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The physiological systems that control the fluidity of blood are both complex and elegant. Blood must remain fluid within the vasculature and yet clot quickly when exposed to subendothelial surfaces at sites of vascular injury. When intravascular thrombi form, rapid activation of the fibrinolytic system restores fluidity. 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.


Composed of platelet aggregates, fibrin, and trapped red blood cells, thrombi can form in arteries or veins. Because of the predominance of platelets and fibrin in thrombi, anti-thrombotic 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. These agents have very different mechanisms of action, but because they target key steps in clot formation, all anti-thrombotic drugs increase the risk of bleeding. With these drugs, toxicity typically represents an extension of the therapeutic effects. The more potent the agent, the greater the risk of bleeding.


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


  • 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


In addition, some of the newer anti-thrombotic drugs in advanced stages of development also are described.




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.


In addition to triggering platelet adhesion and activation, vessel wall injury also exposes tissue factor (TF), which initiates the coagulation system. Platelets support and 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, which reinforces the platelet aggregate and anchors it to the vessel wall. In addition, because it serves as a potent platelet agonist, thrombin also amplifies platelet activation and aggregation.


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 this book's website). The pathway of clot removal, fibrinolysis, is shown in Figure 30–3, along with sites of action of fibrinolytic agents.

Figure 30–1.

Platelet adhesion and aggregation. GPIa/IIa and GPIb are platelet receptors ...

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