of factors such as maternal
age, parity, and mode of delivery. The rate of PPH does not appear to
be appreciably higher in women receiving antepartum LMWH therapy
than in other women when these are taken into account.
• Injection-site bruising is common throughout pregnancy and can vary
by location and injection technique.
Bone • Prolonged UFH use during pregnancy may reduce bone mineral
density and lead to the development of symptomatic vertebral
fractures in up to 2% of women.
{{ Less bone loss is seen with LMWH.
{{ Supplemental calcium may be recommended for some.
HIT • Documented HIT in pregnancy is rare, at <0.01% of women, and this

incidence is lower with LMWH than with UFH.
• In the setting of serologically confirmed HIT in pregnancy, substitute
UFH or LMWH for a DTI.
Skin • Skin rashes can be seen in up to 2% of pregnant women receiving

LMWH and are usually managed with a change in brand. If there is skin
necrosis around the injection sites, HIT-associated skin necrosis should
be excluded.
DTI: direct thrombin inhibitor, HIT: heparin-induced thrombocytopenia, hr: hours, LMWH: low
molecular weight heparin, PPH: postpartum hemorrhage, UFH: unfractionated heparin
TABLE 19-5: Safety of Anticoagulants During Lactation13,16,33,36-39

Anticoagulant Potential Risks During Breastfeedinga
Apixaban • Recommend PI information, which indicates that is unknown if apixaban

is excreted in human milk.
• It is recommended to discontinue nursing or discontinue apixaban in the
nursing mother, considering the importance of therapy to the mother.
• Micromedex Lactation Rating: Infant risk cannot be ruled out.
• ISTH: Breastfeeding women should avoid use.
• AC Forum: It should not be used while breastfeeding.
Argatroban • Rat studies have shown the presence in breast milk.

Aspirin • There is increased association between salicylates and Reye’s syndrome.

• Some available data have suggested that low intermittent doses can be
used safely in breastfeeding.
• AAP Rating: It is associated with significant effects on some nursing
infants and should be given to nursing mothers with caution.
• WHO: Avoid breastfeeding.
• ACCP: For lactating women using low-dose aspirin for vascular
indications who wish to breastfeed, suggest continuing this medication
(Grade 2C).
• AHA: In the presence of a low-risk situation in which antiplatelet therapy
would be the treatment recommendation outside of pregnancy, low-
dose aspirin use may be considered (Class IIb; Level of Evidence C).
Bivalirudin • Unknown whether bivalirudin is excreted into human breast milk.

• Until more data are available, use caution when considering the use of
bivalirudin in lactating women.
Clopidogrel • Available data are limited; weigh the potential risks and benefits before
prescribing.
• Animal data in rats showed that it enters breast milk.
Dabigatran • It is not known whether dabigatran is excreted in human milk. Until

further data are available, exercise caution when administering
dabigatran to a nursing mother.
Dalteparin • Small amounts have been found in breast milk.

• ACCP: Recommends Grade 1B for breastfeeding.
• ACOG: It may be used in women who breastfeed (Level B).
• AHA: It is reasonable to use (Class IIa; Level of Evidence C).
• AC Forum: It is safe for the breastfed infant.
(continued)
PREGNANCY 457

Danaparoidb • It is unknown if it passes into breast milk, and the safety cannot be
established.
• Limited reports suggest that little to no danaparoid appears in the breast
milk, and infant gastric secretions would likely inactivate any amounts
that were passed since danaparoid is not absorbed orally.
Edoxaban • Edoxaban was found in the milk of lactating rats.

• Because potential harm to a nursing infant exists, either edoxaban
or breastfeeding should be discontinued, considering the need for
treatment of the mother.
Enoxaparin • It is unlikely that it passes into breast milk.

Fondaparinux • Animal data showed that it was detected in milk of lactating rats.
• ACCP: Alternative anticoagulants are recommended other than
fondaparinux (Grade 2C).
Prasugrel • Available data are limited; weigh the potential risks and benefits before
prescribing.
• Animal data in rats showed that its metabolites entered breast milk.
Rivaroxaban • Animal studies indicate it is secreted into milk.

• A human case report shows that rivaroxaban passes into human breast
milk, with the ratio of milk to plasma reported at 0.4. No conclusions can
be drawn regarding the safety of rivaroxaban in nursing mothers and
their breastfed infants.
• Due to the potential of serious adverse reactions in breastfeeding
infants, a decision should be made whether to discontinue rivaroxaban
use or to discontinue nursing during therapy, taking into account the
importance of the drug to the mother.
(continued)

Ticagrelor • Ticagrelor is excreted in the milk of lactating rats.

• It is unknown whether ticagrelor or its active metabolites are excreted
in human milk. The manufacturer recommends discontinuing nursing or
discontinuing ticagrelor, considering the importance of the drug to the
mother.
Tinzaparin • Very low levels have been detected in rat breast milk.
• ACOG: It may be used in women who breastfeed (Level B)
UFH • Not secreted in breast milk and is considered safe for nursing mothers.
• Micromedex Lactation Rating: Infant risk is minimal.
• AAP Rating: Maternal medication is usually compatible with
breastfeeding.
• ACCP: Recommends Grade 1A for breastfeeding.
• WHO: It is compatible with breastfeeding.
Warfarin • Not secreted in breast milk and is considered safe for nursing mothers.
• AAP Rating: Maternal medication usually compatible with breastfeeding.
• ACCP: Recommends Grade 1A for breastfeeding.
• WHO: It is compatible with breastfeeding.
• Micromedex: Infant risk is minimal.
Refer to Table 19-2 for definitions on levels of recommendations.

a
b
Not available in the U.S. market at this time.
AAP: American Academy of Pediatrics, ACCP: American College of Chest Physicians, AC Forum:
guidance document endorsed by the Anticoagulation Forum Board of Directors, AHA: American
Heart Association, ISTH: International Society of Thrombosis and Haemostasis, WHO: World
Health Organization
Preconception Planning
Evaluation of a woman who may require anticoagulation during pregnancy
should occur before conception, ideally, or at least early in pregnancy.1,2,40
• Patients with a high risk of maternal mortality due to thrombosis (e.g., mechani-
cal heart valves, chronic thromboembolic pulmonary hypertension, history of
PREGNANCY 459
recurrent thrombosis while fully anticoagulated, history of myocardial infarction)

may be advised against pregnancy.33,38,40
• Patients already on anticoagulation prior to pregnancy will likely need to
continue; counsel them preconception regarding the need to switch from a
vitamin K antagonist (VKA) or DOAC to LMWH.16,41
• ACCP: For women requiring long-term VKAs who are attempting pregnancy and
are candidates for LMWH substitution, performing frequent pregnancy tests and
substituting LMWH for VKAs when pregnancy is achieved—rather than switching
to LMWH while attempting pregnancy—is suggested (Grade 2C).33
• ISTH: Recommends all women of childbearing potential should receive
documented counseling before starting DOACs, with emphasis on avoiding
pregnancy; if pregnancy is desired, switch to an alternative anticoagulant
preconceptually (VKA then switch to LMWH as soon as pregnant and before 6
weeks gestation, or LMWH).16
UFH and LMWH Regimens and Associated Doses as

Defined by ACCP and ACOG
The ACCP’s and ACOG’s definitions to describe UFH and LMWH regimens
and associated doses differ slightly and are listed in Table 19-6.
PREVENTION OF THROMBOSIS DURING

PREGNANCY
Pregnancy as a Risk Factor for VTE1,2,42,43

• Hypercoagulability
{{ Coagulation is not fully corrected until at least 6 weeks postpartum.
{{ Some retrospective data show that the risk for stroke, myocardial
infarction (MI), and VTE is elevated out to 12 weeks postpartum.
{{ True diagnosis of deficiencies (protein C, S, antithrombin) should
wait until at least 6 weeks postpartum and off VKAs for at least 2
weeks.
• Venous stasis
{{ >30% reduction in flow by 15 weeks; >60% reduction by 36 weeks.
{{ 90% of DVTs in left leg due to compression of left iliac vein by the
right iliac artery where they cross.
• Vascular damage
{{ Trauma to pelvic veins during delivery.
{{ Pelvic vein thromboses, rare outside of pregnancy or pelvic surgery,
account for approximately 10% of DVT during pregnancy and the
postpartum period.
TABLE 19-6: UFH and LMWH Regimens and Associated Doses

as Defined by ACCP and ACOG11,33
ACCP ACOG
Mini-dose 5,000 units sub-Q q 12 hr

prophylactic UFH
Prophylactic LMWH Dalteparin 5,000 units sub-Q q Dalteparin 5,000 units sub-Q daily
24 hr Enoxaparin 40 mg sub-Q daily
Enoxaparin 40 mg sub-Q q 24 hr Tinzaparin 4,500 units sub-Q daily
Tinzaparin 4,500 units sub-Q q (At extremes of body weight,
24 hr modification of dose may be
(At extremes of body weight, required.)
modification of dose may be
required.)
Prophylactic UFH UFH 5,000–10,000 units sub-Q

q 12 hr
UFH 5,000–7,500 units q 12 hr
first trimester
UFH 7,500–10,0000 units sub-Q q
12 hr second trimester
UFH 10,000 units sub-Q q 12
hr third trimester unless aPTT
elevated
Intermediate dose Dalteparin 5,000 units sub-Q q Not defined

LMWH 12 hr
Enoxaparin 40 mg sub-Q q 12 hr
Adjusted dose Weight-adjusted, full treatment Enoxaparin 1 mg/kg q 12 hr

LMWH doses of LMWH, given once or Dalteparin 200 units/kg daily
twice daily Tinzaparin 175 units/kg daily
Dalteparin 200 units/kg daily Dalteparin 100 units/kg q 12 hr
Tinzaparin 175 units/kg daily Target anti-Xa 0.6–1 units/ml mL
Dalteparin 100 units/kg q 12 hr for twice daily regimen; slightly
Enoxaparin 1 mg/kg q 12 hr higher doses may be needed for a
once-daily regimen
Adjusted dose UFH UFH sub-Q q 12 hr in doses 10,000 units or more sub-Q q
adjusted to target a mid-interval 12 hr in doses adjusted to target
aPTT into the therapeutic range aPTT 1.5–2.5 x control 6 hr after
injection
Postpartum VKAs for 6 weeks with a target Prophylactic LMWH/UFH 4–6

anticoagulation INR of 2–3, with initial UFH weeks or VKA 4–6 weeks with
or target INR 2–3, with UFH/LMWH
LMWH overlap until the INR is >2, overlap until INR 2 or more for
or prophylactic or intermediate- 2 days
dose LMWH for 6 weeks
(continued)
PREGNANCY 461

ACCP ACOG
Surveillance Clinical vigilance refers to Clinical vigilance and appropriate

patient and physician alertness objective investigation of women
to signs and symptoms of VTE with symptoms suspicious of VTE
and awareness of the need for may be needed.
timely and appropriate objective
investigation.
ACCP: American College of Chest Physicians, ACOG: American College of Obstetrics and
Gynecology, aPTT: activated partial thromboplastin time, hr: hours, INR: international normalized
ratio, LMWH: low molecular weight heparin, sub-Q: subcutaneous, UFH: unfractionated heparin,
VKA: vitamin K antagonist, VTE: venous thromboembolism, x: times
Source: Adapted with permission from Bates SM, Greer IA, Pabinger I, et al. Venous
thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College
of Chest Physicians Evidence-based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6
Suppl):844S-886S.
Risk of VTE in Pregnant Women with Thrombophilia

A strong association exists between inherited thrombophilia and venous
thromboembolism, making detection of these mutations a part of preven-
tion strategies. The risks for VTE associated with different thrombophilia are
described in Table 19-7. However, it is not clear whether inherited thrombo-
philia lead to such adverse pregnancy outcomes as fetal loss, preeclampsia,
intrauterine growth restriction, and placental abruption.
Prevention of VTE During Pregnancy

• ACOG provides recommendations for when to screen pregnant women for
thrombophilia (Table 19-8).
• Low-risk thrombophilia are defined as Factor V Leiden heterozygous; prothrombin
G20210A heterozygous; protein C or protein S deficiency.
• High-risk thrombophilia includes antithrombin deficiency; double heterozygous
for prothrombin G20210A mutation and factor V Leiden; factor V Leiden homozy-
gous or prothrombin G20210A mutation homozygous.
• Both ACCP and ACOG provide slightly different recommendations for VTE
prevention in patients with no prior history of VTE (Table 19-9). These recom-
mendations consider whether or not the patient has a family history of VTE.
Separate recommendations also exist that consider whether the patient has had
a previous VTE (Table 19-10).
TABLE 19-7: Risk of VTE Associated with Different

Thrombophilias11
Thrombophilia Prevalence VTE Risk per VTE Risk per % of all VTE
(%) Pregnancy Pregnancy
(No History) (Previous VTE)
(%) (%)
Antithrombin III activity 0.02 3−7 40 1

(<60%)
Factor V Leiden 1–15 0.5–1.2 10 40

heterozygote
Factor V Leiden homozygote <1 4 17 2
Factor V Leiden/Prothrombin 0.01 4−5 >20 1–3

double heterozygote
Protein C activity (<50%) 0.2–0.4 0.1–0.8 4–17 14
Protein S free antigen 0.03–0.13 0.1 0–22 3

(<55%)
Prothrombin gene 2–5 <0.5 >10 17

heterozygote
Prothrombin gene <1 2-–4 >17 0.5

homozygote
TABLE 19-8: Screening for Thrombophilia in Pregnancy11

Screening for thrombophilia in pregnancy recommended:
• Personal history of VTE associated with a nonrecurrent RF (fracture, surgery, immobilization)
{{ Recurrence risk among untreated pregnant women with such a history and a
thrombophilia was 16% (OR 6.5; 95% CI 0.8–56.3).
• First degree relative with history of high-risk thrombophilia.
In other situations, thrombophilia testing not routinely recommended:

• Testing for inherited thrombophilia in women who have experienced recurrent fetal loss
or placental abruption is not recommended because it is unclear if AC therapy reduces
recurrence (Level B).
• Insufficient evidence to either screen for or treat women with inherited thrombophilia and
obstetric histories that include complications such as IUGR or preeclampsia (Level B).
AC: anticoagulation, IUGR: intrauterine growth restriction, RF: risk factor, VTE: venous
thromboembolism
PREGNANCY 463
TABLE 19-9: ACCP and ACOG Recommendations for VTE

Prevention in Patients with No Prior History of VTE11,33,a
No Prior VTE, No Family ACCP 2012 ACOG 2013
History for VTE From Bulletin #138
Homozygous factor V Leiden AP: Clinical vigilance High-risk thrombophilia

or Prothrombin mutation PP: Prophylactic or AP: Surveillance without AC
intermediate dose LMWH or tx, or prophylactic LMWH/
VKA INR 2–3 for 6 weeks over UFH
routine care PP: AC tx
Antithrombin deficiency, AP: Clinical vigilance over High-risk thrombophilia

double heterozygous pharmacologic prophylaxis AP: Surveillance without AC
Prothrombin G2010A PP: Clinical vigilance over tx or prophylactic LMWH/UFH
mutation, and factor V Leiden pharmacologic prophylaxis PP: AC tx
mutation
All other thrombophilia AP and PP: Clinical vigilance Low-risk thrombophilia

over pharmacologic AP: Surveillance without AC
prophylaxis PP: Surveillance without AC
or PP AC if + risk factors
No Prior VTE + Family History for VTE
Homozygous factor V Leiden AP: Prophylactic or High-risk thrombophilia with

or prothrombin mutation and intermediate dose LMWH 1 prior VTE or 1st degree
+ family history for VTE PP: Prophylactic or relative
intermediate dose LMWH or AP: Prophylactic, intermediate
VKA INR 2–3 for 6 weeks over dose or adjusted dose
no prophylaxis LMWH/UFH
PP: PP AC or intermediate or
adjusted dose LMWH/UFH
6 weeks
Antithrombin deficiency, AP: Clinical vigilance High-risk thrombophilia with

double heterozygous PP: Prophylactic or 1 prior VTE or 1st degree
prothrombin G2010A and intermediate dose LMWH or, relative
factor V Leiden and + family in women who are not protein AP: Prophylactic, intermediate
history for VTE C or S deficient, VKA INR 2–3 dose, or adjusted dose
over routine care LMWH/UFH
PP: PP AC or intermediate or
adjusted dose LMWH/UFH
6 weeks
All other thrombophilia who AP: Clinical vigilance Low-risk thrombophilia

have + family history for VTE PP: Prophylactic or AP: Surveillance without
intermediate dose LMWH or, AC tx
in women who are not protein PP: PP AC or intermediate
C or S deficient, VKA INR 2–3 dose LMWH/UFH
over routine care
Refer to Table 19-2 for corresponding dosing regimens.

a
AC: anticoagulation, ACCP: American College of Chest Physicians, ACOG: American College
of Obstetrics and Gynecology, AP: antepartum, INR: international normalized ratio, LMWH: low
molecular weight heparin, PP: postpartum, tx: therapy, UFH: unfractionated heparin, VKA: vitamin
K antagonist, VTE: venous thromboembolism
Source: Adapted from Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians
Evidence-based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 Suppl):844S-886S.
TABLE 19-10: ACCP and ACOG Recommendations for VTE

Prevention in Patients with Previous VTE11,33,a
VTE Prophylaxis: No ACCP 2012 ACOG 2013 (From Bulletin
Thrombophilia, Prior VTE #138)
Low risk of recurrent VTE AP: Clinical vigilance over AP AP: Surveillance without AC
(single episode of VTE prophylaxis PP: AC tx
associated with transient PP: Prophylactic or
risk factor not related to intermediate dose LMWH
pregnancy or estrogen) or VKA INR 2–3 over no
prophylaxis
Moderate/high risk of AP: Prophylactic or Pregnancy related:

recurrent VTE (single intermediate-dose LMWH AP: Prophylactic LMWH or
unprovoked VTE, pregnancy- over clinical vigilance or UFH
or estrogen-related VTE, or routine care PP: PP AC tx
multiple prior unprovoked PP: Prophylactic or Idiopathic VTE:
VTE not receiving long-term intermediate dose LMWH AP: Prophylactic LMWH/UFH
AC) or VKA INR 2–3 over no PP: PP AC
prophylaxis Multiple VTE not on long
term AC:
AP: Prophylactic or
therapeutic LMWH/UFH
PP: AC
On long-term VKA prior to AP: Adjusted-dose LMWH or AP: Therapeutic dose LMWH
pregnancy 75% of a therapeutic dose of or UFH
LMWH PP: Resume long-term AC
PP: Resume long-term AC
over prophylactic dose
LMWH
VTE Prophylaxis: ACCP 2012 ACOG 2013 (From Bulletin

Thrombophilia and Prior #138)
VTE
Low-risk thrombophilia (factor AP: Prophylactic or

V Leiden heterozygous, intermediate-dose LMWH/
prothrombin G0210A UFH or surveillance without
heterozygous, protein C or AC
protein S deficiency) with PP: PP AC or intermediate
single previous VTE (not dose LMWH/UFH
receiving long-term AC)
High-risk thrombophilia AP: Prophylactic,

(antithrombin deficiency, intermediate-dose, or
double heterozygous for adjusted dose LMWH/UFH
prothrombin G2010A regimen
mutation and factor V Leiden, PP: PP AC or intermediate or
Factor V Leiden homozygous, adjusted dose LMWH/UFH
or Prothrombin G20210A for 6 weeks (therapy level
mutation homozygous) with should be at least as high as
a single previous episode of AP treatment)
VTE (not receiving long-term
AC)
(continued)
PREGNANCY 465

VTE Prophylaxis: ACCP 2012 ACOG 2013 (From Bulletin
Thrombophilia and Prior #138)
VTE
Thrombophilia or no AP: Prophylactic or

thrombophilia with 2 or therapeutic dose LMWH or
more episodes of VTE (not UFH
receiving long-term AC) PP: PP AC or therapeutic
dose LMWH/UFH for 6 weeks
Thrombophilia or no AP: Therapeutic dose LMWH

thrombophilia with 2 or more or UFH
episodes of VTE (receiving PP: Resumption of long-term
long-term AC) AC tx
a
of Obstetrics and Gynecology, AP: antepartum, INR: international normalized ratio, LMWH: low
molecular weight heparin, PP: postpartum, tx: therapy, UFH: unfractionated heparin, VKA: vitamin
K antagonist, VTE: venous thromboembolism
Evidence-based Clinical Practice Guidelines (8th ed). Chest. 2008;133(suppl 6):844S-886S.
• M
ultiple anticoagulants may be acceptable
for use during pregnancy and the postpartum
period. Drug selection decision depends on
efficacy, safety to the mother and the fetus (e.g.,
bleeding risk, risk during lactation), and patient
preferences. Strategies may differ in the United
States and Europe.
• F
or dosing and monitoring of LMWH/UFH for
VTE prophylaxis:11,33
{{ LMWH recommended over UFH for the
prevention and treatment of VTE (ACCP
Grade 2C).
{{ Higher doses of LMWH may be needed to
achieve target prophylactic anti-factor Xa
levels, especially in obese patients (i.e.,
enoxaparin 40 mg twice daily [BID],
dalteparin 5,000 units BID).
{{ Monitoring of anti-factor Xa levels in
this setting is controversial; if performed,
checking every 1–3 months is reasonable.
{{ Target anti-factor Xa levels of 0.1–0.3

International Units/mL have been
recommended by some, while others
recommend 0.2–0.6 International Units/mL.
No comparative studies have been conducted.
• M
onitoring aPTT levels is generally not
recommended for prophylactic dosing of UFH.
ACCP Considerations of Cesarean Section

ACCP has compiled a list of major and minor risk factors used to identify
women at increased risk of VTE after a cesarean section (Table 19-11). The
TABLE 19-11: Risk Factors for VTE with a Baseline Risk of

Postpartum VTE of >3%33
Major risk factors • Immobility (strict bedrest for ≥1 week in the antepartum period)
(OR >6) • Postpartum hemorrhage ≥1,000 mL with surgery
• Previous VTE
• Preeclampsia with fetal growth restriction
• Thrombophilia
{{ Antithrombin deficiency
{{ Factor V Leiden (homozygous or heterozygous)
{{ Prothrombin G20210A (homozygous or heterozygous)
• Medical conditions
{{ Systemic lupus erythematosus
{{ Heart disease
{{ Sickle cell disease
• Blood transfusion
• Postpartum infection
Minor risk factors (OR • BMI >30 kg/m2

>6 when combined) • Multiple pregnancy
• Postpartum hemorrhage >1 Liter
• Smoking > 10 cigarettes/day
• Fetal growth restriction (gestational age + sex-adjusted birth
weight <25th percentile)
• Thrombophilia
{{ Protein C deficiency
{{ Protein S deficiency
• Preeclampsia
OR: odds ratio, VTE: venous thromboembolism

Evidence-Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 Suppl):844S-886S.
PREGNANCY 467
presence of one major or two or more minor risk factors will indicate whether
patients qualify for thrombosis prophylaxis (Table 19-12). When major
risk factors continue in the puerperium, consideration should be given to
extending prophylaxis for the 6 weeks during which pregnancy-associated
prothrombotic changes may persist.
Prevention of Arterial Events During Pregnancy

Prevention of arterial events during pregnancy includes anticoagulation
management of patients with mechanical heart valves, as well as patients
with atrial fibrillation.
TABLE 19-12: ACCP Considerations of Cesarean Section33

Without additional thrombosis risk factors:
• Recommend against the use of thrombosis prophylaxis other than early mobilization
(Grade 1B).
Increased risk of VTE because of 1 major or ≥2 minor risk factors:
• Suggest pharmacologic prophylaxis (prophylactic LMWH) or mechanical prophylaxis
(ES or IPC) in those with contraindications to AC while in hospital after delivery over no
prophylaxis (Grade 2B).
Very high risk for VTE and multiple additional risk factors for TE that persist in the puerperium:
• Suggest prophylactic LMWH be combined with ES and/or IPC over LMWH alone (Grade
2C).
Selected high-risk patients with significant risk factors that persist following delivery:
• Suggest extended prophylaxis (up to 6 weeks after delivery) following discharge from the
hospital (Grade 2C).
ACCP: American College of Chest Physicians, ES: elastic stockings, IPC: intermittent pneumatic
compression, LMWH: low molecular weight heparin, TE: thromboembolism, VTE: venous
thromboembolism
TABLE 19-13: Anticoagulation with Mechanical Heart Valves

During Pregnancy12,33
ACCP Recommend one of the following AC regimens in preference to no anticoagulation
(All Grade 1A):
• Adjusted-dose BID LMWH throughout pregnancy. Suggest that doses be
adjusted to achieve the manufacturer’s peak anti-factor Xa LMWH 4 hr post
sub-Q injection or
• Adjusted-dose UFH throughout pregnancy administered sub-Q every 12
hr in doses adjusted to keep the mid-interval aPTT at least twice control or
attain an anti-factor Xa heparin level of 0.35−0.70 units/mL or
• UFH or LMWH (as above) until the 13th week, with substitution by VKA until
close to delivery when UFH or LMWH is resumed.
In women at very high risk of TE with concerns about efficacy and safety of LMWH or
UFH (older generation prosthesis in mitral position or hx of TE):
• Suggest VKA throughout pregnancy with replacement by UFH or LMWH
close to delivery rather than one of the other regimens (Grade 2C).
Pregnant women with prosthetic valves at high risk of TE:

• Suggest addition of low dose ASA 75–100 mg/day (Grade 2C).
AHA/ACC Therapeutic anticoagulation with frequent monitoring is recommended for all

2014 pregnant patients with a mechanical prosthesis (Grade 1B):
First trimester:
• Warfarin if dose <5 mg/day (Grade IIa B).
• Dose adjusted LMWH at least two x per day (with a target anti-factor Xa level
of 0.8–1.2 units/mL, 4–6 hr postdose) if warfarin dose is >5 mg/day (Grade
IIa B).
• Dose-adjusted LMWH at least two x per day (with a target anti-Xa level of
0.8–1.2 units/mL, 4–6 hr post-dose) if the dose of warfarin is ≤5 mg/day to
achieve a therapeutic INR (Grade IIb B).
• Dose-adjusted continuous infusion IV UFH (with an aPTT at least two x
control) if the dose of warfarin is >5 mg/day to achieve a therapeutic INR
(Grade IIa B).
• Dose-adjusted continuous infusion IV UFH (with aPTT at least two x control) if
the dose of warfarin is ≤5 mg/day to achieve a therapeutic INR (Grade IIb B).
Second and third trimesters:
• Warfarin to goal INR (Grade 1B).
• Discontinuation of warfarin with initiation of IV UFH (with an activated aPTT
>2 x control) is recommended before planned vaginal delivery (Grade IC).
• Low-dose aspirin in addition to anticoagulation with mechanical prosthesis or
bioprosthesis (Grade 1C).
LMWH should not be administered unless anti-factor Xa levels are monitored 4–6 hr
after administration (Grade III B).
AC: anticoagulation, ACC: American College of Cardiology, ACCP: American College of Chest
Physicians, AHA: American Heart Association, ASA: acetylsalicylic acid, aPTT: activated partial
thromboplastin time, hr: hours, hx: history, INR: international normalized ratio, IV: intravenous,
LMWH: low molecular weight heparin, sub-Q: subcutaneous, TE: thromboembolism, UFH:
unfractionated heparin, VKA: vitamin K antagonist, x: times
PREGNANCY 469
For dosing and monitoring of UFH and LMWH for

mechanical heart valves:
• I n pregnancy, particularly in the third trimester,
an increase in heparin-binding proteins—
combined with elevated factor VIII levels—can
attenuate the activated partial thromboplastin
time (aPTT) response leading to heparin
resistance; consider plasma heparin levels if
there is difficulty achieving a therapeutic aPTT
response despite infusing 30,000–35,000 units
intravenously per 24 hours.
• F
or subcutaneous (sub-Q) UFH dosing to achieve
therapeutic aPTT: Initiate doses starting at
18 units/kg × weight (in kg) × 24 hr × 1.2,
divided every 12 hours. (A correction factor of
1.2 can be applied to account for the 10−20%
loss of bioavailability with sub-Q absorption—
see Chapter 3 for more information on dose
adjustments.)
{{ For example, an 80-kg patient would start at
20,000 units sub-Q every 12 hours.
{{ Check aPTT levels 6 hours after dose is
given.
{{ Use 20,000 units/mL single dose,
preservative-free heparin vials.
{{ Increase or decrease dose by 2,000–5,000 units
with follow-up aPTT levels every 3 days.
• he range for peak anti-factor Xa levels in
T
women with mechanical heart valves using
LMWH is controversial. Current ACCP
recommendations do not include a target anti-
factor Xa level, while ACC/AHA recommends
a target peak anti-factor Xa levels (4–6 hours
post-dose) of 0.8–1.2 International Units/mL.
Others have suggested 12-hour trough levels
>0.5 International Units/mL. Clinical judgment
should include the type and location of the valve,
previous history of thromboembolism (TE), and
other risk factors for TE and bleeding.
TABLE 19-14: Atrial Fibrillation and Other Cardiovascular

Diseases During Pregnancy37
For high-risk conditions that would require anticoagulation outside of pregnancy, the following
options are reasonable (Class IIa; Level of Evidence C): LMWH twice daily throughout pregnancy,
with dose adjusted to achieve the LMWH manufacturer’s recommended peak anti-factor Xa
activity 4 hours after injection, or
• Adjusted-dose UFH throughout pregnancy, administered subcutaneously every 12 hr in
doses adjusted to keep the mid-interval activated partial thromboplastin time at least twice
control or to maintain an anti-factor Xa heparin level of 0.35−0.70 units/mL, or
• UFH or LMWH (as above) until the 13th week, followed by substitution of a VKA until close
to delivery, when UFH or LMWH is resumed.
For a low-risk situation in which antiplatelet therapy would be the treatment recommendation
outside of pregnancy (Class IIb; Level of Evidence C):
• UFH or LMWH, or no treatment may be considered during the first trimester of pregnancy
depending on the clinical situation.
hr: hours, LMWH: low molecular weight heparin, UFH: unfractionated heparin, VKA: vitamin K
antagonist
TREATMENT OF THROMBOSIS DURING

PREGNANCY
Diagnosis of VTE During Pregnancy

Early diagnosis of thrombosis during pregnancy is critical so that therapy can
be started and achieve favorable clinical outcomes for both the mother and
fetus. Figure 19-1 shows a suggested algorithm for the diagnosis of DVT
and PE that incorporates clinical features and diagnostic imaging.
• For VTE diagnosis:

{{ Compression ultrasound is the test of choice
in women with suspected DVT but is less
accurate for isolated calf and iliac vein
thrombosis.
{{ Magnetic resonance direct thrombus imaging
(MRDTI) is useful for diagnosis of iliac
vein thrombosis and causes no radiation
exposure.
{{ Computed tomographic (CT scans) causes
low radiation exposure to the fetus but
exposes maternal breast tissue to radiation.
{{ Ventilation/perfusion (V/Q) scans have a low
amount of radiation exposure.
PREGNANCY 471
Clinical Features Suggestive Clinical Features Suggestive

of Deep-Vein Thrombosis of Pulmonary Embolism
Begin low- Begin low-

molecular- molecular-
weight heparin weight heparin
Compression Compression
ultrasonography ultrasonography
Negative Positive Positive Negative
Continue low- Chest

D-Dimer test
molecular- radiography
weight heparin
Asthma or
Positive Negative other abnormality Normal
Suspicion of Clinical Computed Computed tomographic

iliac-vein followup tomographic pulmonary angiography
thrombosis pulmonary or ventilation–perfusion
angiography scanning
Yes No
Repeat compression
MRDTI
ultrasonography
in 5–7 days
Nondiagnostic
result or high
or Positive Negative Normal Positive suspicion
Pulsed Doppler Restart low- Clinical Continue low- Pulmonary angio-

study or computed molecular-weight followup molecular-weight graphy, serial
tomography heparin heparin compression
of iliac veins ultrasonography,
MRDTI, or pulsed
Doppler study
FIGURE 19-1. Diagnosis of VTE During Pregnancy

MRDTI: magnetic resonance direct thrombus imaging
Source: Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl
J Med. 2008;359:2025-2033. Copyright © 2008, Massachusetts Medical Society.
Reprinted with permission from Massachusetts Medical Society.
{{ Negative D-dimer is useful for ruling out DVT

in combination with a negative compression
ultrasound, but there may be false elevations
during pregnancy.
Treatment of VTE During Pregnancy2,33,36

Initiate treatment prior to objective confirmation if no contraindication to
anticoagulation.
• First-line treatment of acute VTE in pregnant women is UFH or LMWH over other
options due to favorable safety profiles and ability to monitor dosing. Points to
consider when choosing between UFH or LMWH are discussed below.
Dosing and Monitoring of UFH33,44-48

• Adjusted dose IV UFH (IV bolus, with continuous infusion to maintain aPTT
within the therapeutic range or SC therapy adjusted to maintain the aPTT 6
hours after injection into the therapeutic aPTT range for at least 5 days) can
be considered in the initial treatment of PE and in situations in which delivery,
surgery, or thrombolysis (indicated for life-threatening or limb-threatening
thromboembolism) may be necessary.
• If the woman is potentially unstable (large PE with hypoxia), presents with
extensive iliofemoral disease and extreme venous congestion, or has significant
renal impairment (e.g., a creatinine clearance of <30 mL/min), initial inpatient
intravenous (IV) adjusted-dose UFH should be considered.
Dosing and Monitoring of LMWH33,38,45-49

• When hemodynamically stable, adjusted dose sub-Q LMWH is preferred over
adjusted dose UFH during pregnancy (ACCP Grade 1B), based on safety data
for both mother and the fetus.
{{ Better bioavailability, longer plasma-half-life, more predictable
dose response, less monitoring, and improved safety profile with
respect to osteoporosis and thrombocytopenia compared to UFH
• Alterations in volume of distribution
{{ Elevated throughout pregnancy and declines postpartum
• Alterations in renal clearance
{{ More rapid during early pregnancy, decreases as pregnancy
progresses
• Some clinicians prefer to use twice-daily LMWH during pregnancy because of
alterations in renal clearance. No comparative studies have been conducted.
Monitoring Strategies for LMWH in Pregnancy

• Controversy exists about the need for monitoring LMWH with anti-factor Xa
levels during pregnancy. Currently acceptable strategies include the following:
{{ Initial dosing based on weight with no further dose adjustment.
{{ Dose adjustment guided by weight changes throughout pregnancy.
{{ Manufacturer-recommended peak anti-factor Xa levels guide dose
adjustment.
• Monthly monitoring throughout pregnancy is reasonable.
• For therapeutic anticoagulation for VTE, peak anti-factor Xa levels measured 4
hours postdose to reach 0.6–1 unit/mL if a twice-daily regimen is used; slightly
PREGNANCY 473
higher if a once-daily regimen is chosen.

• Peak anti-factor Xa levels >1 unit/mL, or 12-hour trough levels >0.5 units/mL
may be targeted for patients with mechanical heart valves.
Duration of Therapy11,33,38
• Treatment of VTE should be continued throughout pregnancy (ACCP Grade 1B)
and continued until at least 6 weeks postpartum (for a minimum total duration
of 3 months) in comparison with shorter durations (ACCP Grade 2C).
PREVENTION OF PREGNANCY LOSS
TABLE 19-15: Recommendations for Prevention of Pregnancy

Complications in Women with Thrombophilia Based on Risk
Categories33,50,a
Prevention of Pregnancy ACCP 2012 ACOG 2012
Complications in Women From Bulletin #132b
with Thrombophilia
Recurrent early pregnancy Recommend screening Testing for inherited thrombophilia

loss (≥3 miscarriages before for APLAs (Grade 1B) in women who have experienced
10 weeks gestation) recurrent fetal loss, or placental
abruption is not recommended
because it is unclear if AC therapy
reduces recurrence (Level B)
APLA screening: 1 fetal loss or 3 or
more embryonic losses (Level B)
History of pregnancy Suggest not to Insufficient evidence to either

complications screen for inherited screen for or treat women with
thrombophilia inherited thrombophilia and
(Grade 2C) obstetric histories that include
Suggest not to complications such as IUGR or
use antithrombotic preeclampsia (Level B)
prophylaxis (Grade 2B)
Testing for APLA in patient No recommendations Recommend testing for APLA in

with past VTE women with a prior unexplained
VTE, a new VTE during pregnancy,
or in those with a history of VTE but
not tested previously (Level B)
Meet laboratory criteria for AP: Prophylactic or In women with APLS and a history
APLA syndrome and meet the intermediate dose UFH of stillbirth or recurrent fetal loss
clinical APLA criteria based or prophylactic LMWH but no prior TE (Level B):
on ≥3 pregnancy losses with low-dose ASA, AP: Prophylactic doses of heparin
75–100 mg/day, over no and low-dose aspirin
treatment (Grade 1B) PP: Continue 6 weeks
(continued)

Prevention of Pregnancy ACCP 2012 ACOG 2012
Complications in Women From Bulletin #132b
with Thrombophilia
Women with APLS who have AP: Prophylactic- or Most experts recommend
had a thrombotic event intermediate-dose prophylactic anticoagulation with
LMWH rather than heparin throughout pregnancy and
clinical vigilance or 6 weeks postpartum (Level C)
routine care (Grade 2C)
PP: Prophylactic or
intermediate-dose
LMWH or VKA INR 2–3
for 6 weeks over no
prophylaxis (Grade 2B

a
b
Reaffirmed in 2017.
of Obstetrics and Gynecology, AP: antepartum, APLAs: antiphospholipid antibodies, APLS:
antiphospholipid antibody syndrome, ASA: aspirin, INR, international normalized ratio, IUGR:
intrauterine growth restriction, LMWH: low molecular weight heparin, PP: postpartum, TE:
thromboembolism, UFH: unfractionated heparin, VKA: vitamin K antagonist, VTE: venous
thromboembolism
USE OF ANTICOAGULANTS DURING LABOR

AND DELIVERY1,2,33,38,51,52
TABLE 19-16: Anticoagulants During Labor and Delivery51,52

Treatment doses of sub-Q Prolonged aPTT can be seen more than 24 hr after the last
UFH every 12-hr dose; consider induction of labor with planned
discontinuation of heparin prior to delivery; aPTT monitoring and/
or administration of protamine sulfate around the time of delivery
may be necessary.
• Protamine has been reported to cause neonatal respiratory
depression.
• Neuraxial anesthesia should not be used in anticoagulated
women.
Treatment doses of Consider induction of labor, with discontinuation of LMWH 24–36

LMWH hr prior to elective induction of labor or cesarean section.
• If induction of labor is not planned, caution patients to
withhold further LMWH doses at the onset of regular
contractions.
• Neuraxial anesthesia should not be used in anticoagulated
women (i.e., within 24 hr of last dose of treatment-dose
LMWH).
(continued)
PREGNANCY 475

Prophylactic doses of Stop treatment 12–24 hr before induction or cesarean delivery.
UFH or LMWH • Wait at least 10–12 hr after the last dose of prophylactic
dose LMWH before placement of epidural catheter or spinal
anesthesia.
• Prophylactic doses of UFH 5,000 units sub-Q every 12 hr
have no contraindications to neuraxial anesthesia; safety and
recommendations with higher doses of UFH are uncertain; a
delay of 12 hr may be warranted in this situation.
Converting from LMWH Wait 10–11 hr after the last dose of LMWH before initiating IV UFH.
to IV UFH prior to delivery
New VTE In patients with new VTE within 4 weeks of delivery, consider
hospital admission with planned induction of therapy with IV UFH,
and/or placement of temporary IVC filter.
Postpartum May be started 12–24 hr after delivery as long as there are no

anticoagulants bleeding concerns; consider IV UFH in women at high risk of
bleeding, with LMWH reasonable for most women.
• Restart warfarin when hemostasis has occurred, bridging with
UFH or LMWH until INR therapeutic.
• Caution with the use of DOACs postpartum due to limited
data and risk of treatment failure during this time.
Postpartum For patients receiving twice daily LMWH: Administer the first
anticoagulants in patients dose no sooner than 24 hr postoperatively, and with adequate
receiving epidural hemostasis in place; remove indwelling catheters prior to the
catheters initiation of LMWH; for patients with continuous technique, the
epidural may be kept in place overnight but must be removed
before the first dose of LMWH; delay the first dose of LMWH for at
least 2 hr after catheter removal.
For patients receiving once daily LMWH: Administer the first dose
6–8 hr postoperatively; the second dose should occur no sooner
than 24 hr after the first; indwelling catheters may be maintained;
the removal of the catheter should occur no sooner than 10–12
hr after the last LMWH dose; further dosing should occur at least
2 hr after catheter removal; no additional hemostasis-altering
medications should be given due to additive effects.
aPTT: activated partial thromboplastin time, DOAC: direct-acting oral anticoagulant, hr:
hours, INR: international normalized ratio, IV: intravenous, IVC: inferior vena cava, LMWH: low
molecular weight heparin, sub-Q: subcutaneous, UFH: unfractionated heparin, VTE: venous
thromboembolism
• F
or patients who have undergone a miscarriage,
withholding anticoagulation until 12–24 hours
after a dilation and curettage has been performed
may be necessary to help minimize risk of
postpartum hemorrhage.
SUMMARY
Anticoagulation in pregnancy remains a challenging area, with pregnant and
postpartum women carrying a higher risk of thrombosis than the nonpregnant
patient. Clinicians need to consider anticoagulant safety and efficacy for
the mother, effects on the fetus, safety during breastfeeding, and optimal
management around labor and delivery. Controversies remain about how
to manage patients with mechanical heart valves, how and when to monitor
laboratory data, and how to manage patients using DOACs.

