Acute Care Update: Causes,

Consequences, and Strategies for

Managing Critical Bleeding


A podcast educational activity based on a live program
conducted on December 8, 2008 in Orlando, Florida









Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding


P R O G R A M A G E N D A

Bleeding in Medical and Surgical Patients: Common Causes, Mechanisms, and
Treatment Options
Robert MacLaren, Pharm.D., FCCP, FCCM

Patient case: Anticoagulant-associated Intracranial Hemorrhage
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM

Patient case: Surgery-associated Bleeding
J eremy D. Flynn, Pharm.D., BCPS




P R O G R A M F A C U L T Y
Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair
Associate Professor
University of Colorado School of Pharmacy
Denver, Colorado

Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Associate Professor of Pharmacy and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia Campus
Richmond, Virginia

Jeremy D. Flynn, Pharm.D., BCPS
Clinical Pharmacist Specialist
UK HealthCare-Pharmacy Services
Assistant Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Lexington, Kentucky

1
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding


D I S C L O S U R E S T A T E M E N T
In accordance with the Accreditation Council for Continuing Medical Educations and the
Accreditation Council for Pharmacy Educations Standards for Commercial Support,
ASHP Advantage requires that all individuals involved in the development of program
content disclose their relevant financial relationships. A person has a relevant financial
relationship if the individual or his or her spouse/partner has a financial relationship (e.g.,
employee, consultant, research grant recipient, speakers bureau, or stockholder) in any
amount occurring in the last 12 months with a commercial interest whose products or
services may be discussed in the CME activity content over which the individual has
control. The existence of these relationships is provided for the information of
participants and should not be assumed to have an adverse impact on presentations.

All faculty and planners for ASHP Advantage education activities are qualified and
selected by ASHP Advantage and required to disclose any relevant financial
relationships with commercial interests. ASHP Advantage identifies and resolves
conflicts of interest prior to an individuals participation in development of content for an
educational activity.

The faculty and planners report the following relationships:


Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair

Dr. MacLaren reports that he has served as a consultant for Novo Nordisk.


Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM

Dr. Brophy reports that she has served as a consultant for and has received research
grant funding from Novo Nordisk.


Jeremy D. Flynn, Pharm.D., BCPS

Dr. Flynn reports that he has served as a consultant for Novo Nordisk and The
Medicines Company.


Kristi Hofer, Pharm.D.

Dr. Hofer reports no relationships pertinent to this activity.
2
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding


P R O G R A M O V E R V I E W
The clinical and economic consequences of serious bleeding in critically ill patients are
significant. Uncontrolled hemorrhage is considered the leading cause of preventable
death in the United States. Because health system formularies include many agents to
promote and inhibit blood coagulation, pharmacists need to know how to use them
safely and appropriately.

Transfusion of blood products is often required to manage serious bleeding in critically ill
patients; however, there are significant risks associated with transfusion of blood
products. Consequently, pharmacologic strategies, including aminocaproic acid,
tranexamic acid, desmopressin, and recombinant activated factor VIIa, are being
investigated for controlling bleeding and reducing the need for transfusions. Pharmacists
practicing in the acute care setting must keep abreast of this evolving body of knowledge
to ensure that these agents continue to be used appropriately. Pharmacists involved in
medication order review and approval, development and implementation of clinical
guidelines and protocols, and formulary decision-making, as well as clinical specialists
practicing in critical care, surgical, and emergency care settings need access to current
information on agents used to manage bleeding in critically ill patients.

This educational activity will examine conditions that may lead to bleeding and strategies
for managing bleeding, including both conventional treatments and emerging therapeutic
alternatives. Using patient case examples and an automated audience response system,
faculty will engage participants in the clinical decision-making process involved in
managing patients with critical bleeding.

L E A R N I N G O B J E C T I V E S
At the conclusion of this knowledge-based educational activity, participants should be
able to:
List the most common causes of bleeding in hospitalized patients.
Analyze recently published data regarding the safety and efficacy of various
agents used to control bleeding in critically ill patients.
When presented with a patient case, suggest therapeutic options for managing
bleeding in the perioperative and acute care settings.
3
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding


C O N T I N U I N G E D U C A T I O N A C C R E D I T A T I O N
The American Society of Health-System Pharmacists is accredited by
the Accreditation Council for Pharmacy Education as a provider of
continuing pharmacy education. The program provides 2.0 hours (0.2
CEUs) of continuing education credit (program number 204-000-08-
455-H01P).



F O R M A T A N D M E T H O D S
This is an online activity consisting of audio for three presentations, a post-test, and an
activity evaluation tool. Participants must listen to all presentations, take the activity
post-test, and complete the course evaluation to receive continuing education credit. A
minimum score of 70% is required on the test for credit to be awarded, and participants
may print their official statements of continuing education credit immediately. The
estimated time to complete this activity is two hours. This activity is provided free of
charge.

4
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

INSTRUCTIONS FOR TAKING POST-TESTS AND
RECEIVING YOUR CE STATEMENTS ONLINE FOR PODCAST ACTIVITIES

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If you have any problems processing your CE, contact ASHP Advantage at
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5
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding


Robert MacLaren, Pharm.D., FCCP, FCCM, Program Chair
Associate Professor
University of Colorado School of Pharmacy
Denver, Colorado



Robert MacLaren, Pharm.D., FCCP, FCCM, is Associate Professor in the Department of
Clinical Pharmacy at the University of Colorado Denver School of Pharmacy in Aurora,
Colorado. In addition, he is a clinical pharmacist in the medical intensive care unit at the
University of Colorado Hospital, which is also located on the Anschutz Medical Campus
in Aurora. Dr. MacLaren also serves as co-director of the critical care residency at the
University of Colorado.

After completing his undergraduate degree in pharmacy at the University of British
Columbia in Vancouver, Canada, Dr. MacLaren earned his Doctor of Pharmacy degree
at the University of Utah in Salt Lake City and completed a critical care specialty
residency in Memphis at the University of Tennessee and Baptist Memorial Hospital. He
worked for two years as a critical care specialist at the Queen Elizabeth II Health
Sciences Centre in Halifax, Canada, before joining the faculty at the University of
Colorado.

Dr. MacLaren is a fellow of the American College of Clinical Pharmacy and the Society
of Critical Care Medicine. His clinical research interests include gastrointestinal motility
dysfunction associated with critical illness and the use of intravenous glutamine as a
supplement to parenteral nutrition. He conducts animal studies of acetaminophen
toxicity and has been involved with outcomes research of pharmacologic therapies and
the impact of pharmacists in the intensive care unit. He has authored several articles
relating to the pharmacologic and nutritional therapies of critically ill patients and has
been an invited speaker at national and international meetings.
6
Bleeding in Medical and Surgical
Patients: Common Causes,
Mechanisms, and Treatment
Robert MacLaren, Pharm.D., FCCM, FCCP
Associate Professor
University of Colorado School of Pharmacy
Denver, Colorado
Case Scenario
Jill is a 58-y.o. woman admitted with septic shock
and oliguria. Her PMH is significant for PE 2 years
ago (no longer requiring anticoagulation, but she
takes aspirin 325 mg daily)
Baseline labs show platelets 37 x 10
9
/L, Hct 24%
(for which 2 units of RBCs are administered for early
goal directed therapy of Hct >30%), INR 1.7, aPTT
48 seconds, BUN 85 mg/dL, ALT 2200 IU/L, and
AST 3450 IU/L
APACHE II score >25, so activated protein C is
started
She receives 8 L normal saline and norepinephrine
0.3 mcg/kg/min, is intubated, and renal support is
started
What risk factors does J ill have for
hemorrhage?
A. Anticoagulant use
(activated protein C,
aspirin)
B. Baseline coagulopathy
C. Thrombocytopenia
D. Liver and renal
dysfunction
7
What risk factors does J ill have for
hemorrhage?
A
n
tic
o
a
g
u
la
n
t u
s
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(a
c
...
B
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a
th
y
T
h
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o
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ia
L
iv
e
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r
e
n
a
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y
s
fu
...
41%
25%
22%
12%
A. Anticoagulant use
(activated protein C,
aspirin)
B. Baseline coagulopathy
C. Thrombocytopenia
D. Liver and renal
dysfunction
How frequently is bleeding the
primary reason for transfusion?
A. < 25%
B. 25-50%
C. 50-75%
D. > 75%
How frequently is bleeding the
primary reason for transfusion?
<
2
5
%
2
5
-5
0
%
5
0
-7
5
%
>
7
5
%
34%
16%
24%
26%
A. < 25%
B. 25-50%
C. 50-75%
D. > 75%
8
Reasons to Transfuse
0
25
50
75
100
L
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w

