Chapter 52
Anticoagulant, Antiplatelet, and
Thrombolytic Drugs
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Physiology and Pathophysiology
of Coagulation
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Hemostasis
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Stage 1: formation of platelet plug
• Platelet aggregation
Stage 2: coagulation
• Intrinsic coagulation pathway
• Extrinsic coagulation pathway
Keeping hemostasis under control
Physiologic removal of clots
Thrombosis


Arterial thrombosis
Venous thrombosis
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Overview of Drugs for
Thromboembolic Disorders
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Three major groups
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Anticoagulants
Antiplatelets
Thrombolytics
See Table 52-1
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Anticoagulants
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
Reduce the formation of fibrin
Two mechanisms of action
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
Inhibit the synthesis of clotting factors
Inhibit the activity of clotting factors
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Heparin and Heparin Derivatives
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Heparin (unfractionated)
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
Enhances antithrombin
Sources
• Lungs of cattle
• Intestines of pigs
 Rapid-acting anticoagulant
 Administered by injection only
• IV

Continuous and intermittent
• Deep subQ
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Heparin (Unfractionated)

Therapeutic uses

Preferred anticoagulant during pregnancy and
when rapid anticoagulation is required
 Pulmonary embolism (PE)
 Stroke evolving
 Massive deep venous thrombosis (DVT)
 Open heart surgery
 Renal dialysis
 Low-dose therapy postoperatively
 Disseminated intravascular coagulation (DIC)
 Adjunct to thrombolytic therapy
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Heparin (Unfractionated)
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Adverse effects
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Contraindicated
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Hemorrhage
Heparin-induced thrombocytopenia
Hypersensitivity reactions
Thrombocytopenia
Uncontrollable bleeding
During and immediately after surgery of the eye, brain, or
spinal cord
Antidote for OD: protamine sulfate
Activated partial thromboplastin time (aPTT)
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Low-Molecular-Weight Heparins
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
Heparin preparations composed of molecules
that are shorter than those found in
unfractionated heparin
Therapeutic uses
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
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Prevention of DVT following surgery
• Including replacement of hip, knee
Treatment of established DVT
Prevention of ischemic complications
• Patients with unstable angina, non–Q-wave MI,
and STEMI
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Low-Molecular-Weight Heparins
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Administered subQ
Dosage based on body weight
Antidote for toxicity: protamine sulfate
Costs more than unfractionated heparin
Does not require monitoring; can be given at home
Adverse effects and interactions



Bleeding (but less than with unfractionated heparin)
Immune-mediated thrombocytopenia
Severe neurologic injury for patients undergoing spinal
puncture or spinal epidural anesthesia
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Other LMW Heparin
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
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In the United States, three LMW heparins are
available:
Enoxaparin
Dalteparin
Tinzaparin
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Warfarin, an Oral Anticoagulant
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
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Originally discovered while cattle were
observed ingesting spoiled clover silage
Used as rat poison
Failed suicide attempt with large dose
brought renewed clinical interest
Clinical use

Oral anticoagulant with delayed onset
 Vitamin K antagonist
 Blocks biosynthesis of factors VII, IX, and X and
prothrombin
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Warfarin, an Oral Anticoagulant

Therapeutic uses
 Not useful in emergencies
 Long-term prophylaxis of thrombosis
• Prevention of venous thrombosis and
associated pulmonary embolism
• Prevention of thromboembolism (in patients
with prosthetic heart valves)
• Prevention of thrombosis during atrial fibrillation
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Warfarin, an Oral Anticoagulant

Monitoring treatment
 Prothrombin time (PT)
 International normalized

ratio (INR)
Adverse effects
 Hemorrhage (vitamin K for toxicity)
 Fetal hemorrhage and teratogenesis
from
use during pregnancy
 Use during lactation
 Other adverse effects
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Warfarin, an Oral Anticoagulant
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Drug interactions
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Drugs that increase anticoagulant effects
Drugs that promote bleeding
Drugs that decrease anticoagulant effects
Heparin
Aspirin
Acetaminophen
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Warfarin, an Oral Anticoagulant

Warfarin overdose
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

Vitamin K
Dietary vitamin K
Contrasts between warfarin and heparin
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Direct Thrombin Inhibitors
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Direct inhibition of thrombin (unlike heparin,
which enhances the activity of antithrombin)
Dabigatran Etexilate
Approved in 2010
Oral prodrug undergoes conversion to
dabigatran
Advantages of dabigatran: doesn’t require
monitoring of anticoagulation, little risk of
adverse interactions, same dose can be used
for all patients regardless of age or weight
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Direct Thrombin Inhibitors