*1. Chunilal SD, Bates SM. Venous thromboembolism in pregnancy: diagnosis,
management and prevention. Thromb Haemost. 2009;101:428-438.
*2. James AH. Prevention and treatment of venous thromboembolism in pregnancy. Clin
Obstet Gynecol. 2012 Sep;55(3):774-787. doi: 10.1097/GRF.0b013e31825cfe7b.
3. Heit JA, Kobbervig CE, James AH, et al. Trends in the incidence of venous
thromboembolism during pregnancy or postpartum: a 30-year population-based study.
Ann Intern Med. 2005;143:697-706.
4. James AH, Jamison MG, Brancazio LR, et al. Venous thromboembolism during
pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J
Obstet Gynecol. 2006;194:1311-1315.
5. James AH, Tapson VF, Goldhaber SZ. Thrombosis during pregnancy and the
postpartum period. Am J Obstet Gynecol. 2005;193:216-219.
6. De Stefano V, Martinelli I, Rossi E, et al. The risk of recurrent venous thromboembolism
in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol.
2006;135:386-391.
7. Blanco-Molina A, Rota LL, Di Micco P, et al. Venous thromboembolism during
pregnancy, postpartum or during contraceptive use. Thromb Haemost. 2010;103:306-
311.
8. Konkle BA. Diagnosis and management of thrombosis in pregnancy. Birth Defects Res C
Embryo Today. 2015 Sep;105(3):185-189. doi: 10.1002/bdrc.21104. Epub 2015 Sep
24. Review.
9. Berg CJ, Callaghan WM, Syverson C, et al. Pregnancy-related mortality in the United
States, 1998 to 2005. Obstet Gynecol. 2010;116:1302-1309.
10. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations
and quality of evidence in clinical guidelines: report from an American College of Chest
Physicians task force. Chest. 2006;129(1):174-181.
11. American College of Obstetricians and Gynecologists Women’s Health Care Physicians.
ACOG Practice Bulletin No. 138: Inherited thrombophilias in pregnancy. Obstet
Gynecol. 2013;122(3):706-717. doi: 10.1097/01.AOG.0000433981.36184.4e.
12. Nishimura RA, Otto CM, Bonow RO, et al; ACC/AHA Task Force Members. 2014 AHA/
ACC Guideline for the Management of Patients with Valvular Heart Disease: executive
Task Force on Practice Guidelines. Circulation. 2014;129:2440-2492. doi: 10.1161/
CIR.0000000000000029.
PREGNANCY 477
13. Micromedex® Healthcare Series [Internet database]. Greenwood Village, CO: Thomson
Healthcare; updated periodically.
14. De Carolis S, diPasquo E, Rossi E, et al. Fondaparinux in pregnancy: Could it be a safe
option? A review of the literature. Thromb Res. 2015;135:1049-1051.
15. Hoeltzenbein M, Beck E, Meixner K, et al. Pregnancy outcome after exposure to the
novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic
events: a case series from the German Embryotox Pharmacovigilance Centre. Clin Res
Cardiol. 2015; Jul 21. [Epub ahead of print]
*16. Cohen H, Arachchillage DR, Middeldorp S, et al. Management of direct oral
anticoagulants in women of childbearing potential: guidance from the SSC of the
ISTH. J Thromb Haemost. 2016;14:1673.
17. Beyer-Westendorf J, Michalski F, Tittl L, et al. Pregnancy outcome in patients exposed
to direct oral anticoagulants—and the challenge of event reporting. Thromb Haemost.
2016;116(3). [Epub ahead of print] PMID: 27384740
18. Product Information: heparin sodium, intravenous subcutaneous injection, heparin
sodium, intravenous subcutaneous injection. New York, NY: Pfizer Labs (per
DailyMed).
19. Product Information: Lovenox® subcutaneous injection, intravenous injection,
enoxaparin sodium subcutaneous injection, intravenous injection. Bridgewater, NJ:
Sanofi-Aventis U.S. LLC (per FDA); 2013.
20. Product Information: FRAGMIN® subcutaneous injection, dalteparin sodium
subcutaneous injection. Woodcliff Lake, NJ: Eisai Inc. (per FDA); 2015. Product
Information: INNOHEP(R) subcutaneous injection, tinzaparin sodium subcutaneous
injection. Boulder, CO: Pharmion Corporation; 2006.
21. Product Information: PLAVIX® oral tablets, clopidogrel bisulfate oral tablets.
Bridgewater, NJ: Bristol-Myers Squibb Sanofi Pharmaceuticals Partnership (per FDA);
2016.
22. Product Information: EFFIENT™ oral tablets, prasugrel oral tablets. Indianapolis, IN:
Eli Lilly; 2009.
23. Product Information: BRILINTA® oral tablets, ticagrelor oral tablets. Wilmington, DE:
AstraZeneca (per Manufacturer); 2015.
24. Product Information: COUMADIN® oral tablets, intravenous injection, warfarin sodium
oral tablets, intravenous injection. Princeton, NJ: Bristol-Myers Squibb Company (per
FDA); 2015.
25. Product Information: argatroban intravenous injection, argatroban intravenous
injection. Research Triangle Park, NC: GlaxoSmithKline (per FDA); 2014.
26. Product Information: ANGIOMAX® intravenous injection, bivalirudin intravenous
injection. Parsippany, NJ: The Medicines Company (per FDA); 2016.
27. Product Information: ARIXTRA® subcutaneous injection solution, fondaparinux sodium
subcutaneous injection solution. Westbury, NY: Aspen Global, Inc. (per FDA); 2014.
28. Product Information: XARELTO® oral tablets, rivaroxaban oral tablets. Titusville, NJ:
Janssen Pharmaceuticals, Inc.; 2016.
29. Product Information: PRADAXA(R) oral capsules, dabigatran etexilate mesylate oral
capsules. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals (per manufacturer);
2015.
30. Product Information: ELIQUIS® oral tablets, apixaban oral tablets. Princeton, NJ:
Bristol-Myers Squibb Company and Pfizer Inc (per FDA); 2016.
31. Product Information: SAVAYSA™ oral tablets, edoxaban oral tablets. Parsippany, NJ:
Daiichi Sankyo, Inc. (per FDA); 2015.
32. Bapat P, Pinto LSR, Lubetsky A, et al. Examining the transplacental passage
of apixaban using the dually perfused human placenta. J Thromb Haemost.
2016;14:1436-1441.
*33. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy,
and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed.
Chest. 2012;141(suppl):e691S-736S.
34. Lefkou E, Khamashta M, Hampson G, et al. Low-molecular-weight heparin-
induced osteoporosis and osteoporotic fractures: A myth or an existing entity? Lupus.
2010;19:3-12.
35. Kominiarek MA, Angelopoulos SM, Shapiro NL, et al. Low-molecular-weight heparin in
pregnancy: peripartum bleeding complications. J Perinatol. 2007;27:329-334.
*36. Thromboembolism in pregnancy. Practice Bulletin No. 123. American College of
Obstetricians and Gynecologists. Obstet Gynecol. 2011;118:718-729.
37. Kernan WN, Ovbiagele B, Black HR, et al; on behalf of the American Heart Association
Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical
Cardiology, and Council on Peripheral Vascular Disease. Guidelines for the prevention of
stroke in patients with stroke and transient ischemic attack: a guideline for healthcare
2014;45:2160-2236.
*38. Bates SM, Middeldorp S, Rodger M, et al. Guidance for the treatment and prevention
of obstetric-associated venous thromboembolism. J Thromb Thrombolysis. 2016; Jan
41(1):92-128. doi: 10.1007/s11239-015-1309-0.PMID:26780741.
39. Wiesen MH, Blaich C, Müller C, et al. The direct factor Xa inhibitor rivaroxaban passes
into human breast milk. Chest. 2016;150(1):e1-4. doi: 10.1016/j.chest.2016.01.021.
40. Duhl AJ, Paidas MJ, Ural SH, et al. Antithrombotic therapy and pregnancy: consensus
report and recommendations for prevention and treatment of venous thromboembolism
and adverse pregnancy outcome. Am J Obstet Gynecol. 2007;197:457.e1–457.e21.
41. Yarrington CD, Valente AM, Economy KE. Cardiovascular management in pregnancy:
antithrombotic agents and antiplatelet agents. Circulation. 2015;132(14):1354-64.
doi: 10.1161/CIRCULATIONAHA.114.003902.
42. Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6-week
postpartum period. N Engl J Med. 2014;370:1307-1315. DOI: 10.1056/
NEJMoa1311485
*43. Leaf R, Karp RK. The role of anticoagulants in the prevention of pregnancy
complications. Clin Appl Thromb Hemost. 2015 Nov 12. pii: 1076029615615972.
[Epub ahead of print]
44. Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med.
2008;359:2025-2033.
45. Salas SP, Marshall G, Gutiérrez BL, et al. Time course of maternal plasma volume
and hormonal changes in women with pre-eclampsia or fetal growth restriction.
Hypertension. 2006;47:203-208.
PREGNANCY 479
46. Barbour L, Oja JL, Schultz LK. A prospective trial that demonstrates that dalteparin
requirements increase in pregnancy to maintain therapeutic level of anticoagulation. Am
J Obstet Gynecol. 2004;191:1024-1029.
47. Casele HL, Laifer SA, Woelker DA, et al. Changes in the pharmacokinetics of the low
molecular weight heparin enoxaparin sodium during pregnancy. Am J Obstet Gynecol.
1999;181:1113-1117.
48. Chunilal SD, Young E, Johnston MA, et al. The aPTT response of pregnant plasma to
unfractionated heparin. Thromb Haemost. 2002;87:92-97.
49. McDonnell BP, Glennon K, McTiernan A, et al. Adjustment of therapeutic LMWH to
achieve specific target anti-FXa activity does not affect outcomes in pregnant patients
with venous thromboembolism. J Thromb Thrombolysis. 2016 Aug 12. [Epub ahead of
print]
50. Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and
Gynecologists. Practice Bulletin No. 132: antiphospholipid syndrome. Obstet Gynecol.
2012;120(6):1514-1521.
*51. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient
receiving antithrombotic or thrombolytic therapy: American Society of Regional
Anesthesia and Pain Medicine Evidence-Based Guidelines (3rd ed.). Reg Anesth Pain
Med. 2010;35(1):64-101.
52. Rudd KM, Winans AR, Panneerselvam N. Possible rivaroxaban failure during the
postpartum period. Pharmacotherapy. 2015;35(11):e164-168. doi: 10.1002/
phar.1662.
20 Chapter
PEDIATRICS
Kirsten H. Ohler
INTRODUCTION
Venous thromboembolism (VTE) is becoming an increasingly common disease state
in pediatric patients, in part, due to advances in pediatric critical care medicine as
well as improvements in diagnostic modalities. Although many recommendations
regarding the management of this population are adapted from adult data, differ-
ences between children with thromboembolic events and their adult counterparts
should be considered and should warrant well-designed pediatric clinical trials.
INCIDENCE OF THROMBOSIS IN PEDIATRIC

PATIENTS1–5
Incidence of thromboembolic events is generally lower than in adults:
• Overall incidence ranges from 0.07–0.14 per 10,000 children.
• >90% of pediatric patients with VTE have at least one risk factor.
• >60% of pediatric patients with VTE have two or more risk factors.
Incidence related to risk factors:
• Age: Highest incidence occurs in infants <1 year old and adolescents >14 years old.
• Gender: Teenage females have twice the rates of males.
• Central venous catheter: Most common risk factor in pediatrics.
{{ Accounts for ~60% of VTE in children and 90% in neonates.
{{ Risk is higher with external catheters than indwelling ports.
• Disease state:
{{ Cancer
Acute lymphoblastic leukemia (ALL) is the most common cancer
type associated with thromboembolism (TE) in children.
Up to 93% of children with an underlying malignancy develop
a VTE at the central venous catheter site.
{{ Trauma
0.3% of children with severe trauma develop a VTE.
Severe spinal, thoracic, and abdominal injuries are associated
with clinically significant VTE.
481
{{ Congenital heart disease

Risk of VTE is dependent on type of defect and surgical
intervention performed.
Incidence related to site of thrombosis:
• Thrombosis in an upper extremity—is more common than in lower extremity.
• Central nervous system—is less common than upper and lower venous systems.
{{ Arterial ischemic events account for ~80% of pediatric strokes.
{{ Cerebral sinovenous thrombosis, the second most common site,
preferentially affects neonates; also children with ALL receiving
asparaginase.
• Renal vein thrombosis (RVT)—most commonly observed in neonates.
DEVELOPMENTAL AND PHARMACOKINETIC

DIFFERENCES AMONG PEDIATRIC
POPULATIONS
See Tables 20-1 and 20-2 for more information on developmental and
pharmacokinetic differences.
TABLE 20-1: Definition of Age Groups

Pediatric Birth–18 yr
Neonate Birth–28 days
Infant 1–12 months
Child 1–12 yr
Adolescent 12–18 yr
yr: years
PEDIATRICS 483
TABLE 20-2: Developmental Aspects of the Coagulation System6

Pediatric Values Compared Age When Adult Values Are
to Adults Achieved
Liver Function and Development
CYP2C9 Present within 1st week of life 3 months
Vitamin K Relative deficiency in Affected by dietary intake

newborns
Coagulation Factors
• Maternal coagulation factors do not cross the placental barrier.
Antithrombin Decreased by ~50% in 6 months

neonates
Protein C Decreased by ~65% to 70% Adolescence

in neonates
Protein S Decreased by ~65% to 70% 3 months

in neonates
Thrombin production Delayed and decreased Increase during first 6 months

but remain 20% below adult
values through childhood
Vitamin K dependent clotting Decreased by ~50% in Increase during first 6 months

factors (II, VII, IX, X) neonates but remain 20% below adult
values through childhood
VTE PROPHYLAXIS AND TREATMENT IN THE

PEDIATRIC POPULATION
See Tables 20-3 and 20-4 for more information on VTE prophylaxis and
treatment.
TABLE 20-3: Recommendations for VTE Prophylaxis in

Pediatrics5,a
Indication Agent Duration
AIS excluding SCD, dissection Aspirin At least 2 yr

or cardioembolism related
AIS secondary to dissection LMWH or warfarin At least 6 weeks; 3 months if

or cardioembolism cardioembolism
Biological and mechanical Follow adult Follow adult

prosthetic heart valves recommendations recommendations
Cardiomyopathy Warfarin (target INR 2–3) Until resolved
CVL for long-term home TPN Warfarin (target INR 2–3) Until catheter removal
Fontan procedure Aspirin (1–5 mg/kg/day) or Optimal duration unknown

warfarin (target INR 2–3)
Glenn shunt Aspirin (1–5 mg/kg/day) or Optimal duration unknown

warfarin (target INR 2–3) or no
post-op anticoagulation
Modified Blalock-Taussig Aspirin (1–5 mg/kg/day) or no Optimal duration unknown

shunt post-op anticoagulation
PPH requiring medical Warfarin (target INR varies by Until resolved

therapy center, 1.7–2.5 or 2–3)
Stage I Norwood procedure Aspirin (1–5 mg/kg/day) or no Optimal duration unknown

post-op anticoagulation
a
VTE prophylaxis is not routinely recommended in the following circumstances: (1) cancer and
CVAD; (2) CVL; (3) hemodialysis catheter; and (4) neonates with an initial AIS.
AIS: arterial ischemic stroke, CVL: central venous line, INR: international normalized ratio, LMWH:
low molecular weight heparin, PPH: primary pulmonary hypertension, SCD: sickle cell disease,
TPN: total parenteral nutrition, yr: years
PEDIATRICS 485
TABLE 20-4: Recommendations for VTE Treatment in

Pediatrics5,a
Indication Agent Duration
Bilateral RVT with any degree UFH/LMWH or tPA Until resolved

renal impairment thrombolysisd followed by
UFH/LMWH
Cancer and VTE LMWH At least 3 months and until

risk factorsc resolved
CVL-related VTE with ongoing Therapeutic anticoagulation Therapeutic for 3 months;

need for access followed by prophylaxis with prophylactic until CVL
warfarin or LMWH removed
Idiopathic VTE Warfarin or LMWH 6 to 12 monthsb
Recurrent idiopathic VTE Warfarin Indefinitely
Unilateral RVT extending into LMWH or UFH 6 weeks to 3 months

IVC without renal impairment
Unilateral RVT without renal Observation for thrombus 6 weeks to 3 months

impairment or extension into extension or LMWH
the IVC
VTE secondary to ongoing Therapeutic or prophylactic Until risk factor resolved

risk factor anticoagulation
VTE secondary to resolved Warfarin or LMWH 3 months

risk factor
a
Clinicians are referred to the American College of Chest Physicians practice guidelines for
recommendations in other less common clinical scenarios.5
b
Lifelong anticoagulation is not generally recommended as the known bleeding risk of long-term
anticoagulation outweighs the unknown incidence of thrombosis recurrence in children without an
identifiable risk factor.
Risk factors include asparaginase, mediastinal mass, and CVL.
c
d
Limited data exist for the use of tPA for this indication. Doses of 0.04–0.5 mg/kg/hour have been
used with variable success. Monitor closely for adverse events such as intracranial hemorrhage.7–9
CVL: central venous line, IVC: inferior vena cava, LMWH: low molecular weight heparin, RVT: renal
vein thrombosis, tPA: tissue plasminogen activator, UFH: unfractionated heparin, VTE: venous
thromboembolism
INITIATING AND MONITORING

ANTICOAGULATION THERAPY
Unfractionated Heparin5
Neonatal Heparin Considerations
• More rapid clearance and larger volume of distribution than older children and
adults generally results in higher dose requirements.
• Reduced plasma concentrations of antithrombin may lead to a reduced response

to heparin therapy.
Dosing Recommendations
• Loading dose: 75 units/kg
• Initial maintenance dose:
Infants <1 year: 28 units/kg/hour
Children >1 year: 20 units/kg/hour
{{ Obese children (BMI >95th percentile for age and sex) may require
lower weight-based doses; consider a maximum initial infusion rate
of 1,000 units/hour.10
See Table 20-5 for sample nomogram for heparin dosage adjustments for
pediatric patients.
TABLE 20-5: Sample Nomogram for Heparin Dosage

Adjustments in Pediatricsa,5
aPTT (seconds) Bolus (units/kg) Stop Infusion Rate Change Repeat aPTT
(minutes) (% of current rate)
<50 50 0 Increase by 10% 4 hr
50–59 0 0 Increase by 10% 4 hr
60–85 0 0 0 Next day
86–95 0 0 Decrease by 10% 4 hr
96–120 0 30 Decrease by 10% 4 hr
>120 0 60 Decrease by 15% 4 hr
Target aPTT range will be institution specific (refer to Chapter 21 for more details).
a
hr: hours
PEDIATRICS 487
• D
ue to the low infusion rates often utilized
in neonatal and pediatric patients, clinicians
should ensure that the concentration of heparin
infusions is sufficiently diluted to allow for the
above suggested rate changes. Many syringe
pumps will allow for rate measurements to the
hundredth decimal place (e.g., 0.25 mL/hr).
However, the actual dosage change in terms
of units/kg/hr should be considered because
a percentage change in the infusion rate, as
suggested in Table 20-5, may or may not
result in a clinically significant change in the
amount of heparin delivered depending on the
concentration of the infusion and the current
dose.
Considerations When Monitoring Heparin Therapy
• “Normal” activated partial thromboplastin time (aPTT) is significantly prolonged
in infants compared to older children; adult values are not achieved until late
adolescence.
• Use of pedi-tubes for laboratory draws should be considered to reduce blood
loss. Blood should not be transferred from a citrated tube to a pedi-tube.
• Variability in aPTT by age has lead to a suggestion that heparin therapy be
monitored by correlating aPTT values with therapeutic anti-factor Xa levels
(0.35–0.70 units/mL) normalized for unfractionated heparin (UFH) activity. Some
institutions directly monitor heparin therapy using anti-factor Xa levels (see
Table 20-6).

Adjustments Using Anti-Factor Xa Levels
Anti-factor Bolus Dose Stop Heparin Rate Change (round Repeat Anti-Factor
Xa Level (units/kg) Infusion (min) to nearest whole Xa Level
(units/mL) number)
≤0.1a 50 0 Increase rate by 20% 4 hr
0.1–0.34 0 0 Increase rate by 10% 4 hr
0.35–0.7 0 0 No change 4 hr after first

anti-factor Xa level
between 0.35–0.7,
then every AM
0.71–0.89 0 0 Decrease rate by 4 hr

10%
0.9–1.2 0 30 min Decrease rate by 4 hr

10%
≥1.2a 0 60 min Decrease rate by 4 hr

15%
Goal anti-factor Xa level = 0.35–0.70 units/mL.

a
hr: hours, min: minutes

Source: Used with permission from Sanford Children’s Hospital, Sioux Falls, SD.
Low Molecular Weight Heparins

Advantages of Low Molecular Weight Heparins (LMWHs) in
Pediatrics
• Reduced monitoring requirements, which minimizes the need for needlesticks
and venous access.
• Lack of drug–drug and drug–food interactions.
• Reduced risk of heparin-induced thrombocytopenia (HIT).
Enoxaparin5,11–13
• Neonates require higher per kg doses than older children to achieve therapeu-
tic anti-factor Xa levels likely due to decreased antithrombin concentrations
in neonates and larger volume of distribution (see Table 20-7 for enoxaparin
dosing).
• Premature neonates have been shown to require higher enoxaparin doses than
term neonates.
• Effective dose to attain a therapeutic anti-factor Xa level has been shown to be
inversely related to age.
PEDIATRICS 489
TABLE 20-7: Enoxaparin Dosing

Age Dose
Standard Treatment Dose
<2 months 1.5 mg/kg sub-Q q 12 hr
>2 months 1 mg/kg sub-Q q 12 hr
Suggested Modified Dose
Preterm neonates 2 mg/kg sub-Q q 12 hr
Term neonates 1.7 mg/kg sub-Q q 12 hr
3–12 months 1.5 mg/kg sub-Q q 12 hr
1–5 yr 1.2 mg/kg sub-Q q 12 hr
6–18 yr 1.1 mg/kg sub-Q q 12 hr
Prophylactic Dose
<2 months 0.75 mg/kg sub-Q q 12 hr
>2 months 0.5 mg/kg sub-Q q 12 hr
hr: hours, sub-Q: subcutaneous, yr: years
• U
tilizing higher initial subcutaneous (sub-Q)
doses of enoxaparin than usually recommended
may reduce the number of venipunctures required
for monitoring therapy and shorten the time to
therapeutic anti-factor Xa levels.
{{ Sub-Q administration may be problematic
in critically ill children with significant
edema or peripheral vasoconstriction due to
vasopressor support or in preterm neonates
with very little subcutaneous fat. Intravenous
(IV) administration is an alternative route in
these situations.
{{ IV administration has been shown to
result in an earlier peak anti-factor Xa
level (1–2 hours after administration)
with subtherapeutic levels by 6–8 hours,
suggesting the need for dose modification if
this route of administration is used.
Dalteparin14-16
• Dalteparin age-based treatment dosing recommendations are based on a small
study of 18 children (ages 0.5 to 19 years old).
{{ Infants (<12 months): 150 units/kg q 12 hours
{{ Children (1–12 years): 125 units/kg q 12 hours
{{ Adolescents (13–19 years): 100 units/kg q 12 hours
• The American College of Chest Physicians also provides dalteparin dosing guide-
lines that are based on a study of 48 children (ages 31 weeks preterm neonate
to 18 years old); however, they do not provide age-based recommendations.
{{ Treatment dose: 129 ± 43 units/kg q 24 hours
{{ Prophylaxis dose: 95 ± 52 units/kg q 24 hours
{{ Required dose per kg of body weight was found to be inversely
related to age.
Dilution Data for Enoxaparin and Dalteparin17–20
• Enoxaparin diluted with sterile water to a final concentration of 20 mg/mL
has been shown to be stable in tuberculin syringes for at least 2 weeks under
refrigeration or at room temperature without a significant loss of anti-factor Xa
activity. A slight, but statistically nonsignificant, loss of anti-factor Xa activity
occurred at 4 weeks of storage.
• Due to potential errors associated with the dilution of any medication, some
practitioners recommend combining rounded, whole milligram dosing with the
use of undiluted enoxaparin 100 mg/mL measured in an insulin syringe such
that 1 unit on the syringe measures 1 mg of enoxaparin.
{{ This approach was shown to achieve therapeutic anti-factor Xa
levels in 514 of 514 children with no associated hemorrhagic side
effects despite five of the children having an initial supratherapeutic
anti-factor Xa level (1.04–1.36 units/mL). Additionally no medication
errors were reported. Similar results have been shown in premature
and term neonates.
• Dalteparin diluted with preservative-free normal saline to a final concentration
of 2,500 units/mL has been shown to be stable in tuberculin syringes for 4 weeks
under refrigeration without a significant loss of anti-factor Xa activity.
Monitoring LMWH with Anti-Factor Xa Levels
• Therapeutic anti-factor Xa levels of 0.5–1 units/mL (obtained 4–6 hours after the
dose) have been extrapolated from adult data; safety and efficacy of this range
has not been validated in children (see Table 20-8).
• Prophylactic anti-factor Xa level = 0.1–0.3 units/mL.
• Target levels are based on twice-daily dosing of LMWH.
PEDIATRICS 491
TABLE 20-8: Sample Nomogram for LMWH Therapeutic Dosage

Adjustment21
Anti-Factor Xa Hold Next Dose Change Repeat Anti-Factor
Level (units/mL) Dose? Xa Level
<0.35 No ↑ by 25% 4 hr after next dose
0.35–0.49 No ↑ by 10% 4 hr after next dose
0.5–1 No No change Next day
1.1–1.5 No No change if once daily dosing Before next dose

(1.5–2 mg/kg enoxaparin;
150–200 units/kg dalteparin)
↓ by 20% if twice daily dosing (1
mg/kg enoxaparin; 100 units/kg
dalteparin)
1.6–2 3 hr ↓ by 30% Before next dose,

then 4 hr after next
dose
>2 Until anti- ↓ by 40% Before next dose, if

factor Xa not <0.5 units/mL
level <0.5 repeat q 12 hr
hr: hours
• A ccurate timing of blood sampling for anti-factor

Xa levels is crucial for proper interpretation. Peak
levels should be obtained 4–6 hours after the dose.
Fondaparinux22-25
• No age-related differences found in pharmacokinetic parameters in children
between 1 and 18 years of age.
• Prospective pharmacokinetic study (FondaKIDS) suggests initial dose of 0.1 mg/
kg sub-Q q 24 hours.
{{ Case reports suggest an initial dose as high as 0.15 mg/kg q 24
hours.
{{ Pharmacokinetic and dosing data for children <1 year are lacking.
• Long-term follow-up study (FondaKIDS II) demonstrated that <1 dose adjustment
was required to achieve therapeutic levels in ~90% of patients.
{{ ~90% of patients had complete or partial resolution of thrombus;
none had progression.
{{ Three patients (8.6%) had major bleeding; 4 patients (11.4%) had
minor bleeding.
{{ Target fondaparinux level = 0.5–1 mg/L.
See Table 20-9 for a sample nomogram for fondaparinux therapeutic dosage
adjustment.
TABLE 20-9: Sample Nomogram for Fondaparinux Therapeutic

Dosage Adjustment22
Peak Fondaparinux Sodium level (mg/L)a Dose Changeb
<0.3 ↑ by 0.03 mg/kg
0.3–0.5 ↑ by 0.01 mg/kg
0.5–1 No change
1–1.2 ↓ by 0.01 mg/kg
>1.2 ↓ by 0.03 mg/kg

a
Using fondaparinux-based chromogenic anti-factor Xa assay; sample obtained 4 hours after
dose.
If 12-hour level is <0.2 mg/L, suggest twice-daily dosing.
b
Direct Thrombin Inhibitors

Heparin-Induced Thrombocytopenia in the Pediatric
Population26-28
• Reported incidence ranges from 0-2.3%, which is similar to adult rates.
• Highest risk in intensive care unit patients and those undergoing cardiac surgery.
• Highest incidences in those 0–2 years and 11–17 years:
{{ This effect may be influenced by the higher likelihood of heparin
exposure in these age groups rather than an age-related phenom-
enon.
Controversy over the Occurrence of HIT in Neonates29,30
• Detection assays have not been well studied and validated in this population.
• The immature immune system of neonates, especially those born prematurely,
may be unable to mount an adequate antibody response to heparin exposure
and therefore would not be detected by available assays.
• In a small prospective study, 24 of 42 premature neonates receiving heparin
developed thrombocytopenia without clinical thrombosis; no patient had
antiheparin/platelet factor 4 antibodies detected by enzyme-linked immuno-
sorbent assay (ELISA) or serotonin release assay (SRA).
Argatroban Use in Pediatrics31-36
• Case reports and uncontrolled studies have reported doses ranging from 0.1–15
mcg/kg/minute; some have reported the use of a bolus dose ranging from 50–250
mcg/kg, typically targeting an aPTT 1.5–2 x baseline.
• Argatroban prescribing information suggests initiating therapy at 0.75 mcg/kg/
minute in children with normal hepatic function with dose adjustments of 0.1–0.25
mcg/kg/minute based on aPTT levels drawn 2 hours after dose adjustment.
• Hepatically metabolized, therefore, dosage adjustment is required in hepatic
dysfunction.
PEDIATRICS 493
{{ Dosing in children with hepatic dysfunction or the effect of various

stages of liver maturation has not been specifically evaluated;
however, argatroban prescribing information suggests an initial
dose of 0.2 mcg/kg/minute with dosage adjustments made in
increments of 0.05 mcg/kg/minute.
See Table 20-10 for a sample nomogram for argatroban therapeutic dosage
adjustment..
Bivalirudin Use in Pediatrics
• May offer benefits in young children, especially those <6 months old, because
of significantly reduced antithrombin concentrations compared to older children
and adults resulting in relative heparin resistance.
• Dose-finding study in infants <6 months of age: Suggested initial bolus dose
of 0.125 mg/kg followed by 0.125 mg/kg/hour.
• Target aPTT: 1.5–2.5 x baseline aPTT.
• Dose-finding study in children 6 months to 17 years of age: Utilized a bolus
dose of 0.125 mg/kg followed by 0.125 mg/kg/hour; final infusion dose range
0.082–0.291 mg/kg/hour.
See Table 20-11 for a sample nomogram for bivalirudin therapeutic dosage
adjustment.
Oral Anticoagulants
Warfarin Dosing Considerations5,40
• Warfarin is generally avoided in neonates due to relative vitamin K deficiency
and reduced concentrations of vitamin K dependent clotting factors (II, VII, IX, X).
• Infants (≤1 year old) have been shown to require a larger dose per kg of body
weight (0.33 mg/kg) than adolescents (0.09 mg/kg), and adolescents require a
larger per kg dose than adults to maintain a therapeutic international normalized
ratio (INR) (see Table 20-12).
TABLE 20-10: Sample Nomogram for Argatroban Therapeutic

Dosage Adjustmenta,37
aPTT (seconds) Dose Change Repeat aPTT
Baseline Initiate 0.75–1 mcg/kg/min by continuous 2 hr after initiation

infusion
<50 ↑ by 0.25–0.5 mcg/kg/min 2 hr
50–59 ↑ by 0.1–0.25 mcg/kg/min 2 hr
60–85 No change 2 hr, then q 24 hr
86–95 ↓ by 0.25 mcg/kg/min 2 hr
>95 ↓ by 0.5 mcg/kg/min 2 hr
a
aPTT: activated partial thromboplastin time

TABLE 20-11: Sample Nomogram for Bivalirudin Therapeutic

Dosage Adjustmenta,37
aPTT (seconds) Hold Infusion? Dose Change Repeat aPTT
Baseline NA Bolus dose: 0.125 mg/kg 3–4 hr after initiation

Initiate 0.125 mg/kg/hr by
continuous infusion
<60 No ↑ by 10% 3–4 hr
60–85 No No change 4 hr, then q 24 hr
86–95 1 hr ↓ by 10% 3–4 hr
>95 1 hr ↓ by 20% 3–4 hr
a
aPTT: activated partial thromboplastin time, hr: hours, NA: not applicable
TABLE 20-12: Sample Nomogram for Warfarin Dosing

Administration and Dosage Adjustment5
INR Adjustment
Day 1 Baseline = 1–1.3 Loading dose = 0.2 mg/kg
Days 2–4 1.1–1.3 Repeat initial loading dose
1.4–1.9 50% of initial loading dose
2–3 50% of initial loading dose
3.1–3.5 25% of initial loading dose
>3.5 Hold until INR <3.5, then restart at 50% less

than previous dose
Maintenance 1.1–1.3 Increase current dose by 20%
1.4–1.9 Increase current dose by 10%
2–3 No change
3.1–3.5 Decrease current dose by 10%
>3.5 Hold until INR <3.5, then restart at 25% less

than previous dose

PEDIATRICS 495
Dosage Formulation and Dispensing Considerations

• There is no commercially available liquid preparation.
• Relatively poor solubility of warfarin creates difficulty in compounding liquid
formulations; there are no stability data.
• Children are often prescribed antibiotics that may interact with warfarin.
• Commercially available enteral infant formulas are high in vitamin K, while breast
milk contains low amounts.
INR Monitoring5,41-44
• No clinical trials have assessed the optimal INR range for children.
• Target INR range is based on recommendations for adult patients despite differ-
ences in the coagulation system, which may suggest the need for age-related
INR ranges.
• Prophylactic target INR: 1.5–1.9
• Therapeutic target INR: 2–3
{{ 2.5–3.5 if indication is mitral valve replacement.
Frequency of Monitoring
• Frequent INR monitoring is required in neonates due to rapid physiologic
changes in vitamin K dependent factors.
• It has been estimated that monthly monitoring is safe in only about 10-20% of
children with most requiring more frequent INR monitoring and dose adjustments.
• Whole blood point-of-care monitors including CoaguChek S (Roche Diagnostics),
CoaguChek XS (Roche Diagnostics), and ProTime (International Technidyne
Corp.) have been validated in pediatric patients.
Potential Factors Affecting Warfarin Anticoagulation in
Children
• Studies have shown variable effects of CYP2C9 and VKORC1 polymorphisms
on warfarin dosing in children; nongenetic factors (e.g., age, height) may have
a greater contribution to dose variability in this population.45
{{ CYP2C9*2, CYP2C9*3, and VKORC1 AA polymorphisms have
been observed and may be a risk factor for overanticoagulation,
especially upon initiation of therapy.46
• Children with disease states associated with fat malabsorption (e.g., cystic fibro-
sis) may be at risk for vitamin K deficiency and, therefore, over-anticoagulation.
Monitoring Considerations Specific to Pediatric Patients
• Whenever possible, arrange blood collection for INR with other necessary labs
to avoid excessive blood loss.
• Additionally, venipuncture may be more difficult in children due to poor periph-
eral vascularity and fear of needlesticks.
• Frequent laboratory blood draws result in missed school days and parental work
absences, which may contribute to noncompliance.
Adverse Effects40,47
• Minor bleeding: Approximately 20% of children.
• Serious bleeding: Less than 3.2% in children with mechanical prosthetic heart
valves and approximately 1.7% with other indications for anticoagulation.
• Reduced bone density: Case-controlled study suggested risk in children with
congenital heart disease receiving warfarin for longer than 12 months.
Patient and Family Education48,49
• A standardized, comprehensive, developmentally appropriate educational
program has been shown to improve patient and family understanding of warfarin
therapy and improve time within a target INR range.
• Education should also include practical issues related to anticoagulation therapy
[e.g., no contact sports, no aspirin, or nonsteroidal anti-inflammatory drugs
(NSAIDs)].
• Parents of all children, including adolescents, should be involved in anticoagulant
education. Adolescents often want to establish autonomy in their medical care,
but may lack understanding of the severity of their disease and the consequences
of nonadherence.
• A s children grow, warfarin and other medication

doses based on weight (e.g., mg/kg/dose) may
need to be adjusted for weight gain. More
frequent monitoring of INR may be needed during
periods of rapid growth to maintain adequate
anticoagulation.
Target-Specific Oral Anticoagulants

Rivaroxaban50,51
• In vitro studies of the anticoagulant effects in neonates and children demonstrate
little difference compared to adults.
• In vivo efficacy and safety studies in the pediatric population are lacking.
Dabigatran52
• In vitro studies demonstrate a similar anticoagulant effect in children compared
to adults; however, clinical trials evaluating appropriate dosing, efficacy, and
safety are lacking.
Apixaban, Betrixaban, and Edoxaban
• Pharmacokinetic, safety, and efficacy studies are ongoing (see www.clinicaltrials.
gov); however, currently no reports are published of the use of these agents
in children.
PEDIATRICS 497
SPECIAL CONSIDERATIONS
Injections in Pediatric Patients

• Injectable therapies may pose several difficulties in this population. For example,
neonates—especially those born prematurely—have very little subcutaneous
fat, making this route of administration less than ideal. Poor venous access and
reduced peripheral perfusion in critically ill children create additional challenges.
Finally, a child’s fear of injections can make the outpatient use of agents, such
as LMWH, problematic.
Insurance Coverage
• Because most anticoagulant therapies and outpatient monitoring devices are
not U.S. Food and Drug administration (FDA)-approved for children, obtain-
ing coverage/reimbursement from insurance companies may require special
measures (e.g., letter of medical necessity) with supporting literature to justify
their use in the outpatient setting. Verification of insurance coverage for both
the anticoagulant agent and the monitoring tests is important.
Extracorporeal Membrane Oxygenation3-57

• UFH is typically used for anticoagulation of the extracorporeal membrane
oxygenation (ECMO) circuit.
• Higher doses (e.g., 20–69.5 units/kg/hour) are needed due to binding to the
ECMO circuit and a large volume of distribution.
{{ A retrospective review of 604 pediatric ECMO patients demon-
strated a correlation between higher heparin doses and improved
survival; for heparin doses of 30, 40, 50, 60, and 70 units/kg/hour,
the corresponding probability of survival was 50%, 58%, 64%, 70%,
and 75%. Survival benefit declined at doses >70 units/kg/hour.
• Low-response activated clotting time (ACT) testing is often used for bedside
monitoring of anticoagulation but has been shown to correlate poorly with
heparin effect and have significant variability among available monitoring
devices; anti-factor Xa levels have been suggested as a better monitoring
method, resulting in fewer blood draws without an increase in bleeding or
thrombotic events.
• Some centers may use aPTT for monitoring, although it is not a direct measure
of UFH effect and may be altered by other clotting factors (e.g., factor VIII,
fibrinogen).
• Low antithrombin concentrations have been observed in patients, especially
neonates, on cardiopulmonary bypass or ECMO. Heparin resistance (i.e.,
subtherapeutic ACT/anti-factor Xa/aPTT levels despite high heparin doses) may
be observed in these patients. Some centers administer recombinant antithrom-
bin in these situations, although this practice remains controversial because
the risks and benefits are unclear. See Chapter 3, Unfractionated Heparin, for
more information.
See Table 20-13 for a sample nomogram for heparin dosage adjustments
using anti-factor Xa levels during ECMO.

Adjustments Using Anti-Factor Xa Levelsa during ECMO55
Anti-Factor Xa Bolus Dose Dose Change
Level (units/mL)b (units/kg)
<0.2 75 Increase dose by 5 units/kg/hr
0.2–0.29 50 Increase dose by 5 units/kg/hr
0.3–0.4 0 Increase dose by 5 units/kg/hr
0.4–0.8 0 No change in dose
0.8–1 0 Decrease dose by 2 units/kg/hr
>1 0 Decrease dose by 5 units/kg/hr

a
Anti-factor Xa level drawn every 2 hours until 2 consecutive levels in goal range; then every 4
hours until 2 consecutive levels in goal range; then every 6 hours.
b
Goal anti-factor Xa level = 0.4–0.8 units/mL.
ECMO: extracorporeal membrane oxygenation, hr: hours
• Please refer to Chapter 5 for a discussion on the use of direct thrombin inhibi-
tors in ECMO.
Interpretation of Laboratory Tests

• Whenever possible, age-specific “normal” ranges should be used.
• Practitioners should be mindful that all therapeutic ranges for anticoagulant
therapy in children have been extrapolated from adult data.
Please refer to Chapter 21 for a discussion of variables that can alter coagu-
lation test results.
INTRAVENOUS CATHETER OCCLUSIONS

• Because sites for venous access are limited in children, especially neonates,
preventing catheter occlusion and ultimately the loss of the catheter are of
utmost importance.
Considerations for Maintaining IV Catheter Patency5,26,58-60

• Saline flushes and locks have been shown to be as effective as heparin in
maintaining the patency of peripheral IV catheters while avoiding the potential
complications of heparin therapy (e.g., HIT, accidental overdose).
• Heparin is commonly added to fluids infusing through peripheral catheters
and peripherally inserted central catheter (PICC) to prolong catheter patency;
however, this practice has not been shown to provide a clinically significant
benefit.
• Heparin at a concentration of 5 units/mL (versus 1 unit/mL) in normal saline
has been shown to prolong the patency of peripheral arterial catheters when
continuously infused at 1 mL/hour.
PEDIATRICS 499
• Heparin low dose (0.25–1 units/mL) continuous infusion has been shown to
reduce umbilical artery catheter (UAC) occlusions.
• A positive pressure device can be attached to the catheter hub of PICC to
prevent backflow of blood, which has been shown to reduce catheter occlusion.
Considerations for Restoring IV Catheter Patency

Developmental Aspects of the Fibrinolytic System61
• Plasminogen concentrations are decreased by 50% in full-term and 75% in
premature neonates compared to adults.
• Adult values are reached by 6 months of age.
• Decreased plasminogen concentrations in neonates may result in a limited
response to thrombolytic agents. Increasing doses of thrombolytic agents do not
seem to result in an improved response in this patient population. However, no
study has specifically evaluated the clinical implications of this developmental
difference on catheter clearance.
Recombinant Tissue Plasminogen Activator for Catheter
Clearance62,63
• If a thrombotic (versus nonthrombotic) occlusion is deemed to be the cause of
intravenous catheter dysfunction, tissue plasminogen activator (tPA) has been
shown to be effective in restoring catheter patency.
• tPA should be diluted to a final concentration of 1 mg/mL and dosed as follows:
{{ Patients <30 kg: Dose equal to 110% of internal catheter volume,
maximum dose 2 mg (2 mL of the 1-mg/mL concentration).
This dose has been shown to be safe and effective
in neonates; however, some investigators suggest for
infants weighing <10 kg a lower dose of 0.5 mg diluted
in a sufficient volume of normal saline to fill the catheter.
{{ Patients >30 kg: 2 mg (2 mL of the 1-mg/mL concentration).
• tPA should be allowed to dwell within the catheter for at least 30 minutes (up
to 120 minutes) prior to attempting aspiration.
• If the initial dose fails to restore patency after 120 minutes of dwell time, the
benefit of a second dose has been shown.

1. Stein PD, Kayali FK, Olson RE. Incidence of venous thromboembolism in infants and
children: data from the national hospital discharge survey. J Pediatr. 2004;145:563-
565.
2. Newall F, Wallace T, Crock C, et al. Venous thromboembolic disease: a single-centre
case series study. J Paediatr Child Health. 2006;42:803-807.
3. Cyr C, Michon B, Pettersen G, et al. Venous thromboembolism after severe injury in
children. Acta Haematol. 2006;115:198-200.
4. Wiernikowski JT, Athale UH. Thromboembolic complications in children with cancer.
Thromb Res. 2006;118:137-152.
*5. Monagle P, Chan A, Goldenberg NA, et al. Antithrombotic therapy in neonates and
children: Antithrombotic Therapy and Prevention of Thrombosis. 9th ed. American
College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest.
2012;141(suppl 2):e737S-e801S.
*6. Kuhle S, Male C, Mitchell L. Developmental hemostasis: pro- and anticoagulant
systems during childhood. Semin Thromb Hemost. 2003;29:329-337.
7. Dillon PW, Fox PS, Berg CJ, et al. Recombinant tissue plasminogen activator for
neonatal and pediatric vascular thrombolytic therapy. J Pediatr Surg. 1993;28:1264-
1269.
8. Farnoux C, Camard O, Pinquier D, et al. Recombinant tissue-type plasminogen
activator therapy of thrombosis in 16 neonates. J Pediatr. 1998;133:137-140.
9. Weinschenk N, Pelidis M, Fiascone J. Combination thrombolytic and anticoagulant
therapy for bilateral renal vein thrombosis in a premature infant. Am J Perinatol.
2001;18:293-297.
10. Taylor BN, Bork SJD, Kim S, et al. Evaluation of weight-based dosing of unfractionated
heparin in obese children. J Pediatr 2013;163:150-153.
11. Malowany JI, Monagle P, Knoppert DC, et al. Enoxaparin for neonatal thrombosis: a
call for a higher dose in neonates. Thromb Res. 2008;122:826-830.
12. Bauman ME, Belletrutti MJ, Bajzar L, et al. Evaluation of enoxaparin dosing
requirements in infants and children. Thromb Haemost. 2009;101:86-92.
13. Crary SE, Van Orden H, Journeycake J. Experience with intravenous enoxaparin in
critically ill infants and children. Pediatr Crit Care Med. 2008;9:647-649.
14. Nohe N, Flemmer A, Rumler R, et al. The low molecular weight heparin dalteparin
for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases. Eur J
Pediatr. 1999;158(suppl 3):S134-S139.
15. O’Brien SH, Kulkarni R, Wallace A, et al. Multicenter dose-finding and efficacy and
safety outcomes in neonates and children treated with dalteparin for acute venous
thromboembolism. J Thromb Haemost. 2014;12:1822-1825.
16. Warad D, Rao AN, Mullikin T, et al. A retrospective analysis of outcomes of dalteparin
use in pediatric patients: A single institution experience. Thromb Res. 2015:136:229-
233.
17. Dager WE, Gosselin RC, King JH, et al. Anti-Xa stability of diluted enoxaparin for use in
pediatrics. Ann Pharmacother. 2004;38:569-573.
18. Bauman ME, Black KL, Bauman ML, et al. Novel uses of insulin syringes to reduce
dosing errors: a retrospective chart review of enoxaparin whole milligram dosing.
Thromb Res. 2009;123:845-847.
19. Goldsmith R, Chan AK, Paes BA, et al. Feasibility and safety of enoxaparin whole
milligram dosing in premature and term neonates. J Perinatol. 2015;35:852-854.
20. Goldenberg NA, Jacobson L, Hathaway H, et al. Anti-Xa stability of diluted dalteparin
for pediatric use. Ann Pharmacother. 2008:42:511-515.
*21. Michelson AD, Bovill E, Monagle P, et al. Antithrombotic therapy in children. Chest.
1998;114(suppl):748S-769S.
22. Young G, Yee DL, O’Brien S, et al. FondaKIDS: a prospective pharmacokinetic and
safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood
Cancer. 2011;57:1049-1054.
PEDIATRICS 501
23. Mason AR, McBurney PG, Fuller MP, et al. Successful use of fondaparinux as
an alternative anticoagulant in a 2-month-old infant. Pediatr Blood Cancer.
2008;50:1084-1085.
24. Sharathkumar AA, Crandall C, Lin JJ, et al. Treatment of thrombosis with
fondaparinux (Arixtra) in a patient with end-stage renal disease receiving hemodialysis
therapy. J Pediatr Hematol Oncol. 2007;29:581-584.
25. Ko RH, Michieli C, Lira JL, et al. FondaKIDS II: long-term follow-up data of children
receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res.
2014;134:643-647.
26. Klenner AF, Fusch C, Rakow A, et al. Benefit and risk of heparin for maintaining
peripheral venous catheters in neonates: a placebo-controlled trial. J Pediatr.
2003;143:741-745.
27. Schmugge M, Risch L, Huber AR, et al. Heparin-induced thrombocytopenia-associated
thrombosis in pediatric intensive care patients. Pediatrics. 2002;109:e10.
28. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br
J Haematol. 2003;121:535-555.
29. Spadone D, Clark F, James E, et al. Heparin-induced thrombocytopenia in the
newborn. J Vasc Surg. 1002;15:306-311.
30. Kumar P, Hoppensteadt P, Pretchel M, et al. Prevalance of heparin-dependent platelet-
activating antibodies in preterm newborns after exposure to unfractionated heparin.
Clin Appl Thromb Hemost. 2004;10:335-339.
31. John TE, Hallisey RK. Argatroban and lepirudin requirements in a 6-year-old patient
with heparin-induced thrombocytopenia. Pharmacotherapy. 2005;25:1383-1388.
32. Potter KE, Raj A, Sullivan JE. Argatroban for anticoagulation in pediatric patients with
heparin-induced thrombocytopenia requiring extracorporeal life support. J Pediatr
Hematol Oncol. 2007;29:265-268.
33. Schmitz ML, Massicotte P, Faulkner SC. Management of a pediatric patient on the
Berlin heart excor ventricular assist device with argatroban after heparin-induced
thrombocytopenia. ASAIO Journal. 2008;54:546-547.
34. Hursting MJ, Dubb J, Verme-Gibboney CN. Argatroban anticoagulation in pediatric
patients. J Pediatr Hematol Oncol. 2006;28:4-10.
35. Argatroban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2009.
36. Young G, Boshkov LK, Sullivan JE, et al. Argatroban therapy in pediatric patients
requiring nonheparin anticoagulation: an open label, safety, efficacy, and
pharmacokinetic study. Pediatr Blood Cancer. 2011;56:1103-1109.
*37. Law C, Raffini L. A guide to the use of anticoagulant drugs in children. Pediatr Drugs.
2015;17:105-114.
38. Young G, Tarantino MD, Wohrley J, et al. Pilot dose-finding and safety study of
bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost.
2007;5:1654-1659.
39. O’Brien SH, Yee DL, Lira J, et al. UNBLOCK: an open-label, dose-finding,
pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.
J Thromb Haemost. 2015;13:1615-1622.
40. Streif W, Andrew M, Marzinotto V, et al. Analysis of warfarin therapy in pediatric
patients: a prospective cohort study of 319 patients. Blood. 1999;94:3007-3014.
41. Marzinotto V, Monagle P, Chan A, et al. Capillary whole blood monitoring of oral
anticoagulants in children in outpatient clinics and the home setting. Pediatr Cardiol.
200;21;347-352.
42. Nowatzke WL, Landt M, Smith C, et al. Whole blood international normalization
ratio measurements in children using near-patient monitors. J Pediatr Hematol Oncol.
2003;25:33-37.
43. Bradbury MJE, Taylor G, Short P, et al. A comparative study of anticoagulant control in
patients on long-term warfarin using home and hospital monitoring of the international
normalised ratio. Arch Dis Child. 2008;93:303-306.
44. Bauman ME, Black KL, Massicotte MP, et al. Accuracy of the CoaguChek XS for
point-of-care international normalized ratio (INR) measurement in children requiring
warfarin. Thromb Haemost. 2008;99:1097-1103.
*45. Vear SI, Stein CM, Ho RH. Warfarin pharmacogenomics in children. Pediatr Blood
Cancer. 2013;60:1402-1407.
46. Biss TT, Avery PJ, Williams MD, et al. The VKORC1 and CYP2C9 genotypes are
associated with over-coagulation during initiation of warfarin therapy in children. J
47. Barnes C, Newall F, Ignjatovic V, et al. Reduced bone density in children on long-term
warfarin. Pediatr Res. 2005;57:578-581.
48. Bauman ME, Black K, Kuhle S, et al. KIDCLOT©: the importance of validated
educational intervention for optimal long term warfarin management in children.
Thromb Res. 2009;123:707-709.
49. Ronghe MD, Halsey C, Goulden NJ. Anticoagulation therapy in children. Pediatr Drugs.
2003;5:803-820.
50. Attard C, Monagle P, Kubitza D, et al. The in vitro anticoagulant effect of rivaroxaban
in children. Thromb Res. 2012;130:804-807.
51. Attard C, Monagle P, Kubitza D, et al. The in-vitro anticoagulant effect of rivaroxaban
in neonates. Blood Coagul Fibrinolysis. 2014;25:237-240.
52. Dietrich K, Stang L, van Ryn J, et al. Assessing the anticoagulant effect of dabigatran in
children: an in vitro study. Thromb Res. 2015;135:630-635.
53. Nankervis CA, Preston TJ, Dysart KC, et al. Assessing heparin dosing in neonates on
venoarterial extracorporeal membrane oxygenation. ASAIO J. 2007;53:111-114.
54. Baird CW, Zurakowski D, Robinson B, et al. Anticoagulation and pediatric
extracorporeal membrane oxygenation: impact of activated clotting time and heparin
dose on survival. Ann Thorac Surg. 2007;83:912-920.
55. O’Meara LC, Alten JA, Goldberg KG, et al. Anti-Xa directed protocol for anticoagulation
management in children supported with extracorporeal membrane oxygenation. ASAIO
J. 2015;61:339-344.
56. Stocker CF, Horton SB. Anticoagulation strategies and difficulties in neonatal and
paediatric extracorporeal membrane oxygenation (ECMO). Perfusion. 2016;3:95-102.
57. Manlhiot C, Gruenwald CE, Holtby HM, et al. Challenges with heparin-based
anticoagulation during cardiopulmonary bypass in children: impact of low
antithrombin activity. J Thorac Cardiovasc Surg. 2016;151:444-450.
58. Kleiber C, Hanrahan K, Fagan, CL, et al. Heparin vs. saline for peripheral i.v. locks in
children. Pediatr Nurs. 1993;19:405-409.
PEDIATRICS 503
59. Paisley MK, Stamper, M, Brown J, et al. The use of heparin and normal saline flushes in
neonatal intravenous catheters. Pediatr Nurs. 1997;23:521-524.
60. Kamala F, Boo NY, Cheah FC, et al. Randomized controlled trial of heparin for
prevention of blockage of peripherally inserted central catheters in neonates. Acta
Paediatr. 2002;91:1350-1356.
*61. Albisetti M. The fibrinolytic system in children. Semin Thromb Hemost. 2003;29:339-
347.
62. Anderson DM, Pesaturo KA, Casavant J, et al. Alteplase for the treatment of catheter
occlusion in pediatric patients. Ann Pharmacother. 2013;47:405-410.
63. Alteplase [package insert]. South San Francisco, CA: Genentech, Inc.; 2001.
PART III.
PRACTICAL MEASURING,
MONITORING, AND
COAGULATION
LABORATORY INSIGHTS
21. Coagulation Laboratory Considerations
22. Thrombophilias
505
21 Chapter
COAGULATION LABORATORY
CONSIDERATIONS
Robert C. Gosselin and Maureen A. Smythe
INTRODUCTION
Coagulation testing is used in a variety of settings: as a screen for factor deficien-
cies (commonly with the prothrombin time [PT] and activated partial thromboplastin
time [aPTT]), in monitoring drug efficacy, and identifying antibodies or excluding
disease states (e.g., D-dimer for venous thromboembolism). A new class of antico-
agulants called direct-acting oral anticoagulants (DOACs) is now available, and
methods are being identified to measure the anticoagulation intensity with these
agents. Variables affecting coagulation testing include preanalytical (e.g., timing
of blood collection, processing, suitability) and analytical (e.g., instrument and
reagent systems), which may impact the accuracy of the reported result.1,2 These
variables can lead to notable differences in reported results between laboratories
and should be taken into consideration when using observations in the literature
or from an outside hospital, and in developing or adjusting the anticoagulant
management plan. Lastly, the laboratory evaluation/testing should be interpreted
as a surrogate marker of the hemostasis process, as these data may not be an
absolute reflection of in vivo coagulation or clinically meaningful outcomes.
COAGULATION TESTING: METHODS