H
g
B
le
e
d
L
o
w

B
P
S
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r
25-30% of all transfusions are in the ICU
Corwin HL et al. Crit Care Med. 2004;32:39-52.
N=4892
patients from
284 ICUs
Causes of Critical Bleeding
Thrombocytopenia (<50 x 10
9
/L): 4- to 5-fold
risk of hemorrhage
Independent risk factor for mortality (OR = 1.9-4.2)
Incidence is 21-41%, but only 5% <20 x 10
9
/L
Coagulopathy: 4- to 5-fold risk of hemorrhage
Independent risk factor for mortality (OR = 1.5-4.3)
Incidence is 14-28%
Levi Met al. Crit Care. 2006; 10:222.
Mercer KWet al. Semin Respir Crit Care Med. 2006; 27:286-96.
Thrombocytopenia
General causes
Decreased platelet production
Congenital or acquired disorders of hematopoiesis
Bone marrow suppression (drugs)
Nutritional deficiencies (folate, vitamin B
12
)
Liver disease
Distributional
Massive blood transfusion
Splenomegaly
Increased platelet destruction
Immunologic vs. non-immunologic mechanisms
Specific causes in the ICU (<150 x 10
9
/L)
Sepsis = 52%
Disseminated intravascular coagulopathy (DIC) = 25%
Drug (anticoagulant)-induced = 10%
Massive blood loss = 8%
Immune thrombocytopenia = 3%
Thrombotic microangiography (e.g., TTP, HUS) = 1%
Heparin-induced thrombocytopenia (HIT) = 1%
Levi Met al. Crit Care. 2006; 10:222. TTP = thrombotic thrombocytopenic purpura, HUS = hemolytic uremic syndrome
9
Coagulopathy
Reflected by prolonged prothrombin time (PT) or
activated partial thromboplastin time (aPTT) of
1.5 times the upper limit of the normal range
General causes:
Test Result Likely Causes
PT prolonged, aPTT normal Factor VII deficiency, mild vitamin K
deficiency, mild liver dysfunction, vitamin K
antagonists
PT normal, aPTT prolonged Factor VIII, IX, XI deficiency, unfractionated
heparin, antiphospholipid antibody
Both prolonged Factor II, V, X deficiency, severe vitamin K
deficiency, global clotting factor deficiency
(lack of synthesis = liver failure, loss =
massive bleeding, consumption = DIC)
Levi Met al. Crit Care. 2006; 10:222.
Thrombocytopenia/Coagulopathy
Diagnosis in the ICU
Platelet count:
<100 x109/L or
Drop >50 x109/L in 24 hours
Normal Prolonged
Present:
DIC
Absent:
Sepsis
Liver failure
HIT antibody present with
heparin exposure
PT?
D-dimer/ fibrin
degradation products?
Schistocytes present, then
thrombotic microangiopathy
Antiplatelet antibodies or
medications
Bone marrow suppression
Levi Met al. Crit Care. 2006; 10:222.
(Collagen)
XII XIIa
XI XIa
IX
Ca++
X
IXa
PF 3
Ca++
VIII
Xa
Ca++
PF 3
V
X
Factor III
Ca++
VIIa VII
XIII
Fibrin
(monomer/
polymer)
Thrombin Prothrombin
(II)
Fibrinogen
(I)
XIIIa
Stable
Fibrin
Polymer
Monitoredby
Prothrombin Time
(PT, INR)
Measures
VII, X, V, II, I
Monitoredby
ActivatedPartial
Thromboplastin
Time
(aPTT)
Measures
XII, XI, X, IX, VIII,
V, II, I
EXTRI NSI C SYSTEM I NTRI NSI C SYSTEM
(Tissue Factor)
The Clotting Cascade
Adapted fromHirsh J et al. Circulation. 2007; 116:552-60.
10
Factors Contributing to Abnormal
Coagulation
Hypocalcemia
Dilution
Hypothermia
Limits platelet activation
and clotting factor function
Mortality OR = 1.2
Dilution and
hypothermia
Hypothermia
Acidosis
Reduces clotting factor function (e.g., VII activity reduced
90% at pH of 7.20) due to altered protease activity and
limited anion exposure of phospholipids
Cohort analysis of recombinant factor VIIa showed pH <7.20
only predictor of bleeding cessation failure (OR = 0.21)
Levi Met al. Crit Care. 2006; 10:222. Mercer KWet al. Semin Respir Crit Care Med. 2006; 27:286-96.
Schreiber MA et al. Curr Opin Crit Care. 2005; 11:590-7. MacLaren R et al. Transfusion. 2005; 45:1434-42.
Pathophysiology of Coagulopathy
Inherited platelet/clotting factor dysfunction
Liver failure
DIC
Massive blood loss
Platelet dysfunction
Drugs
Microangiopathy
Immune-mediated
Anticoagulant-associated
Liver Failure
Defective coagulation
Reduced levels of coagulation factors V, VII, IX, X, XI,
prothrombin
Defective vitamin K-dependent coagulation factors (II,
VII, IX, X)
Increased level of plasminogen activator
Defective anticoagulation and fibrinolysis
Reduced levels of thrombin activatable fibrinolysis
inhibitor and endogenous anticoagulants (proteins C,
S, Z; heparin cofactor II; Z-dependent protease
inhibitor; and antithrombin)
Increased levels of tissue plasminogen activator
inhibitor and von Willebrand factor (vWf)
Thrombocytopenia
Hypersplenism, decreased thrombopoietin, vWf-
induced clumping, uremia, immune-mediated
(hepatitis C)
Trotter J F. Clin Liver Dis. 2006; 10:665-78. Caldwell SH et al. Hepatology. 2006; 44:1039-46. Lisman T et al. Dig Surg. 2007;24:250-8.
11
DIC
Common causes
Sepsis, trauma/surgery/burns, malignancy (solid tumors,
myeloproliferative, or lymphoproliferative), immunologic reactions
(transplant rejection, transfusion, snake bites), obstetrical calamities,
severe liver failure, pancreatitis, vascular abnormalities, cardio-
pulmonary bypass
Underlying themes = systemic inflammatory response and TF exposure
Diagnosis
Laboratory Test 0 Points 1 Point 2 Points 3 Points
Platelet count
(x 10
9
/L)
>100 50-100 <50
Fibrin degradation
products
No increase Moderate
increase
Large
increase
Prolonged PT <3 seconds 3-6 seconds >6 seconds
Fibrinogen (mg/dL) >100 <100
Cumulative score 5 suggests DIC if underlying condition also present
Levi M. Crit Care Med. 2007; 35:2191-5.
DIC Cascade
Insult
Inflammation
Anti-inflam.
Mediators
Pro-inflam.
Mediators
Fibrinolysis
PAI-1 t-PA
TAFI
inhibits
stimulates
or activates
Endothelial
Injury
Coagulation
TF
Thrombin Thrombomodulin
TAFI = thrombin activatable
fibrinolysis inhibitor
TF = tissue factor
t-PA = tissue plasminogen activator
PAI = plasminogen activator inhibitor Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5.
aProtein C
Antithrombin
DIC Cascade
Insult
Inflammation
Anti-inflam.
Mediators
Pro-inflam.
Mediators
Fibrinolysis
PAI-1 t-PA
TAFI
inhibits
stimulates
or activates
Endothelial
Injury
Coagulation
TF
Thrombin Thrombomodulin
TAFI = thrombin activatable
fibrinolysis inhibitor
TF = tissue factor
t-PA = tissue plasminogen activator
PAI = plasminogen activator inhibitor Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5.
aProtein C
Antithrombin
CONSUMPTION of FACTORS
12
The Importance of Exposed Tissue Factor
Adapted fromLevi M. Crit Care Med. 2007; 35:2191-5.
Massive Blood Loss/Transfusion
Defined as hemorrhage requiring 10 units of
RBCs in 24 hours
Bleed causes loss and consumption of
clotting factors, platelets, fibrinogen, etc.
Hemodilution from saline resuscitation (room
temperature and chloride-induced acidosis)
Blood transfusions contain citrate, which
binds calcium, and are acidic (pH 6.3-7)
Napolitano LMet al. Crit Care Clin. 2004; 20:255-68.
Hardy J F et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58.
Spahn DR et al. Br J Anaesth. 2005; 95:130-9.
Storage of donor blood causes biochemical and corpuscular
changes to RBC:
Depletion of adenosine triphosphate and 2,3-DPG
Activate platelets via thromboxane A
2
and adenosine diphosphate
Membrane vesiculation and phospholipid exposure to activate
thrombin
Loss of cell deformability to induce endothelial damage and
margination of platelets
Increased time for pro-inflammatory cytokine production
pH of stored blood ~ 6.3
Old Blood
Napolitano LMet al. Crit Care Clin. 2004; 20:255-68. Hardy J F et al. Can J Anaesth. 2006; 53(6 Suppl):S40-58.
Spahn DR et al. Br J Anaesth. 2005; 95:130-9.
13
Platelet Dysfunction
Drugs: aspirin, NSAIDs, dipyridamole,
clopidogrel, ticlopidine, glycoprotein IIb/IIIa
inhibitors
Microangiopathy
TTP due to deficiency of protease that cleaves vWf to
cause ultra-large vWf multimers that readily attach to
endothelium and platelets
HUS typical of E. coli O157:H7 that releases cytotoxin
responsible for endothelial and platelet activation
Immune-mediated
HIT, drug- and non-drug-induced immune-mediated
mechanisms
Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.
J affer AK. J Thromb Thrombolysis. 2008; 25:85-90.
(Collagen)
XII XIIa
XI XIa
IX
Ca++
X
IXa
PF 3
Ca++
VIII
Xa
Ca++
PF 3
V
X
Factor III
Ca++
VIIa VII
XIII
Fibrin
(monomer/
polymer)
Thrombin Prothrombin
(II)
Fibrinogen
(I)
XIIIa
Stable
Fibrin
Polymer
EXTRI NSI C SYSTEM I NTRI NSI C SYSTEM
(Tissue Factor)
Mechanisms of Anticoagulants
Adapted fromHirsh J et al. Circulation.
2007; 116:552-60.
Heparin
Fondaparinux
DTI
LMWH
APC
Fibrinolytics
Goals of Therapy
Stop or control hemorrhage
Minimize blood product use
Minimize adverse events
Hgb of 7-8 g/dL, Hct of 21-24%
INR <1.5, PT and aPTT <1.5 x upper limit
of normal range, platelets 50 x 10
9
/L,
normal activated clotting time
pH 7.20, temperature 35 C, normal
ionized calcium
Dutton RP. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S.
14
Therapeutic Options
Treat the etiology!
Blood products
Red blood cells (RBCs)
Whole blood
Platelets (plts)
Fresh frozen plasma (FFP)
Prothrombin complex concentrate (PCC)
Cryoprecipitate
Cryosupernatant
Pharmacologic agents
Local hemostatic agents/sealants
Vitamin K
Recombinant activated factor VII (rFVIIa)
Desmopressin (DDAVP)
Conjugated estrogens
Anti-fibrinolytic agents (aprotinin, aminocaproic acid, tranexamic acid)
Others: recombinant activated factor VIII (rFVIIIa), recombinant
activated factor IX (rFIXa), recombinant activated factor XI (rFXIa), vWf
concentrate
Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S.
Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Blood Products
Product Contents Indications and Dose Concerns*
Platelets Thrombocytes in plasma Plts <50 x 10
9
/L (bleeding)
Plts <20 x 10
9
/L
(prevention)
Stored at 20-24C
Bacterial contamination ~1/2000
to 1/3000 units
Worsens immune reactions
FFP Coagulation factors and
fibrinogen in variable
amounts
INR 1.5
15 mL/kg ~30% factor
replacement
Requires thawing
Risk of hypervolemia
PCC Factors II, VII, IX, X and
prothrombin, proteins C, S,
Z in variable amounts
INR 1.5
25-50 IU/kg (based on
factor IX)
Variable amounts of factors
May contain heparin
Numerous donors
Costly
Cryo-
precipitate
Factors VIII, XIII, vWf,
fibrinogen, fibronectin
Fibrinogen <100 mg/dL
1 unit will fibrinogen ~ 5-
10 mg/dL
vWf deficiency
Cryo-
supernatant
Not factor VIII, vWf, and
minimal fibrinogen
TTP
* All products are associated with thrombotic events, transfusion-related acute lung injury, transfusion-related
immunomodulation, infection transmission, and febrile reactions.
Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S.
Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Pharmacologic Agents
Product Contents or MOA Indications and Dose Concerns
Local
hemostatics
A. Cellulose-based
B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin
thrombin
C. Thrombin (human or bovine)
D. Zeolite that causes exothermic reaction
E. Chitason (chitin) that activates platelets and electrophysiologic
endothelial attraction of RBCs
F. Synthetics (PEGs or collagen-fibrin)
A. May not adhere
B. Immune reaction, infection
transmission, aprotonin
C. Immune reaction
D. Heat-induced tissue damage
E. May not adhere
F. Immune reaction, costly
Vitamin K Cofactor for activation of
factors II, VII, IX, K
INR 1.5
0.5-20 mg IV or PO
Slow acting
Variable SC absorption
IV requires slow administration
rFVIIa Activates platelets to
augment thrombin burst
Anticoagulant-induced hemorrhage,
ICH, refractory hemorrhage (surgery,
trauma)
10-90 mcg/kg IV
Short-acting
Thrombosis (<10%)
Costly
Desmopressin Selective V2 agonist to
release factor VIII, vWf, and
t-PA
Platelet dysfunction
0.3 mcg/kg IV
Short-acting
Tachyphylaxis and bleeding risk
with repeat doses
Conjugated
estrogen
antithrombin and protein S
while factors VII, VIII, IX, X,
prothrombin
Platelet dysfunction
25-50 mg IV
Slow acting
Slow offset
Antifibrinolytics
(aprotonin,
EACA, TA)
Inhibit plasminogen
proteases and plasmin
(aprotonin) and some anti-
inflammation
Prevention of surgical blood loss
Refractory hemorrhage
Aprotinin: 2 million units IV, then 0.5
million units/hr
EACA: 150 mg/kg IV, then 15 mg/kg/hr
TA: 10 mg/kg IV, then 1 mg/kg/hr
Aprotinin: hypersensitivity (2.8%)
with 9%mortality, renal dysfunction
(OR~2), CVA (OR~2), MI (OR~1.55), 5-
yr mortality (OR~1.48)
Thrombosis, hypotension (TA)
Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S.
15
Managing Anticoagulant-Induced
Hemorrhage
Anticoagulant Reversing Strategy
Warfarin Vitamin K + FFP or PPC rFVIIa (low dose)
Heparin Protamine
Low molecular weight
heparin
Protamine (anti-IIa, ~60% anti-Xa)
Fondaparinux, direct
thrombin inhibitors
PCC rFVIIa
Fibrinolytics Antifibrinolytics + FFP or PCC rFVIIa
Activated protein C FFP or PCC rFVIIa
Antiplatelet agents Platelets + desmopressin
Zimmerman LH. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.
J affer AK. J Thromb Thrombolysis. 2008; 25:85-90.
Protocols and Targeted Therapy
Several institution-specific protocols and
guidelines directing therapy show similar
patient outcomes while minimizing blood
product use
Targeted therapy based on point-of-care
testing (PT, aPTT, plts fibrinogen
thromboelastography) reduces
procoagulant and blood product use while
improving patient outcomes (shorter
surgical time)
Rebuck J A. Pharmacotherapy. 2007; 27(9 Pt 2):103S-9S.
Despotis Get al. Transfusion. 2008; 48(1 Suppl):2S-30S.
Thromboelastography
Parameter Interpretation Therapy
r (15-23
min)
Quantity of
clotting factors
FFP
K (5-10
min)
Rate of clot
formation
Fibrinogen
(cryoprecipitate)
(22-38) Rate of clot
formation
Fibrinogen
(cryoprecipitate)
MA (47-58
mm)
Strength of
clot and
platelet
activation
Platelets
desmopressin
rFVIIa
A
60
(>
90%)
Fibrinolysis Antifibrinolytics
MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
16
Case Scenario
Jill is a 58-y.o. woman admitted with septic shock and
oliguria. Her PMH is significant for PE 2 years ago (no
longer requiring anticoagulation, but she takes aspirin
325 mg daily)
Baseline labs show platelets 37 x 10
9
/L, Hct 24% (for
which 2 units of RBCs are administered for EGT of Hct
>30%), INR 1.7, aPTT 48 seconds, BUN 45 mg/dL, ALT
2200 IU/L, and AST 3450 IU/L
APACHE II score >25, so activated protein C is started
She receives 8 L normal saline and norepinephrine 0.3
mcg/kg/min, is intubated, and renal support is started
What additional information would you
like to know to minimize J ills risk of
hemorrhage?
A. pH
B. Fibrinogen
C. Temperature
D. Ionized calcium
What additional information would you
like to know to minimize J ills risk of
hemorrhage?
p
H
F
ib
rin
o
g
e
n
T
e
m
p
e
r
a
tu
r
e
Io
n
iz
e
d
c
a
lc
iu
m
41%
30%
7%
22%
A. pH
B. Fibrinogen
C. Temperature
D. Ionized calcium
17
Case Scenario
The next day, Jills Hct and Hgb drop substantially. A
retroperitoneal hematoma is suspected. Her blood
pressure is tenuous and she is too unstable to go to the
OR. Labs show platelets 24 x 10
9
/L, Hct 19% (for which
2 units of RBCs are administered), INR 2.2, aPTT 52
seconds, and fibrinogen 85 mg/dL
Activated protein C is stopped
Which of the following could be
etiologies of J ills hemorrhage?
A. Anticoagulant use
(activated protein C,
aspirin)
B. Massive blood loss
C. DIC
D. Liver and renal
dysfunction
Which of the following could be
etiologies of J ills hemorrhage?
A
n
tic
o
a
g
u
la
n
t u
s
e
(a
c
...
M
a
s
s
iv
e
b
lo
o
d
lo
s
s
D
IC
L
iv
e
r a
n
d
r
e
n
a
l d
y
s
fu
...
0%
20% 20%
60%
A. Anticoagulant use
(activated protein C,
aspirin)
B. Massive blood loss
C. DIC
D. Liver and renal
dysfunction
18
In addition to RBCs, what therapy would
you recommend to treat J ills bleed?
A. FFP for activated protein C
use, liver dysfunction, and
DIC
B. Platelets for
thrombocytopenia and aspirin
use
C. Cryoprecipitate for low
fibrinogen
D. Desmopressin for aspirin use
E. rFVIIa for ???
In addition to RBCs, what therapy would
you recommend to treat J ills bleed?
F
F
P
fo
r
a
c
tiv
a
te
d
p
ro
te
..
P
la
te
le
ts
fo
r
th
ro
m
b
o
...
C
r
y
o
p
r
e
c
ip
ita
te
fo
r
lo
w
...
D
e
s
m
o
p
r
e
s
s
in
fo
r
a
s
p
...
rF
V
IIa
fo
r ?
?
?
57%
20%
6%
8% 9%
A. FFP for activated protein C
use, liver dysfunction, and
DIC
B. Platelets for
thrombocytopenia and aspirin
use
C. Cryoprecipitate for low
fibrinogen
D. Desmopressin for aspirin use
E. rFVIIa for ???
You, the pharmacist, may help by?
A. Correcting factors (e.g., pH,
calcium) to maximize
coagulation
B. Realizing the benefits and
limitations of procoagulant
agents to optimize therapy
C. Targeting therapy based on
point-of-care testing
D. Understanding the
concerns associated with
therapy to minimize
adverse events
19
You, the pharmacist, may help by?
C
o
r
r
e
c
tin
g
fa
c
to
r
s
(e
....
R
e
a
liz
in
g
th
e
b
e
n
e
fit...
T
a
r
g
e
tin
g
th
e
r
a
p
y
b
a
s
..
U
n
d
e
rs
ta
n
d
in
g
th
e
c
...
19%
27%
18%
36%
A. Correcting factors (e.g., pH,
calcium) to maximize
coagulation
B. Realizing the benefits and
limitations of procoagulant
agents to optimize therapy
C. Targeting therapy based on
point-of-care testing
D. Understanding the
concerns associated with
therapy to minimize
adverse events
20
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

