copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 52 anticoagulant,...

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 52

Anticoagulant, Antiplatelet, and Thrombolytic Drugs

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Physiology and Pathophysiology of Coagulation

Hemostasis 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


Overview of Drugs for Thromboembolic Disorders

Three major groups Anticoagulants Antiplatelets Thrombolytics

See Table 52-1


Anticoagulants

Reduce the formation of fibrin Two mechanisms of action

Inhibit the synthesis of clotting factors Inhibit the activity of clotting factors


Heparin and Heparin Derivatives

Heparin (unfractionated) Enhances antithrombin Sources

• Lungs of cattle • Intestines of pigs

Rapid-acting anticoagulant Administered by injection only

• IV Continuous and intermittent

• Deep subQ


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


Heparin (Unfractionated)

Adverse effects Hemorrhage Heparin-induced thrombocytopenia Hypersensitivity reactions

Contraindicated 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)


Low-Molecular-Weight Heparins

Heparin preparations composed of molecules that are shorter than those found in unfractionated heparin

Therapeutic uses 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


Low-Molecular-Weight Heparins

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


Other LMW Heparin

In the United States, three LMW heparins are available:

Enoxaparin Dalteparin Tinzaparin


Warfarin, an Oral Anticoagulant

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



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



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



Drug interactions Drugs that increase anticoagulant effects Drugs that promote bleeding Drugs that decrease anticoagulant effects Heparin Aspirin Acetaminophen



Warfarin overdose Vitamin K

Dietary vitamin K Contrasts between warfarin and heparin


Direct Thrombin Inhibitors

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


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


Other Direct Thrombin Inhibitors

Lepirudin (Refludan) Argatroban (formerly known as Acova) Desirudin (Ipravask) Dabigatran (Pradaxa)


Selective Factor Xa Inhibitors

Produce selective inhibition of factor Xa Fondaparinux

Activation of antithrombin Injection

Rivaroxaban Binds directly with factor Xa to cause inactivation Oral


Fondaparinux (Arixtra)

Synthetic anticoagulant Selective inhibition Therapeutic uses

Prevention of DVT following surgery Treatment of acute PE (in conjunction with warfarin) Treatment of acute DVT (in conjunction with warfarin)

Adverse effects Bleeding Avoid in patients weighing less than 50 kg Thrombocytopenia Spinal or epidural hematoma


Rivaroxaban (Xarelto)

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


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


Antiplatelet Drugs

Aspirin (ASA) Inhibition of cyclooxygenase Adverse effect

• Increases risk for GI bleeding Ticlopidine (Ticlid)

Inhibits ADP-mediated aggregation Adverse effects

• Hematologic effects Clopidogrel (Plavix)

ADP receptor antagonist


Aspirin (ASA)

Therapeutic uses Ischemic stroke Transient ischemic attack (TIA) Chronic stable angina Unstable angina Coronary stenting Acute MI Previous MI Primary prevention of MI


Aspirin (ASA)

Adverse effects Bleeding GI bleeding and hemorrhagic stroke Enteric-coated tablets may not reduce the

risk for GI bleeding


Clopidogrel (Plavix)

Therapeutic uses 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


Antiplatelet Drugs

Glycoprotein (GP) IIb/IIIa receptor antagonists Most effective antiplatelet drugs “Super aspirins” Reversible blockade of platelet GP IIb/IIIa

receptors


Other Antiplatelet Drugs

Dipyridamole Dipyrindamole + aspirin Aggrenox Cilostazol


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


Minimizing the Risk of Bleeding

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)


Streptokinase (Streptase)

Binds to plasminogen to form active complex Therapeutic uses

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


Alteplase (tPa)

Converts plasminogen to plasmin Given in accelerated schedule Therapeutic uses

Myocardial infarction Ischemic stroke Massive pulmonary emboli


Alteplase (tPa)

Adverse effects Bleeding

• Risk for intracranial bleeding higher than with streptokinase

Fever Advantages

Does not cause allergic reactions Does not induce hypotension


Other Thrombolytic Drugs

Tenecteplase Reteplase

copyright © 2013, 2010 by saunders, an imprint of elsevier inc. chapter 52 anticoagulant,...

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