Coagulation testing typically measures either the functional or amount (antigen)
of coagulation protein(s) present using four basic testing principles:
1. Clotting endpoint (functional test)—addition of patient plasma to reagent(s), then
determining the time to clot formation.
2. Chromogenic testing (functional test)—addition of patient plasma to reagent(s), then
determining the amount of color formation.
3. Immunologic (mostly antigenic, occasionally functional)—addition of patient plasma
or serum to beads or microwells containing target antigen or antibody, then assessing
color changes, changes in agglutination, hemagglutination, etc.
4. Aggregation (other functional)—addition of patient plasma (platelet poor or containing
platelets) to platelets and/or agonist(s) and measuring light scattering (agglutination)
or platelet clumping (aggregation).
Most clotting, chromogenic, and aggregation studies use 3.2% sodium citrate
anticoagulant. Immunologic testing can be done using either citrate anticoagulated
507
blood or serum. Consult testing laboratory for specific sample requirements

(e.g., collection tube type).
TABLE 21-1: Available Tests and Methods for Coagulation-

Related Assays
PT/ aPTT ACT Fbg Fx TT Heparin XDP HIT AT PLT
INR Level Function
(anti-Xa
activity)
Clotting • • • • • •
Chromogenic • • •
Immunologic • • • • •
Aggregation • •
Point-of-care • • • • • • • •
ACT: activated clotting time, aPTT: activated partial thromboplastin time, AT: antithrombin,
Fbg: fibrinogen, Fx: factor activity, HIT: heparin-induced thrombocytopenia, INR: international
normalized ratio, PLT: platelet, PT: prothrombin time, TT: thrombin time, XDP: D-dimer
• D
ifferent testing approaches can occur between
laboratories, leading to different reported values
or target ranges. Observations in clinical trials
may also be different. Clinicians should be aware
of the method used and the potential differences
in reported values between methods when
interpreting results or comparing target values to
the literature.
COAGULATION LABORATORY CONSIDERATIONS 509
TABLE 21-2: Calibration of Assays

Coagulation Assays Method
Routine screening tests: PT, aPTT, thrombin • Abnormal results based on normal
time, and platelet function testing have no population
calibration • Normal ranges influenced by reagent,
instrument, and population tested (age)
and, therefore, no universal normal PT or
aPTT range
• INR calibration is recommended,3 but
limited commercial material is available
Fibrinogen, factor assays, anti-factor Xa • Standardized commercially prepared

activity assay calibration (reference) material
most often used
• Calibration performed with each new
reagent lot or at least every 6 months3,4
aPTT: activated partial thromboplastin time, INR: international normalized ratio, PT: prothrombin
time
• N
ote that screening tests for coagulation are
typically not calibrated, and new lots are needed
relatively frequently. Changes in these reagent
lots should be assessed appropriately (see below)
prior to clinical use. Be sure to keep current on
the assays your laboratory performs as methods
and reagents may periodically change.
IMPLEMENTING A LABORATORY TEST FOR

CLINICAL USE
Regulatory Requirements
Implementing a new laboratory test: although most laboratories use commer-
cially available kits and/or reagents, the following evaluations are required
by the performing laboratory (Clinical Laboratory Improvement Amendments
[CLIA] regulation, Subpart K, §493.1253) prior to clinical use.4
• R
egarding sensitivity of laboratory testing, if a
highly sensitive test is negative, then the presence
of the substance or diagnosis is unlikely.
TABLE 21-3: Approaches to Determining the Accuracy,

Imprecision, and Reportable Range for a Testa
Test Evaluation Definition/Requirements
Parameter
Accuracy Comparison of a new method to an existing method or reference

method; the “closer” the new method is to the reference standard,
the better the accuracy. Comparison of samples from selected disease
states (e.g., liver failure, hemophilia) is encouraged.
Imprecision Determining the imprecision of running a single sample multiple times

concurrently (within-run imprecision) as well as the same sample (usually
control material) over a period of days (day-to-day imprecision) to
determine the coefficient of variation (CV); the lower the CV, the more
likely the same value will occur for a sample on repeat testing.
Reportable range Assesses the reportable range (high and low) as well as reproducibility of
(linearity) diluted samples; values that exceed the reportable range may undergo
further testing in the lab (dilute out the sample), or may be reported
as “<” or “>”—the lower or upper limit of the range, respectively, as
determined by the lab.
Verify manufacturer’s Appropriate for laboratory’s patient population; many tests may not
reference interval have age-related reference ranges, and therefore in patients <18 yr old,
(normal range) reference ranges may be cited from acceptable references.
a
If modifications to an FDA-approved test is used, or if in-house test is used, then additional
performance characteristics must be evaluated and documented to include aforementioned
accuracy, imprecision, reportable range, and reference intervals but also the following:
• Analytical sensitivity (see next below for description of sensitivity).
• Analytical specificity, including interfering substances (see below for description of specificity).
• Other performance characteristics required for testing (e.g., reagent stability).
TABLE 21-4: Sensitivity

Ability for test to detect abnormality (diagnostic or monitoring) formula:
True Negative
True Negatives + False Positives
Ideal coagulation reagent: 100% sensitive to all clinical and therapeutic needs.
Realistic coagulation reagent:
• Variable sensitivity for UFH or DTI.
• Variable sensitivity for lupus anticoagulant.
• Variable sensitivity for factor deficiencies (e.g., factor VIII or XI).
• Variability between reagent manufacturers for same test (e.g., aPTT).
• Preanalytical and analytical variables can influence test results causing false negative
results.
Sensitivity is also used to describe the relative response of a test to drug or disease:
• INR is more sensitive to vitamin K antagonists than the aPTT.
• aPTT is more sensitive for measuring UFH targets for treatment for DVT than the ACT.
• Low-response ACT cartridge is more sensitive to low dose UFH (e.g., cardiac
catheterization) anticoagulation than to the high-response ACT cartridges
(e.g., cardiopulmonary bypass procedures).
inhibitor, DVT: deep venous thrombosis, INR: international normalized ratio, UFH: unfractionated
heparin
• R
egarding specificity of laboratory testing, if a
highly specific test is positive, then diagnosis or
presence of a specific substance is more likely.
VARIABLES THAT AFFECT COAGULATION

TESTING
The coagulation study sample in many situations must be placed in a tube
containing citrate, which binds calcium and inhibits the coagulation process
from occurring in vitro. Delays in transferring sample to a citrate environment
may affect results.
TABLE 21-5: Specificity

Ability for test to detect a specific pathologic condition (clinical sensitivity) or abnormality
formula:
True Positives
True Positives + False Negatives
Ideal coagulation reagent: 100% specific to all clinical and therapeutic needs.
Realistic coagulation reagent and anticoagulant monitoring or diagnostic testing:
• Screening tests (e.g., PT, aPTT) measure multiple proteins:
{{ PT and aPTT testing can be influenced by increased factor levels (shortened clotting
times) or decreased factor levels (increased clotting times).
• Preanalytical and analytical variables can influence test results causing falsely increased or
decreased results:
{{ Improperly derived reference range
{{ Improperly assigned ISI and normal geometric mean for INR calculation
{{ Sample age >4 hr for aPTT (>2 hr for UFH samples)
{{ Sample age >24 hr for PT
{{ Expired reagent(s)
• Monoclonal antibody testing (e.g., IgG isotype for HIT testing) may be more specific for
diagnosing HIT than using a polyclonal test (measures IgG, IgM, and IgA antibodies).
• Abnormal result does not necessarily imply pathology:
{{ D-dimer can be elevated as normal physiological response to surgery, trauma, etc., and
elevated result does not imply DIC or venous thromboembolism.
{{ Elevated PT/aPTT from diluted sample drawn above an IV line.
{{ Positive presence of HIT antibodies does not mean they are pathogenic causing clinical
disease.
aPTT: activated partial thromboplastin time, DIC: disseminated intravascular coagulation,

HIT: heparin-induced thrombocytopenia, hr: hours, INR: international normalized ratio, ISI:
International Sensitivity Index, IV: intravenous, PT: prothrombin time, UFH: unfractionated heparin
TABLE 21-6: Potential Flaws with Collecting Samples1

Problem Test Outcome
Samples submitted • Decrease PT due to cold activation of factor VII

on ice • Decreased platelet function
Samples acquired • Delay in anticoagulating blood (>60 sec from syringe to citrate tube)
from syringes • Increased PT/aPTT—clotted sample
• Decreased PT/aPTT—activated sample
• Increased platelet function—activated platelets more responsive to
agonist
• Decreased platelet function—platelet clumping, spent platelet
function
Samples acquired • Increase PT/aPTT/anti-Xa activity due to hemodilution (e.g., above

from in-dwelling IV site)
lines • Increased PT/aPTT due to poor clearance of line prior to adding
blood to citrate tube
• Increase PT/aPTT/anti-Xa activity due to heparin contamination from
line
Timing of sample • LMWH, collect 4–6 hr after last dose

collection • For DOACs, collect just prior to next dose (trough collection)
aPTT: activated partial thromboplastin time, DOAC: direct-acting oral anticoagulant, hr: hours, IV:
intravenous, LMWH: low molecular weight heparin, PT: prothrombin time, sec: seconds
• R
egarding collecting blood samples for
coagulation testing, the longer the sample
remains in the syringe, the greater the error (can
be either shortened or prolonged clotting times)
in reported results.
TABLE 21-7: Variables That Increase PT/INR and aPTT Testing

Preanalytical
• Short draw—excess sodium citrate in plasma
• Elevated HCT (>55%)—common in neonates; excess citrate in plasma
• Clotted sample
• Sample >4 hr old: ↑ aPTT
• Sample >24 hr old: ↑ INR
• Hemodilution drawn above IV site; drawn via arterial line without proper clearance
• Surgical hypothermia
Factor deficiencies
• PT factors VII, X, V, II and to a lesser degree, fibrinogen
• aPTT factors XII, XI, IX, VIII, X, V, II, and to a lesser degree, fibrinogen
• Physiological decrease
{{ Hereditary deficiencies: factor VIII and IX most common with higher incidence of factor
XI deficiencies in Ashkenazi Jewish population
{{ Immature liver: premature infants and neonates
{{ Liver disease ↑ INR with normal or slight ↑ aPTT
{{ Consumptive coagulopathy
{{ Hemodilution
{{ RBC transfusion without FFP
{{ Blood volume expanders
{{ Deficiencies can also be associated with antibody directed against factors
{{ Drugs prolonging PT/INR (reagent sensitivity variable and potentially dependent on the
drug concentration present)
Oral vitamin K antagonists
Daptomycin and other lipoglycopeptides
Direct thrombin inhibitors
Argatroban > bivalirudin, dabigatran or
Direct Xa inhibitors
Rivaroxaban, edoxaban, betrixaban, and to a lesser degree, apixaban
Systemic fibrinolytic activators (e.g., urokinase)
Unfractionated heparin (supratherapeutic > therapeutic)
{{ Drugs prolonging aPTT (reagent sensitivity variable and potentially dependent on the
drug concentration present)
Unfractionated heparin
Direct thrombin inhibitors (bivalirudin, argatroban, dabigatran)
Systemic fibrinolytic activators (e.g., urokinase)
Hydroxy-ethyl starch, Hematin, Suramin, Taularidine
Direct oral anticoagulants (dabigatran > anti-Xa DOACs)
Antiphospholipid antibodies—varies with reagent, may prolong INR and/or aPTT
aPTT: activated partial thromboplastin time, DOAC: direct oral anticoagulant, FFP: fresh frozen
plasma, HCT: hematocrit, hr: hours, INR: international normalized ratio, IV: intravenous, PT:
prothrombin time, RBC: red blood cell
TABLE 21-8: Variables Decreasing the PT/INR and aPTT

Preanalytical
• Low HCT (<25%)
• Elevated calcium levels
• Poorly collected sample: ↓ INR and/or aPTT due to activated sample
• Samples placed on ice: ↓ INR
• Samples >2 hr for patients on UFH: ↓ aPTT due to platelet degranulation and PF4 release,
which neutralizes heparin
Elevated factor levels

• Inflammatory response: ↓ aPTT due to elevated factor VIII and/or fibrinogen
• Cryoprecipitate—contains high levels of factor VIII and fibrinogen
• Drugs decreasing INR
{{ Activated factor VII
{{ Prothrombin complex concentrates
• Drugs decreasing aPTT
{{ Prothrombin complexes
{{ Direct factor therapy
{{ Protamine sulfate
aPTT: activated partial thromboplastin time, HCT: hematocrit, hr: hours, INR: international
normalized ratio, PF4: platelet factor 4, PT: prothrombin time, UFH: unfractionated heparin
EVALUATING LABORATORY DATA
TABLE 21-9: Evaluation Methods Used for Comparison Studies

Evaluation Method Comments
Regression analysis (or • Will assist in assessing relative accuracy to comparison method.
equivalent) • When R value is one, there is perfect agreement between
methods.
• When R value is low, there is poor correlation between methods.
• Does not identify areas of biases.
Bland-Altman plots • Graphically depicts area(s) of bias.

(see Figure 21-1)
Difference: new method –
[ current method + new method
2 ]
• Modified bias plot: difference = new lot – current lot
Students paired t-test • Will determine if statistical differences exist between methods.
(or equivalent) • Statistical software should be used to determine whether sample
size and distribution are acceptable for valid analysis.
• p <0.05 considered significantly different between methods.
FIGURE 21-1. Bland-Altman Bias Plot Demonstrating the

Differences Between Point-of-Care INR Methods
In this example, a modified Bland-Altman bias plot was used to delineate the areas of
bias between three different POC INRs and laboratory INRs. The POC INRs tend to be
higher (positive bias) than central laboratory INRs in this study.
TABLE 21-10: Comparison of INR Measurements Between

Point-of-Care and Central Laboratory
• INR biases are mostly polar: POC provides values higher than laboratory methods on low
end of therapeutic range (1.5–2), and provides values lower than laboratory methods at
high INR levels (>4).5
• Laboratory should establish areas of bias between POC and lab INR methods6 using Bland-
Altman plots.
• Newer methods with lower ISI (<1.5) may demonstrate better correlation with lab.
• POC methods do not match each other.
• Avoid interchanging monitoring methods during course of therapy.
• Consider laboratory INR for POC values >5.
• Dabigatran can substantially prolong POC INR values more than laboratory-based values.
INR: international normalized ratio, ISI: International Sensitivity Index, POC: point of care
• T
he use of different laboratories or methods may
increase the variability in reported prothrombin
time/international normalized ratio (PT/INR)
results between samples and complicate dose
response assessment, leading to more instability
in a regimen.
TABLE 21-11: Comparison of aPTT Measurements Between

Point-of-Care and Central Laboratory
• There is typically a bias between lab and POC aPTTs.
• POC instrument manufacturers may use a mathematical correction factor to partially offset
the bias to more closely correlate with laboratory aPTT results.
• Because there is no incubation period for POC aPTT, results tend to be higher than
laboratory aPTT, despite internal correction factor.6,7
• Avoid interchanging monitoring methods (lab vs. POC) during patient’s course of therapy.
• Consider laboratory aPTT if POC aPTT does not correlate with clinical picture.
aPTT: activated partial thromboplastin time, POC: point of care
PROTHROMBIN TIME AND INTERNATIONAL

NORMALIZED RATIO
TABLE 21-12: Overview of the PT and INR

• The PT is a measure of the extrinsic and final common pathway (II, V, VII, X).
• Vitamin K antagonists decrease the functional activity of factors II, VII, IX, X, protein C and
protein S; the INR only describes the activity of factors II, VII, and X, and not factor IX.
• The PT measures the time it takes for plasma to clot after the addition of calcium and an
activator; the result is expressed in seconds.
• Significant variation in PTs can occur due to differences in the source of thromboplastin
(tissue factor, phospholipids, calcium) and the type of instrument used for clot detection.
• Thromboplastin reagent sensitivity is expressed using the term ISI:

{{ History: Established to mitigate observed differences between U.S.- and European-
reported PT results; ultimately the INR replaced PT ratio for determining oral vitamin K
antagonist effects.
{{ ISI provides an indicator of the thromboplastin responsiveness to the reduction in
vitamin K dependent factors as compared with the WHO reference preparation.
{{ Thromboplastin with low ISI values correlate well with reference standard.
{{ Highly sensitive thromboplastins have an ISI of ~1 and are comprised of human or
recombinant tissue factor.
{{ Less sensitive thromboplastins have higher ISI values and are comprised of rabbit brain
tissue factor.
{{ Reagents with ISI values <1.4 are recommended for warfarin monitoring.
ISI does not reflect sensitivity to anti-Xa DOACs
(continued)

• The INR was created as a mechanism to adjust for variation in PTs due to thromboplastin
reagent sensitivity:
[ ]
ISI
patient PT(s)
INR =
normal reference mean
Note: mean is geometric mean
• CLSI INR calibration guidelines, but limited commercial products and/or availability.3
• Although the INR is an improvement, variations still occur due to the following:
{{ Inaccurate reporting of the ISI by the manufacturer
{{ Pretest variables
{{ Differences resulting from lab instrumentation
{{ Liver disease
{{ DOAC effect
• In hospitalized patients, the PT/INR is typically performed from a venipuncture acquired

sample and analyzed using a laboratory-based coagulation analyzer.
• Once collected in sodium citrate tube, the PT and INR are stable for 24 hr, when
maintained at room temperature.
• The PT/INR is also available as a POC test using a portable coagulation device, which is
available from several different manufacturers:
{{ Capillary blood is used.
{{ The device converts the result to a plasma equivalent PT or INR.
{{ Results vary across manufacturers.
{{ Variations from lab assays are not typically considered clinically significant, except for
elevated INRs.
• Alternative strategies for monitoring oral vitamin K antagonist anticoagulation:

{{ Monitoring using factor levels
{{ Most common is factor X levels (not anti-factor Xa activity levels)
{{ Differences exist between chromogenic and clot-based factor X results
{{ Target factor level results of INRs between 2–38,9
Factor II: ~20–35% for INR 2–3
Factor X: 11–42% for INR 2–3.5 (chromogenic method); small variations in the %
factor range for a given INR value can exist between assays (see Chapter 5)
CLSI: Clinical Laboratory Standards Institute, DOAC: direct oral anticoagulants, hr: hours,
INR: international normalized ratio, ISI: International Sensitivity Index, POC: point of care, PT:
prothrombin time, WHO: World Health Organization
• W
hen an INR is needed and only the aPTT was
recently collected, consider requesting that the
laboratory run an INR off the aPTT sample to
expedite the result and avoid additional needle
sticks or blood draws.
TABLE 21-13: Clinical Applications of PT and INR

• Less accurate during initiation of warfarin therapy as the INR is most responsive initially to
reductions of factor VII, which has the shortest half-life.
• Can be prolonged by lupus anticoagulant, liver disease.
• Heparin can prolong the PT/INR:

{{ Therapeutic dose heparin may increase the PT by 1.2 to 1.8 sec if no heparin-
neutralizing agent (e.g., polybrene) contained in reagent.
{{ High-dose heparin may have a more pronounced effect.
{{ Can obtain an accurate PT in patients on heparin by using a heparin neutralizer like
polybrene to neutralize heparin effect up to 2 units/mL of anti-factor Xa activity, but
can vary between reagents.
• Direct thrombin inhibitors exert a drug laboratory interaction and prolong the INR; this INR
prolongation is not representative of a hemostatic effect10:
{{ The elevation is greatest with argatroban followed by bivalirudin.
{{ INR should not be reported in patients on anti-Xa DOAC therapy.
INR: international normalized ratio, PT: prothrombin time, sec: seconds
• A INR target range of 2−3 assumes steady state

anticoagulation for a vitamin K antagonist.
• C
onsidering that the half-life of factor II is longer
than VII or X, a INR value that is rising rapidly
during the initiation of vitamin K agonist (VKA)
therapy may not fully represent the measured
degree of anticoagulation occurring at steady-
state dosing because the decline in factors VII and
X are faster than II.
{{ Early increases in INR values after initiating
warfarin therapy may represent the early loss
of predominantly factor VII.
{{ In contrast, recovery of factor II may lag
behind VII and X after holding the VKA,
suggesting a greater degree of anticoagulation
for a given INR value. Thus, a declining
INR may represent a higher level of
anticoagulation compared to the same INR
value rising.
• I f a PT reagent has heparin neutralization
capabilities, there will be minimal effect on the
INR for patients receiving heparin. If heparin

neutralization is not part of the PT reagent
system, then the baseline INR may be elevated in
the presence of heparin.
ACTIVATED PARTIAL THROMBOPLASTIN

TIME
TABLE 21-14: Overview of the aPTT Test

• A global assay of coagulation.
• The aPTT is referred to as partial thromboplastin due the absence of tissue factor in the
thromboplastin.
• Can be used to screen for inhibitors and deficiencies of the intrinsic pathway (factors XII,
XI, IX, and VIII) and common pathway (factors X, V, prothrombin), and to a lesser degree,
fibrinogen (of note is that some DTIs can decrease measured fibrinogen values).
• Many preanalytic variables that may affect aPTT results include sample timing, site of
sample, concentration of citrate, and sample handling (e.g., centrifugation, processing
time).
• Instruments to detect the presence of clot may be dependent on plasma turbidity; lipemic
or icteric specimens can affect plasma turbidity; in vitro hemolyzed samples should not be
used for coagulation testing.
• aPTT reagents vary in the type of contact activator, phospholipid composition, and
concentration.
• The relationship between factor activity in the blood and the aPTT result is logarithmic;
therefore, for longer baseline aPTTs, a lower level of change is needed for additional
prolongation.
• aPTT has circadian variation (higher during sleep), which can result in difficulty in
maintaining a therapeutic aPTT once achieved (see Chapter 3).
• POC testing for aPTT adds to the test variability.
• Once appropriately collected into sodium citrate tubes, the aPTT is stable for the following:
{{ Monitoring unfractionated heparin: 2 hr at room temperature
{{ All other indications: 4 hr at room temperature
aPTT: activated partial thromboplastin time, DTI: direct-acting thrombin inhibitor, hr: hours, POC:
point of care
TABLE 21-15: Considerations of Heparin Monitoring Using the

aPTT
• The most common test to monitor unfractionated heparin.
• The heparin therapeutic aPTT range will vary depending on the aPTT reagent and
instrument employed.
• aPTT reagents vary in their responsiveness by manufacturer and lot number (see Figure
21-2).
• aPTT ratios have been reported as an acceptable means for monitoring UFH therapy.11
{{ However, aPTT reagent ratio bias (ranging from 1.7–6.2) have been noted in patients
with 0.3–0.7 units/mL anti-Xa activity.12
aPTT: activated partial thromboplastin time, UFH: unfractionated heparin
• T
he correlation between anti-factor Xa activity
and aPTT is stronger with a laboratory-based
aPTT than with a point-of care (POC) aPTT.
• T
he College of American Pathologists (CAP)
recommends determining the initial heparin
aPTT therapeutic range by regression analysis
between aPTT and heparin levels (anti-factor
Xa activity) on samples from patients receiving
therapeutic unfractionated heparin (UFH) only
(no warfarin). The aPTT therapeutic range
corresponds to 0.3–0.7 units/mL anti-factor Xa
activity, by chromogenic methods (see Figure
21-3).13 The data to support this process
appear more in the venous thrombosis literature
than the acute coronary syndrome literature.
The CAP, however, does not differentiate the
recommended approach for other indications,
such as extracorporeal life support (ECLS), for
determining the heparin therapeutic range.
• T
he heparin therapeutic range may need to
be reestablished with each new lot number of
reagent or change in reagent manufacturer or
instrument.12 The following steps should be
performed to assess reagent drift over time and if
the range needs to be changed:13-15
{{ Compare new lot aPTT versus old lot aPTT
reagents in at least 20 patients on UFH
treatment (no concomitant warfarin). No
more than two samples per single patient are

acceptable.
{{ Track the cumulative sum difference of the
mean aPTT over time with each reagent
change13
{{ If the cumulative sum is <5 seconds, no
change in therapeutic range is necessary.
{{ If the cumulative sum is between 5–7
seconds, change may be necessary.
{{ If the cumulative sum is >7 seconds, a
new therapeutic range is required.
{{ Make sure changes are communicated
in a timely fashion to clinicians so that
adjustments to UFH dosing order sets
can be prepared prior to new lot reagent
implementation.
140 aPTT Reagent C
120 aPTT Reagent D
100 aPTT Reagent F

aPTT, sec
aPTT Reagent B
80 aPTT Reagent E
aPTT Reagent A
60
40
20
0.00 0.10 0.20 0.30 0.40 0.50 0.60
Heparin level, anti-Factor Xa activity units/mL
FIGURE 21-2. Heparin aPTT Response Curve: Impact of Varying

Reagents
aPTT results tested concurrently using six different reagent/instrument combinations on
UFH-treated patients. Note that aPTT reagents that are more sensitive to UFH (steeper
slope and higher aPTT clotting times) may yield different aPTT ratios (patient’s aPTT/
baseline aPTT). Literature-based therapeutic ranges (e.g., 60–80 seconds) will also not
be equivalent between reagent systems.
150
140
130
120
110
100
aPTT, sec
90
80
70
60
50
40
30
20
10
0
0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00
Heparin anti-Factor Xa activity units/mL
FIGURE 21-3. Heparin Response Curve: Determining the aPTT

Therapeutic Range
The recommended method for laboratory determination of unfractionated heparin
therapeutic range by comparing anti-factor Xa activity levels to aPTTs results in patients
receiving therapeutic doses and no concomitant anticoagulant therapy (warfarin). In this
example, the laboratory determined unfractionated heparin therapeutic range would be
50–95 seconds.
160
140
120
100
aPTT, sec
80
60
40
20
0
0 0.2 0.4 0.6 0.8 1
Heparin (units/mL)
FIGURE 21-4. Heparin Response Curve: Impact of In-Vitro

Heparin Spiking
Comparison of regression data from the recommended method of determining the
UFH therapeutic range using anti-factor Xa activities compared to patient aPTTs
(small squares) and using in vitro UFH spiking of plasma (larger triangles in bold). The
therapeutic range for the recommended method is 45–85 seconds, and the therapeutic
range from in vitro spiking would be 70–120 seconds.
UFH therapeutic range:

{{ Using UFH-spiked plasma to determine
therapeutic range may overestimate
drug requirement and lead to excessive
anticoagulation. This method should not
be used, even though it is often attractive to
facilities that rarely utilize heparin.
TABLE 21-16: aPTT Testing of UFH Anticoagulation—Clinical

Applications
• Decisions to adjust heparin infusion therapy based on the aPTT will not always agree with
those based on other tests such as heparin concentration (anti-factor Xa activity level) or
the ACT.
• It is reasonable to validate by repeating the aPTT when results are unexpectedly prolonged
during monitoring for VTE treatment with IV UFH.
• Data supporting a relationship between an elevated aPTT to major bleeding in patients for
VTE is weak; some correlation between bleeding and the frequency of aPTT values above
the target range beyond 48 hr of therapy has been observed.
• Data from ACS trials supports a relationship between increased aPTT and major bleeding.
• Heparin resistance: see Chapter 3.
• LMWH heparin and aPTT:

{{ Therapeutic doses have minimal impact on aPTT—cannot be used to monitor therapy.
ACS: acute coronary syndrome, ACT: activated clotting time, aPTT: activated partial
thromboplastin time, hr: hours, IV: intravenous, LMWH: low molecular weight heparin, UFH:
unfractionated heparin, VTE: venous thromboembolism
TABLE 21-17: Parenteral DTI Monitoring Using the aPTT

• The DTI aPTT therapeutic range is not the heparin aPTT therapeutic range.
• Varying aPTT reagents will produce different aPTT ratios for a clinically relevant
concentration of DTI.16
• The aPTT therapeutic range for DTIs was established in multicenter trials, which used
multiple aPTT reagents.
• With increasing concentrations of DTI, the aPTT dose response curve flattens and
significant changes in plasma level result in only minor change in aPTT.
• Use of aPTT ratios have been reported, but no agreement on whether denominator is
patient baseline or mean reference result.
• Per CAP requirements, each laboratory should determine a therapeutic range for a test used
to monitor an anticoagulant17; for the use of the aPTT during DTI therapy, the following is one
approach to consider spiked normal plasma with DTI corresponding to drug concentrations
of 0.1–1.2 mcg/mL:
{{ Run aPTT and PT/INR.
{{ Repeat with each new lot of reagents (PT and aPTT).
aPTT: activated partial thromboplastin time, CAP: College of American Pathologists, DTI: direct
thrombin inhibitor, INR: international normalized ratio, PT: prothrombin time
90
80
70
60
aPTT, s
50
40
Lot A
30
Lot B
20 Lot C
10
0
0.0 0.2 0.4 0.6 0.8 1.0 1.2
Argatroban mcg/mL
FIGURE 21-5. Comparison of Different aPTT Reagents Lots for

Response to Argatroban in Vitro
Lot A represents increased sensitivity and the possibility of higher reported aPTT values.
However, the base line value may be elevated as well, reducing the impact on the
ratio. A flattening of the curve (or change in the slope) may be observed at higher DTI
concentrations. Note: The target serum DTI level related to clinical outcomes has not
been established. The curve describes how the aPTT range observed may vary between
reagents and could lead to different results if a set range in seconds is established
instead of a ratio.
TABLE 21-18: Clinical Application of the aPTT for Parenteral

DTI Monitoring
Note: Refer to DTI chapter for further information.
• Warfarin can increase the aPTT, which can result in underdosing of DTI if not reversed at
time of HIT diagnosis.
• Elevated aPTTs are associated with increased bleeding.
• Consider aPTT ratio 1.5–2 × baseline or low end of the therapeutic range if high bleeding
risk is present.
• If no elevation in aPTT with increasing dose, verify the amount of drug or switch to another
DTI; an elevation in the INR or ACT may suggest an anticoagulation effect is present
and a problem exists with the aPTT assay in use; consider sending sample to an outside
laboratory for verification using either alternative aPTT method or chromogenic thrombin
inhibitor assay.
• Check aPTT any time thrombosis or major bleeding is suspected.
• With excessive aPTT prolongation, verify aPTT has returned to therapeutic range before
restarting therapy.
• The greater the level of DTI anticoagulation (the higher the aPTT) the greater the impact
on INR elevation.
inhibitor, HIT: heparin-induced thrombocytopenia, INR: international normalized ratio, x: times
HEPARIN LEVEL MONITORING
TABLE 21-19: Overview of Anti-Xa Level Monitoring for Heparin

Products
• Anti-factor Xa activity assays can be clot-based or chromogenic; clot-based assays may
underestimate anti-factor Xa activity relative to chromogenic assays; chromogenic assays
are most often used (see Figure 21-6 for chromogenic method description).
• Anti-factor Xa activity must be determined using either a hybrid, UFH-derived, or LMWH-

derived calibration curve.18 Pentasaccharide anti-factor Xa activity monitoring also requires
a different calibration curve than UFH or LMWH as the drug concentration is measured in
different units (mg vs. anti-factor Xa activity, respectively). Note: Although pentasaccharide
anti-factor Xa activity correlates with dose, a relationship between fondaparinux dose and
clinical outcomes is lacking.
• Assay variability comes from different instrumentation and manufacturers, the addition of
exogenous AT in some assay systems, different lots of heparin, and differences in process
for creating the standard curve.
• Anti-factor Xa activity assays have an advantage over aPTT for heparin monitoring in that
results are less affected by biologic variables.
• Some institutions monitor heparin infusion therapy directly using heparin anti-factor Xa
activity.
• Appropriate calibration is required (e.g., UFH, LMWH, hybrid or pentasaccharide

calibration curves).
• Using the UFH curve for measuring LMWH can underestimate LMWH effect.
• Using the LMWH curve for measuring UFH anticoagulation can overestimate UFH effect.
• Heparin levels determined by chromogenic heparin anti-factor Xa activity are numerically

higher than levels determined by protamine titration; avoid interchange of heparin level/
activity results.
aPTT: activated partial thromboplastin time, AT: antithrombin, LMWH: low molecular weight
heparin, UFH: unfractionated heparin
For comparison of the anti-factor Xa to aPTT assays for heparin management, see
Appendix L.
Optional supplementing
plasma [heparin] + Factor Xa of antithrombin
(Antithrombin)
(AT)-heparin-Xa complex + residual fXa
Chromogenic substrate
Amount of yellow color
produced is inversely
yellow color proportional to amount of
FIGURE 21-6. Schematic of the Chromogenic Process for

Determining Anti-Factor Xa Activity
Anti-factor Xa activity testing:

{{ AT supplemented as part of the test may
demonstrate a greater anti-factor Xa
activity effect (higher value) in patients
with depressed AT activity or levels (<70%)
compared to testing methods that do not
include this step. Infusion of a source of
AT such as fresh frozen plasma (FFP) can
increase reported anti-factor Xa activity in
tests that do not include AT.
{{ Chromogenic anti-factor Xa activity
testing is most commonly used.
{{ It is important to verify that the correct,
calibrated curve is being used for the
agent being tested.
{{ Anti-factor Xa activity targets are different
depending on method used (protamine
titration vs. chromogenic methods).
{{ UFH anti-Xa activity cannot be
differentiated from low molecular weight
heparin (LMWH) or anti-Xa DOAC anti-
factor Xa activity in patients converting from
one to the other. Modifications of the assay
(e.g., addition of heparinase) may be able to
neutralize UFH from anti-Xa DOACs.
TABLE 21-20: Clinical Application of Anti-Xa Monitoring for

Heparins
• Anti-factor Xa activity should be drawn at the time interval as recommended for aPTT
monitoring of UFH anticoagulation.
• Warfarin does not affect the heparin anti-factor Xa activity levels.
• Heparin monitoring with anti-factor Xa activity levels instead of the aPTT has been shown
to result in fewer monitoring tests, fewer dose changes, and a higher percentage of
therapeutic test results; earlier values within the anti-factor Xa activity target range may
result in fewer upward dosing titrations and a lower level of anticoagulation compared to
the use of the aPTT, especially if aPTT targets are set at the upper end of the range (i.e.,
equivalent of 0.5–0.7 anti-factor Xa activity units for VTE treatment).
• Consider anti-factor Xa activity monitoring over aPTT monitoring for continuous infusion
heparin therapy in:
{{ Situations of suspected heparin resistance such as increased levels of factor VIII,
heparin binding proteins, or fibrinogen
{{ Failure to increase aPTT despite heparin dose increases
{{ Lupus anticoagulant
{{ Pregnancy
{{ Situations where a lab cannot adequately perform regression analysis due to a lack of
samples (small facilities, etc.)
• The relationship between anti-factor Xa activity levels and clinical outcomes (thrombosis or
major bleeding) is poorly defined, and any benefits unclear with both UFH and LWMH.
• The level of anti-factor Xa activity accumulation in renal impairment varies between LMWH:
{{ Enoxaparin demonstrates an inverse linear relationship between CrCl and anti-factor Xa
activity level.
{{ With enoxaparin, anti-factor Xa activity levels accumulate significantly with CrCl <40
mL/min.
{{ Dalteparin and tinzaparin do not appear to demonstrate significant anti-factor Xa
activity accumulation with renal impairment (CrCl >20 mL/min) when used for a short
duration of therapy.
• Potential candidates for LMWH anti-factor Xa activity monitoring:
{{ Renal insufficiency
{{ Newborn
{{ Low body weight
{{ Pediatrics
{{ Unexpected thrombosis on therapy
{{ Pregnant women
{{ Morbid obesity—BMI >40 kg/m2 or actual body weight >190 kg
{{ Long-term therapy with therapeutic anticoagulation in patients with moderate renal
impairment
• Data supporting beneficial outcomes of LMWH dose adjustment based on anti-factor Xa
activity levels do not yet exist.
• Correlation with measured results and population parameter (e.g., weight, renal function)
is poor.
• The chromogenic anti-Xa level can be increased by recent (previous) treatment with an
anti-Xa DOAC. A change to aPTT or thrombin time monitoring may be considered for
patients in whom residual anti-Xa DOAC effects are present.19
aPTT: activated partial thromboplastin time, BMI: body mass index, CrCl: creatinine clearance,
DOAC: direct oral anticoagulant, LMWH: low molecular weight heparin, UFH: unfractionated
heparin
{{ Anti-Xa activity methods that supplement

with antithrombin may not accurately
reflect the in-vitro anticoagulation
potential in patients with low
antithrombin levels.
Activated Clotting Time (ACT)
TABLE 21-21: Overview of the ACT Test

• A POC method, with normal range typically 80–130 sec (can vary).
• Used to monitor moderate- to high-dose heparin and DTI monitoring during

cardiopulmonary bypass and other invasive intravascular procedures including cardiac
angiography and intervention, intra-aortic balloon pumps, ECMO, vascular surgery, and
carotid endarterectomy.
• Results are affected by numerous factors including platelet count, platelet function, lupus
anticoagulants, factor deficiency, test method, blood volume, technique employed,
ambient temperature, and hemodilution.
• Warfarin and glycoprotein IIb/IIIa inhibitors can increase the ACT; aprotinin effect is
dependent on the contact activator used (celite >kaolin).
• Devices have a low range and separately high range calibrating cards, which will differ in
reporting the heparin anticoagulation response value.
• Devices vary in contact activator used (celite and/or kaolin), method of clot detection, and
results; therefore, ACT values between devices are not comparable.20
• There are differences between ACT devices, with Medtronic ACT device having positive
bias as compared to Hemochron results.
• The ACT is insufficiently sensitive to assess DOAC anticoagulation.
ACT: activated clotting time, DOAC: direct oral anticoagulant, DTI: direct thrombin inhibitor,
ECMO: extracorporeal membrane oxygenation, POC: point of care, sec: seconds
ACT testing:
• R
eported ACT values can be different depending
on the calibrating range card (low or high range)
used. Not all ACT will be the same, creating
challenges when the specific test used in an
assessment or published report is not stated.
Different methods have given different results in
the cardiac catheterization lab (see Chapter 3).
• I f ACT is not responding to UFH anticoagulation,
be sure that the appropriate cartridge is used prior
to increasing the drug. An aPTT or a heparin
anti-factor Xa activity level can also be checked to
affirm presence of drug effect.
• I n the rare circumstance that a laboratory
value such as the ACT or APTT is not
responding despite sufficient administration
of an anticoagulant (verification of the correct
concentration and dose used), alternative testing
such as a different ACT, aPTT, or anti-factor Xa
activity should be considered. Selected patients
transiently or long term may be uniquely
nonresponsive to a selected test.
TABLE 21-22: Clinical Applications of the ACT

UFH Anticoagulation
• Relationship between ACT and ischemic complications during PCI is controversial;

therefore, the optimal ACT range for heparin in PCI is not well established.
• LMWH does not significantly prolong the ACT.
• Options for patients with lupus anticoagulant undergoing cardiovascular surgery:

{{ Double the baseline ACT.
{{ Use spiked samples to create a patient-specific ACT heparin level titration curve to
identify the ACT, which corresponds to the desired heparin level in the operating room,
typically a whole blood concentration of >3 units/mL.
{{ Hepcon point-of-care device can be used to measure the ACT, which corresponds to
a therapeutic heparin level (heparin levels measured with this device use protamine
titration).
• The ACT is insufficiently sensitive to assess DOAC anticoagulation.
ACT: activated clotting time, DOAC: direct oral anticoagulant, LMWH: low molecular weight
heparin, PCI: percutaneous coronary intervention, UFH: unfractionated heparin
CHROMOGENIC FACTOR X
Understanding the Chromogenic Factor X Assay