S E L E C T E D R E F E R E N C E S - Presentation 1

Caldwell SH, Hoffman M, Lisman T et al. Coagulation disorders and hemostasis in liver
disease: pathophysiology and critical assessment of current management. Hepatology.
2006; 44:1039-46.

Corwin HL, Gettinger A, Pearl RG et al. The CRIT Study: anemia and blood transfusion
in the critically ill--current clinical practice in the United States. Crit Care Med. 2004;
32:39-52.

Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of
perioperative bleeding with cardiac surgery. Transfusion. 2008; 48(1 Suppl):2S-30S.

Dutton RP. Goals of therapy in common bleeding emergencies. Pharmacotherapy. 2007;
27(9 Pt 2):85S-92S.

Hardy JF, de Moerloose P, Samama CM et al. Massive transfusion and coagulopathy:
pathophysiology and implications for clinical management. Can J Anaesth. 2006; 53(6
Suppl):S40-58.

Hirsh J, ODonnell M, Eikelboom JW. Beyond unfractionated heparin and warfarin:
current and future advances. Circulation. 2007; 116:552-60.

Jaffer AK. Managing anticoagulant related coagulopathy. J Thromb Thrombolysis. 2008;
25:85-90.

Levi M. Disseminated intravascular coagulation. Crit Care Med. 2007; 35:2191-5.

Levi M, Opal SM. Coagulation abnormalities in critically ill patients. Crit Care. 2006;
10:222.

Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on
pathophysiology, clinical consequences, and treatment. Dig Surg. 2007; 24:250-8.

MacLaren R, Weber LA, Brake H et al. A multicenter assessment of recombinant factor
VIIa off-label usage: clinical experiences and associated outcomes. Transfusion. 2005;
45:1434-42.

MacLaren R. Key concepts in the management of difficult hemorrhagic cases.
Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.

Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med.
2007; 356:2301-11.

Mercer KW, Gail Macik B, Williams ME. Hematologic disorders in critically ill patients.
Semin Respir Crit Care Med. 2006; 27:286-96.

Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill. Crit
Care Clin. 2004; 20:255-68.

21
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

Rebuck JA. Practical considerations when developing guidelines for managing critical
bleeding. Pharmacotherapy. 2007; 27(9 Pt 2):103S-9S.

Schreiber MA. Coagulopathy in the trauma patient. Curr Opin Crit Care. 2005; 11:590-7.

Shander A, Goodnough LT. Update on transfusion medicine. Pharmacotherapy. 2007;
27(9 Pt 2):57S-68S.

Spahn DR, Rossaint R. Coagulopathy and blood component transfusion in trauma. Br J
Anaesth. 2005; 95:130-9.

Trotter JF. Coagulation abnormalities in patients who have liver disease. Clin Liver Dis.
2006; 10:665-78.

Voils S. Pharmacologic interventions for the management of critical bleeding.
Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.

Zimmerman LH. Causes and consequences of critical bleeding and mechanisms of
blood coagulation. Pharmacotherapy. 2007; 27(9 Pt 2):45S-56S.

22
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Associate Professor of Pharmacy and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia Campus
Richmond, Virginia



Gretchen M. Brophy Pharm.D., BCPS, FCCP, FCCM, is Associate Professor of
Pharmacy and Neurosurgery at Virginia Commonwealth University (VCU) in Richmond,
Virginia. In addition, she is the critical care pharmacist in the Neuroscience Intensive
Care Unit (NSICU) at VCU Health System, Medical College of Virginia Campus.

After earning her Doctor of Pharmacy degree at the University of Arizona, Dr. Brophy
completed pharmacy practice and critical care residencies at the University of Kentucky.
She is a Board Certified Pharmacotherapy Specialist and fellow of the American College
of Critical Care Medicine and the American College of Clinical Pharmacy.

Dr. Brophy is currently a co-investigator in traumatic brain injury biomarker studies
sponsored by the National Institutes of Health and Department of Defense. Her
research interests include neuroprotection, intracranial hemorrhage, acute ischemic
stroke, and biokinetics.
23
Anticoagulant-Associated
Intracerebral Hemorrhage:
Conventional and Emerging
Therapeutic Strategies
Gretchen M. Brophy, Pharm.D., BCPS, FCCP, FCCM
Associate Professor of Pharmacy and Neurosurgery
Virginia Commonwealth University
Medical College of Virginia
Richmond, Virginia
Objectives
Identify pharmacologic options for hemostasis in the
patient with intracerebral hemorrhage (ICH)
Review the evidence for use of hemostatic agents in
patients with anticoagulant-associated ICH
Discuss strategies and guidelines for treatment of life-
threatening ICH
Determine the best therapeutic strategy for a patient who
presents with anticoagulant-associated ICH
Clinical Case
J C is a 72-y.o. African American man who
presents with ICH
HPI: he was found downby his wife after she made a 5-
minute trip to the mailbox
He is currently unconscious, and was intubated for airway
protection
CT scan: left-sided ICH and subdural hematoma
Vitals: BP 184/89 mm Hg; HR 99 bpm; temp 99.8F; height
61; weight 87 kg
Neuro: Glasgow coma scale score of 6
PMH: atrial fibrillation, hypertension, hypercholesterolemia
Home meds: warfarin 5 mg daily, amlodipine 10 mg daily,
atorvastatin 20 mg daily at bedtime
Labs: INR 3.1
J C was admitted to the neuroscience ICU 2 hours after
symptom onset and needs emergent neurosurgical
intervention
24
Anticoagulant-Associated
Intracerebral Hemorrhage (ICH)
ICH accounts for 10-15% of all strokes, and
anticoagulant-associated ICH accounts for ~20% of all
ICH
1,2
Hematoma expansion is an independent risk factor for
poor outcomes and high mortality
3
Warfarin use is a risk factor for hematoma expansion
and almost doubles ICH mortality
2,4
Rapid INR reversal decreases the risk of hematoma
growth and may decrease time to emergent surgery
1
FlahertyML et al. Neurology. 2006; 66:1182-6.
3
Davis SM et al. Neurology. 2006; 66:1175-81.
2
Rosand J et al. Arch Intern Med. 2004;164:880-4.
4
Flibotte J J et al. Neurology. 2004; 63:1059-64.
What pharmacologic treatment options does
J C have for anticoagulant-associated ICH?
Vitamin K
Promotes liver synthesis of clotting factors: II, VII, IX, X
Fresh frozen plasma (FFP)
Coagulation factors and fibrinogen in variable amounts
Prothrombin complex concentrate (PCC)
Factors II, VII, IX, and X and prothrombin, proteins C, S, & Z in
variable amounts
Recombinant activated factor VII (rFVIIa)
rFVIIa only
Liu-DeRyke X et al. Pharmacotherapy. 2008;28:485-95.
Warfarin Reversal Studies and Case Reports
25
Guidelines for Managing Elevated INR or Bleeding
in Patients Receiving Warfarin
Condition Intervention
Serious bleeding at anyelevation of
INR
Withhold warfarin therapyand give vitamin K (10
mg by slow IV infusion), supplemented with FFP,
PCC, or rFVIIa, depending on the urgencyof the
situation; vitamin K can be repeated every12 hr
(Grade 1C)
Life-threatening bleeding
Withhold warfarin therapyand give FFP, PCC, or
rFVIIa supplemented with vitamin K (10 mg by
slowIV infusion). Repeat, if necessary, depending
on INR (Grade 1C)
Warfarin-associated ICH
Vitamin K IV +clotting factor replacement (Class
I, B). PCC, rFVIIa, factor IX complex concentrate
to normalize INR very rapidly with smaller
volumes than FFP but risk of thromboembolism
FFP is a potential choice but requires large
volumes and much longer infusion times (Class
IIb, B)
Ansell J et al Chest. 2008; 133(6
Suppl):160S-98S.
Ansell J et al. Chest. 2008; 133(6
Suppl):160S-98S.
Broderick J et al. Stroke.
2007; 38:2001-23.
Which of the following is the best initial
treatment option for J C after stopping
warfarin?
A. Vitamin K and FFP
B. FFP and PCC
C. PCC and vitamin K
D. Vitamin K, FFP, and
rFVIIa
Which of the following is the best initial
treatment option for J C after stopping
warfarin?
V
ita
m
i n
K
a
n
d
F
F
P
F
F
P
a
n
d
P
C
C
P
C
C
a
n
d
v
ita
m
in
K
V
ita
m
i n
K
, F
F
P
, a
n
d
r
...
52%
32%
12%
3%
A. Vitamin K and FFP
B. FFP and PCC
C. PCC and vitamin K
D. Vitamin K, FFP, and
rFVIIa
26
Emergency Management of
Coagulopathic ICH Patients
Scenari o Agent Dose Comments
Warfarin FFP
or
PCC
and
Vitamin K
15 mL/kg IV
1530 IU/kg IV
10 mg IV
Typically 4-6 units
(200 mL) given
Faster than FFP
1 mg/min max
Warfarin and
emergency
neurosurgical
intervention
Above PLUS
rFVIIa 20-80 mcg/kg IV
Contraindicated in
acute
thromboembolic
disease
Mayer SA et al. Lancet Neurol. 2005; 4:662-72.
Which agent has the fastest
time to INR reversal?
A. Vitamin K
B. FFP
C. PCC
D. rFVIIa
Which agent has the fastest
time to INR reversal?
V
ita
m
i n
K
F
F
P

