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INTRODUCTION

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Blood must remain fluid within the vasculature and yet clot quickly when exposed to subendothelial surfaces at sites of vascular injury. Under normal circumstances, a delicate balance between coagulation and fibrinolysis prevents both thrombosis and hemorrhages. Alteration of this balance in favor of coagulation results in thrombosis. Thrombi, composed of platelet aggregates, fibrin, and trapped red blood cells, can form in arteries or veins. Antithrombotic drugs used to treat thrombosis include antiplatelet drugs, which inhibit platelet activation or aggregation; anticoagulants, which attenuate fibrin formation; and fibrinolytic agents, which degrade fibrin. All antithrombotic drugs increase the risk of bleeding.

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This chapter reviews the agents commonly used for controlling blood fluidity, including:

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  • The parenteral anticoagulant heparin and its derivatives, which activate a natural inhibitor of coagulant proteases

  • The coumarin anticoagulants, which block multiple steps in the coagulation cascade

  • Fibrinolytic agents, which degrade thrombi

  • Antiplatelet agents, including aspirin, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors

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OVERVIEW OF HEMOSTASIS: PLATELET FUNCTION, BLOOD COAGULATION, AND FIBRINOLYSIS

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Hemostasis is the cessation of blood loss from a damaged vessel. Platelets first adhere to macromolecules in the subendothelial regions of the injured blood vessel, where they become activated. Adherent platelets release substances that activate nearby platelets, thereby recruiting them to the site of injury. Activated platelets then aggregate to form the primary hemostatic plug.

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Vessel wall injury also exposes tissue factor (TF), which initiates the coagulation system. Platelets enhance activation of the coagulation system by providing a surface onto which clotting factors assemble and by releasing stored clotting factors. This results in a burst of thrombin (factor IIa) generation. Thrombin then converts fibrinogen to fibrin and amplifies platelet activation and aggregation.

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Later, as wound healing occurs, the platelet aggregates and fibrin clots are degraded. The processes of platelet aggregation and blood coagulation are summarized in Figures 30–1 and 30–2 (see also the animation on the Goodman & Gilman website). The pathway of clot removal, fibrinolysis, is shown in Figure 30–3, along with sites of action of fibrinolytic agents. Coagulation involves a series of zymogen activation reactions, as shown in Figure 30–2. At each stage, a precursor protein, or zymogen, is converted to an active protease by cleavage of 1 or more peptide bonds in the precursor molecule. The final protease generated is thrombin.

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Figure 30–1

Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors that bind to collagen and von Willebrand factor (vWF), causing platelets to adhere to the subendothelium of a damaged blood vessel. PAR1 and PAR4 are protease-activated receptors that respond to thrombin (IIa); P2Y1 and P2Y12 are receptors for ADP; when stimulated by agonists, these receptors activate the fibrinogen-binding protein GPIIb/IIIa and cyclooxygenase-1 (COX-1) to promote platelet aggregation and secretion. Thromboxane A2 (TxA2) is the major product of COX-1 involved in platelet activation. Prostaglandin I2 (prostacyclin, PGI...

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