• Often confused with the chromogenic anti-Xa assay.
• Measures functional activity of factor X.
• Performed by mixing patient plasma, a chromogenic substrate, and a factor X
activator called Russell viper venom; factor X activity is proportional to amount
of chromogenic substrate generated.
• Clinical situations where a chromogenic factor X can be considered:
{{ Warfarin patients with lupus anticoagulant and an elevated baseline
INR.
{{ Heparin-induced thrombocytopenia patients transitioning from
argatroban to warfarin therapy (argatroban produces a false eleva-
tion in INR complicating this transition).
{{ A warfarin patient who develops a clot with a therapeutic INR.
{{ Warfarin resistance.
• Chromogenic factor X levels between 20−40% typically correlate with an INR
of 2–3; each laboratory should establish their own chromogenic factor X range.
• O
utcome studies are needed in lupus
anticoagulant patients to determine if use of the
chromogenic factor X assay improves outcomes.
• I f the chromogenic factor X activity is below the
target range warfarin dose, consider decreasing
the dose. If it is above target range, consider
increasing the warfarin dose.
• U
sing a chromogenic factor X assay allows for
the transition from argatroban to warfarin to
occur without interruption in parenteral direct
thrombin inhibitor (DTI) therapy to assess if the
target range for warfarin has been achieved.
• Factor X levels measured using traditional clot-
based methods are typically higher than factor X
levels measured using chromogenic methods.
Ecarin-Based Testing
Ecarin clotting time (ECT): Based on the effect of the venom from the
saw-scaled viper, Echis carinatus. Ecarin is a metalloprotease that catalyzes
prothrombin (factor II) to an active form, meizothrombin that converts
fibrinogen to fibrin. Instruments that can measure changes in optical density

secondary to fibrin formation can be used to measure ECT.
Ecarin chromogenic assay (ECA): Similar to ECT, this method uses a
chromogenic substrate specific for meizothrombin (e.g., HSY-83) which
enzymatically cleaves the substrate resulting in paranitroanline release and
resultant yellow color. The amount of yellow color produced is proportional
to the amount of meizothrombin generated, therefore inversely proportional
to any anti-II drug (e.g., bivalirudin, dabigatran).
• N
o methods for ECT or ECA are U.S. Food and
Drug Administration (FDA) approved, and would
be considered laboratory developed test (LDT).
• T
here is a linear response for both ECT and ECA
to dabigatran concentration.
• N
either method is responsive or useful to measure
the effects of anti-Xa agents.
• D
rug calibrated ecarin methods can be used to
quantify direct thrombin inhibitors (bivalrudin,
argatroban, dabigatran).
THROMBIN TIME/DILUTE THROMBIN TIME
TABLE 21-23: Thrombin Time and Dilute Thrombin Time for

Dabigatran
• Thrombin time measures final step in coagulation cascade, the conversion of fibrinogen to
fibrin.
• The thrombin time is too sensitive to DTIs, and its role is limited to ruling out the presence
of drug.
• Dilute thrombin time (dTT):

{{ Performed using dabigatran calibrators to create a standard curve and back calculates
dabigatran concentrations from the dTT.
{{ Provides an accurate and precise measurement of dabigatran anticoagulation; a linear
relationship is evident with increasing dabigatran concentrations.
{{ dTT: diluted plasma is mixed with normal pooled plasma. Clotting is initiated through
the addition of a constant amount of purified human thrombin.
{{ Commercial kit is available. No FDA-approved methods, so any dTT performed would
be under laboratory developed test regulations and restrictions. Commercial kit(s) are
currently under FDA investigation.
{{ Provides assessment of dabigatran levels in the concentration range of 50–500 ng/mL:
Dilute thrombin time results vary less across laboratories than the ECT or ECA.
The lower limit of drug detection will vary between methods with dTT methods.
DTIs: direct thrombin inhibitors, ECA: ecarin chromogenic assay, ECT: ecarin clotting time, FDA:
U.S. Food and Drug Administration
dRVVT (Dilute Russell’s Viper Venom Time)

• Used to detect presence of lupus anticoagulant (LA), an autoantibody associated
with increased risk of clotting.
• LA is a nonspecific inhibitor; there is no single test available to identify LA.
• dRVVT is based on ability of the venom of the Russell viper to cause thrombosis.
{{ Venom is a potent activator of factor X.
{{ In presence of phospholipids (provides surface for thrombin genera-
tion) and calcium (initiate clotting), venom converts fibrinogen to
fibrin.
{{ In presence of LA, the autoantibody binds to phospholipids and
prevents activation of factor X; see prolongation of test result.
{{ If prolonged, a mixing study is done (addition of patients plasma
to pooled plasma should normalize test result); a prolonged result
indicates presence of LA.
{{ Demonstrate phospholipid dependence by repeating dRVVT with
addition of excess phospholipids; called confirmatory test.
Ratio of dRVVT screen/dRVVT confirms >1:2 suggest
presence of LA.
• Emerging data suggest the dRVVT may have a role as screening test for DOACs
with greater sensitivity than PT or aPTT; reagent variability has been reported.21,22
THROMBIN GENERATION CURVE

Thrombin generation test (TGT) measures the thrombin-generating potential
in a plasma sample after exposure to activators, typically recombinant tissue
factor (TF). After exposure to activator, a protracted (usually 20 minutes),
continuous measurement of thrombin generation using either a chromogenic
or fluorogenic substrate is assessed. After a mathematical correction for the
alpha-2-macroglobulin inhibition of thrombin, maximal thrombin-generating
potential is calculated.23 TGT parameters (see Figure 21-7) include:
• tlag: Time from initiation of test to start of thrombin generation.
• tmax: Time from initiation of test to time to peak thrombin generation.
• Cmax: The velocity of thrombin generation.
• Area under the curve (AUC): Represents maximal thrombin generation.
400
350
300
250 tmax
Thrombin (µM)
200
150
100 AUC
50 tlag
0
0 5 10 15 20
Time, minutes
FIGURE 21-7. Endogenous Thrombin Potential (ETP) or

Thrombin Generation Test (TGT)
The dark circles represent a normal sample, whereas the open circles would represent a
sample with hypocoagulation, either from drug effect or factor deficiency.
• As with most coagulation assays, there are

variations between commercial TGTs secondary
to TF type and concentration, and phospholipid
type and concentration.
• T
GTs can potentially assess hyper- and
hypocoagulable states.
• M
ost anticoagulants affect all parameters of the
TGT in a dose-dependent manner.
• T
GTs cannot differentiate between different types
of anticoagulation (e.g., UFH, warfarin, DOAC).
• T
GTs may be more sensitive to measuring
the anticoagulant effect than routine clotting
assays.24
• T
here are no FDA-approved TGTs in the United
States.
OVERVIEW OF DOAC MONITORING

There is considerable interest on how best to measure the presence of a
DOAC and the anticoagulant intensity in patients taking DOACs. Although
these agents do not require routine laboratory monitoring as oral vitamin
K antagonists, clinicians may want to know the level of anticoagulation in
many situations. These situations can include25:
• Bleeding
• Thrombosis
• Prior to invasive procedure or surgery
• Measuring the impact of a drug interaction
• Discontinuing overlapping anticoagulant therapy
• Acute kidney injury (all DOACs renally eliminated to some extent)
• Acute liver or heart failure
• Perioperative management
• Anticoagulation reversal
• Adherence assessment
• Extremes of body weight
• Suspected overdose
• Frail elderly
Because the DOAC agents have a relatively short-half life in comparison to
warfarin, the timing of the last dose will be an important consideration in
interpreting test results. Liquid chromatography tandem mass spectrometry
(LC-MS/MS) is reference standard for determining DOAC concentration;
however, this is typically available only at reference laboratories. The DOAC
agents can impact screening coagulation tests such at the PT or the aPTT.
Coagulation test results will differ across laboratories as a result of differ-
ing sensitivity to reagents.26,27 DOAC-specific coagulation tests (e.g., dilute
thrombin time for dabigatran and anti-Xa assays calibrated for the direct Xa
inhibitors) are becoming available at larger institutions and reference labora-
tories. These tests are not FDA-approved and are considered laboratory
developed tests. A considerable challenge is having these tests available 24
hours a day, 7 days a week. Recent data with edoxaban suggest that dose
reduction based on clinical factors is an effective strategy for minimizing
bleeding risk and may negate the need or desire for laboratory monitoring
in certain situations.28 A recent consensus document is now available through
open access to provide laboratory guidance for measuring DOACs.29
DABIGATRAN
TABLE 21-24: Dabigatran and Coagulation Assays

• aPTT is more sensitive to dabigatran than the PT.
• The aPTT should not be used as a screening test for dabigatran, as a normal aPTT does not
exclude therapeutic amounts of drug.
• At peak concentration, the aPTT is typically 2−3 x normal range; at trough concentration
the aPTT is approximately 1.5 x normal or control.
• It is recommended that each laboratory be aware of the sensitivity of their aPTT assay to
dabigatran and use caution when using commercial calibrators to determine same.30
• The relationship between dabigatran and the aPTT is curvilinear with flattening of the curve
beginning at concentrations >200 ng/mL.31
• The dRVVT has been shown to have a linear relationship with drug concentration.
• The thrombin time test is too sensitive to measure anticoagulation intensity. A normal
thrombin time excludes presence of dabigatran.
• The dilute thrombin time, ecarin clotting time, or ecarin chromogenic assay all show a
linear dose-dependent response to increasing dabigatran concentrations; any of these
dabigatran calibrated tests are an acceptable assay for measuring dabigatran levels.
• Dabigatran may not have significant impact on PT in therapeutic concentrations; the PT

from the central laboratory can be elevated with over-anticoagulation depending upon
reagent sensitivity.
• Point-of-care PT may yield higher INR values than central laboratory and should be
avoided.
aPTT: activated partial thromboplastin time, dRVVT: dilute Russell’s viper-venom time, INR:
international normalized ratio, PT: prothrombin time, x: times
Dabigatran Concentration Information

• In a study of spiked dabigatran plasma of 120 ng/mL, the aPTT varied across
sites from 26 seconds to 92 seconds.32
• In a pharmacokinetic study of patients taking dabigatran 150 mg BID, the
median peak plasma concentration was 184 ng/mL with range of 64–443 ng/
mL (5th–95th percentile) while median trough concentration was 90 ng/mL with
range of 31–225 ng/mL. The median trough concentration falls within the range
of peak concentrations.31
{{ Concentration ranges reported from trials should not be used as
a therapeutic range.
• Limited data of limited quality from the RE-LY (randomized evaluation of long-
term anticoagulation therapy) trial suggest that major bleeding with dabigatran
increases with trough concentrations >200 ng/mL without an increase in efficacy
when used for stroke prevention in atrial fibrillation. Some patients with trough
concentrations >800 ng/mL did not suffer major bleeding events, limiting the
use of evaluating bleeding risk based on dabigatran concentration alone.33
• The REALIGN trial of dabigatran use in patients with mechanical heart valves
adjusted the dabigatran dose to achieve a trough concentration of at least
50 ng/mL.34 The trial was halted early for increased thrombosis and increased
major bleeding.
• There is a difference between the thrombin time,

a screening coagulation test, and the dilute
thrombin time (dTT), which has been calibrated
using a dabigatran standard.
• A normal thrombin time essentially rules out the
presence of dabigatran.
• A normal dilute thrombin time may NOT rule out
the presence of dabigatran.
• D
abigatran can produce a significant false
elevation in point-of-care INR.
• A normal aPTT likely excludes excessive
dabigatran anticoagulation.
DIRECT Xa AGENTS
The prothrombin time may be more sensitive than the APTT in detecting
direct Xa agents. However, some PT reagents are exquisitely insensitive to
direct Xa agents with apixaban demonstrating the least effect on PT. Higher
concentrations of direct-acting anti-Xa agents may affect the APTT. Direct
anti-Xa DOAC can be quantified using the same methods used for measur-
ing UFH or LMWH, using specific drug, although no commercial calibrators
are FDA approved. High phospholipid concentration lupus anticoagulant
reagents (e.g., dRVVT) demonstrate a linear response to anti-Xa DOAC
concentration, and drug-calibrated dRVVT methods have been reported.
• A normal PT does not exclude the presence of significant levels of direct Xa
anticoagulants, especially with apixaban.
• The aPTT is generally less response to direct Xa agents than the PT.
• Commonly used lupus anticoagulant reagents (dRVVT) with high phospholipid
concentration (to neutralize lupus anticoagulants) are being explored as a method
for quantifying direct Xa agents.
• Chromogenic anti-Xa assay methods for measuring anti-Xa activity are widely
available and commonly used in the United States.
{{ AT supplementing anti-Xa methods are not recommended for direct

Xa measurements.
{{ Given the similar molecular weights, rivaroxaban and apixaban
appear to have similar responses using chromogenic anti-Xa
methods.
{{ Only tandem mass spectrometry and not chromogenic anti-Xa
methods can differentiate different anti-Xa anticoagulants.
{{ UFH- or LMWH-calibrated anti-Xa methods could potentially be
used to estimate anti-Xa DOAC concentration or rule out presence
of direct-acting Xa agents.35
{{ A drug-specific calibrated anti-Xa (i.e., rivaroxaban anti-Xa) can
provide a quantitative measure of drug concentration.
MONITORING DOAC REVERSAL AGENTS

• Nonspecific reversal agents (e.g., activated prothrombin complex concentrates)
have variable effects of screening laboratory methods.36
• Praxbind (idarucizumab) is approved for dabigatran reversal; andexanet alfa
(Andexxa) is approved for apixaban and rivaroxaban reversal.
• Ciraparantag is a reversal agent in development.
• A single prescribed dose of Praxbind will bind 1,000 ng/mL of dabigatran.
TABLE 21-25: DOAC Reversal Agents

Agent Structure Target Mechanism
Idarucizumab Humanized antibody Oral DTI Noncompetitive

fragment binding to dabigatran
Andexanet alfa Recombinant human Oral direct Xa Competitive binding

FXa catalytically inhibitor, injectable to direct FXa
inactive LMWH, fondaparinux inhibitors
Ciraparantag Small synthetic Oral direct Xa Hydrogen bonding

molecule inhibitor, oral DTI,
injectable LMWH,
heparin, and
fondaparinux
DTI: direct thrombin inhibitor, LMWH: low molecular weight heparin
• Dosing of reversal agents appears to be fixed, independent of weight.

• Rapid correction of laboratory parameters without increased risk for thrombosis.
• The correction of the APTT (ECA or dTT) correlates with decreasing dabigatran
unbound concentrations and may be useful to monitor response to idarucizumab,
but global assays may be more optimal for assessing reversal.
• The correction anti-Xa activity anti-Xa DOAC-specific reversal, but global assays
(e.g., TGT, TEG) may be more optimal for assessing reversal.
• For selected reversal agents in development, available tests may become ineffec-
tive to determine presence of drug or anticoagulation effect.
For anti-IIa DOAC:

• A trough level is the preferred sample collected if
assessing for excessive drug effects.29
• P
resence or absence can be assessed with routine
thrombin clotting time test.
• Q
uantification can be achieved if drug calibrators
used for the test methods:
{{ dTT method
{{ Ecarin clot or chromogenic method
{{ High phospholipid content dRVVT
• T
andem mass spectrometry is considered the gold
standard method.
For anti-Xa DOAC:
• T
rough levels should be the optimal sample
collected.29
• P
resence or absence can be assessed using heparin
calibrated anti-Xa methods.
• Q
uantification can be achieved if drug calibrators
are used for the test methods:
{{ Chromogenic anti-Xa methods
{{ High phospholipid content DRVVT
• T
andem mass spectrometry is considered the gold
standard method.
• U
rinary tests for determining DOACs have been
explored, but there is no relationship between
urinary concentration and plasma levels. Data
obtained from urinary samples should be used
with caution.
• P
OC devices have been explored, and their use
should also be interpreted with caution.
Impact of DOAC on other coagulation assays:
• I mpact of DOAC on coagulation may be
minimized if collecting trough sample.
• Impact of DOAC is highly reagent dependent.
• C
aution must be used, and potential drug effect
on test result must be a consideration when
interpreting coagulation test results for patients
on DOAC therapy.
TABLE 21-26: Impact of DOAC on Other Coagulation Assays37

Test Anti-IIa DOAC Anti-Xa DOAC
PT/INR Reagent and concentration Reagent and concentration

dependent dependent
aPTT Reagent and concentration Reagent and concentration

dependent dependent
Mixing studies Reagent and concentration Reagent and concentration

dependent (false + for dependent (false + for
inhibitor) inhibitor)
Fibrinogen Yes (falsely ↓) No
Thrombin clotting time Yes No
D-dimer No No
Factor assays Reagent and concentration Reagent and concentration

dependent (falsely ↓) dependent (falsely ↓)
Chromogenic factor assays Yes (falsely ↓) Yes (falsely ↓)
Antithrombin activity Factor IIa based: (falsely ↑) Factor IIa based: No

Factor Xa based: No Factor Xa based: (falsely ↑)
Protein C Chromogenic—No Chromogenic—No

Clot based—Yes (falsely ↑) Clot based—Yes (falsely ↑)
Protein S ELISA—No ELISA—No

Clot based—Yes (falsely ↑) Clot based—Yes (falsely ↑)
Lupus anticoagulant Yes (false +) Yes (false +)
Activated protein C ratio Yes (falsely ↑ ratio) Yes (falsely ↑ ratio)
Von Willebrand factor (activity No No

or antigen)
aPTT: activated partial thromboplastin time, DOAC: direct-acting oral anticoagulants, ELISA:
enzyme-linked immunosorbent assay, INR: international normalized ratio, PT: prothrombin time
DOAC TESTING ALGORITHMS

The DOAC testing algorithm should be based on (1) sensitivity of the labora-
tory reagents for PT and aPTT, and (2) whether the clinician only wants to
determine if drug is present, or (3) whether the clinician wants to determine
the level of DOAC present.
Thrombin time
Normal Abnormal
Drug absent Drug present
PT, APTT, Fbg to rule out Quantitative measurement,

other abnormalities if required
FIGURE 21-8. Dabigatran—Testing for Presence of Drug
NOTE: APTT can be used to

estimate drug concentration,
but reagent sensitivity varies APTT
greatly
Normal Abnormal
Thrombin time Quantitative methods
Rapidly No
Normal Abnormal required urgency
Consider other tests (PT, Drug calibrated dTT,

Fbg) if concern for LC-MS/MS
ECA, ECT, dRVVT
bleeding
FIGURE 21-9. Dabigatran – Quantifying or Estimating Amount

of Drug
UFH or LMWH calibrated anti-Xa or dRVVT
<LLQ or Normal dRVVT >LLQ or abnormal dRVVT
Drug absent Drug present
PT, APTT, Fbg to rule out Quantitative measurement,

other abnormalities if required
FIGURE 21-10. Direct Xa DOAC—Testing for Presence of Drug

LLQ: lower limit of quantitation
NOTE: PT can be used to

estimate drug concentration,
but reagent sensitivity varies PT
greatly
Normal Abnormal
Heparin calibrated anti-Xa or Quantitative methods

dRVVT
<LLQ >LLQ or abnormal Rapidly No

dRVVT required urgency
Consider other tests (PT, Drug calibrated anti-

Fbg) if concern for LC-MS/MS
Xa, or confirmatory
bleeding dRVVT reagent
FIGURE 21-11. Direct Xa DOAC—Quantifying or Estimating

Amount of Drug
THROMBOELASTOGRAPHY
Thromboelastography measures the viscoelastic properties of whole blood
or recalcified citrated blood after inducing clot formation under low shear
conditions.38 The results of a thromboelastography (THEG) provides insights
on all stages of thrombin formation in addition to clot stability. There are
two primary instruments used: TEG analyzer (Haemoscope Corporation,
Niles, IL) is mostly used in the United States, and ROTEM (Tem International
GmbH, Munich, GE) is also FDA approved and available. THEG testing has
been used in a variety of clinical settings to monitor hemostasis, including
cardiopulmonary bypass surgery, hepatic surgeries (such as transplantation),
monitoring efficacy of drug therapy, transfusion replacement requirements,
and screening for hypercoagulable conditions.39
Minutes 10 20 30 40 50 60
E
D
A
B
Clot Formation Clot Lysis
FIGURE 21-12. Thromboelastography Recording

Decrease in clotting factors

Treat with FFP or cryoprecipitate; hold anticoagulation
r = 11–14 min: FFP 8 mL/kg
r > 14 min, FFP 16 mL/kg
MA 42-47/G 3.6 –4.4 K: Platelets x 1
MA < 42 mm/G < 3.6 K: Platelets x 2
Treat with antifibrinolytics

(e.g., ε-aminocaproic acid)
Treat with anticoagulants
FIGURE 21-13. Classic Diagnostic TEG Tracings39,40
TABLE 21-27: Interpretation of TEG and ROTEM

Thromboelastogram
Area TEG ROTEM Process
A r: clotting time CT: clotting time Initiation of thrombin

formation, start of clot
polymerization
B k: amplitude to 20 CFT: clot formation time, Rate of clot formation, fibrin

mm amplitude to 20 mm polymerization/crosslinking
and platelet interaction
C ao: slope between ao : angle of tangent a 2
r and k mm amplitude
D MA: maximum MCF: maximum clot Increased stabilization of clot

amplitude firmness by platelets and factor XIII
E CL45; CL60: lysis LY30; LY 45 or ML: lysis at 30 Degree of fibrinolysis after

after 45 and 60 min or 45 min; maximum lysis defined time/hr
hr: hours, min: minutes, ROTEM: rotational thromboelastometry, TEG: thromboelastogram

• Bleeding can sometimes be the result of a

coagulopathy or low platelet function. The TEG
can identify which system is impaired and guide
management.
• W
hen thrombolytic therapy is being used, the
TEG may be employed to identify extent of drug
effect (LYS30). This may be useful to minimize
excessive lytic therapy in selected situations.
• T
he TEG and ROTEM are not sufficiently
sensitive to assess DOAC anticoagulation.

1. Clinical and Laboratory Standards Institute Document H21-A5. Collection, transport,
and processing of blood specimens for testing plasma-based coagulation assays and
molecular hemostasis assay: approved guideline (5th ed). Available at:
http://www.clsi.org.
2. Clinical and Laboratory Standards Institute Document H47-A2. One-stage
prothrombin time (PT) test and activated partial thromboplastin time (APTT) test:
approved guideline (2nd ed.). Available at: http://www.clsi.org.
3. Clinical and Laboratory Standards Institute Document H54-A. Procedures for
validation of INR and local calibration of PT/INR Systems: approved guideline.
Available at: http://www.clsi.org.
4. U.S. Department of Health and Human Services. Title 42 Public Health, Chapter
IV Centers for Medicare & Medicaid Services, part 493: laboratory requirements.
Available at: http://www.cms.gov.
5. Gosselin R, Owings JT, White RH, et al. A comparison of point-of-care instruments
designed for monitoring oral anticoagulation with standard laboratory methods.
6. Kemme MJ, Faaij RA, Schoemaker RC, et al. Disagreement between bedside and
laboratory activated partial thromboplastin time and international normalized ratio for
various novel anticoagulants. Blood Coagul Fibrinolysis. 2001;12:583-591.
7. Reiss RA, Haas CE, Griffis DL, et al. Point-of-care versus laboratory monitoring of
patients receiving different anticoagulant therapies. Pharmacotherapy. 2002;22:677-
685.
8. Le DT, Weibert RT, Sevilla BK, et al. The international normalized ratio (INR) for
monitoring warfarin therapy: reliability and relation to other monitoring methods. Ann
Intern Med. 1994;120:552-558.
9. McGlasson DL, Romick BG, Rubal BJ. Comparison of a chromogenic factor X assay
with international normalized ratio for monitoring oral anticoagulation therapy. Blood
Coagul Fibrinolysis. 2008;19:513-517.
*10. Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin inhibitors, bivalirudin,
lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol.
2004;121:593-599.
11. Cuker A. Unfractionated heparin for the treatment of venous thromboembolism: best
practices and areas of uncertainty. Semin Thromb Hemost. 2012;38(6):593-599.
12. Bates SM, Weitz JI, Johnston M, et al. Use of a fixed activated partial thromboplastin
time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med.
2001;161(3):385-391.
*13. Olson JD, Arkin CF, Brandt JT, et al. College of American Pathologists Conference
XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of
unfractionated heparin therapy. Arch Pathol Lab Med. 1998;122:782-798.
14. Brill-Edwards P, Ginsberg JS, Johnston M, et al. Establishing a therapeutic range for
heparin therapy. Ann Intern Med. 1993;119(2):104-109.
*15. Marlar RA, Clement B, Gausman J. Activated partial thromboplastin time monitoring of
unfractionated heparin therapy: issues and recommendations. Semin Thromb Hemost.
2017;43(3):253-260.
16. Gosselin RC, King JH, Janatpour K, et al. Comparing direct thrombin inhibitors
using aPTT, ecarin clotting time and thrombin inhibitor management testing. Ann
Pharmacother. 2004;38:1383-1388.
17. College of American Pathologists Hematology and Coagulation Checklist. Available at:
http://www.cap.org.
18. Lukito P, Collecutt M, Dauer R, et al. Utilising a hybrid anti-Xa calibration assay in
unfractionated heparin (UFH) monitoring: validation of assay and its correlation with
activated partial thromboplastin time (aPTT). Pathology. 2016;48(5):501-503.
19. Faust AC, Kanyer D, Wittkowsky AK. Managing transitions from oral factor Xa inhibitors
to unfractionated heparin, Am J Health-Syst Pharm. 2016;73:2037-2041.
20. Despotis GJ, Filos KS, Levine V, et al. Aprotinin prolongs activated and nonactivated
whole blood clotting time and potentiates the effect of heparin in vitro. Anesth Analg.
1996;82:1126-1131.
21. Gosselin RC, Adcock Funk DM, Taylor JM, et al. Comparison of anti-Xa and dilute
Russell viper venom time assays in quantifying drug levels in patients on therapeutic
doses of rivaroxaban. Arch Pathol Lab Med. 2014;138:1680-1684.
22. Douxfils J, Chatelain B, Hjemdahl P, et al. Does the Russell Viper Venom time test
provide a rapid estimation of the intensity of oral anticoagulation? A cohort study.
Thromb Res. 2015;135:852-860.
23. Hemker HC, Béguin S. Thrombin generation in plasma: its assessment via the
endogenous thrombin potential. Thromb Haemost. 1995;74(1):134-138. Erratum in:
Thromb Haemost. 1995;74(5):1388.
24. Tripodi A, Padovan L, Chantarangkul V, et al . How the direct oral anticoagulant
apixaban affects thrombin generation parameters. Thromb Res. 2015;135:1186-1190.
25. Tripodi A, Di Iorio G, Lippi G, et al. Position paper on laboratory testing for patients
taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and
CISMEL1). Clin Chem Lab Med. 2012;50(12):2137-2140.
26. Gosselin RC, Hawes E, Moll S, et al. Performance of various laboratory assays in the
measurement of dabigatran in patients receiving therapeutic doses; a prospective study
based on peak and trough plasma levels. Am J Clin Pathol. 2014;141:262-267.
27. Francart SJ, Hawes EM, Deal AM, et al. Performance of coagulation tests in patients on
therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on
peak and trough plasma levels. Thromb Haemost. 2014;111(6):1133-1140.
28. Ruff CT, Giugliano RF, Braunwald E. Association between edoxaban dose,
concentration, anti-factor Xa activity and outcomes: an analysis of data from the
randomized, double-blind ENGAGE AF-TIMI 48 trial. Lancet. 2015; March 10 doi:
10.1016/S0140-6736(14)61943-7.
*29. Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in
Haematology (ICSH) Recommendations for Laboratory Measurement of Direct Oral
Anticoagulants. Thromb Haemost. 2018;118(3):437-450.
30. Gosselin RC, Adcock DM, Hawes EM, et al. Evaluating the use of commercial drug
specific calibrators for determining PT and aPTT reagent sensitivity to dabigatran and
rivaroxaban. Thromb Haemost. 2015;113:77-84.
31. Van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible,
oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of
anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127.
32. Cuker A, Siegal DM, Crowther MA. Laboratory measurement of the anticoagulant
activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol. 2014;64:1128-
1139.
33. Reilly PA, Lehr T, Haertter S, et al. The effect of dabigatran plasma concentrations and
patient characteristics on the frequency of ischemic stroke and major bleeding in atrial
fibrillation patients. J Am Coll Cardiol. 2014;63:321-328.
34. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran use in patients with
mechanical heart valves. New Engl J Med. 2013;369:1206-1214.
35. Gosselin RC, Francart SJ, Hawes EM, et al. Heparin-calibrated chromogenic anti-
Xa activity measurements in patients receiving rivaroxaban: Can this test be used to
quantify drug level? Ann Pharmacother. 2015;49:777-783.
36. Martin AC, Gouin-Thibault I, Siguret V, et al. Multimodal assessment of nonspecific
hemostasis agents for apixaban reversal. J Thromb Haemost. 2015:13:428-436.
*37. Gosselin RC, Gosselin R, Douxfils J, et al. Clinical pearls: Laboratory assessments of
direct oral anticoagulants (DOACS). Hamostaseologie. 2017;37(4). [Epub ahead of
print]
38. Luddington RJ. Thromboelastography/thromboelastometry. Clin Lab Haem.
2005;27:81-90.
39. Shore-Lesserson L, Manspeizer HE, DePerio M, et al. Thromboelastography-guided
transfusion algorithm reduces transfusions in complex cardiac surgery. Anesth Analg.
1999;88:312-319.
40. Mallett SV, Cox DJ. Thromboelastography. Br J Anaesth. 1992;69:307-313.
22 Chapter
THROMBOPHILIAS
Jessica B. Michaud and Canice A. Coan
INTRODUCTION
Testing for thrombophilias, also called hypercoagulable states, is used to determine
patients’ risk of thrombosis. Thrombophilias, which can be inherited or acquired,
are associated with venous thromboembolism and, less commonly, with arterial
thromboembolism as seen in antiphospholipid syndrome (APS) (see Table 22-1).1
Thrombophilia testing is controversial with regard to when, who, and what to
test, and how positive thrombophilia tests influence treatment decisions. Because
several methods can be used for a given test for hypercoagulability, it is important
to know which test is used and any of its potential downfalls. Testing should be
considered if the results alter the management approach.
BASICS OF THE THROMBOPHILIAS
TABLE 22-1: Basic Information about Thrombophilias

Thrombophilia Basic Information about the Thrombophilia
Category
Increased levels or Activated protein C resistance occurs when factor Va is resistant to

function of natural inactivation by activated protein C:
procoagulants • 90-95% of activated protein C resistance is caused by the factor
V Leiden mutation.1-3
• Factor V Leiden mutation is a point mutation on the factor V
gene that codes for the cleavage site of factor V by activated
protein C.2,3
Prothrombin G20210A mutation on the prothrombin gene causes

elevated circulating levels of otherwise normal prothrombin.2,4,5
Elevated levels of otherwise normal factors, especially of factors VIII,

IX, and XI, can also result in a thrombophilia2,6; the cause is unknown
but could be genetic.2
(continued)
549

Thrombophilia Basic Information about the Thrombophilia
Category
Deficiencies of the Antithrombin (formerly termed antithrombin III) inhibits factor IIa
natural anticoagulants (thrombin), factor Xa, and other factors.2
Activated protein C, with its cofactor protein S, inhibits factors Va and

VIIIa.2,4
Deficiencies of antithrombin, protein C, and protein S are caused by

>100 mutations each, making genetic testing impractical.4
APS APS is an acquired thrombophilia where auto-antibodies bind to

phospholipids (e.g., cardiolipin), phospholipid-binding proteins (e.g.,
b2-glycoprotein [GP] I), or both.2
aPL include positive lupus anticoagulant tests, elevated

anticardiolipin antibody levels, and/or elevated anti-b2-GPI levels.
APS is its own distinct disorder but may coexist with rheumatologic
diseases such as systemic lupus erythematosus.
The presence of aPL is associated with anticoagulant (hence the term

lupus anticoagulant) and procoagulant effects on the clotting system,
but the usual eventual net result is a procoagulant effect.7
APS may involve recurrent pregnancy loss, chronic thrombotic

microangiopathy (causing organ dysfunction), cardiac valvulopathy,
thrombocytopenia, livedo reticularis, and a potentially
fatal catastrophic form, in addition to venous and arterial
thromboembolism.7
Hyperhomocysteinemia Hyperhomocysteinemia, the elevation of the amino acid

homocysteine in the plasma, signifies increased risk of
arterial or venous thrombosis. Mutations in several genes
that code enzymes involved in homocysteine metabolism
can lead to hyperhomocysteinemia.8 It is not clear whether
hyperhomocysteinemia causes thrombosis or whether venous
thrombosis and ischemic cardiovascular disease elevate
homocysteine.1, 9
aPL: antiphospholipid antibodies, APS: antiphospholipid syndrome
THROMBOPHILIA PREVALENCE AND RISK

FOR THROMBOSIS
See Table 22-2 for more information on prevalence and risk of thrombosis.10
TABLE 22-2: Prevalence and Thrombosis Risk for Selected Thrombophilias
Antithrombin Protein C Protein S Factor V Leiden Prothrombin Lupus Anti-Cardiolipin Anti-ß2-GPI
Deficiency Deficiency Deficiency 20210A Mutation Anticoagulant* Antibodies* Antibodies
Prevalence in the 0.02% 0.2% 0.03–0.13% 3–7% 0.7–4% 1–8% 5% 3.4%

general population
Relative risk for a first 5–10 4–6.5 1–10 3–5 2–3 3–10 0.7 2.4
venous thrombosis
Relative risk for 1.9–2.6 1.4–1.8 1–1.4 1.4 1.4 2–6 1–6
recurrent venous
thrombosis
Relative risk for No association No No 1.3 0.9 10 1.5–10

arterial thrombosis consistent consistent
association association
Relative risk 1.3–3.6 1.3–3.6 1.3–3.6 1–2.6 0.9–1.3 No consistent No consistent

for pregnancy data data
complications
*In most studies, the presence of these thrombophilic risk factors was assessed only once.
anti-β2-GPI: anti-β2-glycoprotein I
Source: Republished with permission of Middeldorp S. Is thrombophilia testing useful? Hematology Am Soc Hematol Educ Program. 2011;2011:150-155. Permission
conveyed through Copyright Clearance Center, Inc.
THROMBOPHILIAS 551
DIAGNOSTIC CONSIDERATIONS FOR

THROMBOPHILIAS/TESTS
Types of Thrombophilia Laboratory Tests

See Tables 22-3 and 22-4 for more information on thrombophilia labora-
tory tests.
TABLE 22-3: Types of Thrombophilia Laboratory Tests

Type of Thrombophilia Definition and Examples
Laboratory Test
Functional (activity) Measures function of coagulation factors, sometimes based

on a clotting test (e.g., antithrombin functional level, lupus
anticoagulant tests).11-13
Quantitative (antigenic) Measures quantitative levels of coagulation factors or antibodies

using immunoassays such as ELISA (e.g., free protein S level,
anticardiolipin antibody).11-14
Genetic Genetic test (e.g., factor V Leiden mutation, prothrombin

G20210A mutation); genetic tests can be done at any time.
THROMBOPHILIAS 553
Available Laboratory Tests
TABLE 22-4: Available Laboratory Tests for Thrombophilias

Thrombophilia Available Comments
Laboratory Tests
Increased Levels or Function of Natural Procoagulants
APC resistance (factor V APC resistance assay The second-generation assay that uses
Leiden mutation) factor V-deficient plasma is more accurate
than the first-generation assay that does
not use factor V-deficient plasma.3,15 The
APC resistance assay is easier to perform
and less expensive than the factor V
Leiden mutation genetic test.1
Factor V Leiden The genetic test by itself could miss the

mutation genetic test small percentage of patients who have
(by polymerase chain activated protein C resistance not caused
reaction) by factor V Leiden mutation. Consider
as a first test in patients with lupus
anticoagulant or family history of factor V
Leiden mutation. The genetic test is the
only way to determine whether the patient
is homozygous or heterozygous for factor
V Leiden mutation.
Prothrombin G20210A Prothrombin Because the range of factor II

mutation G20210A mutation (prothrombin) values overlap considerably
genetic test (by in patients with and without prothrombin
polymerase chain G20210A mutation, testing for factor II
reaction) functional or antigenic is not useful.1
Elevated factor levels Factors VIII, IX, or A value of 100% is equivalent to 100
XI functional or International Units/dL; inconsistent
antigenic2,4 inter-laboratory test results, unknown
interactions, and unclear reference ranges
make testing challenging.8
Deficiencies of Natural Anticoagulants
Antithrombin deficiency Antithrombin A positive test should be rechecked to

functional confirm the diagnosis.11,16
Antithrombin Testing just antithrombin antigenic can

antigenic miss functionally abnormal antithrombin.
Most tests ordered as “antithrombin” are
antigenic.1,4
Protein C deficiency Protein C functional A positive test should be rechecked to

confirm the diagnosis.12,17
Protein C antigenic Testing just protein C antigenic can miss

functionally abnormal protein C.4
(continued)

Laboratory Tests
Protein S deficiency Protein S functional A positive functional or antigenic test

should be rechecked to confirm the
diagnosis.4,18,19 This test may occasionally
produce falsely normal results, so also
testing total and free protein S antigenic
may be prudent.4,18
Total protein S 60–70% of total protein S is bound to the

antigenic transport protein C4b-binding protein and
is not available as a cofactor for activated
protein C.8
Free protein S The levels of C4b-binding protein, an

antigenic acute-phase reactant, can fluctuate,
influencing the proportion of free protein
S8; free protein S antigenic is the preferred
test for patients with lupus anticoagulant.18
Antiphospholipid Antibodies
(See Table 22-7 for the APS diagnostic criteria)
Lupus anticoagulant Various clotting times One positive lupus anticoagulant test is
(functional) sufficient for diagnosis, but two different
negative tests are required to rule out
lupus anticoagulant.20 Various lupus
anticoagulant tests exist, including those
that measure the intrinsic pathway (aPTT,
CSCT, KCT), the extrinsic pathway (dPT),
and the final common pathway (dRVVT,
taipan venom time, textarin time, ecarin
time).7 INRs, especially point-of-care
INRs, can be inaccurate (typically falsely
elevated) in patients with positive lupus
anticoagulant (see Table 22-14).
Anticardiolipin antibody Anticardiolipin Only anticardiolipin IgG and IgM are

antibodies (IgG, IgM, included in the APS diagnostic criteria (see
IgA) (antigenic) Table 22-7).
Anti-β2-GPI antibody Anti-β2-GPI Only anti-β2-GPI IgG and IgM are included
antibodies (IgG, IgM, in the APS diagnostic criteria (see Table
IgA) (antigenic) 22-7).
(continued)
THROMBOPHILIAS 555

Laboratory Tests
Hyperhomocysteinemia
Hyperhomocysteinemia Homocysteine There are many acquired causes of

plasma level hyperhomocysteinemia. Although fasting
levels are often recommended,9 it is
probably not clinically relevant whether a
patient is fasting or not.1
Genetic tests Genetic tests for mutations causing

hyperhomocysteinemia are not directly
associated with thrombosis. Examples
of these genes are MTHFR (most
commonly C677T and A1298C mutations),
cystathione β synthase, or methionine
synthase.8
anti-β2-GPI: anti-β2-glycoprotein I, APC: activated protein C, APS: antiphospholipid syndrome,

aPTT: activated partial thromboplastin time, CSCT: colloidal-silica clotting time, dPT: dilute
prothrombin time, dRVVT: dilute Russell’s viper-venom time, IgA: immune globulin A, IgG:
immune globulin G, IgM: immune globulin M, INR: international normalized ratio, KCT: kaolin
clotting time, MTHFR: methylene tetrahydrofolate reductase gene
• S ome laboratories may batch routine

thrombophilia tests into a panel that includes
multiple tests. In some situations (i.e., suspicion
for antithrombin deficiency), a selected
thrombophilia test may be requested on a more
emergent basis. Check with the laboratory on the
assay turnaround time and inquire if ordering
differently will expedite the process.
Thrombophilia Laboratory Interactions with Medical

Conditions and Non-Antithrombotic Medications
As detailed in Table 22-5, many thrombophilia tests can be inaccurate in
the setting of acute thrombosis. Other medical conditions can also influence
hypercoagulability tests; therefore, how long an interacting factor takes
to resolve should be considered when determining appropriate timing of
testing. Genetic tests can be checked at any time, without regard to medica-
tions or medical conditions. Nongenetic tests may need to be ordered before
anticoagulation therapy is started or when therapy is discontinued/on hold
(see Table 22-6). Suspicious diagnoses (e.g., protein C deficiency and protein
S deficiency in a single patient) should be rechecked.
TABLE 22-5: Thrombophilia Laboratory Interactions with

Medical Conditions and Non-Antithrombotic Medications
Thrombophilia Factors That May Decrease Value Factors That May Increase
Laboratory Test of Laboratory Testa Value of Laboratory Test
Activated protein C Lupus anticoagulant (false None

resistance assay with positive)3,15,21
factor V-deficient plasma
Factor V Leiden None None

mutation genetic test
Prothrombin G20210A None None

Factors VIII, IX, and XI • Conditions associated with • Acute illness

tests vitamin K deficiency, such as • Chronic inflammation
malnutrition and hepatic or
• Estrogen, pregnancy,
biliary disease (for factor IX)22
oral contraceptives
• Acute, large trauma
• Recent aerobic exercise
• Nephrotic syndrome (for factor
• Aging8,22,23
IX)22
• O blood type compared to
A or B blood types (for factor
VIII)22
Antithrombin tests • Acute thrombotic event • Postmenopausal

• Acquired conditions that impair period8
antithrombin synthesis (e.g.,
liver disease, malnutrition,
premature infancy, IBD,
extensive burns)
• Conditions that result in loss
of protein (e.g., DIC, acute
hemolytic transfusion reaction,
thrombotic microangiopathy,
malignancy, L-asparaginase
therapy, nephrotic syndrome)
• After major vascular surgery
with lowest levels noted the
3rd post-op day8
(continued)
THROMBOPHILIAS 557

Protein C tests • Acute thrombotic event • Ischemic heart disease

• Vitamin K deficiency • Pregnancy
• Liver disease • Postmenopausal period
• DIC • Hormone replacement
• Sepsis therapy
• Renal insufficiency • Oral contraceptive
therapy
• Nephrotic syndrome (functional
level can be low or high) • Nephrotic syndrome
(functional level can be
• Diabetes
low or high)12
• Postoperative state
• Lupus anticoagulant12
• Adult respiratory distress
syndrome
• After plasma exchange
• In breast cancer patients with
some types of chemotherapy
• After massive hemorrhage
and dilution with crystalloid
solutions
• Elevated factor VIII (falsely low
protein C functional)
• Newborns—naturally lower
protein C8
Protein S tests • Acute thrombotic event • Adults compared to

• Female gender compared to newborns
male gender • Postmenopausal state
• Oral contraceptive use • Increasing age in
(depends on product and type women (although
of progestin used) hormonal status
• Pregnancy may account for this
difference)8
• Liver disease
• DIC
• High factor VIII levels and
lupus anticoagulant (falsely low
protein S functional)8
Lupus anticoagulant None None

tests
Anticardiolipin None None

antibodies (IgG, IgM,
IgA)
Anti-β2-GPI antibodies None None

(IgG, IgM, IgA)
(continued)

Homocysteine None • Acute thrombosis (for

up to several months)
• Vitamin B6, B12, or
folate deficiency
• Renal insufficiency
• Hypothyroidism
• Psoriasis
• IBD
• Rheumatoid arthritis
• Organ transplantation
• Drugs (anticonvulsants,
L-dopa, niacin,
methotrexate, thiazides,
cyclosporine)
• Lifestyle factors
(physical inactivity,
smoking, coffee
consumption)
• Aging
• Postmenopausal state
• Male gender9
Mutations None None

associated with
hyperhomocysteinemia
See Clinical Pearl below.

a
DIC: disseminated intravascular coagulation, IBD: inflammatory bowel disease, IgA: immune
globulin A, IgG: immune globulin G, IgM: immune globulin M
• I f a thrombophilia laboratory test is normal

during a medical condition that could potentially
reduce the test value, the laboratory test can be
considered normal (e.g., a normal antithrombin
test during an acute thrombotic event rules out
antithrombin deficiency).
Thrombophilia Laboratory Interactions with

Antithrombotic Medications
See Table 22-6 that follows.
TABLE 22-6: Thrombophilia Laboratory Interactions with Concurrent Antithrombotic Medications
Thrombophilia Laboratory Warfarina Heparin or Low Molecular Weight Direct-Acting Oral Anticoagulants
Test Heparinsa (DOAC)
Activated protein C Reliable8 Reliable if factor-V deficient plasma used8 May be increased (falsely normal) or
resistance assay with factor decreased depending on DOAC and
V-deficient plasma test24,25
Factor V Leiden mutation Reliable8 Reliable8 Reliable

genetic test
Prothrombin G20210A Reliable8 Reliable8 Reliable

Factor VIII tests Reliable4 Reliable4 May be decreased24
Factor IX tests Likely to be decreased4,22 Reliable4 May be decreased24
Factor XI tests Reliable4 Reliable4 May be decreased24
Antithrombin tests May be increased8 May be decreased, although the amidolytic May be increased24
assays should not be affected (waiting at least
5 days after cessation of heparin to test is
safe)4,8,11,16
(continued)
THROMBOPHILIAS 559
Thrombophilia Laboratory Warfarina Heparin or Low Molecular Weight Direct-Acting Oral Anticoagulants
Test Heparinsa (DOAC)
Protein C tests Likely to be decreased (wait until 2–4 weeks May be increased (clot-based functional tests Functional assays may be increased24
after warfarin is discontinued before testing; are most likely to be affected; may also be
the functional amidolytic assays may also be increased by direct thrombin inhibitors)12
overestimated)8,12
Protein S tests Likely to be decreased (wait until 2–4 weeks Reliable8 Functional assays may be increased24
after warfarin is discontinued before testing)8,19
Lupus anticoagulant tests May be increased (false positive)26 May be increased (resulting in a false positive) May be increased (false positive)
depending on heparin level26 depending on test and DOAC27,28
Anticardiolipin antibodies Reliable Reliable Reliable

(IgG, IgM, IgA)
Anti-β2-GPI antibodies (IgG, Reliable Reliable Reliable

IgM, IgA)
Plasma homocysteine level Reliable8 Reliable8 Likely reliable
Mutations associated with Reliable8 Reliable8 Reliable

hyperhomocysteinemia
a
See Clinical Pearl below.
anti-β2-GPI: anti-β2-glycoprotein I, IgA: immune globulin A, IgG: immune globulin G, IgM: immune globulin M
THROMBOPHILIAS 561
• I f a thrombophilia laboratory test is normal

during use of a medication that could potentially
reduce the test value, the laboratory test can
be considered normal (e.g., a normal protein C
test during warfarin therapy rules out protein C
deficiency).
ANTIPHOSPHOLIPID ANTIBODY SYNDROME