P
C
C

rF
V
IIa
7%
66%
13% 13%
A. Vitamin K
B. FFP
C. PCC
D. rFVIIa
27
Time to Reversal
Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.
Mathews M et al. Neurocrit Care. 2006; 5:141-52
Rapid
Rapid
Fast
Prompt
Slow
Huttner HB et al. Stroke. 2006; 37:1465-70.
PCC
Usual dose: 15-50 IU/kg
Dosed based on factor IX content
Individualize therapy based on INR levels:
Dose =actual body weight (kg) X (target % plasma activity
current % plasma activity)
Yasaka M et al. Thromb Res. 2005; 115:455-9. Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.
MacLaren R.Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S. Preston FE et al. Br J Haematol. 2002; 116:619-24.
Infusion rate: 2 mL/min (Bebulin VH); 3-10 mL/min (Profilnine SD)
Reports of infusions as short as 2-10 minutes for Profilnine SD
Expensive
INR Target <1.3
28
PCC
Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.
Factor VIIa: Mechanism of Action
1. INITIATION: Tissue
Factor/FVIIa interaction
leads to thrombin
generation
2. AMPLIFICATION/
PROPAGATION:
rFVIIa activates factor X
on the surface of
activated platelets,
leading to an enhanced
thrombin burst at the
site of injury
3. FIBRIN CLOT
FORMATION:
Thrombin converts
fibrinogen into fibrin,
producing a stable clot
Hoffman M et al. Thromb Haemost. 2001;85:958-65.
29
rFVIIa
Concentration needed for normal hemostasis: 0.075 to 0.125 mcg/mL
(congenital FVII deficiency data)
70-kg patient, 3 L plasma volume: needs 3 to 5 mcg/kg to secure
hemostasis (assuming 100% recovery)
PK
Onset: 10 minutes or less
Half-life: 2.3 hours (range 1.7-2.7)
Duration (INR <1.5): 2 to 6 hours (dose dependent)
No good test for clinical efficacy!
Dose
Warfarin reversal: 5-50 mcg/kg/dose reported
NEW (Aug 2008) roomtemperature stable formulation in 1-mg, 2-mg, and 5-
mg vials
Interference with clinical efficacy
Platelet count: 20,000-50,000 needed
Acidosis and hypothermia decrease efficacy
COST
~U.S. $1 per mcg (AWP)
Kawaguchi C et al. Thromb Haemost. 2002;88:768-72.
NovoSeven prescribing information, 2008.
Dutton RP et al. J Trauma. 2004; 57:709-18.
Erhardtsen E et al. Blood Coagul Fibrinolysis. 1998; 9:741-8.
rFVIIa for Acute ICH:
Phase IIb study
rFVIIa: 40, 80 and 160 mcg/kg in spontaneous ICH
Dose given within 4 hours of symptom onset
Excluded patients with thrombotic or vaso-occlusive disease
Outcomes:
Significantly reduced hematoma growth in a dose-dependent
fashion
Significantly reduced mortality and significantly improved global
functional outcome (mRS and Barthel Index) at 90 days
Was associated with a small increase in the risk of acute
thromboembolic events (7% vs. 2%, arterial 5% vs. 0%, p=0.01)
Mayer SA et al. N Engl J Med. 2005; 352:777-85.
FAST: Phase III Study
Placebo, rFVIIa 20 mcg/kg and rFVIIa 80 mcg/kg in spontaneous ICH
Included patients with vascular risk factors
Primary endpoint mRS at 3 months
Outcomes
Reduced hematoma growth (p=0.001)
No improvement in survival or functional outcome after ICH
More ADRs in higher rFVIIa dose group vs. placebo (arterial - 8%
vs. 4%, p=0.04)
Study limitations
Confounding factors may have limited the treatment effect
Target population for rFVIIa administration
Age <70 yr
Time to dose <3 hours
Baseline volume of ICH <60 mL
Baseline intraventricular hemorrhage volume <5 mL
Mayer SA et al. N Eng J Med. 2008; 358:2127-37.
30
Clinical Case
Repeat CT scan 2 hours after admission shows
no further growth of ICH
INR is now 1.4
J C was rushed to surgery for evacuation of the
hematoma and is doing well postoperatively
Repeat CT at 24 hours shows no hematoma
growth
On day 2, you notice J C has a right facial droop
and right-sided weakness
He is diagnosed with acute ischemic stroke
(AIS)
What should be recommended
at this time?
A. Consider t-PA treatment
for the AIS
B. Consider rFVIIa and
PCC as a potential
cause of the AIS
C. Consider further INR
corrections with vitamin
K and FFP
D. Consider starting
heparin anticoagulation
What should be recommended
at this time?
C
o
n
s
id
e
r
t-P
A
t r
e
a
tm
e
..
C
o
n
s
id
e
r
r
F
V
IIa
a
n
d
P
..
C
o
n
s
id
e
r
fu
rth
e
r
IN
R
...
C
o
n
s
id
e
r
s
ta
r
ti n
g
h
e
p
...
20%
24%
3%
53%
A. Consider t-PA treatment
for the AIS
B. Consider rFVIIa and
PCC as a potential
cause of the AIS
C. Consider further INR
corrections with vitamin
K and FFP
D. Consider starting
heparin anticoagulation
31
Treatment Overview
Vitamin K
Delayed onset: 1-2 hours
Correction of INR: 6-24 hours (INR <1.5)
FFP
Rate of reversal unpredictable and extended
Large volumes and long infusion time
PCC
Short duration of action
Risk of thrombosis and disseminated intravascular
coagulopathy
Limited availability
Expensive
rFVIIa
Short duration of action (dose dependent)
Risk of thrombosis
Expensive
Clinical Case
On day 5, J C is awake and oriented with
slight weakness on the right side
He is transferred out of the ICU
The resident asks your recommendations
for J Cs long-term anticoagulation therapy
What is the best recommendation regarding
J Cs home warfarin therapy?
A. Do not restart warfarin in J C
B. Restart warfarin therapy
today
C. Consider restarting warfarin
in 1 week
D. Change to antiplatelet
therapy
32
What is the best recommendation regarding
J Cs home warfarin therapy?
D
o
n
o
t r
e
s
ta
r
t w
a
r
fa
ri ...
R
e
s
t a
r
t w
a
r
fa
r
i n
th
e
r...
C
o
n
s
id
e
r
r
e
s
ta
rt i n
g
w
...
C
h
a
n
g
e
to
a
n
tip
la
te
l e
t...
5%
40%
35%
21%
A. Do not restart warfarin in J C
B. Restart warfarin therapy
today
C. Consider restarting warfarin
in 1 week
D. Change to antiplatelet
therapy
What if J C was receiving warfarin for deep vein
thrombosis treatment (week 8) instead of for
atrial fibrillation?
A. Do not restart warfarin in J C
B. Restart warfarin therapy
today
C. Consider restarting warfarin
in 1 week
D. Insert an inferior vena cava
filter
What if J C was receiving warfarin for deep vein
thrombosis treatment (week 8) instead of for
atrial fibrillation?
D
o
n
o
t r
e
s
ta
r
t w
a
r
fa
ri ...
R
e
s
ta
r
t w
a
r
fa
r
i n
th
e
r...
C
o
n
s
id
e
r
r
e
s
ta
rti n
g
...
In
s
e
rt a
n
in
fe
r
io
r v
e
n
...
8%
57%
24%
11%
A. Do not restart warfarin in J C
B. Restart warfarin therapy
today
C. Consider restarting warfarin
in 1 week
D. Insert an inferior vena cava
filter
33
Restarting Anticoagulation???
Who?
Benefit >risk
Prosthetic cardiac valves (AIS risk at least 4%)
Secondary prevention in atrial fibrillation (AIS risk 12%)
Risk >benefit
Primary prevention in nonvalvular atrial fibrillation (AIS risk
5%)
When?
No large, prospective trials in ICH patients
Data suggest a low risk of thromboembolic
complications 7-14 days after reversal in patients with
prosthetic valves
Clinical practice: delay for 1-6 weeks after ICH
Eckman E et al. Stroke. 2003;34:1710-6.
Aguilar MI et al. Mayo Clin Proc. 2007; 82:82-92.
Broderick J et al. Stroke. 2007; 38:2001-23.
AHA/ ASA Guideline: Recommendations for
Management of ICH Related to Coagulation
Decision to restart antithrombotic therapy depends on the risk of
subsequent arterial or venous thromboembolism, the risk of recurrent ICH,
and the overall state of the patient
Comparatively lower risk of cerebral infarction (e.g., atrial fibrillation without prior
ischemic stroke) and a higher risk of amyloid angiopathy or verypoor overall
neurological function
Antiplatelet agent maybe an overall better choice for prevention of ischemic stroke than
warfarin
Veryhigh risk of thromboembolismin whomrestarting warfarin is considered
Warfarin therapymaybe restarted at 7 to 10 days after onset of the original ICH (Class
IIb, Level of Evidence B).
Treatment of patients with ICH related to thrombolytic therapy includes
urgent empirical therapies to replace clotting factors (cryoprecipitate that
contains factor VIII) and platelets (6-8 units) (Class IIb, Level of Evidence B)
Broderick J et al. Stroke. 2007; 38:2001-23.
34
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

S E L E C T E D R E F E R E N C E S - Presentation 2

Aguilar MI, Hart RG, Kase CS et al. Treatment of warfarin-associated intracerebral
hemorrhage: literature review and expert opinion. Mayo Clin Proc. 2007; 82:82-92.

Ansell J, Hirsh J, Hylek E et al. Pharmacology and management of the vitamin K
antagonists: American College of Chest Physicians evidence-based clinical practice
guidelines (8th edition). Chest. 2008; 133(6 Suppl):160S-98S.

Broderick J, Connolly S, Feldmann E et al. Guidelines for the management of
spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the
American Heart Association/American Stroke Association Stroke Council, High Blood
Pressure Research Council, and the Quality of Care and Outcomes in Research
Interdisciplinary Working Group. Stroke. 2007; 38:2001-23.

Davis SM, Broderick J, Hennerici M et al. Hematoma growth is a determinant of mortality
and poor outcome after intracerebral hemorrhage. Neurology. 2006; 66:1175-81.

Dutton RP, McCunn M, Hyder M et al. Factor VIIa for correction of traumatic
coagulopathy. J Trauma. 2004; 57:709-18.

Eckman MH, Rosand J, Knudsen KA et al. Can patients be anticoagulated after
intracerebral hemorrhage? A decision analysis. Stroke. 2003; 34:1710-6.

Erhardtsen E, Nony P, Dechavanne M et al. The effect of recombinant factor VIIa
(NovoSeven) in healthy volunteers receiving acenocoumarol to an international
normalized ratio above 2.0. Blood Coagul Fibrinolysis. 1998; 9:741-8.

Flaherty ML, Haverbusch M, Sekar P et al. Long-term mortality after intracerebral
hemorrhage. Neurology. 2006; 66:1182-6.

Flibotte JJ, Hagan N, ODonnell J et al. Warfarin, hematoma expansion, and outcome of
intracerebral hemorrhage. Neurology. 2004; 63:1059-64.

Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001;
85:958-65.

