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Atherosclerosis is a leading cause of cardiovascular disease. Atherosclerotic plaques can acutely rupture, exposing a necrotic core that sets off the coagulation cascade, culminating in vascular occlusion. Activation of platelets is the initial event in this cascade and, depending on the vascular bed involved, can cause acute coronary syndromes, ischemic stroke, mesenteric ischemia, or acute limb ischemia. Antiplatelet therapy forms the core of acute and chronic atherosclerotic disease treatment. In this chapter, we will discuss antiplatelet therapy for the treatment of cardiovascular disease.


After vascular injury, platelets bind to exposed collagen and von Willebrand factor (vWF) and are activated. Activated platelets then secrete thromboxane A2 (TXA2) and adenosine diphosphate (ADP), which leads to platelet aggregation and recruitment of more platelets. The final common pathway of platelet aggregation is mediated by glycoprotein (GP) IIbIIIa receptors that bind to fibrinogen and vWF, leading to platelet plug and clot formation. Antiplatelet agents target different pathways in this cascade (Figure 3–1).

Figure 3–1.

Site of action of antiplatelet drugs. Aspirin inhibits the synthesis of thromboxane A2 (TXA2) by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced TXA2 release attenuates platelet activation and recruitment to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel irreversibly block P2Y12, a key adenosine diphosphate (ADP) receptor on the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12. Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet aggregation by blocking fibrinogen and von Willebrand factor (vWF) binding to activated glycoprotein (GP) IIb/IIIa. Vorapaxar inhibits thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on human platelets. (Reproduced with permission from Kasper D, et al., eds. Harrison’s Principles of Internal Medicine, 19th ed. New York: McGraw-Hill; 2015.)


Figure 3–2.

Classification of antiplatelet drugs based on mechanism of action. PAR-1, protease-activated receptor-1

A. Cyclooxygenase Inhibitors: Aspirin

1. Mechanism of action

Acetylsalicylic acid (ASA, aspirin) in low doses irreversibly inhibits cyclooxygenase-1 (COX-1), which is required to synthesize TXA2, a vasoconstrictor necessary for platelet aggregation. At higher doses, ASA also inhibits COX-2, which is needed for prostacyclin production; prostacyclins are platelet aggregation inhibitors and vasodilators. Thus, an ASA dose between 75 and 325 mg is recommended for optimal antiplatelet effect. For rapid onset of action, in ASA-naïve patients, an initial dose of at least 162 mg should be used.

2. Contraindications

ASA is contraindicated in patients with a history of bronchospasm or anaphylactic reaction.

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