DIAGNOSTIC CRITERIA
For more information on diagnosis of APS, see Table 22-7.
TABLE 22-7: Antiphospholipid Syndrome Diagnostic Criteria20

Criteria for definite APS (revised Sapporo criteria; one clinical and one laboratory criteria must be met).
Clinical Vascular thrombosis: ≥1 clinical episode of arterial, deep

venous, or small vessel thrombosis, or
Pregnancy morbidity: ≥1 unexplained death or premature

birth depending on the normality of the fetus/neonate and the
timing of the event (see reference 20), or ≥3 early unexplained
spontaneous abortions (see reference 20)
Laboratory (≥2 occasions at (+) Lupus anticoagulant, or

least 12 weeks apart)
(+) Medium or high titer (i.e., >40 GPL or MPL, or >99th
percentile), of anticardiolipin antibody IgG and/or IgM or
(+) High titer (>99th percentile) of anti-β2-GPI antibody IgG and/

or IgM
anti-β2-GPI: anti-β2-glycoprotein I, APS: antiphospholipid syndrome, IgG: immune globulin G,

IgM: immune globulin M
Source: Adapted from reference 20.
RECOMMENDATIONS FOR THROMBOPHILIA

LABORATORY TESTING
See Table 22-8 for whether and when to perform thrombophilia testing.
Table 22-9 includes recommendations for whom to test for activated
protein C resistance, prothrombin G20210A mutation, and deficiencies of
antithrombin, protein C, and protein S. Table 22-10 has recommendations
on whom to test for aPL. Recommended laboratory tests are summarized in
Table 22-11. Patients should be tested for thrombophilias only if testing will
influence treatment decisions. Thrombophilia testing in pediatrics (except
where noted below) or in women who are pregnant or planning a pregnancy
is out of the scope of this chapter.
TABLE 22-8: Considerations for Whether and When to Test

Effect of thrombophilias on Thrombophilias confer at most a slightly increased risk for
thrombotic risk recurrent VTE,10,29 perhaps more so if anticoagulation is
discontinued after an initial 6 months;30 however, there are
no randomized trials assessing the benefit of testing on
risk of recurrence.31 Table 22-2 highlights the limited role of
thrombophilias in recurrence of VTE.
Effect of thrombophilias The presence of a thrombophilia does not typically affect the
on decisions regarding duration of anticoagulation. Factors other than thrombophilias
duration and intensity of are more important in determining duration of therapy after a
anticoagulation VTE,29,32 such as unprovoked vs. provoked VTE, presence of
active cancer, proximal vs. distal DVT, and second/subsequent
versus first VTE.32 VTE tends to recur. Patients with unprovoked
VTE have a cumulative risk of about 10% at 1 year, 30% at 5
years, and 50% at 10 years.33 For patients with unprovoked
VTE and a low-to-moderate risk of bleeding, extended
anticoagulation is recommended32—this recommendation
does not change if a patient has a thrombophilia.33 There are
no studies comparing routine and extended anticoagulation
in patients testing positive for thrombophilia,10 but in a large
cohort study, tested patients did not have a lower rate of
recurrence.34
The presence of a thrombophilia also does not influence the
intensity of anticoagulation29 except possibly for APS (see Table
22-14).
When to test The timing of testing is very important. A large proportion of

thrombophilia tests are inappropriately drawn.35
Patients should not be tested during an acute thrombosis as
the results do not typically affect treatment of acute thrombosis
and could be falsely positive (see Table 22-5). Testing should be
delayed at least 6 weeks36 (or possibly up to 6 months37) after an
acute thrombosis.
Patients should not be routinely tested during pregnancy or in
the postpartum period, and the tests should be carefully chosen
if a patient is taking an anticoagulant (see Table 22-6).
The risk of recurrence for heterozygous FVL and heterozygous
prothrombin G20210A is small (OR 1.56, 95% CI 1.14–2.12
and OR 1.45, 95% CI 0.96–2.21, respectively), so the primary
reason to test for these thrombophilias after a thrombotic
event is to determine homozygosity or double heterozygosity
(heterozygous for both mutations),33 even though the clinical
significance of even these results has been questioned.10,31
Other pretesting Before testing, providers should consider that testing is

considerations costly, and positive results may result in psychological harm or
difficulty in obtaining life or disability insurance.10
APS: antiphospholipid syndrome, DVT: deep vein thrombosis, VTE: venous thromboembolism
THROMBOPHILIAS 563
TABLE 22-9: Recommendations for Whom to Test for Activated

Protein C Resistance, Prothrombin G20210A Mutation, and
Deficiencies of Antithrombin, Protein C, and Protein S
Do NOT test • Patients continuing anticoagulation therapy with or without a
diagnosis of thrombophilia.38
• Patients treated for provoked VTE.38
Do NOT routinely test • Patients with unprovoked VTE.29
• Patients who are asymptomatic (no history of VTE) and have

a family history of VTE. Selected family members with a
significant family history may be considered for testing for high-
risk thrombophilias (e.g., deficiency of antithrombin, protein C,
or protein S).
• Patients should not be tested for low-risk thrombophilias,
(e.g., factor V Leiden or prothrombin mutations), or for very
rare homozygosity or compound heterozygous heritable
thrombophilias.29
• Patients who are asymptomatic (no history of VTE) and starting

hormonal contraception or HRT.
• Testing could be considered in patients with a symptomatic
first-degree family member with known heritable thrombophilia
especially if the family member is positive for a high-risk
thrombophilia, as severe thrombophilia may increase risk of
recurrence during hormonal contraceptive use.39 However,
a negative thrombophilia workup in the patient does not
ensure low VTE risk; therefore, consideration of alternative
contraceptive or transdermal HRT is preferred over testing.29
• Patients with a history of VTE and evaluating contraceptive

options. A nonhormonal or progestin-only option will
most likely be recommended whether the patient has a
thrombophilia or not.40
• Patients who are asymptomatic (no history of VTE) and

hospitalized; however, the presence of a known thrombophilia
may influence the assessment of VTE risk.29
• Patients with arterial thromboembolism.10,29
Consider testing • Selected patients who are discontinuing anticoagulation for

unprovoked VTE, for example:
{{ Patients with VTE at an early age (<40 years).29
{{ Patients with a strong family history; for example, more than
2 other symptomatic family members, especially if the VTE
in the family member(s) was unprovoked and/or recurrent.29
• Adults who develop skin necrosis in association with VKAs, for

protein C and S deficiency, after withdrawal of VKA.29
• Children with purpura fulminans, for protein C and S

deficiency.29
HRT: hormone replacement therapy, VKA: vitamin K antagonist, VTE: venous thromboembolism
TABLE 22-10: Recommendations for Whom to Test for

Test patients who have a These patients may include “unprovoked VTE and (unexplained)
significant probability of arterial thrombosis in young patients (<50 years old), thrombosis
having APS at unusual sites, late pregnancy loss, any thrombosis or
pregnancy morbidity in patients with autoimmune diseases
(systemic lupus erythematosus, rheumatoid arthritis, autoimmune
thrombocytopenia, autoimmune hemolytic anaemia)”41(p1737)
and potentially also “moderate”factors including incidentally-
found prolonged aPTT in patients without thrombosis, recurrent
spontaneous early pregnancy loss, and provoked VTE in young
patients.41 However, another expert reported not routinely testing
any subgroup of patients with VTE for APS.42
Patients with SLE should be regularly assessed for APS.43
APS: antiphospholipid syndrome, aPTT: activated partial thromboplastin time, SLE: systemic lupus
erythematosus, VTE: venous thromboembolism
Table 22-11 has recommendations for which tests to order, should testing
be indicated.
TABLE 22-11: Summary of Recommended Thrombophilia

Laboratory Testsa
Thrombophilia Recommended Laboratory Tests
APC resistance (factor V Leiden APC resistance assay with factor V-deficient plasma or
[FVL] mutation) FVL genetic test (or use FVL genetic test as a confirmatory
test for a positive APC resistance assay and to determine
homozygosity vs. heterozygosity)1,3,4,44,45
Prothrombin G20210A mutation Prothrombin G20210A mutation genetic test
Elevated factor levels Not recommended routinely. If tested: Factor VIII

antigenic or functional1,22,46,47
Antithrombin deficiency Antithrombin functional (amidolytic assay).11 Positive

results should be confirmed with a repeat test.29
Protein C deficiency Protein C functional.4,12,17 Positive results should be

confirmed with a repeat test.29
Protein S deficiency Protein S functional and/or free protein S antigenic, ±

total protein S antigenic.4,18 Positive results should be
confirmed with a repeat test.29
Lupus anticoagulant Two clotting tests based on different principles (i.e.,

dRVVT and a sensitive aPTT).41 One positive test is
positive for lupus anticoagulant;41 positive tests should be
confirmed ≥12 weeks later.20
(continued)
THROMBOPHILIAS 565

Thrombophilia Recommended Laboratory Tests
Anticardiolipin antibody Anticardiolipin antibodies (IgG and IgM, ± IgA).
Anti-b2-GPI antibody Anti-b2-GPI antibodies (IgG and IgM, ± IgA).
Hyperhomocysteinemia and Not recommended routinely. If done, should be

associated mutations (e.g. MTHFR drawn after an overnight fast of 10 hr, without vitamin
677TT) supplementation for a few weeks, and on a normal diet.37
a
Testing for thrombophilias should include all recommended tests, because the presence of more
than one thrombophilia (e.g., factor V Leiden mutation + prothrombin G20210A mutation) may
increase the risk beyond that of one thrombophilia.48
anti-b2-GPI: anti-b2-glycoprotein I, APC: activated protein C, aPTT: activated partial thromboplastin
time, dRVVT: dilute Russell’s viper-venom time, IgA: immune globulin A, IgG: immune globulin G,
IgM: immune globulin M, MTHRF: methylene tetrahydrofolate reductase gene
TREATMENT AND PREVENTION

CONSIDERATIONS
See Table 22-8 for considerations on how thrombophilias may or may not
influence decisions on antithrombotic medication. Table 22-12 includes
treatment considerations for hormonal contraception or hormone replace-
ment patients. For more information on treatment considerations, see Table
22-13 for activated protein C resistance, prothrombin G20210A mutation,
and deficiencies of natural anticoagulants, Table 22-14 for APS, and Table
22-15 for hyperhomocysteinemia.
TABLE 22-12: Treatment Options in Patients Considered for

Hormonal Contraception or Hormone Replacement Therapy
Topic Treatment Considerations
Contraception • In patients with thrombophilia considering combined oral

contraception, an alternative effective contraception should be
considered,29 such as progestin-only contraception.40 Combined
hormonal contraception increases the risk of VTE from 2 in
10,000 to 5–10 in 10,000 women per year, and the risks seem
to be higher for women with thrombophilias and positive family
history.31 It should be noted that pregnancy itself also increases
the risk of VTE in women with thrombophilia.40
Hormone replacement • In patients with thrombophilia considering HRT, reevaluate

therapy whether HRT is necessary; if so, consider nonoral routes (e.g.,
transdermal), which have a significantly lower risk of VTE than oral
dosing.29
HRT: hormone replacement therapy, VTE: venous thromboembolism

TABLE 22-13: Treatment Considerations for Activated Protein C

Resistance, Prothrombin G20210A Mutation, and Deficiencies
of Antithrombin, Protein C, and Protein S
Thrombophilia Treatment Considerations
Antithrombin, protein C, and • Replacement of antithrombin, protein C, or protein

protein S deficiencies S in patients with a deficiency could be considered
in certain situations (e.g., difficulty achieving
adequate anticoagulation, very severe thrombosis,
neonatal purpura fulminans, recurrent thrombosis
despite adequate anticoagulation, need for
prophylaxis perioperatively or peripartum).
• Replacement products are plasma-derived or
recombinant antithrombin for antithrombin, fresh
frozen plasma or prothrombin complex concentrate
for protein C or S, and plasma-derived protein C
concentrate for protein C.8,49
Antithrombin deficiency • Patients with antithrombin deficiency may have

difficulty reaching therapeutic anticoagulation with
UFH, LMWH, or fondaparinux, because they rely on
antithrombin for their mechanism of action.42
• However, a 1992 review of 70 thrombotic events
in 57 patients with antithrombin deficiency found
heparin resistance to be infrequent and no increased
risk for on-treatment recurrence or extension of
thrombosis.29
• Increasing drug dosages31 or using a direct thrombin
inhibitor (e.g., argatroban, lepirudin)8 may overcome
this problem.
Protein C and S deficiency • Patients with protein C or S deficiency starting or

restarting warfarin should be given UFH, LMWH,
or fondaparinux at the same time until the INR is
therapeutic and stable.
• Warfarin initiation rapidly lowers protein C and S
levels before factors II, VII, IX, and X are sufficiently
suppressed, which can precipitate warfarin skin
necrosis or other thrombotic events, especially in
patients with underlying deficiency of protein C or S;
loading doses of warfarin should also be avoided in
these patients.8
Activated protein C resistance, • Literature on use of DOACs in these thrombophilias

prothrombin G20210A mutation, is limited to case reports and one post-hoc
and deficiencies of antithrombin, analysis.50 The post-hoc analysis included three
protein C, and protein S major VTE treatment trials of dabigatran vs. warfarin
in which 10% were positive for a thrombophilia out
of the 34–49% that were tested, and the results
suggest that the safety and efficacy was not affected
by the presence of thrombophilia.51
DOACs: direct-acting oral anticoagulants, INR: international normalized ratio, LMWH: low
molecular weight heparin, UFH: unfractionated heparin
THROMBOPHILIAS 567
TABLE 22-14: Treatment Considerations for Antiphospholipid

Syndrome
Treatment of pregnant patients with APS is covered in Chapter 19.
Thrombotic risk • The type of aPL profile is important to determine risk. The higher
the titer, the more antibodies involved (lupus anticoagulant
versus anticardiolipin antibody vs. anti-β2-GPI antibody),
the involvement of lupus anticoagulant specifically, and the
persistence of the positivity over time all increase the risk of
thrombosis. For example, high-risk aPL profiles include positive
lupus anticoagulant, triple positivity, or isolated persistently
positive anticardiolipin antibodies at medium-high titers;
low-risk profiles would include isolated intermittently positive
anticardiolipin or anti-b2-GPI antibodies at low-medium titers.43
• Other concomitant thrombotic risk factors and the presence of
an autoimmune disease are also important.43
• The recurrence rate is high despite antithrombotics.52
Treatment in patients • Patients with SLE and lupus anticoagulant or persistent

without history of medium-high titers of anticardiolipin antibodies should receive
thrombosis hydroxychloroquine and low-dose aspirin.43,53
• Patients with aPL but without SLE should also be considered for
low-dose aspirin, especially when other thrombotic risk factors or
a high-risk aPL profile is present.43,53
Treatment in patients • Patients with aPL but who do not meet the criteria for definite
with venous or arterial APS should be managed as if they are aPL negative.43
thromboembolism • Patients with definite APS and VTE should receive warfarin with
goal INR 2–3 indefinitely.43 However, patients with first VTE, low-
risk aPL profile, and transient risk factors at the time of the VTE
could be treated for a shorter duration (i.e., 3–6 months).43
• Patients with definite APS and arterial thromboembolism should
receive treatment of indefinite duration with either warfarin
targeted to an INR of >3, or warfarin targeted to an INR of 2–3 in
combination with an antiplatelet.43
• Case reports and series of DOAC use in APS have described
both thrombotic complications and no recurrence. Recurrence
mainly occurred when DOACs were used for secondary
prevention of arterial thrombosis or in patients with triple aPL
positivity.54
• RAPS—A randomized, noninferiority, controlled trial of
rivaroxaban vs. warfarin in 116 patients with previous VTE
and APS with or without SLE—did not meet noninferiority for
rivaroxaban as measured by percent change in endogenous
thrombin potential, but overall thrombogram indicated no
difference in thrombotic risk, and neither group had thrombosis
or major bleeding during up to 210 days of follow-up. Triple
positivity was present in 28% of the subjects.55
• Other trials of rivaroxaban (TRAPS, another RAPS) and apixaban
(ASTRO-APS) are ongoing.54
(continued)

Use of warfarin • Lupus anticoagulant itself increases the INR in a reported

6.5–10% of patients, most often in patients with a prolonged
baseline INR.56 The extent and duration of effect depends on the
thromboplastin used for the INR and any fluctuation in antibody
level.42
• Suggestions for this problem include using a thromboplastin
that is not sensitive to lupus anticoagulant, using a different
antithrombotic medication, or monitoring chromogenic factor X
or prothrombin (factor II) levels in place of or in conjunction with
the INR.56 The chromogenic factor X assay may be preferable
to prothrombin levels.57 Because it has been found that 39% of
patients require an INR >3 and 11% require an INR >4 to reach
a therapeutic chromogenic factor X level, testing chromogenic
factor X at least once at a therapeutic INR or more regularly
during therapy should be considered in patients with lupus
anticoagulant plus baseline elevated INR, recurrence on warfarin,
or persistent lupus anticoagulant positivity.57
• There has been some controversy about the appropriate goal
INR for patients with APS. Two randomized trials have shown that
INRs of >3 or 3.1 do not reduce thrombotic events compared to
INRs of 2–3, although there was considerable overlap in the INR
ranges.58,59 These trials did not include many patients with arterial
thrombosis, so conclusions cannot be made on the appropriate
goal INR for these patients.
Use of heparins • As patients with lupus anticoagulant by definition may have an

elevated aPTT, monitoring UFH therapy can be challenging.
Most laboratories use aPTT assays that are not sensitive to lupus
anticoagulants,39 but if under-dosing is a concern, anti-factor Xa
can be used to monitor UFH.
• Other suggested strategies in nonsurgical patients include
determining an individualized therapeutic aPTT range, doubling
the baseline aPTT, using an aPTT reagent insensitive to lupus
anticoagulant, and switching to LMWH or fondaparinux.60
anti-β2-GPI: anti-β2-glycoprotein I, aPL: antiphospholipid antibodies, APS: antiphospholipid

syndrome, aPTT: activated partial thromboplastin time, DOAC: direct-acting oral anticoagulant,
INR: international normalized ratio, LMWH: low molecular weight heparin, SLE: systemic lupus
erythematosus, UFH: unfractionated heparin, VTE: venous thromboembolism
THROMBOPHILIAS 569
TABLE 22-15: Treatment Considerations for

Thrombophilia Treatment Considerations
Hyperhomocysteinemia and • The American Heart Association/American Stroke

associated mutations Association does not recommend routine testing for
hyperhomocysteinemia in patients with recent stroke or
transient ischemic attack.
• In secondary prevention, supplementation with folic acid,
vitamin B6, and vitamin B12 safely reduces homocysteine
level but has not been shown to reduce stroke risk in
patients with a recent event and mild-to-moderate
hyperhomocysteinemia.61
• The effectiveness of B vitamins in primary prevention is
unclear, but supplementation could be considered.62
PROS AND CONS OF THROMBOPHILIA

TESTING
For more information on pros and cons of thrombophilia testing see Table
22-16.
TABLE 22-16: Pros and Cons of Thrombophilia Testing

Pros Cons
• Identification of patients who may • High cost of testing

benefit from indefinite anticoagulation • Low likelihood of detecting hereditary
• Identification of patients who may thrombophilias
benefit from anticoagulation during • Limited data for indefinite anticoagulation
high-risk periods in hereditary thrombophilias
• Prevention of pregnancy complications • Lack of universal physician awareness of
• Detection of potential increased how to interpret test results
thrombotic risk for family members • Risk of being denied health insurance
• Explanation of possible cause of coverage or of higher premium payments
thrombosis • Potential for laboratory error
• False reassurance to patients with negative
results
SUMMARY
Thrombophilias increase thrombotic (generally venous) risk to varying
degrees, with a lower risk for recurrence compared to that for an initial
event. Many medical conditions and medications can influence the results
of thrombophilia tests; therefore, laboratory tests must be carefully timed,
and unclear diagnoses should be confirmed by repeat testing. Whether to
test patients for thrombophilias and how a positive result affects treatment
decisions depends greatly on the clinical situation; however, most patients

should not be tested, and the presence of a thrombophilia does not typically
influence duration or intensity of treatment.

1. Moll S. Blood coagulation, thrombosis, antithrombotics, and hypercoagulable states.
In: Ansell JE, Oertel LB, Wittkowsky AK, eds. Managing Oral Anticoagulation Therapy
Clinical and Operational Guidelines. 3rd ed. St. Louis, MO: Wolters Kluwer Health;
2009:85-104.
2. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous
thrombosis: a qualitative overview and proposed classification system. Ann Intern Med.
2003;138:128-134.
3. Press RD, Bauer KA, Kujovich JL, et al. Clinical utility of factor V Leiden (R506Q)
testing for the diagnosis and management of thromboembolic disorders. Arch Pathol
Lab Med. 2002;126:1304-1318.
4. Moll S. Thrombophilias—practical implications and testing caveats. J Thromb
Thrombolysis. 2006;21:7-15.
5. McGlennen RC, Key NS. Clinical and laboratory management of the prothrombin
G20210A mutation. Arch Pathol Lab Med. 2002;126:1319-1325.
6. Chandler WL, Rodgers GM, Sprouse JT, et al. Elevated hemostatic factor levels as
potential risk factors for thrombosis. Arch Pathol Lab Med. 2002;126:1405-1414.
7. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med.
2002;346:752-763.
8. Nutescu EA, Michaud JB, Caprini JA. Evaluation of hypercoagulable states and
molecular markers of acute venous thrombosis. In: Gloviczki P, ed. Handbook of Venous
Disorders. 3rd ed. London, UK: Hodder Arnold; 2009:113-128.
9. Key NS, McGlennen RC. Hyperhomocyst(e)inemia and thrombophilia. Arch Pathol Lab
Med. 2002:126:1367-1375.
*10. Middeldorp S. Is thrombophilia testing useful? Hematology Am Soc Hematol Educ
Program. 2011;2011:150-155.
11. Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis.
Arch Pathol Lab Med. 2002;126:1326-1336.
12. Kottke-Marchant K, Comp P. Laboratory issues in diagnosing abnormalities of protein
C, thrombomodulin, and endothelial cell protein C receptor. Arch Pathol Lab Med.
2002;126:1337-1348.
13. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, et al. A review of the technical,
diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med.
2002;126:1349-1366.
14. Ortel TL. The antiphospholipid syndrome: What are we really measuring? How do we
measure it? And how do we treat it? J Thromb Thrombolysis. 2006;21:79-83.
15. Rosendorff A, Dorfman DM. Activated protein C resistance and factor V Leiden: a
review. Arch Pathol Lab Med. 2007;131:866-871.
16. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia.
2008;14:1229-1239.
THROMBOPHILIAS 571
17. Goldenberg NA, Manco-Johnson MJ. Protein C deficiency. Haemophilia.

2008;14:1214-1221.
18. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, et al. A review of the technical,
diagnostic, and epidemiologic considerations for protein S assays. Arch Pathol Lab Med.
2002;126:1349-1366.
19. Ten Kate MK, Van der Meer J. Protein S deficiency: a clinical perspective. Haemophilia.
2008;14:1222-1228.
20. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an
update of the classification criteria for definite antiphospholipid syndrome (APS). J
21. Le DT, Griffin JH, Greengard JS, et al. Use of a generally applicable tissue factor-
dependent factor V assay to detect activated protein C-resistant factor Va in patients
receiving warfarin and in patients with a lupus anticoagulant. Blood. 1995;85:1704-
1711.
22. Chandler WL, Rodgers GM, Sprouse JT, et al. Elevated hemostatic factor levels as
potential risk factors for thrombosis. Arch Pathol Lab Med. 2002;126:1405-1414.
23. Lippi G, Maffulli N. Biological influence of physical exercise on hemostasis. Semin
Thromb Hemost. 2009;35:269-276.
24. Undas A, Goralczyk T. Direct oral anticoagulants in patients with thrombophilia:
challenges in diagnostic evaluation and treatment. Adv Clin Exp Med.
2016;25(6):1321-1330.
25. Gessoni G, Valverde S, Gessoni F, et al. The effect of dabigatran and rivaroxaban on a
prothrombinase-based assay for activated protein C resistance: a preliminary study in
subjects heterozygous for factor V Leiden. Blood Transfus. 2015;13:666-668.
26. Teruya J, West AG, Suell MN. Lupus anticoagulant assays: questions answered and to
be answered. Arch Pathol Lab Med. 2007;131:885-889.
27. Hoxha A, Banzato A, Ruffatti A, et al. Detection of lupus anticoagulant in the era of
direct oral anticoagulants. Autoimmun Rev. 2017;16(2):173-178.
28. Moore GW. Current controversies in lupus anticoagulant detection. Antibodies.
2016;5(4):22.
*29. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable
thrombophilia. Br J Haematol. 2010;149:209-220.
30. Garcia-Horton A, Kovacs MJ, Abdulrehman J, et al. Impact of thrombophilia screening
on venous thromboembolism management practices. Thromb Res. 2017;149:76-80.
*31. MacCallum P, Bowles L, Keeling D. Diagnosis and management of heritable
thrombophilias. BMJ. 2014;349:g4387.
32. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease.
Antithrombotic Therapy and Prevention of Thrombosis. 9th ed: American College of
Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141(suppl
2):e419S-e494S.
*33. Moll S. Who should be tested for thrombophilia? Genet Med. 2011;13(1):19-20.
34. Coppens M, Reijnders JH, Middeldorp S, et al. Testing for inherited thrombophilia does
not reduce recurrence of venous thrombosis. J Thromb Haemost. 2008;6(9):1474-
1477.
35. Somma J, Sussman II, Rand JH. An evaluation of thrombophilia screening in an

urban tertiary care medical center: a “real world” experience. Am J Clin Pathol.
2006;126:120-127.
36. Stegnar M. Thrombophilia screening—at the right time, for the right patient, with a
good reason. Clin Chem Lab Med. 2010;48(Suppl 1):S105-S113.
37. Margetic S. Diagnostic algorithm for thrombophilia screening. Clin Chem Lab Med.
2010;48:S27-S39.
38. National Institute for Health and Care Excellence. Venous thromboembolic diseases:
diagnosis, management, and thrombophilia testing [internet]. London: Royal College
of Physicians (UK);2015. Available from: http://www.nice.org.uk/guidance/cg144.
Accessed August 2017.
39. Suchon P, Al Frouh F, Henneuse A, et al. Risk factors for venous thromboembolism
in women under combined oral contraceptive. The PIL1 Genetic RIsk Monitoring
(PILGRIM) Study. Thromb Haemost. 2016;115(1):135-142.
*40. Maxwell WD, Jacob M, Spiryda LB, et al. Selection of contraceptive therapy
for patients with thrombophilia: a review of the evidence. J Women’s Health.
2014;23(4):318-326.
41. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant
detection. J Thromb Haemost. 2009;7:1737-1740.
*42. Kearon C. Influence of hereditary or acquired thrombophilias on the treatment of
venous thromboembolism. Curr Opin Hematol. 2012;19(5):363-370.
*43. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations
for the prevention and long-term management of thrombosis in antiphospholipid
antibody-positive patients: Report of a Task Force at the 13th International Congress
on Antiphospholipid Antibodies. Lupus. 2011;20:206-218.
44. Van Cott EM, Laposata M, Prins MH. Laboratory evaluation of hypercoagulability with
venous or arterial thrombosis: venous thromboembolism, myocardial infarction, stroke,
and other conditions. Arch Pathol Lab Med. 2002;126:1281-1295.
45. Van Cott EM, Soderberg BL, Laposata M. Activated protein C resistance, the factor
V Leiden mutation, and a laboratory testing algorithm. Arch Pathol Lab Med.
2002;126:572-582.
46. Christiansen SC, Cannegieter SC, Koster T, et al. Thrombophilia, clinical factors, and
recurrent venous thrombotic events. JAMA. 2005;293:2352-2361.
47. Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arterioscler Thromb Vasc
Biol. 2009;29:332-336.
48. Dalen J. Should patients with venous thromboembolism be screened for thrombophilia?
Am J Med. 2008;121:458-463.
49. Lexicomp Online®, Lexi-Drugs®, Hudson, OH: Lexi-Comp, Inc.; June 15, 2015.
50. Skelley JW, White CW, Thomason AR. The use of direct oral anticoagulants in inherited
thrombophilia. J Thromb Thrombolysis. 2017;43:24-30.
51. Goldhaber SZ, Eriksson H, Kakkar A, et al. Efficacy of dabigatran versus warfarin
in patients with acute venous thromboembolism in the presence of thrombophilia:
findings from RE-COVER®, RE-COVER II™, and RE-MEDY™. Vasc Med.
2016;21(6):506-514.
*52. Pengo V. ISTH guidelines on lupus anticoagulant testing. Thromb Res. 2012;130:
S76-S77.
THROMBOPHILIAS 573
53. Punnialingam S, Khamashta MA. Duration of anticoagulation treatment for thrombosis

in APS: is it ever safe to stop? Curr Rheumatol Rep. 2013;15(4):318.
54. Cohen H, Efthymiou M, Gates C, et al. Direct oral anticoagulants for
thromboprophylaxis in patients with antiphopholipid syndrome. Semin Thromb
Hemost. 2017;doi: 10.1055/s-0036-1597902.
55. Cohen H, Hunt BJ, Efthymiou M, et al. Rivaroxaban versus warfarin to treat
patients with thrombotic antiphospholipid syndrome, with or without systemic lupus
erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority
trial. Lancet Haematol. 2016;3(9):e426-436.
56. Kasthuri RS, Roubey RA. Warfarin and the antiphospholipid syndrome: does one size fit
all? Arthritis Rheum. 2007;57(8):1346-1347.
57. Crowl A, Schullo-Feulner A, Moon JY. Warfarin monitoring in antiphospholipid
syndrome and lupus anticoagulant. Ann Pharmacother. 2014;48(11):1479-1483.
58. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin
for the prevention of recurrent thrombosis in patients with the antiphospholipid
antibody syndrome. N Engl J Med. 2003;349:1133-1138.
59. Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity
warfarin vs. conventional antithrombotic therapy for the prevention of recurrent
thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb
Haemost. 2005;3:848-853.
60. Mehta TP, Smythe MA, Mattson JC. Strategies for managing heparin therapy in
patients with antiphospholipid antibody syndrome. Pharmacother. 2011;31(12):1221-
1231.
61. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke
in patients with stroke and transient ischemic attack: a guideline for healthcare
2014;45(7):2160-2236.
62. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of
stroke: a statement for healthcare professionals from the American Heart Association/
American Stroke Association. Stroke. 2014;45(12):3754-3832.
PART IV.
ESSENTIALS FOR
PRACTICE SUCCESS
23. Models and Standards of Anticoagulation Care Delivery
24. Regulatory and Practice Resources
575
23 Chapter
MODELS AND STANDARDS

OF ANTICOAGULATION CARE
DELIVERY
Nathan P. Clark and Paul B. Shaw
INTRODUCTION
Anticoagulant medications are highly effective for the treatment and prevention of
thrombosis, but continued efforts are necessary to optimize the safety and efficacy
of this drug class. Anticoagulants are a common source of medication errors in
the hospital and adverse drug events (ADEs) for patients at home.1,2 As a class,
anticoagulants cause approximately 10% of drug-related adverse outcomes among
hospitalized patients and more than 30% of ADEs among Medicare beneficiaries. 3,4
The direct-acting oral anticoagulants (DOACs) have the potential to improve the
safety of oral anticoagulant therapy, but each new medication brings an additional
layer of complexity in anticoagulation management.
The Department of Health and Human Services’ National Action Plan for Adverse
Drug Event Prevention report underscores that quality improvement efforts for
anticoagulant medications are necessary to improve patient safety and reduce
cost. 5 The report stressed a need for sharing best practices and highlighted
organizations like the Anticoagulation Forum (ACF) and their Anticoagulation
Centers of Excellence program (excellence.acforum.org), which includes a resource
center for sharing references, documents, and protocols/guidelines. This chapter
will review models and standards of anticoagulation management service (AMS)
practices for optimal anticoagulation therapy management in the inpatient and
ambulatory care settings.
INPATIENT ANTICOAGULATION CARE DELIVERY
Structure
Comprehensive pharmacy services are essential for successful delivery of safe and
effective anticoagulation therapy in the acute care setting.6 Overall structure of the
inpatient AMS may vary, but multidisciplinary stakeholders should be represented
to establish hospital procedures and protocols/guidelines relating to anticoagulant
therapy, including:
577
• Physician champion
• Pharmacy services
{{ Clinical
{{ Operational
• Nursing
• Physician groups
{{ Cardiology
{{ Hematology
• Information technology
• Laboratory
• Dietary
• Outpatient anticoagulation clinic
The reporting structure for the AMS should be clearly defined in hospital
policy, procedure, and collaborative drug therapy management agreements.6
Front-line staff operating under collaborative drug therapy management
(CDTM) agreements should be educated as to the appropriate steps for
managing clinical scenarios that are out of scope or beyond their clinical
expertise. Strong leadership from both administrative executives as well as
a clinical physician champion is essential to support the AMS throughout the
organization.6 An example of inpatient anticoagulation service operational
structure is provided in Figure 23-1. Individual health systems may need to
tailor anticoagulation service structure according to local regulatory require-
ments and infrastructure limitations.
Standards of Practice
The AMS should ensure the anticoagulation delivery processes are standard-
ized wherever possible.6 A summary of inpatient AMS standards is provided
in Table 23-1. The use of protocols/guidelines to provide evidence-based
decision support improves accuracy of anticoagulation dose decisions,
ensures the timeliness of appropriate laboratory monitoring, and minimizes
errors. Protocols/guidelines should be widely available, and all prescribers
should be encouraged to use them. Anticoagulant protocols/guidelines
should identify commonly prescribed oral and parenteral anticoagulants (e.g.,
unfractionated heparin [UFH], low molecular weight heparin [LMWH], factor
Xa inhibitors, direct thrombin inhibitors, warfarin) and highlight appropriate
dosing, monitoring, and follow-up. In addition, special situations affecting
drug selection and dosing should also be covered, including:
• Renal insufficiency and dialysis
• Pediatric patients
• Liver disease
• Pregnancy
• Obesity
• Low weight or malnourished
MODELS AND STANDARDS OF ANTICOAGULATION CARE DELIVERY 579
Policy and Procedure Clinical Content

Executive Director
Resource Pharmacy and

Stewardship Therapeutics
Committee Committee
Multidisciplinary Cardiology and

Anticoagulation Hematology
Subcommittee Physician Lead
AMS
Leadership
Team
Pharmacy or AMS Advanced Practice Physician Champion

Manager Anticoagulation Provider
Anticoagulation Clinic
Frontline Staff
FIGURE 23-1. Example Inpatient Anticoagulation Management

Service Hierarchy
Additional example is available in reference 6.
AMS: anticoagulation management service
• Drug interactions
• High bleeding risk
• Transitions between anticoagulants
Anticoagulation protocols/guidelines should identify formulary or preferred
agents. In addition to cost containment, this can facilitate development of
provider familiarity, expertise with dosing, drug and disease state interactions,
and anticoagulant management. Creation of guidelines for all nonformulary
TABLE 23-1: Summary Recommendations for Optimized

Inpatient Anticoagulation Management
Section Recommendation
Process System-based processes should be established for safe and effective

anticoagulation care delivery.
AMS processes should be assessed periodically for vulnerability to errors
or other known or potential deficiencies.
Accountability Leadership and supervision should be established to ensure a clearly

defined reporting structure and promote accountability.
A culture of safety should be established to promote transparency
regarding errors, near-misses, and deficiencies in system processes.
Integration The healthcare organization should facilitate integration of the AMS

with all other patient care areas to promote seamless communication of
anticoagulation drug therapy details to providers across the organization.
Practice standards Evidence-based practice standards should be established for use by the
AMS to direct safe and effective use of anticoagulant drug therapy in both
typical and special circumstances.
Practice standards should be reviewed at regular intervals to ensure they
are up-to-date and consistent with rapidly evolving evidence.
These standards should also be consistent with other institutional
processes, policies, and procedures.
Patient education Anticoagulant therapy patient education should be provided to promote

safe and effective use of anticoagulant medications.
Care transitions The AMS should be designed to facilitate safe and effective care
transitions for patients receiving anticoagulant therapy.
Outcomes AMS performance should be assessed at least annually and reported to

multidisciplinary stakeholders. Quality indicators, including surrogate and
clinical outcome measures, should be included to assess impact patient
outcomes and to identify both areas for improvement and the impact of
quality improvement initiatives.
Education and Initial training and ongoing education and development should be
competency of provided by the AMS.
personnel Competency should be documented for all frontline providers in the
inpatient AMS.
Quality assurance or peer-review activities should be completed regularly
to ensure practice standards are being met.
See reference 6 for additional details.

AMS: anticoagulation management service
parenteral anticoagulants is not necessary because they are most often initi-
ated in the hospital. However, familiarity and guidance for use of all available
oral anticoagulants is recommended because patients will be admitted while
taking any of these medications. Information is limited regarding therapeutic
interchange of DOACs during hospitalization; thus, this should generally be
avoided. Anticoagulant protocols/guidelines can be arranged by drug and
disease state to facilitate their identification and implementation.6 Disease
state anticoagulation protocols/guidelines may include:
• Acute management of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Atrial fibrillation
• Heart valve replacement
• Venous thromboembolism (VTE) risk assessment and prophylaxis recommenda-
tions for medical and surgical populations
• Anticoagulation management around surgery or invasive diagnostic procedures
• Malignancy-associated VTE
• Management of anticoagulant adverse events
{{ Bleeding
Warfarin
Heparin
LMWH
Factor Xa inhibitors
Direct thrombin inhibitors
{{ Heparin-induced thrombocytopenia
A systematic process should exist to support timely review of drug therapy
protocols/guidelines to ensure currency and consistency with the latest
evidence-based guidelines and clinical trial findings.6 Additional drug-specific
standards are provided in Table 23-2.
TABLE 23-2: Standards of Practice for Use of Anticoagulants in

the Hospital Setting
Baseline assessment
Accurate patient height, weight, and age
Assessment for active bleeding and bleeding risk factors
Identify potential drug interactions prior to anticoagulant selection
Assessment of renal and liver function prior to anticoagulant initiation
Assessment of CBC prior to anticoagulant initiation
Anticoagulant dosing guidelines
Oral anticoagulant dosing guidelines and/or nomograms
Direct thrombin inhibitor Dabigatran
Factor Xa inhibitors Rivaroxaban

Apixaban
Edoxaban
Betrixaban
Vitamin K antagonist Warfarin
(continued)

Parenteral anticoagulant dosing and/or infusion guidelines
Direct thrombin inhibitors Argatroban

Bivalirudin
Desirudin
Factor Xa Inhibitors Fondaparinux
LMWHs Dalteparin
Enoxaparin
Unfractionated heparin Heparin
Use of LMWHs, factor Xa inhibitors, and DTIs in renal failure and dialysis
Use of warfarin, UFH, LMWHs, factor-Xa inhibitors, and DTIs in pregnancy
Use of warfarin, UFH, LMWHs, factor-Xa inhibitors, and DTIs in pediatric patients
Drug interaction recognition and management
Use of anticoagulants around neuraxial procedures
Selection of dosing and reversal therapies according to anticoagulant exposure
Anticoagulant dosing and monitoring in the critically ill patient, including extremes of weight
Anticoagulant administration
Infusion pump policies and procedures
Acceptable subcutaneous injection sites for LMWH, fondaparinux, and UFH
Timing of initiation of VTE prophylaxis for surgical and high-risk medical patients
Timing of resumption of full-intensity anticoagulation in postoperative patients
Time of day for administration of anticoagulants
Anticoagulant monitoring
Target INR and INR goal range for various indications
Frequency of INR monitoring
Target aPTT or anti-factor Xa assay and goal range for various indications
Frequency of aPTT or anti-factor Xa monitoring
Patient monitoring for signs and symptoms of bleeding and thrombosis
See reference 6 for additional details.

aPTT: activated partial thromboplastin time, CBC: complete blood count, DTI: direct thrombin
inhibitor, INR: international normalized ratio, LMWH: low molecular weight heparin, UFH:
unfractionated heparin, VTE: venous thromboembolism
• A MS policies and procedures should be reviewed

and updated at least annually plus whenever
revised national or international guidelines
become available.
Regulatory Standards
The Joint Commission renewed its patient safety goals in 2015 with continued
focus on reduction in patient harm during therapeutic anticoagulation for
conditions such as atrial fibrillation, VTE disease, and heart valve replace-
ment.7 They emphasize the value of face-to-face patient education to improve
patient comprehension of anticoagulation risks, the need for regular monitor-
ing, and recommend precautions to improve anticoagulation safety. The
elements for performance on the Joint Commissions’ 03.05.01 goal include7:
1. Use only oral unit-dose products, prefilled syringes, or premixed infusion bags
when these types of products are available.
Note: For pediatric patients, prefilled syringe products should be used only if
specifically designed for children.
2. Use approved protocols/guidelines for initiation and maintenance of anti-
coagulant therapy.
3. Before starting a patient on warfarin, assess the patient’s baseline coagulation
status; for all patients receiving warfarin therapy, use a current international
normalized ratio (INR) to adjust this therapy. The baseline status and current
INR are documented in the medical record.
Note: The patient’s baseline coagulation status can be assessed in a number of
ways, including through a laboratory test, or by identifying risk factors such as
age, weight, bleeding tendency, and genetic factors.
4. Use authoritative resources to manage potential food and drug interactions for
patients receiving warfarin.
5. When administering heparin intravenously and continuously, use programmable
pumps to provide consistent and accurate dosing.
6. Establish a written policy that addresses baseline and ongoing laboratory tests
required for anticoagulants.
7. Provide education regarding anticoagulant therapy to prescribers, staff, patients,
and families. Patient/family education includes the following:
a. The importance of follow-up monitoring
b. Compliance
c. Drug−food interactions
d. The potential for adverse drug reactions and interactions
8. Evaluate anticoagulation safety practices, take action to improve practices, and
measure the effectiveness of those actions in a timeframe determined by the
organization.
Quality Improvement
Quality improvement efforts rely on the availability of performance outcome
measures, including reliable surrogate endpoints (e.g., rate of appropriate
prophylaxis) as well as clinical outcomes (e.g., bleeding, thrombosis, death).
As mentioned earlier, standardization of processes and protocols/guidelines
directing anticoagulation therapy is a key element of high-quality care.5,6
The Agency for Healthcare Research and Quality (www.ahrq.gov), Institute
for Safe Medication Practices (www.ismp.org), and National Quality Forum
(www.qualityforum.org) have general recommendations to improve medica-
tion safety that can be applied to anticoagulant therapies to improve quality.
The National Action Plan for ADE Prevention provides recommendations for
anticoagulant therapy in the outpatient setting, and several of these are also
applicable to the inpatient setting (Table 23-3).
In addition to the process standards mentioned above, quality improve-
ment interventions can leverage technology such as computerized physician
order entry, bar code scanning, programmable infusion pumps, and dose
range checking that reduces errors and improves safety and quality.6 Alerts
programmed into the electronic medical record (EMR) can also improve rates
of appropriate VTE prophylaxis, and pharmacy-directed anticoagulation
management services have also been associated with improved anticoagu-
lation care delivery.8-10
COMMON ELEMENTS FOR INPATIENT

AND OUTPATIENT ANTICOAGULATION
MANAGEMENT SERVICES
Patient Education
Patient education is an essential element of high-quality anticoagulation
care in both the inpatient and outpatient settings. Informed patients are
more likely to be engaged in their care, and knowledge of anticoagulation
therapy has been associated with improved time-in-therapeutic range (TTR)
among anticoagulated outpatients.11 Printed and published materials should
be written at the eighth-grade reading level. Additional methods of educa-
tion may include group sessions, audio-visual presentations, web-based
training, and printed materials. Tools to assess knowledge and retention,
including teach-back and validated anticoagulation knowledge tests, can
assist AMS providers in verifying patient comprehension. Elements that
should be included in patient education checklists are shown in Table 23-4.
Patient education in the ambulatory care setting should be reinforced on an
ongoing basis, and patient resources should be accessible for new questions
that arise and to refresh education points.
TABLE 23-3: Opportunities for Anticoagulant Therapy Adverse

Drug Event Prevention from the National Action Plan for
Adverse Drug Event Prevention
Goal Description
Safer care • Improve provider knowledge of high-quality

outpatient anticoagulation management through
provider education
• Improve uptake of evidence-based anticoagulation
management models, including anticoagulation clinic
services and warfarin PST/PSM
• Address provider concerns and resultant under
treatment
• Address gaps in evidence and provider knowledge
with regard to management of DOACs through
development of guidelines/algorithms for safe use
Patient and family engagement • Improve incorporation of anticoagulation-specific

patient management into chronic disease education
programs and other patient education/health literacy
tools
Effective communication and • Better integrate anticoagulation-specific targets into

coordination of care currently existing care transition models
Science-driven prevention and • Address factors that contribute to interfacility

treatment variability in anticoagulation services (e.g., outpatient
clinic services)
• Better address safe use of DOACs in national
healthcare quality/patient safety measures and
nationally recognized clinical guidelines
• Address gaps in guidelines to identify patients at high
risk for bleeding events (e.g., effectiveness of bleeding
scores in relation to DOACs)
Promotion of best practices • Identify and promote adoption of standards that

within communities constitute high-quality anticoagulation management
(e.g., Anticoagulation Center of Excellence)
• Improve dissemination and sharing of strategies and
results from large-scale, quality-improvement learning
initiatives targeting anticoagulant ADE prevention
among healthcare systems/facilities
From: http://www.health.gov/hcq/pdfs/ade-action-plan.pdf
ADE: adverse drug event, DOAC: direct-acting oral anticoagulant, INR: international normalized
ratio, PSM: patient self-management, PST: patient self-testing
TABLE 23-4: Anticoagulant Therapy Patient Education Checklist

Reason for anticoagulation
Name of the anticoagulant medication (trade and generic)
How the medication works
Onset and duration of activity
Dosing, frequency, storage, and duration of therapy
Common signs/symptoms of bleeding and instructions for follow-up when they occur
Common signs/symptoms of thrombosis and instructions for follow-up when they occur
Implications for pregnancy and the need for effective birth control
Reinforce appropriate use of safety equipment for recreation and motor-vehicle

operation
Avoidance of high-risk behavior for traumatic injury
Common side effects other than bleeding
Recommendations to notify other healthcare providers of anticoagulant therapy
When to notify AMS provider (e.g., invasive procedures, new dietary habits, recent
hospitalization)
Options for anticoagulation identification (e.g., bracelet or medication card)
Use one pharmacy for all prescription drugs to facilitate drug interaction screening
Risk of nonadherence or taking too much anticoagulant medication
Limit or avoid alcohol
Instructions for timing of administration and missed dose
Reason for and timing of laboratory monitoring
Meaning of the INR, target INR range, and the rationale for timely testing (warfarin only)
Influence of vitamin K and the rationale for dietary consistency (warfarin only)
• I nstructional videos paired with the teach-

back method reduced pharmacist time for new
warfarin education by more than 8 minutes,
compared to traditional face-to-face education,
without compromising patient comprehension.12
Patient-Centered Care and Shared Decision Making

Patients who are actively engaged and understand their care are more likely
to adhere to their medication regimen as well as experience better outcomes
and greater patient satisfaction.13 Shared decision making, in which patients
and providers collaborate to make healthcare decisions together, may result
in lower cost of care. This patient-centered approach is particularly important
in the realm of anticoagulation, both in terms of specific drugs chosen and
how patients are monitored or managed. The American College of Cardiol-
ogy and American Heart Association strongly recommend antithrombotic
therapy for atrial fibrillation be individualized to patients’ preferences after
they are informed of the risks, benefits, and alternatives, particularly when
the benefit-to-risk ratio of a particular therapy is equivocal.14
Provider Training and Competency

A training program should be established to ensure anticoagulation provider
competency in the following areas15:
• Applied physiology and pathophysiology of thromboembolic disorders
• Patient assessment and management
• Patient education
• Applied pharmacology of antithrombotic drugs
Training optimally includes internal education, “hands-on” training, and
formal didactic learning opportunities. Several organizations provide special-
ized anticoagulation training programs, which are listed in Table 23-5.
On-the-job training generally begins with new staff observing experienced
providers to learn the basic clinical and operational aspects of the job. The
new provider then may navigate the system independently and provide
experienced personnel provisional treatment recommendations for review
prior to implementation. Finally, new providers can operate independently
with supervisors regularly reviewing the work for quality assurance purposes.
Transitions of Care
Coordination of care is especially important in anticoagulation management
to ensure proper hand-off between care settings.6 Often these transitions
occur when a patient is in an unstable or new period of anticoagulation
requiring close follow-up and/or frequent INR and warfarin dose adjustment
is necessary. Patients are often experiencing new onset of acute illness (e.g.,
transition from outpatient to emergency/inpatient care) or recovery from
recent acute illness (e.g., discharge from hospital to outpatient manage-
ment) that can affect anticoagulation status.16 All of these factors necessitate
close attention and a systematic approach to ensuring the medical team/
clinician receiving the patient has access to accurate, up-to-date information
about anticoagulant regimen, laboratory results, and plan. A care transi-
tion anticoagulation checklist is recommended.6 It should include at least
the following: patient/family education, ability to administer parenteral
TABLE 23-5: Anticoagulation Training and Resources

Provider Description and Contact Information
Anticoagulation Forum Boot Live, interactive education presented in a condensed day-

Camp and-a-half agenda. Presented by the Anticoagulation Forum:
http://acforumbootcamp.org
Arizona Pharmacy Association Combination of home study and live didactic anticoagulation
Anticoagulation Certificate instruction: http://www.azpharmacy.org/events/event_list.asp
Program
ISTH Academy Online courses and webinars and video podcasts.