Huttner HB, Schellinger PD, Hartmann M et al. Hematoma growth and outcome in
treated neurocritical care patients with intracerebral hemorrhage related to oral
anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh
frozen plasma, and prothrombin complex concentrates. Stroke. 2006; 37:1465-70.

Kawaguchi C, Takahashi Y, Hanesaka Y et al. The in vitro analysis of the coagulation
mechanism of activated factor VII using thrombelastogram. Thromb Haemost. 2002;
88:768-72.

Liu-DeRyke X, Rhoney D. Hemostatic therapy for the treatment of intracranial
hemorrhage. Pharmacotherapy. 2008; 28:485-95.

35
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

MacLaren R. Key concepts in the management of difficult hemorrhagic cases.
Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.

Mathews M, Newman R, Chappell ET. Management of coagulopathy in the setting of
acute neurosurgical disease and injury. Neurocrit Care. 2006; 5:141-52.

Mayer SA, Brun NC, Begtrup K et al. Recombinant activated factor VII for acute
intracerebral hemorrhage. N Engl J Med. 2005; 352:777-85.

Mayer SA, Rincon F. Treatment of intracerebral haemorrhage. Lancet Neurol. 2005;
4:662-72.

Mayer SA, Brun NC, Begtrup K et al. Efficacy and safety of recombinant activated factor
VII for acute intracerebral hemorrhage. N Engl J Med. 2008; 358: 2127-37.

NovoSeven prescribing information. Novo Nordisk Inc: Princeton, NJ; 2008.

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; 116:619-24.

Rosand J, Eckman MH, Knudsen KA et al. The effect of warfarin and intensity of
anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med. 2004;
164:880-4.

Yasaka M, Sakata T, Naritomi H et al. Optimal dose of prothrombin complex concentrate
for acute reversal of oral anticoagulation. Thromb Res. 2005; 115:455-9.

36
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

Jeremy D. Flynn, Pharm.D., BCPS
Clinical Pharmacist Specialist
UK HealthCare-Pharmacy Services
Assistant Professor
Department of Pharmacy Practice and Science
University of Kentucky College of Pharmacy
Lexington, Kentucky



J eremy D. Flynn, Pharm.D., BCPS, is Assistant Adjunct Professor of Pharmacy at the
University of Kentucky (UK) College of Pharmacy Department of Pharmacy Practice in
Lexington, Kentucky. He is also Assistant Adjunct Professor of Surgery at the UK
College of Medicine. Dr. Flynn is a clinical pharmacy specialist in cardiothoracic surgery
and critical care at the University of Kentucky Chandler Medical Center. He is actively
involved with the critical care residency program at UKHealthcare.

