Adiuvante Dei Gratia Doctorumfactionis 2014-2015

HEMATOLOGY: ANTI-THROMBOTIC DRA. SAMSON-

DRUGS AND TRANSFUSION MED CRUZ, MD

Reference: PATHOPHYSIOLOGY
Harrison’s Principles of Internal Medicine - Trauma to the veins
Old Trans - Venous stasis
- Decreased oxygen supply to the avascular valve cusps
ANTIPLATELET, ANTI-COAGULANT AND FIBRINOLYTIC DRUGS - Endothelial cells express adhesion molecules on surface
INTRODUCTION - Tissue factor-bearing leukocytes adhere to activated
endothelial cells
ANTI-THROMBOTIC THERAPY - Coagulation
1. Anti-platelets
2. Anti-coagulants MANAGEMENT
3. Fibrinolytic agents - ANTI-COAGULANT
o Mainstay
INDICATION: o
- Prevent thrombotic events
- Prevent complications THROMBUS FORMATION
- Restore vascular patency - Impaired blood flow
- Reduced clearance of activated clotting factors
- Extends into proximal veins
ARTERIAL THROMBOSIS - Thrombus fragments dislodge
- To lungs -> Pulmonary Embolism
- Rich in platelet d/t high shear in the injured arteries.
- White in color
ANTI-PLATELETS
Most common cause of: INTRODUCTION
o MI
o CVA - Inactive platelets are maintained by:
o Limb gangrene o NO
 Potent vasodilator
PATHOPHYSIOLOGY  Potent inhibitor of platelet aggregation
- Plaque rupture o Prostacyclin
- Exposes thrombogenic material to blood - Endothelial Cells release:
- Triggers platelet aggregation & fibrin formation o Prostacyclin
- Results to platelet-rich thrombus o CD39
- Occlude bloodflow  Membrane-associated ADPase
 Degrades ADP released from
MANAGEMENT activated platelets
- Inhibit platelet formation
o ANTI-PLATELET AGENT ROLE OF PLATELETS IN ARTERIAL THROMBOSIS
 ACUTE SETTING: - Injury
 Anti-platelet - Vessel wall damage
 Anti-coagulants - Exposure of subendothelial matrix and Tissue Factor
 Fibrinolytic - Platelets adhere to exposed collagen by:
o A2b1
o Glycoprotein (GP) VI
VENOUS THROMBOSIS o vWF
o GPIba
- Forms under low-shear conditions o GPIIb/IIIa (aIIbB3) – most abundant receptor
- Few platelets - Conformational change (adhered platelet)
- Composed predominantly of RBCs. - Secrete ADP and TxA2
- Red in color o Activate ambient platelets and recruit to vascular
injury
DEEP VEIN THROMBOSIS - TF initiates coagulation where activated platelets potentiate
- Complication: coagulation by binding clotting factors
o Pulmonary Embolism - In activated platelets, GPIIb/IIIa – conformational change
o Post-phlebitic Syndrome o Binds to:
 Fibrinogen
 vWF
You’re gonna do it anyway, why not give it your best shot 

5
Page 1 of
#fiercegirls #Nika
 Adiuvante Dei Gratia Doctorumfactionis 2014-2015

HEMATOLOGY: ANTI-THROMBOTIC DRA. SAMSON-

DRUGS AND TRANSFUSION MED CRUZ, MD

- Divalent fibrinogen +/ multivalent vWF - Indications:

o Bridge adjacent platets o 1* Prevention
 Forms Platelet/FibrinMesh  Age : > 40y/o
 Risk Fx : 2 or >
1. Aspirin o 2* Prevention
2. Thienopyridines  Age : > 50y/o
3. Dipyridamole  Risk Fx : 1 or >
4. GPIIb / IIIa Receptor Antagonist - Dosing:
o Usual dosing:
PNEUMONICS:  75-325mg OD
 D-TAG o Prevention of dose-related S/E:
o D ipyridamole  75-100mg OD
o T hienopyridines o For Rapid Platelet inhibition
o A spirin  160mg –initial dose
o G PIIb/IIIa Receptor Antagonist - S/E:
o GI
 Dyspepsia
 Erosive gastritis / peptic ulcers
 Bleeding
 perforation