Presented by the International Society of Thrombosis and
Haemostasis: http://academy.isth.org
National Certification Board Established the Certified Anticoagulation Care Provider (CACP)
for Anticoagulation Providers certification and exam: https://www.ncbap.org/index.aspx
University of Connecticut Options include web-based anticoagulation continuing

School of Pharmacy education or a 2-day practice-based anticoagulation
traineeship: http://pharmacy.uconn.edu/academics/ce/
anticoagulation/
University of Florida College Twelve-week anticoagulation certificate program for

of Pharmacy pharmacists provided through independent learning modules
via multimedia presentations and online assignments: http://
cpe.pharmacy.ufl.edu/courses/certificate/anticoagulation/
University of Southern Indiana Online 6-week anticoagulation therapy management certificate

program: https://www.usi.edu/health/certificate-programs/
anticoagulation-therapy-management-certificate-program
ISTH: International Society of Thrombosis and Haemostasis
anticoagulant (if applicable), assurance of affordability/coverage, accurate

prescriptions written, safety net phone number, referral to outpatient AMS,
follow-up appointment scheduled, discharge summary with anticoagulation
plan forwarded to receiving provider, and follow-up call to patient/family
within 2−3 days.6
OUTPATIENT ANTICOAGULATION THERAPY

The complexity of warfarin therapy necessitated the creation of outpatient
AMS to improve the quality of management and reliability of patient follow-
up. An organized system of care, paired with specialized provider training,
has had an important impact on anticoagulation care delivery in the outpa-
tient setting and has liberated significant physician time previously spent
on anticoagulation management. Although the provision of anticoagulant
therapy via AMS rather than usual care is generally accepted to improve
quality and outcomes, the data are inconsistent. Observational studies have
demonstrated improved TTR and a decrease in bleeding and thromboembolic
outcomes with AMS, whereas prospective randomized trials fail to identify
significant differences in clinical outcomes, thrombotic or bleeding, between

AMS and usual care.9,17,18 As a result, the evidence-based CHEST guidelines
do not express a preference for AMS or usual care whereas the ACF suggests
the benefits of AMS have been sufficiently documented to recommend for
widespread use.15,17 Despite the ACF endorsement, most patients receiving
anticoagulant therapy in the United States do not have access to an AMS.15
Structure
Front-line AMS staff should be licensed healthcare providers (e.g., physicians,
nurses, pharmacists) with specialized training in thrombosis and hemostasis,
prothrombotic disease state pathophysiology, anticoagulant pharmacol-
ogy, and practical knowledge of anticoagulant drug therapy management.
However, guidelines do not provide specific detail regarding the organi-
zational structure.15 Several structural elements are shared with inpatient
AMS, specifically the need for a physician champion and relationships with
leadership in medical specialties (e.g., cardiology, hematology). A close
working relationship with primary care and/or internal medicine is equally
important as most AMS referrals will originate from physicians in general
practice. The outpatient AMS structure generally includes front-line provid-
ers, clerical staff, and supervisor/manager. Clerical staff can include clerks,
medical assistants, and pharmacy technicians. It is important to maximize
the utility of support staff to minimize the amount of time spent by front-line
providers on nonclinical duties. Front-line clinical providers may include:
• Licensed practical nurse
• Registered nurse
• Advanced practice nurse
• Nurse practitioner
• Pharmacist
• Clinical pharmacy specialist
One or more of these healthcare professionals may be included in the AMS
team. Some successful AMS models have established divisions of responsibil-
ity according to staff training background and patient acuity. For example,
a licensed practical nurse may manage stable warfarin patients while a
registered nurse may manage less stable patients or those with out-of-range
INRs. Warfarin initiation and invasive procedure planning may be referred
to a nurse practitioner or pharmacist for follow-up. Many options for AMS
structure are available, and no method has been clearly established to be
superior to others.
In addition to provider structure, there are also different AMS work load
structure options. These can be categorized as either a panel-based or
team-based AMS approach.
Panel-Based Outpatient AMS Structure
In a panel-based approach, patients are bonded to their AMS provider much
like their primary care physician. The same AMS provider is responsible for
follow-up without regard to the clinical circumstances or acuity of patient care

(e.g., stable INR versus new drug interactions or invasive procedures). The
AMS provider “owns” the patient and is trained and capable of managing
all aspects of their anticoagulant therapy. When possible, laboratory orders
can be placed under the AMS provider’s name so results return directly to
that provider’s EMR in-basket.
The panel-based approach facilitates formation of a relationship between
the patient and provider, which can be mutually rewarding. Another advan-
tage is the AMS provider becomes familiar with the clinical picture of his or
her panel’s patients. The AMS provider assigned to the patient can readily
recall historical challenges with patient memory, adherence, or previous
adverse events as opposed to a team-based approach where a relatively
unfamiliar AMS team member must rely on complete documentation and
chart review for the necessary information. Vacation and sick day coverage
can be a challenge in a panel-based AMS.
Team-Based AMS Structure
In a team structure, the work is divided among the front-line staff accord-
ing to acuity or volume on a daily basis. An AMS of providers with differing
skillsets lends itself to dividing the work according to acuity in a team-based
approach. In an AMS of a relatively homogenous group of healthcare provid-
ers (e.g., all pharmacists), assignments may be made according to volume
(e.g., equally split according to the alphabet or morning shift/late shift) or
by rotating assignment of activities by acuity, for example:
• New referrals and invasive procedure planning
• Stable patients and in-range INRs
• Out-of-range INRs and incoming patient/provider calls
• Nonadherence and drug interactions
Patients managed in an AMS with a team-based approach may interact with
numerous other providers throughout their anticoagulation care.
Advantages to a team-based structure include facilitating AMS staff
working to their maximal scope of practice. The AMS workload can be
assigned according to escalating acuity to providers with advanced degrees
or greater training and development. There is also potential for an assembly-
line approach when managing large volumes of patients and laboratory results
with a team-based approach. Consistency in documentation is required in all
AMS settings, but it is particularly crucial in a team-based structure where
AMS providers are less familiar with patients.
Pharmacist-Run versus Nurse-Run AMS
The two most common disciplines found within AMS structure are pharmacy
and nursing; each brings unique and valuable expertise to AMS care delivery.
The outpatient AMS will typically operate according to CDTM agreements
under which patients are referred by physicians and managed according
to an approved protocol without regard to underlying AMS discipline.
Observational studies supporting AMS benefit have typically evaluated a

pharmacy-led approach in both the inpatient and outpatient settings.8-10,18-19
Lab versus Point-of-Care INR Testing
Point-of-care (POC) testing utilizes a drop of blood from a fingerstick, which
is then rapidly analyzed by the POC device to determine INR. Depending
on AMS model, the POC device may be located in a physician’s office or
within a nurse- or pharmacist-run AMS. The POC instrument may also reside
at the patients’ home to facilitate patient self-testing (PST) or patient self-
management (PSM). The use of POC testing is less invasive than traditional
laboratory venipuncture; INR results are rapidly available, facilitating rapid
warfarin dose management decisions. There are also several challenges to
POC device use. The clinician or patient must be trained to use the device
properly to provide accurate INR results. The POC device requires an initial
capital investment, takes up storage space, and must be regularly maintained
and calibrated to ensure accuracy. Both traditional laboratory and POC INR
testing are viable options.15 There is potential for lack of agreement between
two methods, so it is advisable for patients to utilize a single methodology
and not switch between them.
Patient Self-Testing and Patient Self-Management
When the patient performs INR monitoring at home using a POC device,
this is referred to as patient self-testing (PST). Patient self-management
(PSM) occurs when the patient uses the INR result to independently adjust
the warfarin dose without review or input from a medical provider accord-
ing to previous education or established protocols/guidelines.17,20 PST may
occur without PSM. In this model, the patient determines the INR at home
and communicates results to the managing clinician who advises the patient
regarding warfarin dose decisions. Patient engagement is a key concept
in this management technique; it allows patients to take control of their
health. It is also a favored technique among patients who travel frequently,
live far from a laboratory, or have difficulty coming to a laboratory routinely
for INR testing.
Challenges to PST/PSM include the need for relatively frequent monitor-
ing due to the reimbursement structure and the associated cost of the POC
device and test strips. Programs providing POC instruments for PST/PSM
generally require INR testing weekly or at least every 2 weeks, even in very
stable warfarin patients. Evidence shows that PST/PSM is a safe and effective
AMS when used in select patients. Patients engaged in their healthcare who
demonstrate competency in POC procedures and warfarin dose adjustment
are good candidates for PST/PSM.17 Although a large, randomized controlled
trial comparing PST to high-quality AMS care did not identify important
differences, meta-analysis suggests a decreased rate of thrombotic events
in patients managed through PST/PSM but no significant effect on bleeding
or mortality.21,22
• A lthough clinical trials have not consistently

identified a benefit to PST/PSM over AMS-
provided high-quality anticoagulant care,
guidelines support PST/PSM for motivated,
competent patients.17
In-Clinic versus Telephonic AMS Care Delivery
Telephone and clinic-based follow-up are the two predominant AMS care
delivery options. Advantages to AMS care delivery via face-to-face visits
include:
• Facilitate show-and-tell education
• Enhance nonverbal communication
• Generate revenue through billable visits
• Refer patients for immediate physical assessment, where indicated
Advantages to telephone-based AMS care delivery include:
• High volume
• No appointments required
{{ Limited impact by nonadherence
• Ideal for non-revenue generating healthcare models (e.g., managed care,
Veterans Administration)
• Patient convenience
{{ Flexible time and laboratory locations
{{ Limit travel
• S tudies comparing telephonic management to in-

clinic care have yielded conflicting results.18,23,24
The optimal AMS model depends on the needs of
the healthcare system as well as patient access
and whether the AMS is able to bill for services.
AMS Care Delivery through Electronic Media
As the technologic capabilities of the EMR grow, more healthcare is being
delivered virtually via electronic media. Some examples include secure
patient emails, texts, smart phone applications, web portals, and video/
virtual visits. As patients demand more efficient, convenient, and economical
options for healthcare delivery, the AMS must plan for including these media
into their communication processes during anticoagulation care delivery.
Leveraging social media may be the next frontier because Facebook accounts
for warfarin, DVT, and PE support groups are already available to patients.
The Twitter hashtag “#warfarin” doesn’t have many followers yet, but one
day we may be tweeting anticoagulant education or reminders.
Role of the AMS in Managing Patients Taking DOACs

Although warfarin is still the predominantly used oral anticoagulant in the
United States in number of prescriptions sold, the DOACs are gaining
market share.25 Five DOACs are currently approved for use and available
in the United States: dabigatran, rivaroxaban, apixaban, edoxaban, and
betrixaban.26-29 The DOACs differ from warfarin in that they require no routine
laboratory monitoring (e.g., INR) to assess anticoagulant effect. However,
renal function should be monitored periodically. Currently, data are limited
that demonstrate the benefit of AMS during DOAC use versus usual care
through routine physician follow-up. A study performed across Veterans
Administration sites established that pharmacist-led monitoring of patients
taking dabigatran was associated with better medication adherence.30 To
date, no guidelines/protocols or consensus statements have been issued
by professional societies on the preferred management for patients taking
DOACs. Areas where an AMS can be helpful in the use of DOACs:
• Patient education
• Financial implications of oral anticoagulant options
• Dose adjustment
{{ DVT/PE treatment
Acute management
Parenteral anticoagulants
Yes (dabigatran, edoxaban)
No (rivaroxaban, apixaban)
Duration of intensified oral therapy
7 days (apixaban)
21 days (rivaroxaban)
Not applicable (dabigatran, edoxaban)
Intermediate management
Duration of therapy
All anticoagulants
Long-term secondary management
Dose reduction (apixaban)
{{ Renal function
{{ Clinical factors (body weight, serum creatinine, age, and drug
interactions)
• Perioperative management
• Adherence monitoring
• Drug interaction screening
• Annual or ongoing assessment of dose requirement according to clinical factors
• Bleeding management
• Transitions between anticoagulant therapies
Ensuring these areas are effectively managed is essential for optimal anti-
coagulant therapy during DOAC administration, and the outpatient AMS is
particularly well suited to facilitate these processes.
• A lthough DOACs do not require routine

monitoring of their anticoagulant effects, patients
should still be referred to an AMS whenever
possible. The AMS can provide consistent and
thorough patient education; order necessary
laboratory work; ensure appropriate dosing
according to age, weight, renal function,
indication, and timing; and design and
coordinate plans for invasive procedures.
Managing Patient Nonadherence

An AMS should have explicit procedures for managing patient nonadher-
ence, including documentation requirements and the communication plan
for the patient and referring provider.
Warfarin Nonadherence
Patients may be nonadherent with warfarin dosing, follow-up INR recheck,
and/or dietary recommendations. Nonadherence with pill-taking can result
from patient fear of being “too thin” or “too thick.” It is important to have
clear communication regarding roles and responsibilities and to set appro-
priate expectations with anticoagulated patients up-front, as nonadherence
during warfarin therapy can degrade TTR and increase the risk of adverse
events.31,32 Referring providers are important allies, and the AMS should
leverage physician support in managing patient nonadherence.
• T
he Morisky Medication Adherence Scale has
been widely used to assess medication adherence.
Patients who are adherent to warfarin, according
to the Morisky Scale, are more likely to have
therapeutic INR control.33
Nonadherence with DOACs
There is no summary statistic of anticoagulation control for patients
prescribed DOACs, but adherence is likely an important surrogate marker
for quality care. The proportion of days covered (PDC) has been evaluated
as a marker of adherence patients with atrial fibrillation prescribed dabiga-
tran.30,34 The PDC is obtained by calculating the number of medication days
supplied by the outpatient pharmacy divided by the total number of days in
the observation period minus hospitalization days. A PDC of ≥80% has been
defined as adherent in available studies. A 10% reduction in PDC among
atrial fibrillation (AF) patients treated with dabigatran was associated with
a 13% increased hazard of the combined outcome of stroke and all-cause
mortality.30 Monitoring adherence of patients taking DOACs is an important
AMS role. AMS should explore the feasibility of evaluating and reporting
PDC to target interventions and, thereby, improve patient adherence and
outcomes during DOAC therapy.
Standards of Practice
A summary of recommendations for outpatient AMS standards is provided in
Table 23-6. The development of AMS policy and procedure is necessary to
reduce variability and improve the quality of care. 12 These policies and proce-
dures should be reviewed annually to ensure they remain up-to-date with
recent research and evidence-based guidelines. Common clinical scenarios
encountered in the day-to-day AMS operation should be included and be
available to AMS personnel at all times. Anticoagulant patient care activities
should be documented in a location that is easily located and readily available
to the referring physician and other members of the healthcare team. 12 The
outpatient AMS should facilitate communication between healthcare team
members regarding anticoagulation issues because suboptimal anticoagulant
therapy is often the result of fragmented systems of care.35 Systems should
be in place to minimize the risk of patients lost to follow-up.12
TABLE 23-6: Summary of Recommendations for Optimized

Outpatient Anticoagulant Therapy
Qualifications of Licensed healthcare providers in pharmacy, nursing, or medicine engaged

personnel in anticoagulant care delivery should possess core competency in
anticoagulant management.
Leadership and If day-to-day management of anticoagulant therapy has been delegated

reporting to an AMS, CDTM practice agreements should be in place with the
healthcare provider ultimately responsible for the patient’s care. The CDTM
should be as descriptive and explicit as possible in the description of AMS
responsibilities, job description, and accountability.
Care AMS leadership and the provider/provider group responsible for

management and patient care should establish and approve policies and procedures for
coordination anticoagulant care delivery.
These policy and procedures should enable communication regarding
anticoagulation care delivery between healthcare providers accountable for
high-quality anticoagulation care delivery.
A patient scheduling and tracking system should be utilized to facilitate
efficient anticoagulant care delivery.
(continued)

Documentation The AMS documentation should be accurate and readily available to

members of the healthcare team.
Documentation should include relevant anticoagulant therapy details with
current and historical information.
Patient education The AMS should provide thorough patient education, which is tailored
according to the educational needs of patients and their caregivers.
Provision of patient education should be documented in the medical
record and/or the AMS program.
Patient selection Anticoagulant therapy should be initiated only after careful consideration of
the risk and benefit for an individual patient.
The goals of anticoagulant therapy should be periodically reassessed
to ensure the risk−benefit profile and patient preferences favor ongoing
therapy.
Laboratory Optimal anticoagulation should include regular laboratory monitoring of

monitoring warfarin with use of the prothrombin time test and reported as an INR.
Warfarin monitoring using the prothrombin time should be performed on
either plasma samples in a clinical laboratory or on whole blood capillary
(fingerstick) samples utilizing point-of-care devices.
Routine monitoring of the anticoagulant effect of DOACs is not necessary.
Routine coagulation monitoring for long-term LMWH is rarely indicated.
Anti-factor Xa concentration is the appropriate test to assess LMWH if
necessary.
Anticoagulation Anticoagulation should be initiated using a systematic, evidence-based

initiation approach.
A reminder mechanism to support timely anticoagulation drug-therapy
transitions for acute DVT/PE should be established.
Anticoagulation Anticoagulant care delivery should employ a systematic process for

maintenance ongoing patient assessment, anticoagulant dose adjustment, and
scheduling of follow-up laboratory monitoring.
Renal function should be periodically assessed for patients receiving long-
term (e.g., >45 days) DOAC or LMWH therapy.
A systematic approach should be established for management of
anticoagulant therapy around elective invasive procedures.
AMS should systematically assess and document unexpected events such
as bleeding and thrombosis.
Anticoagulation A systematic approach should be established for determining appropriate

cessation patient-specific duration of anticoagulant therapy.
AMS should clearly document anticoagulation discontinuation date and
reason.
For additional details, see reference 12.

AMS: anticoagulation management service, DOAC: direct-acting oral anticoagulant, DVT: deep
vein thrombosis, INR: international normalized ratio, LMWH: low molecular weight heparin, PE:
pulmonary embolism
Several computer programs designed to manage patients taking warfa-

rin have been developed, and some have specific functionality for tracking
patients taking DOACs as well. Large, centralized AMS are more likely to
benefit from the efficiency and functionality of specialized anticoagulation
software package. When a stand-alone anticoagulation program is used,
communication between the program and the EMR is required to ensure
anticoagulation care details are available to the healthcare team. Automated
connection or communication between the anticoagulation and the EMR is
preferred to limit double-documentation and transcription errors.
Consideration of at least the following factors should be done routinely
at the outset of therapy: patient height, weight, age, gender, renal function,
comorbidities, drug−drug interactions, thrombotic risk, bleeding risk,
pregnancy status, diet, assessment of adherence, drug cost, patient ability to
pay, ability/willingness to comply with laboratory monitoring, and indication
for anticoagulation.12 Review of these parameters, along with a discussion
with the patient to ensure shared decision-making, should guide (1) whether
to initiate anti-coagulation, and (2) if starting anticoagulation, what agent
and starting dose is most appropriate.
Practices vary with regard to the frequency of INR monitoring both at
warfarin initiation and during maintenance therapy. Frequent INR monitoring
is necessary during warfarin initiation or after a dose change or in the setting
of dietary changes or new drug interactions. Professional society guidelines
provide little specific direction other than to monitor INR every few days
during initiation or dose change.17 The ACF recommends INR checks at least
2−3 times per week in the first 7−10 days or until a stable warfarin dose is
achieved.12 The maximum interval between INR tests in very stable warfarin
patients is between 4−12 weeks.14,36,37
Quality Metrics
Surrogate Measures
A summary of available surrogate measures for anticoagulation quality
assessment is provided in Table 23-7.
Time-in-Therapeutic Range
Time-in-therapeutic range (TTR) calculated using the Rosendaal method has
become the standard metric for reporting anticoagulation control among
patients receiving warfarin.38 Studies have correlated higher TTR with fewer
stroke/systemic embolism events among patients receiving warfarin for AF as
well as lower bleeding rates in large heterogeneous anticoagulation popula-
tions.18,39 Although there is no minimum threshold established for AMS TTR
performance, center-level TTR (cTTR) ≥70% should generally be considered
high-quality anticoagulation care. Individual patient TTR (iTTR) <40% during
warfarin has been associated with more strokes compared to no anticoagula-
tion in the AF population, and patients at this level of TTR after a suitable
warfarin challenge (e.g., 6 months) should be considered for an alternative
TABLE 23-7: Quality Metrics for Outpatient Anticoagulation

Management Services
Surrogate Measures Correlated Comments
with Outcomes
Cross-section of files ? Simplest method of quality assessment but has not

been related to outcomes.
Proportion of INRs in + Simple to calculate but less strongly linked to

range outcomes and influenced by sampling frequency.
TTR ++ Rosendaal method of linear interpolation

Not simple to calculate.
Associated with thrombotic outcomes but less
strongly linked to bleeding.
Risk-adjusted TTR ? Incorporates demographic and clinical data

to account for differences in patient mix when
comparing TTR across sites.
INR variability +++ Measures the variability between INRs or between

the INR and the target INR value.
Strongly linked to bleeding outcomes.
Clinical Outcomes Comments
Bleeding May categorize as clinically relevant and major hemorrhage.
Thromboembolic Stroke, ATE, DVT, PE, MI, or valve thrombosis.*

outcomes
All-cause mortality Often difficult to attribute cause of death.
*May be targeted according to indication for anticoagulation.

ATE: arterial thromboembolism, DOAC: direct-acting oral anticoagulant, DVT: deep vein
thrombosis, INR: international normalized ratio, MI: myocardial infarction, PE: pulmonary
embolism, TTR: time-in-therapeutic range
agent. 40 The iTTR predicts major hemorrhage, thrombosis, and all-cause

mortality more strongly than cTTR. Risk-adjusted cTTR was developed in
the Veterans Administration Health System to account for demographic and
clinical differences in populations compared across multiple sites of care.41
Risk adjusting can provide an expected cTTR according to patient mix at
each individual site, which can be compared to actual cTTR. Anticoagulation
clinics can then compare their performance relative to expected cTTR (e.g.,
clinics may be exceeding or falling short of expected TTR).
Variability of the INR
One limitation of TTR is that it does not account for large swings in the INR
or INR stability over time. Several estimates of INR variability have been
investigated and associated with bleeding and thrombotic outcomes in anti-
coagulated patients.42-44 The measure of INR variability is also referred to as
variance growth rate.42 Variance growth rate can be assessed in several ways.
In the earliest assessment by Fihn and colleagues, the difference between

measured INR and the target INR (e.g., 2.5) was quantified.43 More recent
methods have quantified the difference between successive INRs rather than
comparing to the target INR.42 Patients with unstable INRs as measured by
variance growth rate have a greater risk of bleeding and thromboembolic
events compared to stable controls.42 In fact, the risk of bleeding was more
pronounced among unstable patients in the 3 months preceding the event
than those with poor iTTR.42
Proportion of INRs in Range
The challenge for many AMS settings is that TTR and variance growth rate
measures are not readily available and are difficult to calculate. Anticoagula-
tion software packages often provide one or more of these measures, but
accessing these metrics can be a challenge for an AMS working without
these tools. Proportion of INRs in range (i.e., count of INRs in range/count of
INRs drawn in the given time period) is a simple alternative that directionally
aligns with TTR and is simpler to calculate than linear interpolation. 45 In most
AMS settings, the value for proportion of INRs in range will be lower than
TTR because INRs are drawn more frequently when they are out-of-range,
and the retest interval is often extended for stable, therapeutic patients.17
• Two simple things an AMS can do to improve

TTR are: (1) use a warfarin dosing nomogram
and (2) recheck the INR within 1−2 weeks of an
out-of-range result.
Clinical Endpoints
Although TTR is an important surrogate measure of the quality of warfa-
rin management, avoidance of thromboembolic, hemorrhagic, and fatal
outcomes are the primary objective of optimal anticoagulant management. 18
Thromboembolic outcomes that should be reported by an AMS include:
• Symptomatic DVT and PE
• Unusual site VTE
• Stroke
• Systemic embolism
• Heart valve thrombosis
Bleeding events may be categorized as major (e.g., fatal bleeding) or
non-major according to the definition by the International Society of Throm-
bosis and Haemostasis definition. 46 All-cause mortality may also be included
in event reporting.
There are several methods to track clinical outcomes in an AMS. The
patient or provider may self-report events and include them in the AMS
documentation. However, self-reporting often results in under-reporting. To
mitigate this risk, diagnosis codes (i.e., ICD-10) may be queried from claims
and billing data to identify hospitalizations associated with bleeding and

thrombosis. There is often a high degree of false-positive results when relying
on diagnosis codes alone to identify outcomes. Manual review is advisable
to ensure the outcomes were corroborated by healthcare staff or objectively
confirmed as new or acute events rather than historical diagnoses that were
coded during the clinic or hospital visit. Manual review is labor intensive and
may not be feasible in all AMS settings.
Optimal rates of bleeding and thrombosis during outpatient anticoagula-
tion management have not been established and are dependent on many
factors in addition to the quality of anticoagulation care. These include clini-
cal factors known to influence bleeding and thrombotic risk (e.g., age, heart
failure, stroke) as well as uncontrolled comorbidities (e.g., cancer, diabetes,
hypertension), indication for anticoagulation (AF versus VTE), target INR, and
experienced versus anticoagulation naïve status.47-49 Comparing the rates
of clinical outcomes between AMS settings is problematic due to inherent
differences in patient population. Tracking clinical outcomes within an AMS
over time remains an important element of optimal anticoagulant therapy
to measure the success of local quality improvement efforts.
• A lthough minimizing bleeding and

thromboembolic events is the central function
of an AMS, when events occur, it is often during
periods of therapeutic anticoagulation. A recent
study of patients with intracranial hemorrhage
on warfarin found only 28.1% had an elevated
INR on admission.50
Quality Improvement
Improving oral anticoagulation quality in the outpatient setting remains an
elusive goal. Many of the recommendations for quality improvement in the
inpatient setting apply (e.g., consistent processes, policy and procedures,
drug therapy protocols/guidelines, staff training and development, thorough
patient education). In addition, several items specific to the outpatient setting
should be considered:
• Appropriate risk−benefit assessment
{{ Ensure patients without a compelling indication for anticoagula-
tion are not receiving anticoagulants (e.g., atrial fibrillation and a
CHA2DS2-VASc score of 0)
• Minimize drug interactions
{{ Discontinue concomitant antiplatelet therapy when possible
{{ Avoid highly potentiating antimicrobials (e.g., co-trimoxazole,
metronidazole, fluconazole) whenever possible
• Manage adherence
{{ Timely laboratory monitoring
{{ Timely refill history for DOACs
• Optimize warfarin management
{{ More frequent INR testing after out-of-range INRs
{{ Use computerized decision support when possible
Follow the nomogram/computer-assisted dosing unless
there are temporary or transient factors contributing to
out-of-range INR result
{{ Consider PST/PSM for appropriate patients
{{ Focus on patients with poor iTTR (e.g., <50%)
Additional education
Enriched dietary vitamin K
Appropriate warfarin tablet strength (i.e., not too large
to make necessary adjustments)
Patients requiring long-term anticoagulation with poor iTTR, despite efforts
to improve the quality of warfarin management, should be considered for an
alternative agent. Although there is no direct evidence that transition to a
DOAC will improve patient outcomes, it remains an attractive option in this
setting because warfarin is providing little or no benefit.40 Patients unable
to afford a DOAC may alternatively consider single or dual antiplatelet
therapy.14,51
• I n the continued pursuit of optimal anticoagulant

therapy outcomes, AMS models must be prepared
to adapt to an evolving healthcare landscape
with diversifying drug therapy options and
technological progress.

1. Bond CA, Raehl CL. Adverse drug reactions in United States hospitals.
2. Budnitz DS, Lovegrove MC, Shehab N, et al. Emergency hospitalizations for adverse
drug events in older Americans. N Engl J Med. 2011;24:365(21): 2002-2012.
3. Lucado J, Paez K, Elixhauser A. Medication-Related Adverse Outcomes in U.S.
Hospitals and Emergency Departments, 2008: Statistical Brief #109. Healthcare Cost
and Utilization Project (HCUP) Statistical Briefs 2011; U.S. Department of Health and
Human Services, Agency for Healthcare Research and Quality, Rockville, MD. www.
hcup-us.ahrq.gov/reports/statbriefs/sb109.pdf. Accessed March 20, 2017.
4. U.S. Department of Health and Human Services, Office of Inspector General (OIG).
Adverse events in hospitals: national incidence among Medicare beneficiaries. Report
No.: OEI-06-09-0090. November 2010; Washington, DC. http://oig.hhs.gov/oei/
reports/oei-06-09-00090.pdf. Accessed March 20, 2017.
5. U.S. Department of Health and Human Services Office of Disease Prevention and
Health Promotion. National action plan for adverse drug event prevention. http://www.
health.gov/hcq/pdfs/ade-action-plan.pdf. Accessed March 20, 2017.
*6. Nutescu EA, Wittkowsky AK, Burnett A, et al. Delivery of optimized inpatient
anticoagulation therapy: consensus statement from the Anticoagulation Forum. Ann
Pharmacother. 2013;47(5):714-724.
7. The Joint Commission. National Patient Safety Goals Effective January 1, 2015.
Hospital Accreditation Program. http://www.jointcommission.org/assets/1/6/2015_
NPSG_HAP.pdf. Accessed March 20, 2017.
8. Donovan JL, Drake JA, Whittaker P, et al. Pharmacy-managed anticoagulation:
assessment of in-hospital efficacy and evaluation of financial impact and community
acceptance. J Thromb Thrombolysis. 2006;22(1):23-30.
9. Locke C, Ravnan SL, Patel R, et al. Reduction in warfarin adverse events requiring
patient hospitalization after implementation of a pharmacist-managed anticoagulation
service. Pharmacotherapy. 2005;25(5):685-689.
10. Schillig J, Kaatz S, Hudson M, et al. Clinical and safety impact of an inpatient
pharmacist-directed anticoagulation service. J Hosp Med. 2011;6(6):322-328.
11. Barcellona D, Contu P, Marongui F. Patient education and oral anticoagulant therapy.
Haemotologica. 2002;87:1081-1086.
12. Moore SJ, Blair EA, Steeb DR, et al. Impact of video technology on efficiency of
pharmacist-provided anticoagulation counseling and patient comprehension. Ann
Pharmacother. 2015;49(6):631-638.
13. Agency for Healthcare Research and Quality. Achieving patient-centered care with
shared decision making. April 2014; AHRQ 14-0034-9-EF. https://www.ahrq.gov/sites/
default/files/wysiwyg/professionals/education/curriculum-tools/shareddecisionmaking/
tools/tool-9/share-tool9.pdf. Accessed March 20, 2017.
*14. January CR, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the
management of patients with atrial fibrillation: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines and the
Heart Rhythm Society. Circulation. 2014 Dec 2;130(23):2071-2104. http://circ.
ahajournals.org/content/early/2014/03/27/CIR.0000000000000041.citation.
*15. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized anticoagulant therapy:
consensus statement from the Anticoagulation Forum. Ann Pharmacother.
2008;42(7):979-988.
16. Clark NP, Delate T, Riggs C, et al. Warfarin interactions with antibiotics in the
ambulatory care setting. JAMA Intern Med. 2014;174(3):409-416.
*17. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of
anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis. 9th
Chest. 2012;141(suppl 2):e152S-e184S.
18. Witt DM, Sadler MA, Shanahan RL, et al. Effect of a centralized clinical pharmacy
anticoagulation service on the outcomes of anticoagulant therapy. Chest. 2005;
(5):1515-1522.
19. Rudd KM, Dier JG. Comparison of two different models of anticoagulation management
services with usual medical care. Pharmacotherapy. 2010;30(4):330-338.
20. McCahon D, Murray ET, Jowett S, et al. Patient self-management of oral
anticoagulation in routine care in the UK. J Clin Pathol. 2007;60(11):1263-1267.
21. Matchar DB, Jacobson A, Dolor R, et al. Effect of home testing of international
normalized ratio on clinical events. N Engl J Med. 2010;363(17):1608-1620.
22. Heneghan C, Ward A, Perera R, et al. Self-monitoring of oral anticoagulation:
systematic review and met-analysis of individual patient data. Lancet.
2012;379(9813):322-334.
23. Goldberg Y, Meytes D, Shabtai E, et al. Monitoring oral anticoagulant therapy by
telephone communication. Blood Coagul Fibrinolysis. 2005;16(3):227-330.
24. Wittkowsky AK, Nutescu EA, Blackburn J, et al. Outcomes of oral anticoagulant therapy
managed by telephone vs in-office visits in an anticoagulation clinic setting. Chest.
2006;130(5):1385-1389.
25. Mahan CE. Practical aspects of treatment with target specific anticoagulants: initiation,
payment and current market, transition, and venous thromboembolism treatment. J
Thromb Thrombolysis. 2015;39:295-303.
26. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.
ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.
pdf. Pradaxa® package labeling. Accessed March 20, 2017.
27. https://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf.
Xarelto® package labeling. Accessed March 20, 2017.
28. http://packageinserts.bms.com/pi/pi_eliquis.pdf. Eliquis® package labeling. Accessed
March 20, 2017.
29. http://dsi.com/prescribing-information-portlet/getPIContent?productName=Savaysa
&inline=true. Savaysa® package labeling. Accessed March 20, 2017.
*30. Shore S, Carey EP, Turakhia MP, et al. Adherence to dabigatran and longitudinal
patient outcomes: insights from the Veterans Health Administration. Am Heart J.
2014;167(6):810-817.
31. Parker CS, Chen Z, Price M, et al. Adherence to warfarin assessed by electronic pill
caps, clinician assessment, and patient reports: results from the IN-RANGE study. J
Gen Intern Med. 2007;22(9):1254-1259.
32. Witt DM, Delate T, Clark NP, et al. Non-adherence with INR monitoring and
anticoagulation complications. Thromb Res. 2013; 132(2):e124-130.
33. Ababneh MA, Al-Azzam SI, Alzoubi KH, et al. Adherence in outpatients taking warfarin
and its effect on anticoagulation control in Jordan. Int J Clin Pharm. 2016 Mar 25
[Epub ahead of print].
34. Gorst-Rasmussen A, Skjoth F, Larsen RB, et al. Dabigatran adherence in atrial
fibrillation patients during the first year after diagnosis: a nationwide cohort study. J
Thromb Haemost. 2015;13(4):495-504.
35. Ryan E. Risk management and anticoagulation therapy. In: Ansell J, Oertel L,
Wittkowsky A, eds. Managing Oral Anticoagulation Therapy. 2nd ed. St. Louis, MO:
Wolters Kluwer Health, 2005:5A-2, 1-11.
36. Schulman S, Parpia S, Stewart C, et al. Warfarin dose assessment every 4 weeks versus
every 12 weeks in patients with stable international normalized ratios: a randomized
trial. Ann Intern Med. 2011;155(10):653-659.
37. Witt DM, Delate T, Clark NP, et al. Twelve-month outcomes and predictors of very stable
INR control in prevalent warfarin users. J Thromb Haemost. 2010; 8(4):744-749.
38. Rosendaal FR, Cannegieter SC, van der Meer FJM, et al. A method to determine the
optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69:236-239.
*39. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran
compared with warfarin at different levels of international normalised ratio control
for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet.
2010;376(9745):975-983.
40. Morgan CL, McEwan P, Tukiendorf A, et al. Warfarin treatment in patients with atrial
fibrillation: observing outcomes associated with varying levels of INR control. Thromb
Res. 2009;124(1):37-41.
41. Rose AJ, Hylek, EM, Ozonoff A, et al. Risk-adjusted percent time in therapeutic range
as a quality indicator for outpatient oral anticoagulation. Cardiovas Qual Outcomes.
2011;4:22-29.
42. Ibrahim S, Jespersen J, Poller L, on behalf of the European Action on Anticoagulation.
The clinical evaluation of international normalized ratio variability and control in
conventional oral anticoagulant administration by use of variance growth rate. J
Thromb Haemost. 2013;11:1540-1546.
43. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic
anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study
Group. Ann Intern Med. 1993;118:511-520.
44. van Leeuwen Y, Rosendaal FR, Cannegieter SC. Prediction of haemorrhagic and
thrombotic events in patients with mechanical heart valve prostheses treated with oral
anticoagulants. J Thromb Haemost. 2008;6:451-456.
45. Nelson WW, Desai S, Damaraju CV, et al. International normalized ratio stability in
warfarin-experienced patients with nonvalvular atrial fibrillation. Am J Cardiovas
Drugs. 2015;15(3):205-211.
46. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost.
2005;3:692-694.
47. Rose AJ, Hylek EM, Ozonoff A, et al. Patient characteristics associated with
oral anticoagulation control: results from the Veterans Affairs Study to Improve
Anticoagulation (VARIA). J Thromb Haemost. 2010;8(10):2182-2191.
48. Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk
for intracranial hemorrhage among patient taking warfarin for atrial fibrillation. Ann
Intern Med. 2004;141(10):745-752.
49. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to
assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart
Survey. Chest. 2010;138(5):1093-1100.
50. Witt DM, Clark NP, Martinez K, et al. Risk of thromboembolism, recurrent hemorrhage,
and death after warfarin therapy interruption for intracranial hemorrhage. Thromb
Res. 2015;136:1040-1044.
51. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation:
Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141:e531s-
e575s.
24 Chapter
REGULATORY AND PRACTICE

RESOURCES
Michael P. Gulseth and William E. Dager
INTRODUCTION
Anticoagulation therapy continues to expand across the world as the popula-
tion ages, has improved access or advances in healthcare, and has increasing
management choices. Optimal use of anticoagulants and related outcomes has
its own challenges; however, because available agents have associated risks for
adverse events or treatment failures that impact healthcare both at the individual
and national/international level. To maximize benefits for anticoagulation therapy,
responsible agencies may create incentives to improve cost-effectiveness and
safer management. Practitioners, in return, will expect that the resources meet
the following goals: encourage optimal care, minimize adverse events, and have
the necessary funding to sustain their existence.
Healthcare in the United States is moving away from established reimburse-
ments such as a fee-for-service model, to one that rewards practitioners for keeping
patients healthy and out of the hospital. The push toward value-based purchasing
has led to efforts to pay facilities based on process-of-care measures and patient
outcomes. Unfortunately, the specific measures and outcomes used to measure
performance are constantly changing, so this chapter is geared toward providing
clinicians with insights on understanding current measures and outcomes.
REGULATORY/QUALITY RESOURCES
605
TABLE 24-1: Regulatory Agencies and Their Role

Agency Role
Centers for Medicare & Part of the Department of Health and Human Services—charged
Medicaid Services (CMS) with delivering the Medicare program, and in concert with the
states, the Medicaid program; previously known as the Health
Care Financing Administration (HCFA).
Det Norske Veritas (DNV) Part of the DNV group; an independent foundation; DNV
Healthcare, Inc. accreditation allows an organization to participate in the
Medicare program.
Healthcare Facilities Not-for-profit organization that accredits and certifies healthcare

Accreditation Program organizations and programs; HFAP accreditation allows an
(HFAP) organization to participate in the Medicare program.
The Joint Commission Not-for-profit organization that accredits and certifies healthcare
(TJC) organizations and programs; TJC accreditation allows an
organization to participate in the Medicare program.
National Quality Forum Organization of over 400 organizations that develops consensus
(NQF) standards; NQF-endorsed measures are subsequently often
required by accreditation and/or government bodies.
TABLE 24-2: The Joint Commission Regulatory Resources

Topic Web Address Comment
Joint Commission www.jointcommission.org/ Home page

home page
National Patient Safety www.jointcommission.org/ Current NPSGs, currently

Goals (NPSGs) standards_information/npsgs. 03.05.01 covers anticoagulation
aspx therapy.
Performance Measures www.jointcommission.org/ Links to all current TJC measures.

performance_measurement.aspx
Current Core www.jointcommission.org/core_ Links to all current TJC core

Measurements measure_sets.aspx measures; many core measures
affect anticoagulation practice.
Current Specification www.jointcommission.org/ Manual provides specifics

Manual for National specifications_manual_for_ on how core measures are
Hospital Inpatient national_hospital_inpatient_ abstracted.
Quality Measures quality_measures.aspx
Standards Manual www.jointcommission.org/ Site provides links to purchase

standards_information/standards. full TJC standards.
aspx
REGULATORY AND PRACTICE RESOURCES 607
TABLE 24-3: Value-Based Purchasing, Pay-for-Performance,

and Merit-Based Incentive Pay Resources
Site Web Address Comment
Centers for Medicare & www.cms.gov Home page; site is difficult to

Medicaid Services (CMS) navigate.
Hospital Inpatient Quality www.cms.gov/Medicare/ Requires reporting of quality

Reporting Program Quality-Initiatives-Patient- indicators.
Assessment-Instruments/
HospitalQualityInits/
HospitalRHQDAPU.html
Medicare Value-Based www.medicare.gov/ Good site to find quality

Purchasing hospitalcompare/data/ reporting, measures, and
hospital-vbp.html surveys affecting Medicare
payment rates; many items
pertinent to anticoagulation
practice.
Hospital Consumer www.hcahpsonline.org/home. Detailed information on

Assessment of Healthcare aspx HCAHPS survey.
Providers and Systems Survey
(HCAHPS)
Hospital Acquired Condition www.qualitynet.org/dcs/ Detailed information on HAC.

(HAC) Reduction Program ContentServer?c=Page& Patient Safety and Adverse
pagename=QnetPublic% Events Composite (PSI
2FPage%2FQnetTier2&c 90) measure affects
id=1228774189166 anticoagulation practice.
Readmission Reduction www.cms.gov/medicare/ Detailed information on RRP.