Following completion of pharmacy practice and critical care residencies at UK, Dr. Flynn
completed an ACCP Critical Care fellowship under the guidance of W. Scott Akers.
Dr. Flynn has been active in the field of cardiovascular and critical care
pharmacotherapy. His teaching, research, and patient care activities focus on the
pharmacotherapeutic management of the cardiothoracic surgery and heart / lung
transplant populations. Recent areas of research include an evaluation of antifibrinolytic
therapy in cardiac surgery patients and the treatment and prevention of atrial
arrhythmias following thoracic surgery. Dr. Flynn serves as a journal referee for
Pharmacotherapy, The Annals of Pharmacotherapy, and Critical Care Medicine.
37
Surgery-Associated Bleeding:
A Cardiac Surgery Case
J eremy Flynn, Pharm.D., BCPS
Clinical Pharmacist Specialist, Cardiothoracic Surgery
Assistant Professor
University of Kentucky College of Pharmacy
Department of Pharmacy Practice and Science
Lexington, Kentucky
Objectives
List the most common risk factors for bleeding
associated with cardiac surgery
Describe the preoperative interventions commonly
employed to reduce bleeding, including the available
pharmacologic agents for prophylaxis
Explain the therapeutic options available for the
treatment of bleeding in the cardiac surgical patient
Apply the information discussed to a patient case and
select appropriate therapy
Patient Case
AB is a 70-y.o. woman who presents with chest
pain (found to be NSTEMI) and is taken for PCI
UFH started, 600-mg clopidogrel loading dose given
before catheterization (ACC/AHA Class IA
recommendation)
Catheterization shows 3-vessel CAD w/60% left
main coronary artery occlusion
Lesions not amenable to angioplasty/stenting
Ongoing chest pain not relieved by IABP (Intra-aortic balloon pump)
PMH:
CAD, HTN, chronic renal insufficiency (SCr 2.0 mg/dL),
DM, aortic valve replacement in 1998
Hct 34%; BSA 1.5 m
2
It is determined that the patient will need CABG
Anderson JL et al. J Am Coll Cardiol. 2007; 50:e1-157.
38
Which of the following is NOT a risk factor
associated with increased bleeding with
cardiac surgery?
A. Advanced age
B. Urgent/emergent
operation
C. Obesity
D. Use of antiplatelet/
antithrombotic agents
E. Redo sternotomy
Which of the following is NOT a risk factor
associated with increased bleeding with
cardiac surgery?
A
d
v
a
n
c
e
d
a
g
e
U
r
g
e
n
t/e
m
e
rg
e
n
t o
p
e
...
O
b
e
s
ity
U
s
e
o
f a
n
tip
la
te
le
t/ a
n
...
R
e
d
o
s
te
r
n
o
to
m
y
3%
23%
16%
2%
55% A. Advanced age
B. Urgent/emergent
operation
C. Obesity
D. Use of antiplatelet/
antithrombotic agents
E. Redo sternotomy
Predictors of Postoperative Bleeding
1) Advanced age
2) Small body size or preoperative anemia (low
RBC volume)
3) Prolonged operation (cardiopulmonary bypass
time) high correlation with type of surgery
4) Emergency operation
5) Other comorbidities (e.g., CHF, COPD, HTN,
peripheral vascular disease, renal failure)
6) Use of antiplatelet & antithrombotic drugs
Redo sternotomy can also increase risk
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86. Ferraris VA et al. Ann Surg. 2002; 235:820-7.
10-20% of patients consume 80% of blood products
39
Critical Stages of Cardiac Surgery
Preoperative
Risk factor assessment
Medications
Prophylaxis strategy
Intraoperative
Type and length of procedure
Cardiopulmonary bypass (CPB)
Anticoagulation strategy
Postoperative
Monitoring
Coagulopathy
What do we need to know to continually assess bleeding risk, severity
of bleed, and/or treatment options?
What is the best option for prophylaxis
to minimize the bleeding risk for this patient?
A. Aprotinin loading dose
and infusion
B. Wait 5 days prior to
proceeding with CABG
C. Give platelet
transfusion prior to
surgery
D. -aminocaproic acid
(EACA)
E. Desmopressin
(DDAVP)
What is the best option for prophylaxis
to minimize the bleeding risk for this patient?
A
p
r
o
tin
in
lo
a
d
in
g
d
o
s
...
W
a
it 5
d
a
y
s
p
r
io
r
to
...
G
iv
e
p
la
te
le
t tr
a
n
s
fu
s
...
D
e
s
m
o
p
r
e
s
s
in
(D
D
A
V
P
)
12%
16%
19%
18%
34%
A. Aprotinin loading dose
and infusion
B. Wait 5 days prior to
proceeding with CABG
C. Give platelet
transfusion prior to
surgery
D. -aminocaproic acid
(EACA)
E. Desmopressin
(DDAVP)
40
Preoperative/Prophylactic Treatment
Anticoagulation discontinuation/reversal
Heparin, LMWH, warfarin, fondaparinux
Blood products
Platelet transfusions for clopidogrel exposure?
Antifibrinolytics
Lysine analogues
-aminocaproic acid (EACA)
Tranexamic acid (TXA)
Aprotinin
No longer available in U.S. due to safety concerns
Antifibrinolytic DataMeta-Analysis
Total of 19 trials randomizing 2430 subjects
10 aprotinin vs. TXA -- 3 TXA vs. EACA
6 aprotinin vs. EACA
Aprotinin vs. TXA
(1707 patients)
Aprotinin vs. EACA
(399 patients)
Blood Loss Aprotinin superior
106 mL (37-176)
Aprotinin superior
184 mL (134-235)
Transfusion
(rate and total)
ND ND
Re-operation
ND Insufficient data
Mortality, MI, and stroke
No trends observed favoring any of the agents
No differences found between TXA and EACA
Carless PA et al. BMC Cardiovasc Disord. 2005; 5:19.
Blood Conservation Using Antifibrinolytics
in a Randomized Trial (BART) Study
Compared the three antifibrinolytic products
Similar demographics, risk profiles, and operative data
Modest reduction in massive bleeding with aprotinin
Mortality?
Fergusson DA et al. N Engl J Med. 2008; 358:2319-31.
Number needed to
harm: 50 patients
Doubling of death from
cardiac causes
41
BART Study - Efficacy
Aprotinin
(%)
TXA
(%)
EACA
(%)
Aprotinin vs.
TXA
(RR 95% CI)
Aprotinin
vs. EACA
(RR 95% CI)
Bleeding from chest
tubes
5.3 7.5 8.3
0.70
(0.47-1.03)
0.63
(0.43-0.92)
Massive transfusion 2.1 2.2 2.8
0.93
(0.47-1.83)
0.73
(0.38-1.37)
Death due to
hemorrhage
1.4 1.0 0.5
1.36
(0.55-3.36)
2.75
(0.88-8.60)
Re-operation 5.5 8.1 8.2
0.68
(0.47-1.00)
0.67
(0.46-0.98)
Any massive
bleeding
9.5 12.1 12.1
0.79
(0.59-1.05)
0.79
(0.59-1.05)
Fergusson DA et al. N Engl J Med. 2008; 358:2319-31.
No differences identified in major adverse effects:
Stroke, MI, DVT, PE, or renal failure
AB proceeded to urgent CABG and was given appropriate
doses of -aminocaproic acid for prophylaxis.
Patient Case
The patient experienced significant generalized oozing after
separation from CPB and reversal of heparin, leading to
significant blood loss and pooling of blood in the thoracic cavity
Unable to close until bleeding is corrected
Time on CPB
X-clamp time
220 minutes
160 minutes
Anticoagulation
Monitoring
Reversal
Heparin 300 units/kg bolus
ACT (POC) Goal >550 sec
Protamine 3 mg/kg
Total dose
550 units/kg
Packed RBC (PRBC)
transfusions
Total of 4 units through the
case to maintain Hct 26-28%
What is the first intervention you would
make to correct the bleeding?
A. Send coagulation labs
and hemogram
B. Transfuse blood products
(e.g., packed RBCs,
platelets, fresh frozen
plasma, fibrinogen)
C. Check activated clotting
time (ACT)/point-of-care
(POC) testing
D. Give desmopressin
E. Give recombinant factor
VIIa (rFVIIa)
42
What is the first intervention you would
make to correct the bleeding?
S
e
n
d
c
o
a
g
u
la
tio
n
la
b
...
T
r
a
n
s
fu
s
e
b
lo
o
d
p
r
o
...
C
h
e
c
k
a
c
tiv
a
te
d
c
lo
tti..
G
iv
e
d
e
s
m
o
p
r
e
s
s
in
G
iv
e
re
c
o
m
b
in
a
n
t fa
c
t..
11%
30%
31%
11%
17%
A. Send coagulation labs
and hemogram
B. Transfuse blood products
(e.g., packed RBCs,
platelets, fresh frozen
plasma, fibrinogen)
C. Check activated clotting
time (ACT)/point-of-care
(POC) testing
D. Give desmopressin
E. Give recombinant factor
VIIa (rFVIIa)
Bleeding and Cardiac Surgery
Surgically correctable (<3% cases)
Associated with brisk hemorrhage (>200 mL/hr)
Normal coagulation studies
Clotting in mediastinal drainage tubes
Coagulopathy related (generalized oozing)
Common occurrence after exposure to extracorporeal
circulation (severity related to duration of CPB)
Related to abnormal:
Clotting parameters Platelet quantity and quality
Fibrinogen levels Residual drug effect
Sabiston DC J r, Spencer F, eds. Surgery of the chest. 6
th
ed. Philadelphia, PA: W.B. Saunders; 1995.
Evidence from Randomized Trials for Massive
Hemorrhage in the Cardiac Surgery Patient
Some of the issues are addressed in the clinical practice guideline from the
Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists:
Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
43
Key Points to Consider
Planning is essential
Identify high-risk patients
Have treatment options immediately available
Protocols
Massive transfusion protocol or service-specific
bleeding protocol
Monitoring strategy
Anticoagulation strategy
Complete reversal of heparin
Residual heparin or rebound effect
Goals of Therapy
Stop or control hemorrhage
Minimize blood product use
Minimize adverse events
Correct coagulation tests and blood counts
pH 7.20, temperature 35C, normal
ionized calcium
Avoid re-exploration for bleeding
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
Dutton RP. Pharmacotherapy. 2007; 27(9 Pt 2):85S-92S.
Monitoring
Point-of-care vs. central laboratory?
Point-of-care preferred
ACT monitoring
Platelet function
Thromboelastography (TEG)
