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LEARNING OBJECTIVES
After studying this chapter you should be able to:
Understand the physiologic consequences of platelet activation.
Name the zymogens and cofactors in the coagulation cascade and know how they relate to one another.
Identify the mechanisms that limit blood clot formation.
Describe the laboratory tests that are most useful in the diagnosis and monitoring of bleeding disorders.
Understand the mechanisms underlying the action of anticoagulant drugs.
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Hemostasis is a vital host defense system that has evolved in man and other vertebrates to maintain the integrity of a high-pressure closed circulatory system. Following a break in the vasculature, the formation of a blood clot either prevents hemorrhage or lessens its extent. An exquisitely modulated orchestration of cells and plasma proteins enables clot formation to be rapid, self-limited, and reversible. The classic paradigm of blood coagulation begins with the formation of a platelet thrombus at the site of vessel injury. Initially, platelets adhere to collagen exposed on the denuded surface of the injured vessel. This adhesion event then triggers activation of platelets by collagen, thrombin generated by tissue factor, or both, allowing them to aggregate and form a tight platelet plug that stanches the further egress of blood from the injured vessel. The clot is then reinforced and strengthened by the activation of the coagulation cascade, which results in the deposition of insoluble polymers composed of fibrin. The recruitment of specific inhibitors prevents unwanted extension of the clot beyond the site of injury. The final step, fibrinolysis, enables the vessel to be recanalized, thereby restoring blood flow. Recent studies have shown that these phases are less clearly demarcated in vivo than this idealized scenario would suggest. Indeed, the use of specific fluorescent molecular markers clearly shows that fibrin deposition occurs as the platelet plug is being formed.
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Hemostatic system
latent but poised for immediate participation
Blood coagulation
limited to region of vessel injury
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This chapter will first present the dynamic sequence of events involved in formation of the platelet thrombus and the initiation, propagation, limitation, and lysis of the fibrin clot. This conceptual framework will guide the discussion of the pathophysiology, diagnosis, and treatment of bleeding and thrombotic disorders in this and the following chapters.
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PLATELET ADHESION AND ACTIVATION
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Plasma contains a large, elongated protein called von Willebrand factor (vWF) that forms multimeric polymers with molecular weights as high as 15 million Daltons. As discussed later in this chapter, vWF binds to and transports factor VIII, the protein deficient in patients with classic hemophilia. In addition, vWF fulfills a vital role in the formation of the primary platelet plug. It has binding sites for collagen as well as for a glycoprotein complex on the surface of platelets, GPIb-IX-V (hereafter referred to simply as the GPIb complex). Under high shear stresses, such as occur within flowing blood, vWF "unwinds" to an extended conformation in which it ...