THIENOPYRIDINES

- ADP receptor inhibitor

1. Ticlodipine
o Reduces risk of the following in Atherosclerotic
patients:
 CVD
 MI
 Stroke
o S/E (occurs usually within first few months of
treatment)
 GI
 Hema
 Neutropenia
 Thrombocytopenia

2. Clopidogrel
o Reduces risks by 8.7% > aspirin
o Expensive > Aspirin
o S/E : rare

- THIENOPYRIDINE RESISTANCE
ASPIRIN o Variability in the capacity of the thienopyridines
to inhibit ADP-induced platelet aggregation and
- Most widely used genetic polymorphisms in the CYP isoenzymes
- Cheap involved in the metabolic activation of the drugs.
- Effective
- Mechanism of Action:
o Irreversibly acetylating and inhibiting COX-1 DIPYRIDAMOLE
 Enzyme for biosynthesis of TxA2
o High doses: - Weak anti-platelet agent
 Inhibits COX-2 - Extended-release formulation of dypiridamole combined
 Decrease synthesis of with low-dose aspirin
prostacyclin o Aggrenox for prevention of stroke in patients with
TIA
You’re gonna do it anyway, why not give it your best shot 

5
Page 2 of
#fiercegirls #Nika
 Adiuvante Dei Gratia Doctorumfactionis 2014-2015

HEMATOLOGY: ANTI-THROMBOTIC DRA. SAMSON-

DRUGS AND TRANSFUSION MED CRUZ, MD

- Mechanism of Action:
o Inhibits phosphodiesterase
o Blocks the breakdown of cAMP
 Increased levels of cAMP reduce IC Ca
and inhibit platelet activation
o Blocks adenosine uptake by platelets and other
cells
 Further increase in local cAMP levels
because of platelet adenosine A2
receptor – adenylate cyclase coupling.

GP IIB / IIIA RECEPTOR ANTAGONISTS

- Cell attachment for fibrinogen is inhibited

- Parenteral: - Monitoring the anticoagulant effect
o Abciximab o aPTT
o Eptifibatide o Antifactor Xa level
o Tirofiban - Dosing
o Prophylaxis
 5000 units SC 2-3x/day (fixed dose)
ANTI-COAGULANTS o Therapeutic Doses (monitoring is essential)
INTRODUCTION  Fixed-dose
 Weight-based heparin nomograms
- Heparin / UFH - Limitation
o Pharmacokinetic Limitations
- Low-Molecular Weight Heparin (LMWH)
 Binding to endothelial cells explains its
- Pentasaccharides dose-dependent clearance
- Heparinoids  Binding to plasma proteins results in a
- Direct Thrombin Inhibitors variable anticoagulant response and can
lead to heparin resistance
- Warfarin
o Biophysical Limitations
 Reflect the inability of the heparin-anti-
thrombin complex to:
HEPARIN / Unfractionate Heparin  Inhibit Factor Xa when it is
incorporated into the
- From bovine lung or porcine intestinal mucosa prothbombinase complex, the
- Heterogenous mixture of highly sulfated polysaccharides complex that converts
(glycosaminoglycans) with molecular mass ranging from 4- prothrombin to thrombin
30kDa (45 saccharide units)  Inhibit thrombin bound to
- Mechanism of heparin: fibrin
o S/E
 Bleeding
 Thrombocytopenia
 Osteoporosis
 Elevated transaminases
o Resistance
 True Heparin Resistance
 Inadequate anti-coagulant and
anti-thrombotic responses
from what would otherwise
be perceived as an adequate
heparin dose
 Prolonged aPTT

