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Antithrombotic therapy is standard for both arterial and venous thromboembolic conditions, including ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), unstable angina, deep venous thrombosis (DVT), pulmonary embolism (PE), transient ischemic attack, and ischemic stroke. Moreover, antithrombotic agents help prevent occlusive vascular events in patients at risk for thrombosis. These agents, however, also have the potential to cause life-threatening complications, primarily serious hemorrhage. This chapter provides an overview of antithrombotic agents, including mechanisms of action, indications, and contraindications, as well as evaluation and management of acute bleeding complications associated with their use. Detailed management strategies for thromboembolic disorders are discussed in their respective chapters (see Chapter 53, Acute Coronary Syndromes: Acute Myocardial Infarction and Unstable Angina; Chapter 60, Thromboembolism; and Chapter 161, Stroke, Transient Ischemic Attack, and Cervical Artery Dissection).

Hemostasis—whether physiologic after accidental injury or pathologic after rupture of an atherosclerotic plaque—is initiated by platelet interaction with the vascular subendothelium and continues with a series of reactions among plasma coagulation proteins that generate the final product of cross-linked fibrin incorporated within the initial platelet plug (see Chapter 227, Tests of Hemostasis). Arterial thrombi, composed primarily of platelets bound by thin fibrin strands, develop under high-flow conditions, especially at sites of ruptured plaques. Both anticoagulants and platelet-inhibiting drugs may effectively prevent and treat arterial thrombosis. In contrast, venous thrombi form in areas of sluggish blood flow and are composed mainly of red blood cells and large fibrin strands. Anticoagulant drugs are effective in preventing and treating venous thromboembolism, whereas platelet-suppressing agents are less useful.

Both arterial and venous thrombi may result in local vascular obstruction or distant embolization. Antithrombotic agents interfere with these processes either by preventing formation of the platelet-fibrin net (blocking thrombin activation or platelet function) or by accelerating clot breakdown (fibrinolysis). Antithrombotic agents are classified by mechanism of action. Anticoagulants block the synthesis or activation of clotting factors, interfering with the coagulation cascade at one or more steps. Antiplatelet agents interfere with platelet activation or aggregation. Fibrinolytic agents (often but inaccurately referred to as thrombolytic agents) enzymatically dissolve the fibrin component of thrombi.


Clinical Pharmacology

Oral anticoagulants are used to (1) stop further thrombosis when the condition already exists (as in DVT), (2) reduce the risk of embolism in patients with thrombotic disease (e.g., DVT or left ventricular mural thrombus), and (3) prevent thrombi from forming in patients with risk factors for their development (e.g., prolonged immobilization, prosthetic heart valve, or venous disease) (Table 234-1). Sodium warfarin, a hydroxy coumarin compound, is the most widely used oral anticoagulant in North America.1 Readily absorbed from the gut, it reaches peak blood concentrations in 90 minutes and has a circulating half-life of 36 to 42 hours. Warfarin is bound to albumin, metabolized by the liver, and excreted in the urine. Warfarin blocks activation of vitamin K ...

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