Program (RRP) medicare-fee-for-service-
payment/acuteinpatientpps/
readmissions-reduction-
program.html
Merit-Based Incentive www.qpp.cms.gov/mips/ Information on MIPS program;

Payment System (MIPS) overview replaced Meaningful Use.
Physician Quality Reporting www.medicare.gov/ Detailed information on

System (PQRS) physiciancompare/ PQRS; these are developing
staticpages/data/pqrs.html ambulatory quality measures.
Hospital Compare web site www.medicare.gov/ Site that allows consumers to

hospitalcompare compare hospital quality on
many of the above required
measures.
National Quality Forum (NQF) www.qualityforum.org Site contains progress

information on current
projects that could lead to
new measures.
TABLE 24-4: Helpful Organizations for Regulatory/Quality

Issues
Agency Web Address Comment
American Society www.ashp.org Extensive materials are available on

of Health-System best practices, quality resources,
Pharmacists and current regulatory/patient
safety issues.
Health and Medicine www.nationalacademies.org/hmd Produced seminal publications that

Division (formally the led to improvements in medication
Institute of Medicine safety.
or IOM)
Institute for www.ihi.org Organization dedicated to

Healthcare improving healthcare quality
Improvement improvement; extensive resources
on their site and consulting
available.
Institute for Safe www.ismp.org Recognized leaders in numerous

Medication Practices medication safety issues, including
anticoagulant safety.
The Joint www.jointcommission.org The Joint Commission not only has

Commission (TJC) extensive resources on their site
but also has a consulting arm, Joint
Commission Resources.
Texas Medical www.safetyleaders.org Research organization dedicated

Institute of to accelerating performance
Technology solutions that save lives; videos on
the impact and need to prevent
medication errors are particularly
powerful.
PRACTICE-BASED RESOURCES
TABLE 24-5: Helpful Journals for Anticoagulation Clinicians

Journal Web Address Comment
American Journal www.ajhp.org Official publication of the

of Health-System American Society of Health-
Pharmacy System Pharmacists (ASHP)
Annals of Internal annals.org Official publication of the

Medicine American College of Physicians
(ACP); ACP guidelines are
published in this journal
Annals of aop.sagepub.com
Pharmacotherapy
Blood www.bloodjournal.org Official publication of the

American Society of Hematology
CHEST journal.publications.chestnet.org Official publication of the

American College of Chest
Physicians (ACCP); publisher of
the ACCP guidelines
Circulation circ.ahajournals.org Official publication of the

American Heart Association
(AHA); American College
of Cardiology (ACC)/AHA
guidelines are published in this
journal
Journal of Thrombosis https://link.springer.com/

and Thrombolysis journal/11239
Journal of Thrombosis onlinelibrary.wiley.com/journal/10 Official publication of the

and Haemostasis .1111/%28ISSN%291538-7836 International Society of
Thrombosis and Haemostasis
New England Journal of nejm.org Provides many of the key

Medicine randomized clinical trials in
thrombosis management using
pharmacotherapy. Also provides
a periodic listing of cardiology-
related articles in recent issues.
Pharmacotherapy onlinelibrary.wiley.com/ Official publication of the

journal/10.1002/(ISSN)1875-9114 American College of Clinical
Pharmacy
Thrombosis and th.schattauer.de

Haemostasis
TABLE 24-6: Helpful Textbooks for Anticoagulation Clinicians

Books Comment
Ansell JE, Oertel LB, Wittkowsky A, eds. Covers both clinical and operational material
Managing Oral Anticoagulation Therapy: geared toward the outpatient anticoagulation
Clinical and Operational Guidelines, 3rd management practitioner; some material is
ed. St Louis, MO: Wolters Kluwer, 2008 dated.
Marder VJ, Aird WC, Bennett JS, et al., Covers the physiology of hemostasis- and
eds. Hemostasis and Thrombosis: Basic thrombosis-related disorders.
Principles and Clinical Practice, 6th ed.
Philadelphia. PA: Lippincott Williams &
Wilkins, 2012
Kitchens C, Konkle B, Kessler C, eds. Covers management of bleeding and clotting

Consultative Hemostasis and Thrombosis, disorders.
3rd ed. Philadelphia, PA: Saunders, 2013
Gulseth MP (ed). Managing Covers both clinical and operational material

Anticoagulation Patients in the Hospital; geared toward the inpatient anticoagulation
the Inpatient Anticoagulation Service. management practitioner; some material is
Bethesda, MD: American Society of Health- dated.
System Pharmacists, 2007
TABLE 24-7: Helpful Organizations for Anticoagulation

Clinicians
Organization Web Address
American College of Clinical Pharmacy www.accp.com
American Society of Health-System Pharmacists www.ashp.org
American Society of Hematology www.hematology.org
Anticoagulation Forum acforum.org
ClotCare www.clotcare.com
College of American Pathologists www.cap.org
International Society of Thrombosis and Haemostasis www.isth.org
National Blood Clot Alliance www.stoptheclot.org
North American Society of Thrombosis and Hemostasis www.nasth.org
North American Thrombosis Forum www.natfonline.org

TABLE 24-8: Training Programs/Credentials for Anticoagulation

Clinicians
ASHP www.ashpfoundation.org/
MainMenuCategories/Traineeships/
PharmacotherapyTraineeship
Anticoagulation Forum acforumbootcamp.org
National Certification Board for www.ncbap.org

Anticoagulation Providers
University of Connecticut pharmacy.uconn.edu/academics/ce/

anticoagulation
University of Florida cpe.pharmacy.ufl.edu/courses/certificate/

anticoagulation
University of Southern Indiana www.usi.edu/health/certificate-programs/

anticoagulation-therapy-management-
certificate-program
TABLE 24-9: Independent Diagnostic Testing Facilities That

Facilitate Home INR Monitoring
Alere ptinr.com
mdINR www.mdinr.com
Remote Cardiac Services inrselftest.com
Roche www.coaguchekpatientservices.com
WebCareHealtha www.webcarehealth.com
a
Note that WebCareHealth is not a true independent testing facility, but will assist in setting up
your organization as a home testing equipment provider.
TABLE 24-10: Anticoagulation Forum Practice Standards

Articles
Document Web Address
Delivery of Optimized Anticoagulant http://acforum.org/docs/Anticoagulation%20

Therapy: Consensus Statement from the Guidelines.pdf
Anticoagulation Forum
Delivery of Optimized Inpatient http://acforum.org/docs/Inpatient_AC_Guidelines_

Anticoagulation Therapy: Consensus AC_Forum_AnnPT_042013.pdf
Statement from the Anticoagulation
Forum
Management of Venous http://acforum.org/landing/index.html

Thromboembolism: Clinical Guidance
from the Anticoagulation Forum
PATIENT EDUCATION RESOURCES
Health Literacy Resources

• The Office of Disease Prevention and Health Promotion at health.gov/commu-
nication—two notable features of this site:
{{ Provides help to prepare usable web sites and digital tools for
those with low health literacy.
{{ Provides numerous external links to outside organizations with
helpful health literacy resources.
• The Agency for Healthcare Research and Quality has pharmacy-specific resources
available at www.ahrq.gov/professionals/quality-patient-safety/pharmhealthlit/
index.html.
Cultural Competence Resources

• The Office of Minority Health at www.thinkculturalhealth.hhs.gov contains helpful
resources on cultural competence—notable features:
{{ Provides educational materials on culturally competent care.
{{ Link to the The National Standards for Culturally and Linguistically
Appropriate Services in Health and Health Care (National CLAS
standards).
{{ Link to the Guide to Provide Effective Communication and
Language Assistance Services.
{{ Links to external helpful materials.
General Patient Education Resources, Technique-Based

See Table 24-11.
TABLE 24-11: General Patient Education Resources

Source Web Address Comment
American Society of Health- www.ajhp.org/ Guidelines on how to provide

System Pharmacists content/54/4/431 effective patient counseling.1
Agency for Healthcare www.ahrq.gov/professionals/ Good information on how

Research and Quality education/curriculum-tools/ to use patient “teach back”
shareddecisionmaking/tools/ methods.
tool-6/index.html
Missouri Board of Pharmacy www.youtube.com/watch?v=- Excellent presentation

hMFMfw623o on effective counseling
techniques, including use
of the Indian Health Service
“prime questions.”
Royal Pharmaceutical Society www.pharmaceutical- Excellent resource on how to

journal.com/learning/ use motivational interviewing
learning-article/using- to improve medication
motivational-interviewing- adherence.
to-improve-medicines-
adherence/20200954.article
REVENUE-GENERATION RESOURCES
See Table 24-12.
TABLE 24-12: Revenue-Generation Resources

Site Web Address Comment
Pharmacist Billing in the www.ashp.org/doclibrary/ ASHP document covers

Ambulatory Clinic Setting policy/ambulatory-care/ physician clinic-based (CMS
pharmacist-billing-in- 1500) billing.
physician-based-clinic-faq.pdf
American Pharmacists aphameeting.pharmacist. Presentations provided by

Association Billing Boot com/sites/default/files/slides/ the American Pharmacists
Camp Billing%20Bootcamp%20 Society; covers hospital- and
1-2_handout.pdf physician-based billing.
SUMMARY
Although this chapter cannot cover every resource you will need to manage
a successful anticoagulation practice, the resources provided here are invalu-
able. They can aid clinicians in understanding the drivers that influence
our approaches to anticoagulation care. Challenges are ever-present with
meeting regulations or the available evidence when practicing in the “real
world” and meeting patients’ individual needs. Additional keys to optimal
performance may include identification of gaps and designing your system to
optimize performance. In addition, consider consulting these resources from
time to time to be aware of changes and any subsequent needs to adjust

management practice. We encourage all practices to have a standing body
that includes major disciplines involved in managing anticoagulation, such
as the Pharmacy and Therapeutics Committee, to regularly review practices,
identify both safety and treatment gaps, and strive to make systematic
improvements.
REFERENCE
1. ASHP guidelines on pharmacist-conducted patient education and counseling. Am J
Health-Syst Pharm. 1997;54(4):431-434.
APPENDIXES
Appendix A. Coagulation Cascade 617
Appendix B. Agents Implicated in Drug-Induced

Thromboembolic Diseases 618
Appendix C. Nutrition Influence on Anticoagulation 623
Appendix D. Anticoagulants in Management of Ischemic

Stroke or Transient Ischemic Attacks 625
Appendix E. Citrate Anticoagulation 627
Appendix F. Examples of Available Bleeding Definitions 629
Appendix G. Types of CNS Hemorrhage 631
Appendix H. Disseminated Intravascular Coagulation 632
Appendix I. Nondrug
Causes of
Thrombocytopenia 633
Appendix J. Drug-
Related Causes of
Thrombocytopenia 634
Appendix K. Examples of Transfusion-

Related Reactions 637
Appendix L. Considerations for

Transitioning from aPTT to Anti-Xa
to Manage Heparin Therapy 638
Appendix M. PIONEER AF-PCI 641
Appendix N. Betrixaban APEX Trial 642
615
A APPENDIX
COAGULATION CASCADE
Unfractionated Heparin (bound to AT*)

Intrinsic system Extrinsic system
(surface contact) (tissue damage)
XII XIIa
Tissue factor (TF)
XI XIa VKA
IX IXa TF/VIIa VII
VIII VIIIa
Fondaparinux (Bound to AT*)
Direct: Apixaban, Betrixaban,
Xa Edoxaban, Rivaroxaban
X
Va LMWH(Bound to AT*)
V
DTIs: Argatroban,
VKA II IIa Bivalirudin, Dabigatran
(Prothrombin) (Thrombin)
Fibrinogen Fibrin
Key = Inactive clotting factor

VKA= Vitamin K Antagonist (example warfarin)
AT= Antithrombin = Active clotting factor
DTIs= Direct Thrombin Inhibitors
DXaIs= Direct Xa Inhibitors = Inhibits production
Note: Agents bound to AT are indirect and = Enhances/promotes production
require AT for activity = Inactivates factor
617
APPENDIX
B
AGENTS IMPLICATED IN
DRUG-INDUCED
THROMBOEMBOLIC DISEASES
Drug Incidence Level of Evidencea
Hemostatic Agents
Aminocaproic acid NK C
Aprotinin 1% B
Cyanoacrylate NK C
Desmopressin NK C
Eptifibitide NK C
Protamine sulfate NK B
Activated prothrombin complex NK B

concentrate
3-factor prothrombin complex 0.7% B

concentrate
4-factor prothrombin complex 1.8% B

concentrate
Recombinant factor VIIa 7–9.4% A
Tranexamic acid NK C
Anticoagulants
Heparin 1–5% develop HIT, 25–50% of Ba

those develop HITT
Low-molecular-weight heparin 2.2% Ba
Pentosan NK B
Streptokinase NK C
Urokinase NK C
Warfarin (coumarin derivatives) NK B
(continued)
618
APPENDIXES 619
Hematopoietic Agents
Darbepoetin 3.3–8% A
Erythropoietin 3.3–26.7% A
G-CSF NK B
GM-CSF NK B
Estrogen-Containing Agents
Diethylstilbestrol 6.8–7% A
Oral contraceptives 6 times the risk of nonusers; A

1–2/10,000 woman-year
Hormone replacement 0.2–5.9/100 woman-year A
Antiandrogens
Cyproterone 5.23 increased odds B
Flutamide 5% Ba
Goserelin 1–5% B
Leuprolide 16.7% A
Selective Estrogen-Receptor Modulators
Raloxifene 9.5/100 woman-year A
Tamoxifene 3.6–12/100 woman-year A
Toremifene 1.5% B
Aromatase Inhibitors
Anastrazole 1–2.2% A
Letrazole NK C
Androgenic Agents
Danazol NK C
Nandrolone NK C
Megestrol 4.9% Ba
Follicle-Stimulating Hormone
Follitropin alfa NK C
Antineoplastic Agents
Aldsleukin <1% B
Asparaginase 11–36.7% A
Basiliximab 3–10% B
(continued)
Bevicizumab 4.4–5% A
Bleomycin NK B
Carboplatin NK B
Cisplatin 0.67% B
Dacarbazine NK C
Denileukin1 11% Ba
Docetaxel 8.8% A
Estramustine 0 ≥20% A
Etoposide NK A
Fluorouracil NK B
Gemcitabine
Imatinib NK B
Irinotecan 12.5% B
Lenalidomide 8% A
Paclitaxel NK B
Ponatinib NK A
Ranibizumab NK B
Rituximab NK B
Soraftnanib NK B
Thalidomide 3.4–26% A
Immunologic Agents
Cyclosporine NK B
Dexamethasone NK A
Foscarnet NK C
Infliximab NK B
Immunoglobins 3–3.8% A
Interferon gamma NK B
Interferon alfa-2a NK B
Interferon alfa-2b NK C
Interferon beta NK C
(continued)
APPENDIXES 621
Interleukin-3 NK C
Methylprednisolone NK B
Muromonab <1% Ba
Prednisone NK A
Sirolimus NK B
Tacrolimus NK B
Antipsychotic Agents
Chlorpromazine NK B
Clozapine 1.35% B
Olanzapine 1.17% B
Quetiapine 1.35% B
Risperidone 1.25% B
Thioridazine NK B
Other Psychotropic Agents
Clomipramine NK C
Escitalopram NK C
Lithium NK C
Contrast Agents
Iohexol 22.2% B
Iomeprol 0.8–4.2% Ba
Iopamidol 9–22.2% Ba
Iothalamate 8–28.6% B
Ioxaglate 2.7–4.8% Ba
Miscellaneous
Acetohydroxamic acid NK B
Botulinin toxin NK C
Bromocriptine NK C
Calcium gluconate NK C
Cocaine NK C
Dihydroergotamine NK C
(continued)
Ecstasy (3,4-Methylenedioxy- NK C
methamphetamine; MDMA)
Ergotamine NK C
Metolazone NK C
Papaverine NK B
Procainamide NK C
Sildenafil NK C
Topiramate 6.1% A
Tretinoin NK B
a
Definitions for Levels of Evidence: Level A—evidence from one or more randomized, controlled
clinical trials; Level B—evidence from nonrandomized clinical trials, prospective observational
studies, cohort studies, retrospective studies, case-control studies, meta-analyses, and/or
postmarketing surveillance studies; and Level C—evidence from one or more published case
reports or case series.
G-CSF: granulocyte colony-stimulating factor, GM-CSF: granulocyte /macrophage
colony-stimulating factor, HIT: heparin-induced thrombocytopenia, HITT: heparin-induced
thrombocytopenia and thrombosis, NK: not known
Source: Garwood CL. Thromboembolic diseases. In: Tisdale JE and Miller DA, eds. Drug-Induced
Diseases: Prevention, Detection, and Management. 3rd ed. Bethesda, MD: American Society of
Health-System Pharmacists; 2018:1064–1066.
C APPENDIX
NUTRITION INFLUENCE ON
ANTICOAGULATION
Setting Warfarin Rivaroxaban Apixaban Dabigatran
Dietary Warfarin 15- and 20-mg 2.5- and 5-mg Capsules may not
concerns resistance may tablets may be tablets may be be opened; not
occur due crushed and crushed and compatible with
to a binding suspended in 50 suspended in feeding tubes.
interaction with mL of water for 60 mL D5W and
the enteral administration immediately given
nutrition or the via nasogastric/ via nasogastric
surface of the gastric tube; tube.
feeding tube. administer
Consider holding suspension
the enteral feed within 4 hours
for 1 hour before of preparation
and after warfarin and follow
administration. administration
Warfarin dose immediately
should be with enteral
concentrated, feed. Avoid
administered administration
quickly with a distal to stomach.
flush before
and after
administration.
Short Dietary changes 15- and 20-mg None. No data at Decreased

bowel may affect tablets must this time. absorption and
syndrome INR. Warfarin be taken with bioavailability
resistance may food. Small case may reduce
occur due to series suggests anticoagulant
diminished minimal impact of effects.
absorptive surface bioavailability.
area of the
proximal small
bowel.
(continued)
623
Setting Warfarin Rivaroxaban Apixaban Dabigatran
Bariatric Warfarin sensitivity No dose No data at this Subtherapeutic

surgery may occur in adjustments time. anticoagulation
the early post- necessary. may occur due
operative period Patients in to diminished
due to gastric the early absorptive surface
pH changes and postoperative area.
dietary changes. period after
bariatric surgery
should not receive
rivaroxaban
for either atrial
fibrillation or VTE
treatment due to
low caloric diets
post-operatively.
Feeding Warfarin sensitivity Limited data No data at this Avoid—capsules

tubes may occur in at this time— time—primarily should not be
the early post- administration absorbed in broken.
operative period distal to the the upper GI
due to gastric stomach should tract with lower
pH changes and be avoided. bioavailability
dietary changes. Bioavailability when administered
may decline with on the lower GI
administration tract.
into the intestine.
D5W: 5% dextrose in water, GI: gastrointestinal, INR: international normalized ratio, VTE: venous
thromboembolism
D APPENDIX
ANTICOAGULANTS IN
MANAGEMENT OF ISCHEMIC
STROKE OR TRANSIENT
ISCHEMIC ATTACKS
Cardioembolic Stroke or TIA
Atrial fibrillation See Chapter 14

(Noncardiogenic: antiplatelet therapy preferred over
warfarin)
Acute MI with LV thrombus Warfarin (INR 2–3) for 3-month minimum
Cardiomyopathy The benefits of warfarin with a cardiomyopathy and

history of a stroke of TIA has not been determined;
considerations to prevent recurrent ischemic events
include
• Warfarin (INR 2–3)
• ASA 81 mg daily
• Clopidogrel 75 mg daily
• ASA 25 mg/dipyridamole 200 mg twice daily
Native valvular disease Warfarin (INR 2–3) is reasonable; avoid combination with
antiplatelet agent if possible
• Add aspirin if ischemic stroke or TIA while being
treated with adequate warfarin therapy
Antiplatelet therapy can be considered:
• Mitral annular calcification
• Native aortic/nonrheumatic mitral valve and no AF
• Mitral valve prolapsed (long-term antiplatelet
therapy)
Prosthetic heart valve Mechanical valves—warfarin (aortic valve: INR 2–3;

mitral valve: INR 2.5–3.5); add ASA 75–100 mg/day if
stroke or TIA occurs with therapeutic anticoagulation
and bleeding risk is not high.
Bioprosthetic—warfarin (INR 2–3) for 3– 6 months if no
other source identified*
• Beyond 3−6 months, long-term therapy with ASA
75–100 mg/day preferred over long-term warfarin
(continued)
625
Anticoagulation Post-Intracranial Hemorrhage
ICH, SAH, and SDH Consider stopping all anticoagulants and antiplatelet
agents and reversing their effects; hold anticoagulation
for 1–2 weeks.
Restarting therapy after an ICH will depend on the risk
of recurrent thrombosis or ICH; in patients with a high
risk of thromboembolism, warfarin may be restarted
7–10 days after the onset of the original ICH.
Hemorrhagic cerebral infarction Depending on the situation and risk of

thromboembolism, it may be reasonable to continue
anticoagulation.
*ACCP 2008: “In patients with mechanical heart valves who have additional risk factors for
thromboembolism, such as AF, hypercoagulable state, or low ejection fraction, or who have a
history of atherosclerotic vascular disease, we recommend the addition of low-dose ASA (50
to 100 mg/day) to long-term VKA therapy (Grade 1B). We suggest ASA not be added to VKA
therapy in patients with mechanical heart valves who are at particularly high risk of bleeding, such
as in patients with history of GI bleed or in patients >80 years of age (Grade 2C).”
AF: atrial fibrillation, ASA: aspirin, ICH: intracranial hemorrhage, INR: international normalized
ratio, LV: left ventricular, MI: myocardial infarction, SAH: subarachnoid hemorrhage, SDH:
subdural hematoma, TIA: transient ischemic attack
Sources: Furie KL, Kasner SE, Adams RJ, et al. on behalf of the American Heart Association Stroke
Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary
Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in
patients with stroke or transient ischemic attack. A guideline for healthcare professionals from
the American Heart Association/American Stroke Association. Stroke. 2010, published online
October 21, 2010; http://stroke.ahajournals.org/cgi/content/full/42/1/227.
Salem DN, O’Gara PT, Madias C, et al. American College of Chest Physicians. Valvular and
structural heart disease: American College of Chest Physicians Evidence-based Clinical Practice
Guidelines (8th ed.). Chest. 2008;133(6 Suppl):593S-629S.
E APPENDIX
CITRATE ANTICOAGULATION
Mechanism Regional citrate anticoagulation chelates calcium required for the

coagulation cascade to create clotting factors involved in thrombus
formation.
Cautions Hypocalcemia will occur, requiring supplemental calcium during use;

metabolic complications including hyponatremia, metabolic acidosis and
citrate toxicity can occur.
Note: Blood products are preserved in citrate to prevent clotting;
transfusion of a large amount of blood products or use of systemic citrate
infusions can lead to hypocalcemia and reduced blood pressure unless
concurrent calcium supplementation is provided.
ACD-A Solution • Dextrose 2.45 g/100 mL

(224 mmo/L • Sodium citrate 2.2 g/100 mL
sodium, 112.8
• Citric acid 730 mg/100 mL
mmol/L citrate)
Catheter Flush 4% citrate solutions have been assessed in maintaining catheter patency,
but are not commercially available in large quantities; ACD-A solution
has been used as an alternative; more concentrated citrate solutions have
been explored for additional antimicrobial properties but can lead to
metabolic effects if instilled into the systemic circulation.
Renal Regional citrate is one option to heparin to prevent thrombosis of the

Replacement hemodialysis circuit; protocols for its use should be developed in advance
Therapy and persons responsible for managing trained; protocols will vary
between dialysis circuits; in general, citrate anticoagulation can maintain
circuits and preserve filters longer than heparin-related anticoagulants.
(continued)
627
Example Citrate Citrate infusion:

and Calcium • Rate = circuit blood flow x 0.03
Protocol (using • Check ionized calcium q 6 hr
ACD-A solution in
• Adjust rate according to circuit ionized calcium level (1.0–1.4 mg/dL
CRRT)
(e.g., if rate 200 mL/hr, increase rate 30 mL/hr if <1 mg/dL, decrease
by 30 mL/hr if >1.4 mg/dL)
Calcium infusion:
• Make a calcium gluconate IV solution of 12 g in 0.9% NaCl total
volume of 250 cc (or 24 g in 500 cc 0.9% NaCl)
• Infuse 30 mL/hr via the central line
• Calcium level every 6 hr (target ionized calcium of 3.7–4.4 mg/dL)
• <3 mg/dL: stop citrate for 30 min; give 4 g calcium gluconate IV
over 2 hr via central line; increase calcium infusion by 20 mL/hr and
decrease citrate infusion by 30 mL/hr
• 3.0–3.19 mg/dL: give 2 g calcium gluconate IV over 1 hr via central
line; increase calcium infusion by 15 mL/hr
• 3.2–3.6 mg/dL: increase calcium gluconate infusion by 10 mL/hr
• 4.5–4.8 mg/dL: decrease calcium gluconate infusion by 10 mL/hr
• 4.9–5.6 mg/dL: decrease calcium gluconate infusion by 15 mL/hr
• >5.6 mg/dL: hold calcium infusion
At very low or high levels, physician notification should be considered.
hr: hours, IV: intravenous, min: minutes, NaCl: sodium chloride, q: every
Source: Burry LD, Tung DD, Hallett D, et al. Regional citrate anticoagulation for PrismaFlex
continuous renal replacement therapy. Ann Pharmacother. 2009;43:1419–1425.
F APPENDIX
EXAMPLES OF AVAILABLE
BLEEDING DEFINITIONS a
Bleeding TIMI GUSTO-1 Landefeld ISTH

Severity Bleeding Index (Nonsurgical)
Severe ICH or Fatal—death

or Life- bleeding with Life-threatening—
Threatening hemodynamic producing MI,
compromise stroke, surgical
requiring intervention
intervention Potentially life-
threatening (two
of the following):
• severe blood
loss
• hypotension
(>20% drop
in SBP to
<90 mm Hg)
• critical
anemia (↓
Hct 20% to
25% or less)
Major ICH Fatal Fatal

↓ Hct ≥15% Severe ≥3 units of Symptomatic
↓ Hgb ≥5 g/dL blood loss bleeding in a
Each transfused critical area or
unit counts as 1 organ
g/dL Hgb or 3% ↓ Hgb ≥2 g/
Hct dL leading to
transfusion of
≥2 units of whole
blood or red cells
Moderate Bleeding that ≥2 units and

requires blood <3 units
transfusion with
hemodynamic
compromise
(continued)
629
Bleeding TIMI GUSTO-1 Landefeld ISTH

Severity Bleeding Index (Nonsurgical)
Minor GI or GU bleeding Overt bleeding:

observed: GI, hemoptysis,
↓ Hct ≥10% hematuria
↓ Hgb ≥3 g/dL Transfusion ≥1
Not observed: unit and <2 units
↓ Hct ≥12% of blood
↓ Hgb ≥4 g/dL Blood loss ≥1
unit/week or ↓
Hct
>20% discharge
Hct <30% +
blood loss of ≥1
unit/week + drop
of Hct of 20% or
more
a
The definition of bleeding has varied between clinical trials. A universally accepted approach is
not currently in place.
GI: gastrointestinal, GU: genitourinary, Hct: hematocrit, Hgb: hemoglobin, ICH: intracerebral
hemorrhage, MI: myocardial infarction, SBP: systolic blood pressure
Sources: Landefeld CS, Anderson PA, Goodnough LT, et al. The bleeding severity index:
validation and comparison to other methods for classifying bleeding complications of medical
therapy. J Clin Epidemiol. 1989;42:711–718; Schulman S, Kearon C. Subcommittee on Control
of Anticoagulation of the Scientific and Standardization Committee of the International Society
on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694;
Rao SV, O’Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by
two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol.
2006;47:809–816.
G
APPENDIX
TYPES OF CNS HEMORRHAGE
ICH: Types
Skull
Subdural
Epidural Hemorrhage
Hemorrhage
Dura
Arachnoid
Subarachnoid
Hemorrhage Pia
Pia
Dura Intraventricular
Hemorrhage
Intracerebral
Midline Shi
Hemorrhage
631
APPENDIX
H
DISSEMINATED INTRAVASCULAR
COAGULATION
Disseminated intravascular coagulation (DIC) is characterized as a systemic intravas-

cular activation of coagulation, which is triggered by a clinical situation, leading to
microvascular deposition of fibrin that can lead to organ dysfunction. The activation
of coagulation may deplete platelets and coagulation factors leading to bleeding.
Causes Sepsis/severe infection

Malignancy
Trauma
Obstetrical (amniotic fluid embolism, abruptio placentae)
Severe toxic or immunologic reactions
• Snake bites
• Recreational drugs
• Transfusion reactions/ABO-incompatible transfusion reaction
• Transplant rejection
• Vascular abnormalities (aortic aneurysm and Kaposiform hemangioendothelioma
or Kasabach Merrit syndrome)
• Severe hepatic failure
Acute pancreatitis
Acute promyelocytic leukemia
Brain injury
Severe burns
Hypothermia/hyperthermia
Fat emboli
Diagnosis Severe thrombocytopenia

Elevated fibrin markers (D-dimer, fibrin degradation products)
Prolonged international normalized ratio or prothrombin time
Fibrinogen level <1 g/L
Management Treat underlying disorder

Transfuse only for active bleeding
Tranexamic acid if still significantly bleeding after trying blood components
Heparin in selected circumstances
LMWH as treatment for patients who develop thrombosis (acral ischemia) in the
context of DIC and also as prophylaxis in those at risk of thrombosis but not bleeding
Antithrombin (laboratory indices improved, mortality benefit unclear)
Thrombomodulin
632
I
APPENDIX
NONDRUG CAUSES OF
THROMBOCYTOPENIA
Alcoholism
Anemia
Antiphospholipid syndrome
Blood transfusions/massive transfusion
Burns
Disseminated intravascular coagulation
Extracorporeal circulation
Hemolytic uremic syndrome/uremia
Human immunodeficiency virus (HIV)
Hyperthyroidism
Hypothermia
Idiopathic thrombocytopenic purpura
Intra-aortic balloon pump
Liver disease/hypersplenism
Myelodysplastic or metastatic disease
Nutritional deficiencies
Paroxysmal nocturnal hemoglobinuria
Pregnancy
Primary hematologic disorder
Pseudothrombocytopenia
Sepsis/infection
Systemic lupus erythematosus
Thrombotic thrombocytopenic purpura
Vasculitis
633
APPENDIX
J
DRUG-RELATED CAUSES OF
THROMBOCYTOPENIA
Agents Implicated in Drug-Induced Thrombocytopenia
Abciximab 0.5–1%: first exposure A

10–14%: second exposure
Acetaminophen NK C
Adefovir dipivoxil NK C
Alfuzocin NK C
Alprenolol NK C
Aminoglutethimide NK C
Amiodarone NK C
Aminosalicylic acid NK C
Amphotericin B NK C
Ampicillin NK C
Captopril NK C
Carbamazepine NK C
Chlordiazepoxide–clidinium bromide NK C
Chlorothiazide NK C
Chlorpromazine NK C
Chlorpropamide NK C
Cimetidine NK C
Danazol NK C
Diazepam NK C
Diatrizoate meglumine <1% C
Diazoxide NK C
Deferoxamine NK C
(continued)
634
APPENDIXES 635
Diclofenac <1% C
Digoxin NK C
Efalizumab 0.3% A
Ethambutol NK C
Etretinate NK C
Eptifibatide 0.2–0.5% A
Famotidine NK C
Fenofibrate NK C
Fluconazole NK C
Glyburide NK C
Gold salts 1–2% C
Haloperidol NK C
Heparin 3–6% A
Hydrochlorothiazide NK C
Interferon alfa NK C
Ibuprofen <1% C
Iloprost NK C
Isoniazid NK C
Linezolid 21% C
Levamisole NK C
Lopinavir/ritonavir NK C
Methyldopa NK C
Minoxidil NK C
Meloxicam NK C
Moxifloxacin NK C
Nalidixic acid NK C
Naphazoline NK C
Naproxen <1% C
Nitroglycerin NK C
Octreotide NK C
(continued)
Oxprenolol NK C
Pentoxifylline NK C
Phenytoin NK C
Piperacillin NK C
Procainamide 1% C
Quinidine <1% C
Quinine <1% C
Ranitidine NK C
Rifampin NK C
Simvastatin <0.1% C
Sulfasalazine <1% C
Sulindac <1% C
Tamoxifen NK C
Terbinafine NK C
Thiothixene NK C
Tirofiban 0.2–0.5% A
Tolmentin <1% C
Trimethoprim–sulfamethoxazole NK C
Sulfisoxazole NK C
Valproate 220% C
Vancomycin NK A
a
Definitions for Levels of Evidence: Level A—evidence from one or more randomized, controlled
clinical trials; Level B—evidence from nonrandomized clinical trials, prospective observational
studies, cohort studies, retrospective studies, case-control studies, meta-analyses, and/or
postmarketing surveillance studies; and Level C—evidence from one or more published case
reports or case series.
NK: not known
Source: Weddle KJ, Kiel PJ. Thrombocytopenia. In: Tisdale JE and Miller DA, eds. Drug-Induced
Diseases: Prevention, Detection, and Management. 3rd ed. Bethesda, MD: American Society of
Health-System Pharmacists; 2018;1050–1051.
K APPENDIX
EXAMPLES OF TRANSFUSION-
RELATED REACTIONS
Noninfectious Infectious Immunologic
Transfusion reactions Bacterial Multisystem organ failure

• hemolytic • Creutzfeldt-Jakob Infections and sepsis
• disseminated intravascular Viral T-cell dysfunction
coagulation (DIC) • hepatitis (A,B,C,E,G) Macrophage dysfunction
Alloimmunization
• febrile nonhemolytic • HIV, HTLV I, and II
Graft-versus-host disease
• anaphylaxis • Epstein-Barr (GCHD) (immune compromised
• post-transfusion purpura • parovirus patients)
• acute lung injury • cytomegaloviris
• incompatibility reactions Parasitic
from blood typing errors • malaria
Embolism • babesiosis
• air of fat • Chagas’ disease
Hypotension
Hypothermia
Metabolic disturbances
• citrate-related
anticoagulation (if calcium
co-administration not
included)
• hypocalcemia
• hyperkalemia
• acidosis
• hyperammonemia
637
APPENDIX
L
CONSIDERATIONS FOR
TRANSITIONING FROM aPTT TO
ANTI-Xa TO MANAGE HEPARIN
THERAPY
1. Identify who will be coordinating the process and members of the working group.
It should include laboratory services, hospital informatics, pharmacy, nursing, and
selected physicians.
2. Determine the timeframe available for implementing the change where the current
aPTT lot may run out or expire.
3. Assign an individual who will coordinate the process and meetings to assign tasks
and deadlines.
4. Research available literature to understand current knowledge of the two assay
approaches.
5. Determine that reporting turnaround times to report values are the same.
6. Assign champions to develop the necessary education materials customized to all
clinicians impacted (e.g., laboratory, nursing, prescribers, pharmacy).
7. Identify all order sets that include heparin therapy and the test (aPTT) used for manage-
ment; order sets that include a test (aPTT) intended to assess if heparin effects are
present prior to an intervention.
a. When making changes to order sets, identify prescribing champions to
review changes.
b. Make sure order sets comply with hospital policy.
8. Identify all policies involved, and make the necessary changes.
9. Consider a role for the aPTT as a baseline test to determine any independent drivers
for bleeding. Adding a baseline anti-factor Xa may assist in determining presence of
an oral anti-factor Xa antagonist.
10. Adjust reports and any customized data flow sheets generated in the electronic records
to show the reported anti-Xa activity result.
11. The common goal is 0.3−0.7 units/mL; however, lower goals may be considered in
higher bleeding risk situations or when lower thrombosis risks are present. Values <0.3
units/mL may be considered for thromboprophylaxis targets.
12. After implementation, provide resources to assist with questions. A document on
frequently asked questions should be prepared in advance and include the following:
a. Instructions on where information is found and descriptions of the test.
638
APPENDIXES 639
b. Clinical Information such as the difference between tests, target

ranges, baseline values, how to respond to unexpected values such
as high baseline values, etc.
c. Pharmacy information on approaches to customize orders and what
should be avoided, target range modification if bleeding concerns
are present, continued assessment for other adverse effects (e.g.,
heparin-induced thrombocytopenia, bleeding), sampling time
relative to bolus dosing.
d. Laboratory Information such as assay turnaround time, collection
tube, how to order laboratory tests, common items interfering
with the anti-Xa assay (e.g., hemolysis), how to contact laboratory
for questions.
e. Additional resources available and where to access.
Observations:
1. Variability between anti-Xa and aPTT values will occur. Samples may show high
anti-factor Xa and low aPTT, or low anti-factor Xa and high aPTT values. Therefore,
the response between assays may not be consistent. This is expected because
correlation has always been known to be poor. (See Chapter 21 on laboratory
measures on determining therapeutic aPTT levels based on anti-factor Xa levels.)
2. If other anti-factor Xa tests are also available but utilize a different calibrator,
make sure this is clearly described in the ordering process. It is strongly recom-
mended to list the test in your electronic medical record based on the agent
you want to estimate the level, not the assay type used (i.e., list as “heparin
level” or “apixaban level,” or anti-factor Xa—heparin, anti-factor Xa—apixaban
instead of “anti-factor Xa” to ensure correct test is used).
3. The aPTT most likely cannot be fully replaced if parenteral direct thrombin
inhibitors are used, or testing necessary to hemophilia’s heparin is used after
Xa inhibiting direct oral anticoagulants, etc.
4. No test is perfect, and there are situations impacting the aPTT or anti-Xa
independently or together.
5. Review of revised electronic order sets should be carefully done before going
live. It is important for a pharmacist to review dose titrations, even if nurses
primarily handle dose titrations, to ensure drips receive critical review.
6. In the presence of an oral anti-factor Xa inhibitor, the baseline anti-factor Xa
assay may be elevated. The process for patient care and change to heparin
in this setting may depend on the situation, including the indication for anti-
coagulation, history of the oral anticoagulant, and observed anti-factor Xa value.
Handling these titrations is still an evolving science, but one consideration is
to use the aPTT in the short term if the patient has an active thrombosis, or
withholding heparin therapy if no active thrombosis and it is likely the patient is
still fully anticoagulated. (Laboratory testing may be helpful to determine this.)
Anti-Factor Xa aPTT Influencing Situation
Increase Increase Poor blood sampling

Underfilled tubes
Impaired renal function (↓ elimination)
Increase Little/no effect Recent use of other anti-Xa agents

Triglyceride >360 mg/dL
Decrease Increase Inadequate centrifugation (inadequate platelet removal)
Decrease Little/no effect Gross hemolysis in sample

Total bilirubin >6.6 mg/dL
Decrease Decrease Increased heparin binding proteins

Obesity (higher tissue distribution)
AT deficiency (depending if anti-Xa test adds AT)
Little/no effect Increase High citrate concentration in collection tube

↓ Clotting factors (vitamin K antagonists or liver disease)
Consumptive coagulopathy
Lupus anticoagulant
Specific low clotting factors (factor IX, XI, XII, prekallikrein)
Elderly
aPTT: activated partial thromboplastin time

M APPENDIX
PIONEER AF-PCI
The PIONEER AF-PCI evaluated 2,124 patients who had atrial fibrillation and
needed percutaneous coronary intervention with stenting.
• Patients were randomized to low-dose rivaroxaban (15 mg once daily) plus a clopido-
grel, ticagrelor, or prasugrel inhibitor for 12 months, very low-dose rivaroxaban (2.5 mg
twice daily) plus dual antiplatelet therapy for 1, 6, or 12 months, or standard therapy
with a dose-adjusted vitamin K antagonist (once daily) plus dual antiplatelet therapy
for 1, 6, or 12 months. The primary safety outcome was clinically significant bleeding.
Note the trial was powered based on bleeding outcomes, not thrombotic outcomes.
• Lower rates of clinically significant bleeding were found in the two groups receiving
rivaroxaban than in the standard warfarin triple therapy group. No clear differences
were seen in efficacy outcomes, however broad confidence intervals warrant caution
in interpreting the findings.
Reference
1. Gibson CM, Mehran R, Bode C, et. al. Prevention of bleeding in patients with atrial fibrillation
undergoing PCI. N Engl J Med. 2016;375:2423-2434.
641
APPENDIX
N
BETRIXABAN APEX TRIAL
Betrixaban is the only agent approved for extended prophylaxis in medically ill
patients. In the APEX trial (Acute Medially Ill VTE Prevention with Extended Duration
Betrixaban), an 180 mg loading dose, followed by 80 mg once daily for 35–42 days
provided a statistically significant 32% relative reduction in VTE events compared to
enoxaparin for 6–10 days, without a significant increase in major bleeding. Clinically
relevant non-major bleeding was significantly increased with betrixaban. Although
a reduced dose of betrixaban (80 mg loading dose, followed by 40 mg daily) was
used in patients with a CrCl of 15–29 mL/min or with a P-glycoprotein inhibitor,
the efficacy of this reduced dose was not different than enoxaparin followed by
placebo, and did increase clinically relevant non-major bleeding.
Reference
1. Cohen AT, Harrington RA, Goldhaber SZ, et al., for the APEX investigators. Extended
thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med.
2016;375:534-544.
642
INDEX
bleeding in, 366, 369

A diagnostic criteria for, 365
Abciximab, 379 direct oral anticoagulants in, 385-386
Acenocoumarol, 14 dosing in, 258
Activated clotting time, 530-531 dual antiplatelet therapy in, 383-384
clinical applications of, 531 electrocardiographic findings in, 364
Activated partial thromboplastin time (aPTT), epidemiology of, 363
520 glycoprotein IIb/IIIA inhibitors in, 379
argatroban and, 525 heparin-induced thrombocytopenia,
bivalirudin and, 91 442-443
coagulation testing and, 520-521 injectable anticoagulant monitoring in, 376
direct thrombin inhibitors and, 92, 96, 97, major bleeding risk factors in, 371
525-526 pathophysiology of, 364
measurements between point-of-care and P2Y12 inhibitor in, 377
central lab, 517
risk stratification for NSTE in, 366-369
transitioning to anti-Xa for heparin
signs of, 363, 365
management, 638-640
symptoms of, 365
unfractionated heparin and, 366-367, 370,
521-524 triple antithrombotic therapy in, 380-383
variables in, 514-515 Acute liver dysfunction, 19
Activated protein C resistance Acute spinal cord injury, 303, 304
with factor V-deficient plasma, 556 Agency for Healthcare Research and Quality,
612, 613
testing, 563
Aggregation, 507
treatment considerations, 566
Alere, 611
Activated prothrombin complex concentrates,
166, 202 Alteplase
Activated thrombin time, 49 catheter occlusion and, 114
Acute coronary syndrome deep vein thrombosis and, 112
anticoagulant guidelines for, 371-375 frostbite and, 117
anti-factor Xa activity with low molecular intracranial hemorrhage risk with, 122
weight heparin, 370-371 ischemic stroke and, 113
aPTT and anti-factor Xa for unfractionated mechanical circulatory support devices
heparin, 366-367, 370 and, 116
arterial femoral sheath and, 376 peripheral arterial occlusion and, 114
aspirin therapy in, 377 pleural effusion/empyema and, 115
bivalirudin dosing in, 92 prosthetic heart valve thrombosis and, 116
bivalirudin efficacy and, 385 pulmonary embolism and, 111
643
ultrasound-facilitated, catheter Anticoagulation Centers of Excellence, 577

directed, low-dose thrombolytics Anticoagulation Forum, 5, 577, 610, 611,
and, 117, 118-119 612
See also Recombinant tissue plasmino- Boot Camp, 588
gen activator
Anticoagulation management service
American College of Cardiology, 4, 587 (AMS)
evidence grades of, 7 clinical endpoints for, 599-600
American College of Chest Physicians disease state protocols/guidelines for,
(ACCP), 4 580-581
anticoagulation recommended duration direct oral anticoagulants and, 593-595
by, 340
electronic media care delivery in, 592
atrial fibrillation stroke risk stratification
by, 351 hospital setting standards of practice
for, 581-583
evidence grades of, 6
in-clinic vs. telephonic care delivery
grading recommendations of, 450 in, 592
guidelines of, 5, 271 inpatient care structure in, 577-578
platelet count monitoring by, 61, 427 inpatient service hierarchy in, 579
venous thrombolytic embolism bleed- inpatient standards of practice in,
ing and, 340 578-580
American College of Clinical Pharmacy, INR in range and, 599
610
INR variability and, 598-599
American College of Obstetrics and
Gynecology, 450 lab vs point-of-care INR testing in, 591
American Heart Association (AHA), 4, 587 nonadherence management in, 594
evidence grades by, 7 outpatient panel-based workload in,
589-590
grading recommendations of, 405
outpatient structure in, 589
guidelines of, 5
outpatient team-based workload in,
American Journal of Health-System 590
Pharmacy, 609
outpatient therapy and, 588-589
American Pharmacists Association, Billing
Boot Camp, 613 patient education and, 584, 586
American Society of Clinical Oncology, patient self-testing, self-management
treatment guidelines of, 271 and, 591-592
American Society of Health-System patient-centered care, shared decision
Pharmacists (ASHP), 608, 610, 611, 613 making and, 587
guidelines, 5 pharmacist run vs. nurse run in,
American Society of Hematology, 610 590-591
Aminocaproic acid, 174, 180 provider training, competency in, 587,
588
Amiodarone, cardioversion, 356
quality improvement in, 584, 600-601
Andexanet alfa, 139, 178-179, 200, 206,
209, 539 quality metrics for, 598
Androgenic agents, 619 regulatory standards for, 583
Annals of Internal Medicine, 609 standards of practice for, 595-597
Annals of Pharmacotherapy, 609 time-in-therapeutic range in, 597-598
Antiandrogens, 619 transitions of care and, 587
Anticardiolipin antibodies, 554, 557 Anticoagulation resources, 588
Anticoagulant monitoring Anticoagulation therapy
in hospital setting, 582 ACCP recommended duration for, 340
injectable, 376 nutrition and, 623-624
Anticoagulants. See specific anticoagu- restarting, 218-219
lants
INDEX 645
risk factors to determine length of, reversal of, 209