You’re gonna do it anyway, why not give it your best shot 

5
Page 3 of
#fiercegirls #Nika
 Adiuvante Dei Gratia Doctorumfactionis 2014-2015

HEMATOLOGY: ANTI-THROMBOTIC DRA. SAMSON-

DRUGS AND TRANSFUSION MED CRUZ, MD

 Result from nonspecific - Heparinoid dermatan SO4

binding to WBC, vascular EC o Act as anti-coagulant by activating Heparin
and acute phase proteins cofactor II
 Apparent Heparin Resistance - Danaproid
 Results from elevated factor o Derived from porcine intestinal mucosa
VII levels o Composed of:
 aPTT maybe normal or near  Heparin SO4 - 84%
normal  Dermatan SO4 - 12%
 Chondroitin SO4 - 4%
o Longer half-life (24hrs)
LOW-MOLECULAR-WEIGHT HEPARIN (LMWH) o Potential heparin cross-reactivity

- Derived from enzymatic or chemical cleavage of UFH into

mixture of glycosaminoglycans with mean molecular mass DIRECT THROMBIN INHIBITORS
of 5kDa (15 saccharide units)
o Binds to AT via the same pentasaccharide - Do not require a plasma cofactor
sequence as UFH - Agents bind directly to thrombin and block its interaction
- Superior bioavailability with its substrates
- Non-dose dependent half-lives facilitating once or twice o Lepirudin
daily SC dosing o Argatroban
- No monitoring of aPTT o Bivalirudin
- Cleared by renal mechanism o Ximelagatran
- Less immunogenic
- Associated with less HIT and osteopenia than UFH
- Partially 60% neutralized by Protamine SO4 WARFARIN
- Mechanism of Action
- Vitamin K antagonist
- Leads to synthesis of hypofunctional coagulation proteins
that are unable to bind to cellular surfaces to mediate
coagulation reactions
- Half-life or warfarin in plasma is 36hrs
- Reduction of all Vitamin K-dependent coagulation proteins
into the therapeutic range (20% of normal) requires 4-5days
of therapy.
o PT assay
 Useful to monitor warfarin therapy
because this assay measures three
Vitamin K-dependent coagulation
proteins:
- S/E  Factor VII
o Bleeding  Factor X
o Thrombocytopenia  Prothrombin
o Osteoporosis o INR
 Standardizes PT assays
 INR 2.0-3.0
PENTASACCHARIDES  Recommended for all
indications except:
1. Fondaparinux o Prosthetic
o Selective indirect inhibition of Factor Xa Mechanical Heart
o Less HIT than UFH and LMWH Valves
2. Idraparinux o Prophylaxis for
o Half-life of 130hrs facilitating Recurrent MI
o Once weekly dosing

HEPARINOIDS

You’re gonna do it anyway, why not give it your best shot 

5
Page 4 of
#fiercegirls #Nika
 Adiuvante Dei Gratia Doctorumfactionis 2014-2015

HEMATOLOGY: ANTI-THROMBOTIC DRA. SAMSON-

DRUGS AND TRANSFUSION MED CRUZ, MD

FIRBRINOLYTIC DRUGS
INTRODUCTION

- Streptokinase
- Urokinase
- tPA

STREPTOKINASE

- From cultures of B-haemolytic streptococcus

- When complexed with plasminogen can convert other
plasminogen molecule to plasmin
- Not fibrin selective
- Platelet function may be perturbed
- Half-life : 20mins
- Antigenic
- Indications:
o VTE
o MI
o Central Venous Line associated thrombosis

UROKINASE

- Native Urokinase obtained from human fetal kidney cell

cultures
- Recombinant high molecular weight Urokinase produced
using non-human, mammalian tissue culture
- Not fibrin selective
- Half-life : 20mins
- Indications:
o DVT
o PE
o MI
o Peripheral arterial thrombosis
o Occluded catheters

tPA

- Produced by recombinant technology

- Half-life : 5mins
- Fibrin specific
- Indications:
o DVT
o PE
o Acute MI
o Acute thrombotic stroke
o Dysfunctional venous line

You’re gonna do it anyway, why not give it your best shot 

5
Page 5 of
#fiercegirls #Nika