Hiruden Analog: Bivalirudin (Angiomax)

Prevents clot formation (combined with aspirin) in patients
with unstable angina who are undergoing coronary
angioplasty


Mechanism of action
• Facilitates the actions of antithrombin
• Prevents conversion of fibrinogen to fibrin
• Prevents activation of factor XIII
Adverse effects
• Bleeding
• Back pain
• Nausea, headache
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Other Direct Thrombin Inhibitors
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Lepirudin (Refludan)
Argatroban (formerly known as Acova)
Desirudin (Ipravask)
Dabigatran (Pradaxa)
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Selective Factor Xa Inhibitors
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Produce selective inhibition of factor Xa
Fondaparinux

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Activation of antithrombin
Injection
Rivaroxaban


Binds directly with factor Xa to cause inactivation
Oral
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Fondaparinux (Arixtra)
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
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Synthetic anticoagulant
Selective inhibition
Therapeutic uses
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Prevention of DVT following surgery
Treatment of acute PE (in conjunction with warfarin)
Treatment of acute DVT (in conjunction with warfarin)
Adverse effects

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

Bleeding
Avoid in patients weighing less than 50 kg
Thrombocytopenia
Spinal or epidural hematoma
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Rivaroxaban (Xarelto)
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
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Oral anticoagulant approved in 2011
Does not require laboratory monitoring
Patients who received rivaroxaban were
found to be much less likely to experience
DVT, VTE, PE, or death
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Antithrombin (AT)



Endogenous compound that suppresses
coagulation, primarily by inhibiting thrombin
and factor Xa
Used to prevent thrombosis in patients with
inherited AT deficiency
Two preparations, marketed as Atryn and
Thrombate III
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Antiplatelet Drugs

Aspirin (ASA)
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Ticlopidine (Ticlid)
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

Inhibition of cyclooxygenase
Adverse effect
• Increases risk for GI bleeding
Inhibits ADP-mediated aggregation
Adverse effects
• Hematologic effects
Clopidogrel (Plavix)

ADP receptor antagonist
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Aspirin (ASA)
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Therapeutic uses
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Ischemic stroke
Transient ischemic attack (TIA)
Chronic stable angina
Unstable angina
Coronary stenting
Acute MI
Previous MI
Primary prevention of MI
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Aspirin (ASA)

Adverse effects
 Bleeding
 GI bleeding and hemorrhagic stroke
 Enteric-coated tablets may not reduce
the
risk for GI bleeding
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Clopidogrel (Plavix)
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Therapeutic uses

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
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Prevents blockage of coronary artery stents
Reduces thrombotic events in patients with acute
coronary syndromes
• MI, ischemic stroke, and vascular death
Similar adverse effects to those of aspirin
Use with caution in combination with other
drugs that promote bleeding
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Antiplatelet Drugs

Glycoprotein (GP) IIb/IIIa receptor
antagonists



Most effective antiplatelet drugs
“Super aspirins”
Reversible blockade of platelet GP IIb/IIIa
receptors
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Other Antiplatelet Drugs


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
Dipyridamole
Dipyrindamole + aspirin
Aggrenox
Cilostazol
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Thrombolytic Drugs


Streptokinase (Streptase); Alteplase (tPa)
Major adverse effect – bleeding (minor oozing
to life-threatening amount)

Likely sites of bleeding
• Recent wounds, needle puncture sites, invasive
procedure sites


Anticoagulants increase the risk for
hemorrhage
Blood replacement may need to be
considered
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Minimizing the Risk of Bleeding
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Minimizing physical manipulation of the
patient
Avoiding subQ and IM injections
Minimizing invasive procedures
Minimizing concurrent use of anticoagulants
(eg, heparin, warfarin, dabigatran)
Minimizing concurrent use of antiplatelet
drugs (eg, aspirin, clopidogrel)
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Streptokinase (Streptase)


Binds to plasminogen to form active complex
Therapeutic uses

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Acute coronary thrombosis (acute MI)
Deep venous thrombosis (DVT)
Massive pulmonary emboli
Adverse effects




Bleeding – excessive fibrinolysis can be reversed with IV
aminocaproic acid (Amicar)
Antibody production
Hypotension
Fever
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Alteplase (tPa)



Converts plasminogen to plasmin
Given in accelerated schedule
Therapeutic uses



Myocardial infarction
Ischemic stroke
Massive pulmonary emboli
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Alteplase (tPa)

Adverse effects

Bleeding
• Risk for intracranial bleeding higher than with
streptokinase


Fever
Advantages


Does not cause allergic reactions
Does not induce hypotension
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Other Thrombolytic Drugs


Tenecteplase
Reteplase
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