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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, ultimately 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 treatment for both acute and chronic atherosclerotic disease. In this chapter, we will discuss antiplatelet therapy in the treatment of cardiovascular disease.

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After vascular injury, platelets are bound to exposed collagen and von Willebrand factor (vWF) and 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).

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Figure 3–1.
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Site of action of antiplatelet drugs. Aspirin inhibits thromboxane A2 (TXA2) synthesis 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. SCH530348 and E5555 inhibit thrombin-mediated platelet activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin receptor on human platelets. (Reproduced with permission from Longo DL, et al. Harrison's Principles of Internal Medicine, 18th ed. New York: McGraw-Hill; 2012.)

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Figure 3–2.
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Classification of antiplatelet drugs based on mechanism of action.

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Cyclooxygenase Inhibitors: Aspirin

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Mechanism of action

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

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Contraindications

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

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Side effects

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Dyspepsia, peptic ulcer, erosive gastritis, and upper gastrointestinal bleeding are ...

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