Timing of treatment
Do NOT wait for test results from lab
Use visual cues in the OR
44
Transfusion Therapy
Primary means of treating/controlling acute
intraoperative bleeding
Product Contents Indications and Dose Concerns
PRBC Maintain target Hgb/Hct
Platelets Thrombocytes in
plasma
Plts <50 x 10
9
/L (bleeding)
Plts <20 x 10
9
/L (prevention)
Stored at 20-24C
Bacterial contamination ~1/2000
to 1/3000 units
Worsens immune reactions
FFP Coagulation factors
and fibrinogen in
variable amounts
INR 1.5
15 mL/kg ~ 30% factor
replacement
Requires thawing
Risk of hypervolemia
Cryo-
precipitate
Factors VIII, XIII, vWf,
fibrinogen, fibronectin
Fibrinogen <100 mg/dL
1 unit will fibrinogen ~5-10
mg/dL
vWf deficiency
Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.
Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
Pharmacologic Agents
Product Contents or MOA Indications and Dose Concerns
Local
hemostatics
A. Cellulose-based
B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin
thrombin
C. Thrombin (human or bovine)
D. Zeolite that causes exothermic reaction
E. Chitason (chitin) that activates platelets and electrophysiologic
endothelial attraction of RBCs
F. Synthetics (PEGs or collagen-fibrin)
A. May not adhere
B. Immune reaction, infection
transmission, aprotonin
C. Immune reaction
D. Heat-induced tissue damage
E. May not adhere
F. Immune reaction, costly
Vitamin K Cofactor for activation of
factors II, VII, IX, K
INR 1.5
0.5-20 mg
Slow acting
Variable SC absorption
IV requires slow administration
rFVIIa Activates platelets to
augment thrombin burst
Anticoagulant-induced hemorrhage,
ICH, refractory hemorrhage (surgery,
trauma)
10-90 mcg/kg IV
Short-acting
Thrombosis (<10%)
Costly
Desmopressin Selective V2 agonist to
release factor VIII, vWf, and t-
PA
Platelet dysfunction
0.3 mcg/kg IV
Short-acting
Tachyphylaxis and bleeding risk
with repeat doses
Conjugated
estrogen
antithrombin and protein S
while factors VII, VIII, IX, X,
prothrombin
Platelet dysfunction
25-50 mg iv
Slow acting
Slow offset
Antifibrinolytics
(aprotonin,
EACA, TXA)
Inhibit plasminogen
proteases and plasmin
(aprotonin) and some anti-
inflammation
Prevention of surgical blood loss
Refractory hemorrhage
Aprotinin: 2 million units IV, then 0.5
million units/hr
EACA: 150 mg/kg IV, then 15 mg/kg/hr
TXA: 10 mg/kg IV, then 1 mg/kg/hr
Aprotinin: hypersensitivity (2.8%)
with 9%mortality, renal dysfunction
(OR~2), CVA (OR~2), MI (OR~1.55), 5-
yr mortality (OR~1.48)
Thrombosis, hypotension (TXA)
Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S.
Pharmacologic Agents
Product Contents or MOA Indications and Dose Concerns
Local
hemostatics
A. Cellulose-based
B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin
thrombin
C. Thrombin (human or bovine)
D. Zeolite that causes exothermic reaction
E. Chitason (chitin) that activates platelets and electrophysiologic
endothelial attraction of RBCs
F. Synthetics (PEGs or collagen-fibrin)
A. May not adhere
B. Immune reaction, infection
transmission, aprotonin
C. Immune reaction
D. Heat-induced tissue damage
E. May not adhere
F. Immune reaction, costly
Vitamin K Cofactor for activation of
factors II, VII, IX, K
INR 1.5
0.5-20 mg
Slow acting
Variable SC absorption
IV requires slow administration
rFVIIa Activates platelets to
augment thrombin burst
Anticoagulant-induced hemorrhage,
ICH, refractory hemorrhage (surgery,
trauma)
10-90 mcg/kg IV
Short-acting
Thrombosis (<10%)
Costly
Desmopressin Selective V2 agonist to
release factor VIII, vWf, and t-
PA
Platelet dysfunction
0.3 mcg/kg IV
Short-acting
Tachyphylaxis and bleeding risk
with repeat doses
Conjugated
estrogen
antithrombin and protein S
while factors VII, VIII, IX, X,
prothrombin
Platelet dysfunction
25-50 mg iv
Slow acting
Slow offset
Antifibrinolytics
(aprotonin,
EACA, TXA)
Inhibit plasminogen
proteases and plasmin
(aprotonin) and some anti-
inflammation
Maybe
Some data with EACAfor treatment of hemorrhage.
Continue infusion for 6 hours post-op.
Mannucci PMet al. NEngl J Med. 2007; 356:2301-11. MacLarenR. Pharmacotherapy. 2007; 27(9Pt 2):69S-102S.
45
Desmopressin
Use of desmopressin acetate (DDAVP) is not unreasonable
to attenuate excessive bleeding and transfusion in certain
patients with demonstrable and specific platelet dysfunction
known to respond to this agent (Class IIb, Level of evidence B)
Uremic or CPB-induced platelet dysfunction
Type I von Willebrand disease
Not shown to be effective as prophylaxis
Typical dose 0.3 mcg/kg IV
Laupacis A et al. Anesth Analg. 1997; 85:1258-67.
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
Recombinant Factor VIIa
Use of recombinant factor VIIa concentrate is not
unreasonable for the management of intractable nonsurgical
bleeding that is unresponsive to routine hemostatic therapy
after cardiac procedures using CPB (Class IIb, level of evidence
B)
Issues to consider pH, temperature, platelet count
Place in therapy? Early, prerequisite blood products, salvage
Patient-specific risk CVA, PVD, PE, mechanical valve, VAD, etc.
Dose? Round to nearest vial size, dose cap,
multiple doses?
Ferraris VA et al. Ann Thorac Surg. 2007; 83(5 Suppl):S27-86.
VAD = ventricular assist device
The team has decided to give AB rFVIIa after an
inadequate response to blood products (8 PRBCs,
6 FFP, 4 Plts, and 1 Cryo)
What is the most appropriate dose?
A. 1 mg
B. 30 mcg/kg
C. 90 mcg/kg
D. 120 mcg/kg
46
The team has decided to give AB rFVIIa after an
inadequate response to blood products (8 PRBCs,
6 FFP, 4 Plts, and 1 Cryo)
What is the most appropriate dose?
1
m
g
3
0
m
c
g
/k
g
9
0
m
c
g
/k
g
1
2
0
m
c
g
/k
g
43%
3%
24%
30%
A. 1 mg
B. 30 mcg/kg
C. 90 mcg/kg
D. 120 mcg/kg
rFVIIa Dosing
No published randomized, controlled trials to guide
dosing
Should consider
Severity of bleeding (urgency)
Patient risk factors
Ease of evaluating response
Doses reported in the literature for cardiac surgery
11 to 180 mcg/kg
Trend toward smaller doses
Warren O et al. Ann Thorac Surg. 2007; 83:707-15.
Karkouti K et al. Can J Anaesth. 2007; 54:573-82.
The Safety and Efficacy of Recombinant Factor VII for the
Treatment of Bleeding following Cardiac Surgery: A
Multinational, Randomized, Placebo-controlled Trial
172 patients randomized to 1 of 3 groups (single bolus in ICU)
Placebo (n=68)
rFVIIa 40 mcg/kg (n=35)
rFVIIa 80 mcg/kg (n=69)
Primary Outcome
Critical serious adverse events at 30 days
Death
Acute MI
Cerebral infarction
Clinical symptomatic PE or other thromboembolic events
Secondary endpoints
Rates of re-operation, blood loss volumes, and transfusion
ClinicalTrials.gov Identifier: NCT00154427;
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
47
Authors cautiously concluded that rFVIIa is probably safe and
may be beneficial to treat bleeding after cardiac surgery.
Outcome Placebo
rFVIIa
40 mcg/kg
rFVIIa
80 mcg/kg
Critical Serious
Adverse Events
7%
14%
(p=0.25)
12%
(p=0.43)
Re-operation 25%
14%
(p=0.21)
12%
(p=0.04)
Allogeneic Blood
Transfusion volumes
825 ml
640 ml
(p=0.047)
500 ml
(p=0.042)
Median Drainage Rate
(4 hours after drug)
51 ml/hr
35 ml/hr
(p=0.763)
24 ml/hr
(p=0.018)
Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs
(critical, serious adverse events)
The Safety and Efficacy of Recombinant Factor VII for the
Treatment of Bleeding following Cardiac Surgery: A
Multinational, Randomized, Placebo-controlled Trial
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
Authors cautiously concluded that rFVIIa is probably safe and
may be beneficial to treat bleeding after cardiac surgery.
Outcome Placebo
rFVIIa
40 mcg/kg
rFVIIa
80 mcg/kg
Critical Serious
Adverse Events
7%
14%
(p=0.25)
12%
(p=0.43)
Re-operation 25%
14%
(p=0.21)
12%
(p=0.04)
Allogeneic Blood
Transfusion volumes
825 ml
640 ml
(p=0.047)
500 ml
(p=0.042)
Median Drainage Rate
(4 hours after drug)
51 ml/hr
35 ml/hr
(p=0.763)
24 ml/hr
(p=0.018)
Age, CPB time, and type of surgery (emergent/urgent) predicted cSAEs
(critical, serious adverse events)
The Safety and Efficacy of Recombinant Factor VII for the
Treatment of Bleeding following Cardiac Surgery: A
Multinational, Randomized, Placebo-controlled Trial
Ravi G et al. Presented at AHA Scientific Sessions. New Orleans, LA; 2008 Nov 9.
ICU Management of Hemorrhage
following Cardiac Surgery
Patient evaluation
Hemodynamically stable or not
Surgical bleed or generalized oozing
Rebound of anticoagulation (heparin)
Monitoring?
Chest tube drainage
Lab values (CBC, PT/INR, aPTT, fibrinogen, etc)
Treatment strategies?
Return to OR (if unstable or unresponsive to treatment)
Directed by lab values for stable patients
Correct coagulopathy (blood products and drugs)
48
What If Scenarios
What if AB had a recent history of HIT and was
anticoagulated for CPB with bivalirudin?
What if the hospital routinely used TEG monitoring
for cardiac surgery and the tracing suggested?
Abnormal TEG
Segment
Blood Product
Indicated
Increased r-time
(start of clot formation)
FFP
Decreased MA
(overall clot strength)
Platelets
Decreased angle
(speed of clot formation)
Cryoprecipitate
Luddington RJ. Clin Lab Haematol. 2005; 27:81-90.
49
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