341-342 as secondary acute coronary syndrome
Anti-factor Xa antagonists prevention, 385-386
potential antidotes for, 207-208 stroke prophylaxis dosing for, 257
chromogenic process for activity in, venous thrombolytic embolism and,
528 255, 256
Antifibinolytic agents, 180 warfarin, other direct oral anticoagu-
Antineoplastic agents, 619-620 lants comparison for, 134-139
Antiphosholipid antibody syndrome, 561 Argatroban
testing for, 564 acute coronary syndromes, 442-443
treatment considerations in, 567-568 aPTT reagents for response to, 525
Antiplatelet agents dosing/administration of, 86-88
mechanical circulatory support, 409 elimination of, 203, 204
regional anesthesia and, 238-239 fetus and, 451
Antipsychotic agents, 621 hemodialysis and, 90
Antithrombin deficiencies, 553, 563 heparin-induced thrombocytopenia
and, 91, 435, 437
treatment considerations in, 566
hepatic dysfunction and, 89, 264, 265
Antithrombin tests, natural anticoagulant
deficiencies, 556 influence on selected assays by, 98
Anti-ß2-GPI antibodies, 554, 557 lactation and, 456
APC resistance testing, 553 mechanical circulatory support and,
409
Apixaban, 48, 203
open heart surgical procedures and, 99
andexanet alfa antidote for, 179
pediatric heparin-induced thrombocy-
body weights studied and, 267 topenia and, 444
commercial availability of, 131 in pediatric patients, 101, 492-493
dosing of, 154, 155 pharmacokinetics of, 86
drug interactions with, 140 pregnancy, lactation and, 102
in elderly patients, 266, 267 renal impairment and, 89, 253
fetus and, 451 side effects, precautions, contraindica-
hepatic dysfunction and, 264 tions for, 103
heparin-induced thrombocytopenia Aripazine, 179
and, 436 Arizona Pharmacy Association Anticoagu-
lactation and, 456 lation Certificate Program, 588
measuring, reversing, 206 Aromatase inhibitors, 619
medically ill and, 456 Arterial femoral sheath management, 376
nutrition and, 623-624 Aspirin (ASA), 306, 341, 349
orthopedic surgery and, 300-301, 302 for acute coronary syndrome, 377
patient and agent selection for, 149, bioprosthetic valves and, 402
150, 151 fetus and, 451
patient counseling for, 158 lactation and, 456
in pediatrics, 496 in mechanical valve replacement, 399
periprocedural management of, 232 in orthopedic surgery, 299
pharmacodynamic properties of, 233 patient, agent selection and, 150
pharmacokinetics of, 268, 269 pediatric venous thrombolytic
pharmacology of, 132-133 embolism prophylaxis and, 484
phase III trials of, 135-138, 144, secondary acute coronary syndrome
146-148, 339 prevention with, 385-386
renal impairment and, 253, 308 thrombolytic agents and, 123-127
Aspirin plus clopidogrel, 123-127, 349 mechanical circulatory support and,

Atrial fibrillation, 347 409
antithrombotic therapy and, 349 NSTE acute coronary syndrome guide-
lines for, 375
bridging and, 245
open heart surgical procedures and, 99
catheter ablation and, 359
PCI and, 385
classification of, 348
echocardiography and, 354 topenia and, 444
morbidity, mortality and, 347 in pediatric patients, 101, 493, 494
nonpharmacologic prevention and, pharmacokinetics of, 86
357-359
pregnancy, lactation and, 102
nonvalvular stroke risk, treatment
guidelines, 349, 351-355 renal impairment and, 89, 253
optimal warfarin intensity in, 355 reversal of, 203, 204
pregnancy and, 470 side effects, precautions, contraindica-
tions of, 103
rate vs. rhythm control and, 348
STEM1 primary PCI guidelines for, 372
stroke prevention algorithm for, 350
thrombolytic agents and, 123-127
Bland-Altman plots, 515, 516
B Bleeding
definitions for, 369, 629-630
Bariatric surgery, 269
interventions for, 415
venous thrombolytic embolism treat-
ment and, 295, 298 mechanical circulatory support devices
and, 415
Baseline assessment, in hospital setting,
581 risk factors for, 188
Betrixaban, 48, 203 risk scoring systems for, 31-32
in APEX trial, 642 thrombosis risk and, 190
medically ill and, 295 Blood, 609
in pediatrics, 496 Bridge to decision, 406
Bileaflet mechanical heart valve, 394, 396, Bridge to recovery, 406
397 Bridge to transplant, 406
Biodegradable polymer stent, 383 Bridge to transplant candidacy, 406
Biolimus stent, 383 Bridging therapy, 223
Bioresorbable stent, 383 atrial fibrillation and, 245
Bivalirudin, 85-86 between parenteral anticoagulants,
acute coronary syndrome dosing of, 240, 241-242
92, 258-259, 442 clinical trials summary for, 229-231
administration/dosing of, 87-88 direct oral anticoagulants and, 228
aPTT range for heparin-induced throm- low molecular weight heparin and,
bocytopenia, 91 226-228
arterial femoral sheath management mechanical/bioprosthetic heart valves
and, 376 and, 243-244
cardiac surgery and, 443 parenteral anticoagulation to oral
fetus and, 452 warfarin and, 240
hemodialysis and, 90 venous thrombolytic embolism and,
245-246
hepatic dysfunction and, 89, 264
VKA to parenteral therapy transition
heparin-induced thrombocytopenia in, 226
and, 91, 435, 437
warfarin to parenteral therapy and, 226
influence on selected assays by, 98
Burns, 303, 305
lactation and, 456
INDEX 647
Clotting endpoint, 507

C Coagulation assays, direct Xa agents,
538-539, 543
Caged-ball mechanical heart valve, 394,
395, 397 Coagulation cascade, 617
Cancer, 270 Coagulation factor VIIa. See Recombinant
activated factor VIIa
Khorana Scale and, 272
Coagulation testing
low molecular weight heparin dosing
for, 273-274 activated clotting time and, 530-531
-related thromboembolism, 272-273 aPTT, 520-521
treatment guidelines for, 271 aPTT and parenteral direct thrombin
inhibitor monitoring, 525-526
Cardiac surgery
aPTT and unfractionated heparin,
atrial fibrillation ablation, unfraction-
521-524
ated heparin in, 45
assay calibration in, 509
heparin-induced thrombocytopenia
and, 443 available assay tests for, 508
Cardiopulmonary bypass surgery, heparin- chromogenic factor X assay for, 532
induced thrombocytopenia evaluation dabigatran for, 537
and, 430
direct oral anticoagulants and, 536-542
Cardiovascular diseases, pregnancy and,
dRVVT (dilute Russell’s Viper Venom
470
Time) and, 534
Cardioversion
ecarin-based testing and, 532-533
electrical vs. pharmacologic, 356
heparin and anti-Xa level in, 527
stroke prevention considerations in,
implementing new, 509-511
355-357
laboratory data evaluation for, 515-517
treatment algorithm for, 356
methods of, 507-508
Catheter ablation, 45, 359-360
prothrombin time, INR and, 514-515,
Centers for Medicare & Medicaid Services,
517-520
606, 607
sample collection for, 513
Central nervous system hemorrhage types,
631 specificity in, 512
CHADS2 score, 351-353, 360 thrombin generation curve in, 534-535
CHA2DS2 VASc score, 353-354, 360 thrombin time, dilute thrombin time
in, 533
Chemotherapy-associated venous throm-
bolytic embolism, 272 thromboelastography and, 544-546
CHEST, 609 variables affecting, 511-515
Chromogenic factor X assay, 532 College of American Pathologists, 521,
610
Chromogenic testing, 507
Compression devices, 306
Ciraparantag, 539
Compression ultrasound, 470
Circulation, 609
Computed tomographic scans, 470
Citrate anticoagulation, 627-628
pulmonary angiography, 326
Clinical trials, 4-8, 9. See also specific drug
phase III trials Continuous renal replacement therapy,
heparin adjustments in, 56
Clopidogrel
Contraception, thrombophilia and, 565
in acute coronary syndrome, 377-378
Contrast agents, 621
fetus and, 452
Coronary artery, cross section of, 364
lactation and, 456
Coronary artery bypass graft (CABG)
in secondary ACS prevention, 385-386
unfractionated heparin in graft, 45
Clopidogrel plus aspirin, 123-129, 349
venous thrombolytic embolism treat-
ClotCare, 5, 610
ment in, 295, 299
Critical care, 303, 305 Dabigatran etexilate, 86

Critically ill patients Dalteparin, 65
direct thrombin inhibitors and, 91, 92 ACCP/ACOG regimens for, 460-461
low molecular weight heparin and, 82 acute coronary syndromes dosing for,
venous thrombolytic embolism prophy- 258-259
laxis in, 303-306 acute spinal cord injury and, 304
Cultural competence resources, 612 bariatric surgery and, 308
body weights studied with, 267
burns and, 305
D in critical care, 305
Dabigatran, 203 FDA-approved indications, dosages
body weights studied for, 267 for, 68-69
coagulation assays and, 537 fetus and, 452
commercial availability of, 131 in general surgery, 296
compared to direct oral anticoagulants, hemodialysis circuit and, 260, 263
134-139 lactation and, 456
compared to warfarin, 134-139, 401 low molecular weight heparin and, 201
concentration information for, 537-538 in orthopedic surgery, 300-301
drug interactions with, 141 in pediatrics, 490
elderly patients and, 266, 267 pharmacokinetics of, 67, 268, 269
estimating amount of, 542 pharmacology of, 67
fetus and, 452 renal impairment and, 80-81, 253, 254,
hepatic dysfunction and, 264 307
heparin-induced thrombocytopenia strengths, formulations available, 71
and, 435 trauma and, 304
lactation and, 456 venous thrombolytic embolism and,
measuring, reversing, 205 255, 256, 294, 337, 465
nutrition and, 623-624 Danaparoid, 443, 444
orthopedic surgery and, 300-301, 302 fetus and, 452
patient, agent selection and, 149-152 heparin-induced thrombocytopenia
and, 435, 438-439
patient counseling for, 158
lactation and, 457
in pediatrics, 496
periprocedural management of, 232 topenia and, 444
pharmacodynamic properties of, 233 DAPT, patient and agent selection, 150
pharmacokinetics of, 268 D-Dimer testing, 319-320
pharmacology of, 132-133 Decompensated heart failure, 21
phase III trials of, 135-138, 143, 145, Deep vein thrombosis (DVT), 313
147-148, 339
diagnosis of, 319
prolonged thrombin time and ecarin
clotting time with, 204 diagnostic algorithms for, 322-324
renal impairment and, 253, 308 diagnostic testing for, 319-320
reversal of, 207-208, 209 embolus crossover in, 318
stroke prophylaxis dosing of, 257 pathophysiology of, 314
testing for presence of, 542, 543 signs/symptoms of, 319
thrombin time, dilute thrombin time thrombolytic agents and adjunctive
for, 533 therapy for, 125
venous thrombolytic embolism and, Deep veins of lower leg, 315
255, 256 Delivery, anticoagulants and, 474
INDEX 649
Desirudin, 85 administration, dosing of, 86-90

Destination therapy, 406 antidote for, 177-178
Det Norske Veritas Healthcare, Inc., 606 aPTT and, 92, 96, 97, 525-526
Dialysis, unfractionated heparin in, 45, in lactation, 102
46, 47 measuring, reversing parenteral, 203,
Dilute Russell’s Viper Venom Time (dRVVT), 204
534 for mechanical circulatory devices,
Direct factor Xa inhibitors, 203 98-101
Direct oral anticoagulants, 131-132 monitoring considerations for, 95
anti-IIa, 540 in open heart surgery, 99
anti-Xa, 540 in pediatrics, 101
anticoagulation management service pharmacokinetics/pharmacodynamics
and, 593-594 of, 86
discharge checklist for, 157 pharmacology of, 85
dosing of, 153-155 in pregnancy, 102
drug interactions with, 139-142 reversal plan for, 202-203
in elderly patients, 265-266 side effects, precautions, contraindica-
tions for, 103
fetus and, 453
in special populations, 91-93, 98
in home treatment, 337
titrating infusion with bleeding
impact on other coagulation assays concerns and, 96
by, 541
transitioning and, 97-98, 234
interactions altering exposure to, 142
Direct Xa agents, 538-539
mechanical valve replacement and, 401
estimating amount of, 543
mechanism of action for, 133
testing for presence of, 543
monitoring of, 536
Disseminated intravascular coagulation,
nonadherence and, 594-595 632
in obesity, 308 Drug eluting stents, 383
overdose of, 207 Drug incompatibilities, with heparin, 58
patient, agent selection for, 149-152 Drug-induced thromboembolic diseases,
patient counseling for, 156, 157-158 agents implicated in, 618-622
pharmacokinetics/pharmacodynamics Duplex ultrasonography, 320
of, 134
pharmacology of, 132
phase III trials of, 134-138, 339 E
preconception planning and, 459 Ecarin
pregnancy and, 308 -based testing, 532-533
regional anesthesia and, 238-239 chromogenic assay, 533
reversal of, 203-207, 209, 539 Echocardiography, 354
safety, efficacy of, 142-149 Edoxaban, 48, 203
as stroke prophylaxis, 257-258, 262 commercial availability of, 131
testing algorithms for, 541-542 compared to warfarin, other direct oral
thrombophilia laboratory reactions anticoagulants, 134-139
with, 559-560 dosing of, 154-155
transitioning and, 228, 232, 234-237 drug interactions with, 141
in transitions of care, 156 in elderly patients, 266, 267
venous thrombolytic embolism and, fetus and, 452
262, 337-338 hepatic dysfunction and, 264
Direct thrombin inhibitors, 85 heparin-induced thrombocytopenia
adjustment scale for, 94 and, 436
lactation and, 457 STEM1 with fibrinolytics guidelines

measuring, reversing, 206 for, 373
patient, agent selection and, 150, 151 strengths, formulations available for, 71
patient counseling for, 158 trauma and, 304
in pediatrics, 496 venous thrombolytic embolism and,
255-256, 294-295, 336-337, 465
periprocedural management of, 232
Eponesesterol, 443
pharmacodynamic properties of, 233
Epoprostenol, 445
pharmacokinetics of, 268, 269
Eptifibatide, 379
pharmacology of, 132-133
Estrogen-containing agents, 619
phase III trials for, 135-138, 144,
146-148, 339 Everolimus stent, 383
renal impairment and, 253 Evidence grades, 6-7
stroke prophylaxis dosing for, 257, 258 Evidence-based guidelines, 4-11
in venous thrombolytic embolism, 255, Extracorporeal life support, 57-58
256 Extracorporeal membrane oxygenation,
Elderly patients, 265-267 57-58, 497-498
low molecular weight heparin and
fondaparinux in, 81
unfractionated heparin and, 60
F
Electronic media care delivery, 592 Factor levels elevation, 553
Enoxaparin, 65 Factor V Leiden mutation genetic test, 556
ACCP/ACOG regimens for, 460-461 Factor VIII test, 556
in acute coronary syndrome, 258-259, Factor IX test, 556
370-371, 442 Factor XI test, 556
in acute spinal cord injury, 304 Falling, 219
arterial femoral sheath management Fetus, anticoagulants and, 449-453
and, 376
Fibrinolytic system development, 499
in bariatric surgery, 308
Fibrinolytic therapy, 238-239
bleeding rates with, 71
Follicle-stimulating hormone, 619
body weights studied for, 267
Fondaparinux, 65, 443-444
burns and, 305
acute coronary syndromes dosing,
in elderly patients, 267 258-259
FDA-approved indications, dosages acute thrombosis, 18
for, 68-69
anti-factor Xa and, 75
fetus and, 452
bleeding rates for, 71
in general surgery, 296
body weights studied with, 267
hemodialysis circuit and, 260-261, 263
in critically ill patients, 303
lactation and, 457
dosing of, 67
low molecular weight heparin and, 201
in elderly patients, 81
low-weight patients and, 70
multiple-dose vials for, 70 FDA-approved indications, dosages for,
68-69
NSTE acute coronary syndrome guide-
lines for, 374 fetus and, 452
in orthopedic surgery, 300-301, 302 fixed-dose unfractionated heparin to,
242
in pediatrics, 488-489, 490
flushing and, 39
pharmacokinetics of, 67, 268, 269
in general surgery, 296
pharmacology of, 67
in heparin-induced thrombocytopenia,
renal impairment dosing, monitoring 435, 440
of, 80-81, 253, 254, 307
INDEX 651
in home treatment, 337 GUSTO bleeding, 369

lactation and, 457 Gynecologic surgery, 295, 298
in low-weight patients, 79
mechanism of action for, 66
monitoring parameters for, 75 H
morbid obesity and, 78-79 Health and Human Services, U.S. Depart-
ment of, 577
in neuraxial procedures, 74
Health and Medicine Division, 608
NSTE ACS guidelines for, 375
Health literacy resources, 612
in oncology patients, 79
Healthcare Facilities Accreditation
in orthopedic surgery, 300-301
Program, 606
patient education for, 76-77
Hematopoietic agents, 619
in pediatrics, 78, 491, 492
Hemodialysis
pharmacokinetics of, 65-67, 268, 269
circuit dosing considerations, 260-261
pharmacology of, 65-67
dabigatran removal by, 208
in pregnancy and pediatrics, 78
as reversal agent, 205
prothrombin complex concentrate and,
Hemolysis, 415-416
175-176
Hemostatic agents, 618
renal impairment and, 79-81, 253, 308
Heparin
reversal of, 199, 202
acute thrombosis and, 18
route of administration for, 67
anti-factor Xa and, 527-530
self-injection steps for, 77
antiphospholipid considerations for,
side effects, precautions, contraindica-
tions for, 71-72 568
STEM1 with fibrinolytics guidelines assay differences and, 432
for, 373 estimating subcutaneous regimen
strengths, formulations available for, 71 when transitioning from IV, 44
sub-Q to IV unfractionated heparin in hemodialysis, 261
and, 241-242 mechanical circulatory support and,
syringes, 70 407
thrombolytic agents and, 123-127 morbidly obese patients and, 269
transitioning from direct oral antico- thrombophilia lab reactions and,
agulants to, 237 559-560
in venous thrombolytic embolism, 255, in venous thrombolytic embolism, 256
256, 294, 336 Heparin locks, 38
Food and Drug Administration, guidelines Heparin-induced thrombocytopenia (HIT),
of, 5 72, 308, 423
Fresh frozen plasma, 166 in acute coronary syndromes, 442-443
administration considerations for, agents used for, 435-441
170-171 alternative agents in bypass graft
prothrombin complex concentrate and, surgery, 445
174 assays for potential presence of, 431
Frostbite, 127 in cardiac surgery, 443
cardiopulmonary bypass surgery and,
430
G development factors for, 426
Gastrointestinal bleeding, 219 direct thrombin inhibitors and, 86-87,
General surgery, 295-296 89
Glycoprotein IIb/IIIA inhibitors, 379 disorders mimicking, 426
GRACE risk score, 368 identification of, 423-424
initial pharmacotherapy management anticoagulation management service

of, 433-434 and, 591, 598-599
maintaining lines in, 444 applications of, 519-520
in pediatrics, 492 coagulation testing and, 514-515,
phases of, 425 517-520
platelet count monitoring in, 427 diagnostic testing facilities for, 611
post probability assessment tool for, laboratory data evaluation and, 516
430, 431 measurements between point-of-care
in pregnancy, 443-444 and central lab, 516
pretest probability scoring for, proportion in range, 599
428-429, 431 prosthetic valves and, 400, 401-402
related disorders and, 424 variability in, 598-599
terminology for, 424 Vitamin K and, 211
when to begin therapy for, 442 warfarin and, 26, 28-30
Hepatic impairment, 19 International Society of Thrombosis and
agents used in, 264 Haemostasis, 453-454, 610
Child-Pugh score for, 263 Academy, 588
Homocysteine test, 558 Intra vena catheter filter, 305
Hormone replacement therapy, 565 Intravenous catheter occlusions, 498-499
Hospital Acquired Condition Reduction Ischemic stroke
Program, 607 anticoagulants and, 625-626
Hospital Compare web site, 607
thrombolytic agents and adjunctive
Hospital Consumer Assessment of Health- therapy in, 126
care Providers and Systems Survey, 607
Hospital Inpatient Quality Reporting
Program, 607 J-K
Hypercoagulable states. See Thrombo-
philias Joint Commission, The, 606, 608
Hyperhomocysteinemia, 555, 558, 569 03.05.01 goal, 583
Hypothermia, 46 National Patient Safety Goal for anti-
coagulation, 3-4
Journal of Thrombosis and Haemostasis,
I 609
Journal of Thrombosis and Thromolysis,
Idarucizumab, 139, 177-178, 205, 207-209, 609
539
Knee arthroscopy, 299
Immunologic agents, 620-621
Immunologic testing, 507-508
Immunomodulation, 445 L
Impella, unfractionated heparin in, 46
Labetalol, 333
Inferior vena cava filters, 291, 294, 334
Labor, anticoagulants and, 474
comparisons of, 293
Laboratory data evaluation methods,
placement of, 292, 334-335 515-517
potential complications with, 335 Laboratory data evaluation
Inpatient care delivery aPTT measurements between point-of-
standards of practice for, 578 care and central lab, 517
structure of, 577-578 INR measurements between point-of-
Institute for Healthcare Improvement, 608 care and central lab, 516
Institute for Safe Medication Practices, 608 Lactation
International normalized ratio (INR), anticoagulant safety and, 456-458
517-518 direct thrombin inhibitors in, 102
INDEX 653
Left atrial appendage obliteration, strengths, formulations available for, 71

357-358 sub-Q to IV unfractionated heparin,
Lepirudin, 85, 444 241-242
Low body weight, 267-270 syringes for, 70
Low molecular weight heparin (LMWH) 65 thrombocytopenia and, 72-73
acute coronary syndrome and, 370-371 thromboembolism and, 262, 306,
acute thrombosis and, 18 336-337, 465, 472-473
administration of, 70 thrombolytic agents and, 123-127
anti-factor Xa monitoring and, 75-76 thrombophilia laboratory reactions and,
559-600
bridging with, 226-228
transitioning considerations for, 234,
cancer and, 270, 273-274 237
in critically ill patients, 82, 303, 305 twice-daily dosing for, 76
dosing of, 67 venous thrombolytic embolism and, 50
in elderly, 81 Low-weight patients
FDA-approved indications, dosages direct thrombin inhibitors and, 91
for, 68-69
low molecular weight heparin and
fetus and, 452 fondaparinux for, 79
fixed dose unfractionated heparin to, unfractionated heparin and, 60
242
Lupus anticoagulant, 554, 557
in home treatment, 337
in labor, delivery, 474-475
in low-weight patients, 79 M
maternal safety and, 455
Magnetic resonance direct thrombus
in mechanical valve anticoagulation imaging, 470
bridging, 398
Maternal safety, 455
mechanism of action in, 66
Maze procedure, 358
monitoring of, 75, 490-491
mdNR, 611
neuroaxial procedures and, 73-74, 233
Mechanical circulatory support devices
obesity and, 78-79, 269-270, 308
anticoagulation by device, 410-412
in oncology patients, 79, 81
antithrombotic considerations with,
patient education for, 76-77 406-407, 413-414
in pediatrics, 484-485, 488-489 bleeding and, 415
pharmacology, pharmacokinetics of, in cardiac support, 408
65-67
complications management for,
platelet count monitoring and, 61 414-419
in pediatrics, 78
diagnoses requiring, 405-406
in pregnancy, 78, 308, 459, 465, 470,
direct thrombin inhibitors and, 98-101
472-473
durable support devices for, 407, 408,
protamine and, 199
411-412
prothrombin complex concentrate and,
175-176 hemolysis and thrombosis with,
415-417
regimens for, 460-461
indications for, 406-407
regional anesthesia and, 238-239
temporary support devices and, 407,
renal dysfunction and, 79 408, 410-411
reversal of, 73, 200, 201 Mechanical/bioprosthetic heart valves
route of administration for, 67 bridging and, 243-244
self-injection steps for, 77 pregnancy and, 468-469
side effects, precautions, contraindica- Medicare Value-Based Purchasing, 607
tions of, 71-72
Merit-Based Incentive Payment System, venous thrombolytic embolism treat-

607 ment in, 308
Meta-analysis interpretation, 8 Observational studies, 8
Metronidazole, 24 Office of Disease Prevention and Health
Miscarriage, 475 Promotion, 612
Missouri Board of Pharmacy, 613 Office of Minority Health, 612
Morisky Medication Adherence Scale, 594 Off-label use, 5
Myocardial infarction Oncology patients, 79, 81
classification of, 366 Open heart surgical procedures, 99
grading during angiography, 118 Orthopedic surgery, 299-303
step-down therapy for, 385
universal criteria for, 365
P
P2Y12 inhibitor, 377-378
N Paclitaxel stent, 383
National Action Plan for Adverse Drug Parenteral anti-factor Xa, 200-201
Event Prevention, 577, 584, 585 Parenteral dosing/infusion guidelines,
National Blood Clot Alliance, 610 hospital setting, 582
National Certification Board for Anticoagu- Paroxysmal embolism, 318
lation Providers, 611 Patient acuity, 10
National Comprehensive Cancer Network, Patient education, 584, 586
treatment guidelines, 271 resources for, 612
National Quality Forum, 606, 607 technique-based resources for, 613
Neonates Patient self-testing, self-management,
heparin considerations in, 486-488 591-592
heparin-induced thrombocytopenia Patient treatment, 8, 10-11
and, 492 Patient-centered care, 587
Neuraxial anesthesia, 233, 238-239 Pediatric patients
Neurosurgery, 295, 297 argatroban for, 492-493
New England Journal of Medicine, 609 bivalirudin use in, 493
New laboratory testing coagulation factors and, 483
determining accuracy, imprecision, dalteparin dilution for, 490
reportable range for, 510
direct thrombin inhibitors and, 101,
implementing, 509-510 492
sensitivity and, 511 enoxaparin dilution for, 488-489, 490
Nicardipine, 333 extracorporeal membrane oxygenation
Nitroglycerin, 333 and, 497-498
Nonadherence management, 594 fibrinolytic system development in, 499
North American Society of Thrombosis and fondaparinux and, 79, 491-492
Hemostasis, 610 heparin monitoring in, 487
North American Thrombosis Forum, 610 heparin-induced thrombocytopenia in,
Nutrition, anticoagulation and, 623 444, 492
injections in, 497
insurance coverage and, 497
O intravenous catheter occlusions and,
Obesity, 267-270 498-499
low molecular weight heparin, laboratory test interpretations for, 498
fondaparinux and, 79 liver function, development in, 483
unfractionated heparin and, 47-48
INDEX 655
low molecular weight heparin and, 79, Pregnancy

488-491 anticoagulants during, 449-453
neonatal heparin considerations for, arterial event prevention in, 467-469
486-488
atrial fibrillation in, 470
nomograqms for, 487-488, 491
cesarean section considerations in,
oral anticoagulants and, 496 466-467
pharmacokinetic differences by age direct thrombin inhibitors during, 102
groups for, 482-483
grading recommendations for, 450
thrombosis incidence in, 481-482
heparin-induced thrombocytopenia
venous thrombolytic embolism treat- in, 445
ment in, 483-485
indications for, 450
warfarin considerations for, 493.
494-496 low molecular weight heparin,
fondaparinux in, 79
PEG asparaginase, 273
Peripheral arterial occlusion, 127
mechanical heart valves anticoagula-
Periprocedural bridging tion during, 468-469
bleeding risk assessment for, 224, 227 preconception planning and, 458-459
direct oral anticoagulants and, 232 preventing loss and, 473-474
hemorrhage risk assessment for, thrombophilia, 461, 462
224-226
venous thrombolytic embolism in,
principles of, 223 459-461, 463-465, 470-473
thromboembolic risk assessment for, warfarin and, 308
224
Prosthetic heart valves, 393
Pharmacist Billing in the Ambulatory Clinic
Setting, 613 bioprostheses and, 395-397, 402
Pharmacotherapy, 609 direct oral anticoagulants and, 401
Phenprocoumon, 14 INR adjustments and, 400, 401-402
Physician Quality Reporting System, 607 mechanical valve and, 394-396, 398
risk factors in, 398
Phytonadione, 174
thrombosis risk factors in, 394
Pioneer AF-PCI, 641
valve position and thrombogenicity,
Plasmapheresis, 445
397-398
Platelet
Protamine, 60, 166, 199
aggregation assay, 432
administration considerations for, 168,
count monitoring, 61, 427 202
Factor 4 immunoassays, 432 low molecular weight heparin and,
Porcine bioprosthetic valve, 396 200, 201
Postpartum anticoagulants, 475 risks associated with, 168
Practice resources, 605, 608 Protamine sulfate, 73
articles, 612 Protein C deficiencies, 553, 563
diagnostic testing facilities for INR tests for, 557
home monitoring, 611 treatment considerations for, 566
journals, 609 Protein S deficiencies, 563
organizations, 610 tests for, 557
textbooks, 610 treatment considerations for, 566
training programs, credentials, 611 Prothrombin complex concentrate (PCC),
165, 166
Prasugrel
administration considerations for, 171,
acute coronary syndrome and, 377-378
174
fetus and, 452 combined with other reversal agents,
lactation and, 457 174-175
heparin and, 175 low molecular weight heparin,

specific dosing considerations for, 174 fondaparinux and, 79-81
as reversal agent, 205-207, 213-218 risk factors in, 252-254
Prothrombin G20210A mutation genetic venous thrombolytic embolism and,
test, 553, 556 307-308
tests for, 563 Reteplase, 107
treatment considerations for, 566 characteristics of, 108
Prothrombin time, 517-518 frostbite and, 117
clinical applications of, 519-520 intracranial hemorrhage risk and, 122
Provider training, competency, 587, 588 peripheral arterial occlusion and, 114
Psychotropic agents, 621 STEM1 dosages for, 110
PubMed, 5 Revenue-generation resources, 613
Pulmonary embolism, 313 Reversal plan, 163, 166-167
diagnosis of, 325, 329, 330 administration considerations for,
diagnostic testing for, 326 168-171, 202
pathophysiology of, 314 anti-factor Xa inhibitor antidotes and,
178
pretest probability scoring for, 326, 328
antifibinolytic agents and, 180
right ventricular dysfunction in, 333
approaches to, 163-165
severity index scoring for, 331-332
broad spectrum, 179
signs/symptoms of, 325-326
coagulation factor products, 172-173
thrombolytic agents and adjunctive
therapy, 124 considerations for, 183-187, 192-193
decay patterns and, 186
development of, 184
Q-R development steps for, 189, 191-192
Quality improvement, 584, 600-601 for direct oral anticoagulants, 203-207
R-acencoumarol, 14 for direct thrombin inhibitors, 177,
Readmission Reduction Program, 607 202-203
Recombinant activated factor VIIa (rFVIIa), end target goal for, 184
165, 167 factors impacting extent, speed of,
adverse events associated with, 177 198-199
fondaparinux and, 202 during invasive procedures, 188-189
prothrombin complex concentrate and, measuring, reversing parenteral anti-
174 factor Xa agents with, 199
Recombinant tissue plasminogen activator monitoring approach for, 197
(rt-PA), 107 non-urgent reversal and, 195-196
characteristics of, 108 options for, 189-192
pediatric catheter clearance and, 499 patient-specific considerations in, 187
STEM1 dosages for, 110 semi-urgent reversal and, 195
Regional anesthesia guidelines, 238-239 survival rates and, 196
Regression analysis, 515 urgent reversal and, 194
Regulatory resources, 605 for warfarin, 165, 210-216
agencies and their role, 606-608 Rivaroxaban, 48, 203
Joint Commission, 660 andexanet alfa antidote and, 179
Regulatory standards, 583 body weights studied with, 267
Remote Cardiac Services, 611 commercial availability of, 131
Renal impairment, 251 compared to warfarin, other direct oral
anticoagulant pharmacokinetic changes anticoagulants, 134-139
in, 253
INDEX 657
in critically ill, 295 obesity, low body weight consider-

dosing of, 153, 155 ations for, 267-270
drug interactions with, 140 renal impairment and, 251-254,
261-262
in elderly patients, 266, 267
stroke prophylaxis in atrial fibrillation
fetus and, 452 and, 257-258
hepatic dysfunction and, 264, 265 venous thrombolytic embolism and,
heparin-induced thrombocytopenia 255-257
and, 436 S-phenprocoumon, 14
lactation and, 457 STEM1
measuring, reversing, 206 with fibrinolytics, 373
orthopedic surgery and, 300-301, 302 primary PCI for, 372
patient, agent selection for, 149, 150, thrombolytic agents, adjunctive
151 therapy for, 123
patient counseling with, 158 Streptokinase, 107
in pediatrics, 496 characteristics of, 108
periprocedural management of, 232 in deep vein thrombosis, 112
pharmacodynamic properties of, 233 intracranial hemorrhage risk with, 122
pharmacokinetics of, 268 in pleural effusuib/empyema, 115
pharmacology of, 132-133 in prosthetic heart valve thrombosis,
phase III trials for, 135-138, 143, 116
147-148, 154, 339 in pulmonary embolism, 111
renal impairment and, 253, 308 STEM1 dosage for, 110
secondary ACS prevention with, Stroke prevention, 147-148, 355-357
385-386
Students paired t-test, 515
stroke prophylaxis dosing for, 257
S-warfarin, 14, 23
venous thrombolytic embolism and,
143, 145, 255, 256 Syringes, 70
Roche, 611
Royal Pharmaceutical Society, 613
T
R-phenprocoumon, 14
Telephonic care delivery, 592
R-warfarin, 14, 23
Tenecteplase (TNK), 107
characteristics of, 108
S frostbite and, 117
S-acenocoumarol, 14 intracranial hemorrhage risk with, 122
Saddle pulmonary embolism, 326, 327 ischemic stroke and, 113
Selective estrogen-receptor modulators, pulmonary embolism and, 111
619 STEM1 dosages for, 110
Serotonin release assay, 432-433 Texas Medical Institute of Technology, 608
Shared decision making, 587 Thoracic surgery, 295, 298
Sirolimus stent, 383 Thrombin generation curve, 534-535
Special management population, 11 Thrombocytopenia, 72-73
Special populations, 251 drug-related causes of, 634-636
acute coronary syndromes and, heparin-induced. See Heparin-induced
258-259 thrombocytopenia
cancer and, 270-273 nondrug causes of, 633
hemodialysis and, 260-262 Thromboelastography, 544-546
hepatic impairment and, 263-265 TEG and ROTEM interpretation in,
545, 546
Thromboembolic diseases, drug-induced, Ticagrelor

618 acute coronary syndrome and, 377-378
Thrombolytic anticoagulants fetus and, 452
adjunctive therapy strategies for, lactation and, 458
122-127
myocardial infarction step down
bleeding risk with, 121 therapy with, 385
clinical properties of, 108 Tilting disk mechanical heart valve, 394,
contraindications to, 120 395
indications, dosage, administration of, TIMI
108-109 non-coronary artery bypass graft
intracranial hemorrhage risk with, 122 related bleeding and, 369
mechanism of action for, 107-108 risk score for NSTE acute coronary
monitoring, 118-119 syndrome, 367
pharmacology, pharmacokinetics of, Tinzaparin, 65
107 ACCP/ACOG regimens for, 460-461
reversal of, 219 acute spinal cord injury and, 304
side effects, precautions, consider- body weights studied for, 267
ations for, 120-121 fetus and, 452
ST segment elevation myocardial general surgery and, 296
infarction and, 109, 121
lactation and, 458
Thrombophilia, 549
low molecular weight heparin and, 201
antiphospholid antibody syndrome,
treatment for, 561, 567-568 orthopedic surgery and, 300-301
categories of, 549-550 pharmacokinetics of, 268, 269
hormone contraception, hormone renal impairment and, 253, 307
replacement therapy and, 565 venous thrombolytic embolism and,
hyperhomocysteinemia considerations 294
in, 569 Tirofiban, 379, 443, 445
laboratory interactions and, 555-561 Tranexamic acid, 180
laboratory tests for, 552-555, 562-565 Transcatheter aortic valve replacement,
pregnancy and, 461-462, 473-474 396, 397, 402
prevalence, risk for thrombosis and, Transesophageal echocardiography, 394
551 Transfusion-related reactions, 637
proposed treatment algorithm for, 343 Transient ischemic attacks, 625-626
testing and, 342, 569 Transitional care, 11
treatment, prevention considerations Transitioning. See individual drugs
for, 565 Transitions of care, 587
Thrombosis Trauma, 303, 304
algorithm of diagnosis, management of Travel venous thrombolytic embolism
pump for, 419 prophylaxis, 306
ECMO oxygenator with clot formation Trousseau syndrome, 273-274
and, 418
interventions for, 416-419
mechanical circulatory support devices U
and, 416-418
Unfractionated heparin (UFH)
pregnancy and, 459-460, 470-471
ACCP, ACOG regimens for, 460-461
pump in outflow bearing of Heartmate
II LVAD, 418 acute coronary syndrome and,
366-367, 370, 374
Thrombosis and Haemostasis, 609
acute spinal cord injury and, 303, 304
Thyroid status, 21
aPTT considerations for, 37, 51-53,
INDEX 659
521-524 therapy initiation with, 38-42

arterial femoral sheath management thrombolytic agents and, 123-127
and, 376 transitioning considerations for, 44, 48,
burns and, 305 234, 236-237, 241-242
calibrators change for, 37 trauma and, 304
catheter flushing with, 38-39 venous thrombolytic embolism and,
in continuous infusion, 39, 41 43-44, 52, 294, 295, 336, 465, 466
in critically ill, 303, 305 United States Pharmacopeia, heparin and,
37
direct oral anticoagulants and, 228
University of Connecticut, 611
dosing considerations for, 39-46, 52-55
School of Pharmacy, 588
fetus and, 453
University of Florida, 611
general surgery and, 296
College of Pharmacy, 588
hemodialysis and, 308
University of Southern Indiana, 611
indications for, 36
certificate program, 588
in-vitro spiking and response curve,
523 Upper extremity deep vein thrombosis,
317
laboratory tests for monitoring, 49
Urokinase, 107
in labor and delivery, 474-475
catheter occlusion and, 114
lactation and, 458
characteristics of, 108
locks for selected devices, 38
deep vein thrombosis and, 112
intracranial hemorrhage risk with, 122
mechanical valve anticoagulation
bridging with, 398 peripheral arterial occlusion and, 114
mechanism of action for, 66 prosthetic heart valve thrombosis and,
116
neonatal considerations with, 486-488
pulmonary embolism and, 111
NSTE ACS guidelines for, 374
STEM1 dosage of, 110
obesity weight considerations and,
47-48 Urologic surgery, 295, 298
orthopedic surgery and, 299
PCI and, 385
V
in pediatrics, 485
Vascular damage, 459
pharmacology of, 35
Vascular reconstruction, 45
pharmacokinetics/pharmacodynamics
of, 36-37 Vascular surgery, 295, 297
platelet count monitoring with, 61 VATS/MAZE procedure, 358
pregnancy and, 308, 470, 472 Venous anatomy
protamine and, 199, 201 lower extremity, 315, 316
regional anesthesia and, 238-239 upper extremity, 316, 317
renal impairment and, 254 Venous stasis, 459
resistance and, 55-57 Venous thrombolytic embolism (VTE), 283
reversal considerations for, 200 anticoagulant therapy and, 335-336
side effects, precautions, contraindica- bleeding risk stratification for, 340
tions for, 58-60, 71 bridging and, 245-246
special population considerations for, cancer and, 287, 337
60-61
common areas for, 314
STEM1 guidelines for, 372-373
compression guide for, 290
target anti-factor Xa activity level and,
in critically ill patients, 294-295,
50
303-306
direct oral anticoagulants for, 143-146, mechanical valve and, 398-399

337-338 preconception planning and, 459
dosing for, 256 Von Willebrand disease, 409, 415
general surgery and, 296-299
graduated socks for, 289-290
guidelines, resources for, 284 W
heparin dosing with catheter-directed Warfarin
fibrinolysis, 333-334
amiodarone and, 356
heparins and systemic fibrinolysis, 333
antiphospholipid considerations for,
home treatments for, 337 568
inferior vena cava filters and, 291-294, atrial fibrillation and, 196, 349
334
bridging and, 26-28
low molecular weight heparins/
catheter ablation and, 359-360
fondaparinux treatment for,
336-337 coagulation factor decline over time
with, 18
nonpharmacological options for, 288
concentrated clotting factors for rever-
orthopedic surgery and, 255, 299-303
sal of, 217
overview of, 313
disease state interactions and, 19-21,
phase III trials for, 143-144 23
prophylaxis for, 288, 306, 307 direct oral anticoagulants and,
quality improvement and, 309 134-139, 232
recurrent, 341, 342 dosage considerations for, 19, 24-29,
213-215
risks for, 285-286, 319
drug-drug interactions with, 21-24
special populations and, 307-308
fetus and, 453
systemic fibrinolysis treatment and,
331, 333 hemodialysis and, 261
unfractionated heparin and, 336 hemorrhagic risk assessment for, 30-33
warfarin for, 338 heparin-induced thrombocytopenia
and, 435, 441
Ventilation perfusion lung scan, 326, 327
hepatic dysfunction and, 264
Ventilation/perfusion scans, 470
INR and, 26, 28-30
Vitamin K, 18-19, 165, 167
lactation and, 458
administration considerations for,
168-169 maintenance therapy monitoring for, 29
adverse effects with parenteral, 170 management of complications with,
29-30
dependent proteins and, 14
mechanical circulatory support and,
dispensing of, 170
409
dosage of, 216-217
monotherapy and venous limb
injectable, 30 gangrene, 426
INR value reversal and, 211 nonadherence and, 594
IV formulation administered orally, 210 nutrition and, 623-624
oral vs. intravenous, 212 orthopedic surgery and, 300-301
oral vs. subcutaneous, 212 patient, agent selection for, 149, 150,
procedure/surgery planned and, 212 151, 152
prothrombin complex concentrate and, in pediatrics, 484-485, 493-496
174 pharmacokinetics, pharmacodynamics
reversal dose factors for, 210-211 of, 13-18
Vitamin K antagonist pharmacology of, 13-14
bioprosthetic valves and, 402 pregnancy and, 308
proteins and half life with, 14, 18
INDEX 661
prothrombin complex concentrate and, Warfarin plus aspirin, 349

174 WATCHMAN device, 357-358
R and S enantiomers differences, 14 WebCareHealth, 611
renal impairment and, 254 Wells Pretest Probability Score, 320-321,
reversal of, 165, 167, 210-217 328
tablet color scheme for, 15-16 World Health Organization, heparin
tablet strengths, colors for, 24 standards, 37
thrombophilia laboratory reactions
with, 559-560
transitioning considerations with,
Z
97-98, 226, 228, 235-236 Zotarolimus stent, 383
venous thrombolytic embolism and,
294, 338

Anticoagulan Therapy PDF

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Anticoagulan Therapy PDF

Enviado por

Direitos autorais:

Formatos disponíveis

A CLINICAL PRACTICE GUIDE

WILLIAM E. DAGER, PharmD, BCPS (AQ Cardiology), FCSHP,

MICHAEL P. GULSETH, PharmD, BCPS, FASHP

EDITH A. NUTESCU, PharmD, MS CTS, FCCP

Because of ongoing research and improvements in technology, the information and

Acquisitions Editor: Beth Campbell

Library of Congress Cataloging-in-Publication Data

© 2018, American Society of Health-System Pharmacists, Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any

ASHP is a service mark of the American Society of Health-System Pharmacists, Inc.;

Part I. Anticoagulation Medication Management

Part II. Conditions Requiring Anticoagulation Therapy

Part III. Practical Measuring, Monitoring, and Coagulation Laboratory

Part IV. Essentials for Practice Success

MICHAEL P. GULSETH, PharmD, BCPS, FASHP

EDITH A. NUTESCU, PharmD, MS CTS, FCCP

Kelsey Aker, PharmD Laura Baumgartner, PharmD, BCPS, BCCCP

Scott A. Chapman, PharmD Thaddaus Hellwig, PharmD, BCPS

Jessica Rimsans, PharmD, BCPS Sarah A. Spinler, PharmD, FCCP, FAHA,

Ensuring the safe and appropriate use of anticoagulants continues to be major

New features of this second edition include:

As with the first edition, the book is:

Lydia D. Chen, PharmD

AAOS American Association of Orthopedic Surgery

AAP American Academy of Pediatrics

ACA anticardiolipin antibody (also often abbreviated as aCL)

ACC American College of Cardiology

ACC/AHA American College of Cardiology/American Heart Association

ACCP American College of Chest Physicians

ACS acute coronary syndrome

ACT activated clotting time

AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management

AHA American Heart Association

AHA/ASA American Heart Association/American Stroke Association

AIS arterial ischemic stroke

ALL acute lymphoblastic leukemia

ALT alanine aminotransferase

AMI acute myocardial infarction

APC activated protein C

APLAs antiphospholipid antibodies

aPTT activated partial thromboplastin time

ASSENT Assessment of the Safety and Efficacy of a New Thrombolytic

AST aspartate aminotransferase

AUC area under the serum concentration versus time curve

AVR aortic valve replacement

BID twice daily dosing

BMI body mass index

CABG coronary artery bypass graft

CAD coronary artery disease

CAP College of American Pathologists

CBC complete blood count (including platelets)

CHD coronary heart disease

CLIA Clinical Laboratory Improvement Amendments

Cmax maximum serum concentration

CPK creatinine phosphokinase

CPR cardiopulmonary resuscitation

CrCl creatinine clearance

CRRT continuous renal replacement technique

CSCT colloidal-silica clotting time

CVA cerebrovascular accident

CVAD central venous access device

CVL central venous line

D5W 5% dextrose in water