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CHAPTER 25 most commonly used drugs in medicine because thrombotic diseases
Antithrombotic agents are highly effective and are among the
ANTITHROMBOTIC THERAPY are the leading cause of mortality and morbidity in Western countries.
Antithrombotic agents are characterized separately as anticoagulants,
antiplatelet agents, or fibrinolytic drugs, depending on their primary
mechanism, although there is overlap in their activities and clinical
Gregory C. Connolly and Charles W. Francis indications (Table 25–1). Their greatest use is in prevention of thrombo-
sis in patients at high risk, but they also have important applications for
treating acute thrombosis. For many agents, the risk-to-benefit ratio is
narrow, with the result that bleeding complications occur, and bleeding
SUMMARY is the most common adverse effect. Consequently, the clinician should
carefully weigh the risks and benefits for each patient when selecting
Antithrombotic drugs are among the most commonly used drugs in medi- treatment. Generally, these drugs do not cause bleeding by themselves;
cine and are generally separated into anticoagulants, fibrinolytic agents, and instead, they exacerbate preexisting bleeding or predispose to bleed-
platelet inhibitors based on their primary mechanism of action. For many ing from pathologic lesions that may be found in the gastrointestinal
decades, warfarin, which acts by inhibiting vitamin K action, was the only or genitourinary tracts or central nervous system. A careful review of
oral anticoagulant available. Vitamin K antagonists have a prolonged effect, comorbid conditions that may increase bleeding risk is important when
unpredictable pharmacokinetics, and require monitoring, but warfarin was deciding on therapy.
widely used for prevention and treatment. The introduction of novel targeted Anticoagulant therapy acts to decrease fibrin formation by inhib-
oral anticoagulants has changed the landscape of anticoagulation. Rivarox- iting the formation and action of thrombin, and its most common uses
aban, apixaban, and edoxaban are novel oral inhibitors of factor Xa, whereas are in preventing systemic embolization in patients with atrial fibril-
lation and for secondary prevention of venous thromboembolism.
dabigatran is an orally available inhibitor of thrombin. Unfractionated heparin Anticoagulant therapy is sometimes monitored using coagulation test-
and the low-molecular-weight heparins are the most commonly used rap- ing because of marked biologic variation in effect with some agents.
idly acting parenteral anticoagulants; they inhibit activated serine proteases Antiplatelet agents act to inhibit platelet function, and their primary
through antithrombin. One synthetic agent in this class, fondaparinux, is spe- uses are in preventing thrombotic complications of cerebrovascular
cific for inhibition of factor Xa, and is effective for prevention and treatment of and coronary artery disease. They also have a role in treatment of acute
venous thromboembolism. Several parenteral direct thrombin inhibitors have myocardial infarction and some effect in preventing venous thrombosis.
excellent anticoagulant action and offer an alternative to heparins. A num- Fibrinolytic agents accelerate lysis of thrombi by increasing conversion
ber of fibrinolytic agents are available, all of which convert plasminogen to of plasminogen to plasmin, and are primarily used in the acute manage-
plasmin to accelerate clot lysis. Differences among them include their degree ment of myocardial infarction, in clearing occluded catheters and also
of fibrin specificity, half-life, and antigenicity. Antiplatelet agents play an in selected patients with stroke or venous thromboembolism. Fibrino-
important role in prevention and treatment of arterial thrombosis. Aspirin is lytic therapy is associated with a higher risk of bleeding complications
than treatment with either anticoagulants or antiplatelet agents. Treat-
a cyclooxgenase-1 inhibitor that is effective and widely used in the preven- ment of acute thrombosis often involves combinations of agents with
tion of stroke and myocardial infarction. Drugs that modulate cyclic adenosine multiple actions for maximum effect.
monophosphate levels include dipyridamole, pentoxifylline, and cilostazol, Antithrombotic therapy has changed considerably with the
and are primarily used in treatment of peripheral vascular disease. Adenosine introduction of several novel target-specific oral anticoagulants.
diphosphate receptor blockers such as ticlopidine, clopidogrel, and prasugrel These drugs offer more predictable pharmacokinetics and fewer drug
are effective in treatment of coronary and peripheral arterial disease. Exam- interactions than warfarin, thus eliminating the need for frequent
ples of inhibitors of fibrinogen interaction with α β are abciximab, tirofiban, monitoring. These agents have been studied in numerous phase III
IIb 3
and eptifibatide. These drugs are highly effective in treatment of patients with randomized clinical trials that have compared these agents to stan-
acute coronary syndromes. dard anticoagulation therapies. In most cases, the new anticoagulants
are equivalent to conventional anticoagulation in reducing throm-
botic events, while in many cases they are associated with lower rates
of major bleeding complications.

VITAMIN K ANTAGONISTS
Acronyms and Abbreviations: ACT, activated clotting time; ADP, adenosine The development of vitamin K antagonists as oral anticoagulants began
diphosphate; aPTT, activated partial thromboplastin time; cAMP, cyclic adenosine in the 1920s with investigation of a hemorrhagic disease in cattle, the
monophosphate; COX, cyclooxygenase; CYP, cytochrome P450; DVT, deep vein cause of which was eventually traced to ingestion of moldy hay leading
thrombosis; FFP, fresh-frozen plasma; Gla, γ-carboxyglutamic acid; HIT, hep- to hypoprothrombinemia. A coumarin that inhibited vitamin K was
1
arin-induced thrombocytopenia; INR, international normalized ratio; ISI, inter- purified and eventually introduced into clinical practice in the 1940s.
national sensitivity index; LMWH, low-molecular-weight heparin; MI, myocardial Several coumarin derivatives with differing pharmacologic properties
infarction; NSAID, nonsteroidal antiinflammatory drug; PE, pulmonary embolism; are now available as anticoagulants worldwide, and are collectively
PG, prostaglandin; PGI , prostacyclin; PRP, platelet-rich plasma; PT, prothrombin referred to as vitamin K antagonists, but warfarin is nearly universally
2
time; TNK, tenecteplase; t-PA, tissue-type plasminogen activator; VTE, venous used in North America. These agents are widely used to prevent or treat
thromboembolism. common thrombotic diseases and represent the most commonly used
oral anticoagulant currently available. 2

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