S E L E C T E D R E F E R E N C E S - Presentation 3

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. J Am Coll Cardiol. 2007; 50:e1-157.

Carless PA, Moxey AJ, Stokes BJ et al. Are antifibrinolytic drugs equivalent in reducing
blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-
head trials. BMC Cardiovasc Disord. 2005; 5:19.

Clinicaltrials.gov. Identifier NCT00154427. Use of activated recombinant human factor
VII in cardiac surgery. http://clinicaltrials.gov/ct2/show/NCT00154427 (accessed
2008 Nov 6).

Dutton RP. Goals of therapy in common bleeding emergencies. Pharmacotherapy. 2007;
27(9 Pt 2):85S-92S.

Fergusson DA, Hbert PC, Mazer CD et al. A comparison of aprotinin and lysine
analogues in high-risk cardiac surgery. N Engl J Med. 2008; 358:2319-31.

Ferraris VA, Ferraris SP, Joseph O et al. Aspirin and postoperative bleeding after
coronary artery bypass grafting. Ann Surg. 2002; 235:820-7.

Ferraris VA, Ferraris SP, Saha SP et al. Perioperative blood transfusion and blood
conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of
Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;
83(5 Suppl):S27-86.

Karkouti K, Beattie WS, Crowther MA et al. The role of recombinant factor VIIa in on-
pump cardiac surgery: proceedings of the Canadian Consensus Conference. Can J
Anaesth. 2007; 54:573-82.

Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery:
meta-analyses using perioperative blood transfusion as the outcome. The International
Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg. 1997;
85:1258-67.

Luddington RJ. Thrombelastography/thromboelastometry. Clin Lab Haematol. 2005;
27:81-90.

MacLaren R. Key concepts in the management of difficult hemorrhagic cases.
Pharmacotherapy. 2007; 27(9 Pt 2):93S-102S.

Mannucci PM, Levi M. Prevention and treatment of major blood loss. N Engl J Med.
2007; 356:2301-11.

Sabiston DC Jr, Spencer F, eds. Surgery of the chest. 6th ed. Philadelphia, PA: W.B.
Saunders; 1995.

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Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding

Voils S. Pharmacologic interventions for the management of critical bleeding.
Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.

Warren O, Mandal K, Hadjianastassiou V et al. Recombinant activated factor VII in
cardiac surgery: a systematic review. Ann Thorac Surg. 2007; 83:707-14.

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Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding
Table 1. Blood Products
Product Contents Indications and Dose Concerns*
Platelets Thrombocytes in plasma Plts <50 x 10
9
/L (bleeding)
Plts <20 x 10
9
/L
(prevention)
Stored at 20-24C
Bacterial contamination ~1/2000
to 1/3000 units
Worsens immune reactions
FFP Coagulation factors and
fibrinogen in variable
amounts
INR 1.5
15 mL/kg ~30% factor
replacement
Requires thawing
Risk of hypervolemia
PCC Factors II, VII, IX, X and
prothrombin, proteins C, S,
Z in variable amounts
INR 1.5
25-50 IU/kg (based on
factor IX)
Variable amounts of factors
May contain heparin
Numerous donors
Costly
Cryo-
precipitate
Factors VIII, XIII, vWf,
fibrinogen, fibronectin
Fibrinogen <100 mg/dL
1 unit will fibrinogen ~ 5-
10 mg/dL
vWf deficiency
Cryo-
supernatant
Not factor VIII, vWf, and
minimal fibrinogen
TTP
* All products are associated with thrombotic events, transfusion-related acute lung injury, transfusion-related
immunomodulation, infection transmission, and febrile reactions.
Shander A et al. Pharmacotherapy. 2007; 27(9 Pt 2):57S-68S.
Voils S. Pharmacotherapy. 2007; 27(9 Pt 2):69S-84S.
52
Acute Care Update: Causes, Consequences, and Strategies
for Managing Critical Bleeding
Table 2. Pharmacologic Agents
Product Contents or MOA Indications and Dose Concerns
Local
hemostatics
A. Cellulose-based
B. Fibrin (human or bovine) fibrinolytic inhibitor aprotonin
thrombin
C. Thrombin (human or bovine)
D. Zeolite that causes exothermic reaction
E. Chitason (chitin) that activates platelets and electrophysiologic
endothelial attraction of RBCs
F. Synthetics (PEGs or collagen-fibrin)
A. May not adhere
B. Immune reaction, infection
transmission, aprotonin
C. Immune reaction
D. Heat-induced tissue damage
E. May not adhere
F. Immune reaction, costly
Vitamin K Cofactor for activation of
factors II, VII, IX, K
INR 1.5
0.5-20 mg IV or PO
Slow acting
Variable SC absorption
IV requires slow administration
rFVIIa Activates platelets to
augment thrombin burst
Anticoagulant-induced hemorrhage,
ICH, refractory hemorrhage (surgery,
trauma)
10-90 mcg/kg IV
Short-acting
Thrombosis (<10%)
Costly
Desmopressin Selective V2 agonist to
release factor VIII, vWf, and
t-PA
Platelet dysfunction
0.3 mcg/kg IV
Short-acting
Tachyphylaxis and bleeding risk
with repeat doses
Conjugated
estrogen
antithrombin and protein S
while factors VII, VIII, IX, X,
prothrombin
Platelet dysfunction
25-50 mg IV
Slow acting
Slow offset
Antifibrinolytics
(aprotonin,
EACA, TA)
Inhibit plasminogen
proteases and plasmin
(aprotonin) and some anti-
inflammation
Prevention of surgical blood loss
Refractory hemorrhage
Aprotinin: 2 million units IV, then 0.5
million units/hr
EACA: 150 mg/kg IV, then 15 mg/kg/hr
TA: 10 mg/kg IV, then 1 mg/kg/hr
Aprotinin: hypersensitivity (2.8%)
with 9% mortality, renal dysfunction
(OR~2), CVA (OR~2), MI (OR~1.55), 5-
yr mortality (OR~1.48)
Thrombosis, hypotension (TA)
Mannucci PMet al. N Engl J Med. 2007; 356:2301-11. MacLaren R. Pharmacotherapy. 2007; 27(9 Pt 2):69S-102S.
53