Harpers

Hemostasis & Thrombosis 51Margaret L. Rand, PhD, & Robert K. Murray, MD, PhDBIOMEDICAL IMPORTANCEBasic aspects of the proteins of the blood coagulationsystem and of fibrinolysis are described in this chapter.Some fundamental aspects of platelet biology are alsopresented. Hemorrhagic and thrombotic states cancause serious medical emergencies, and thromboses inthe coronary and cerebral arteries are major causes ofdeath in many parts of the world. Rational managementof these conditions requires a clear understandingof the bases of blood clotting and fibrinolysis.HEMOSTASIS & THROMBOSIS HAVETHREE COMMON PHASESHemostasis is the cessation of bleeding from a cut orsevered vessel, whereas thrombosis occurs when the endotheliumlining blood vessels is damaged or removed(eg, upon rupture of an atherosclerotic plaque). Theseprocesses encompass blood clotting (coagulation) andinvolve blood vessels, platelet aggregation, and plasmaproteins that cause formation or dissolution of plateletaggregates.In hemostasis, there is initial vasoconstriction of theinjured vessel, causing diminished blood flow distal tothe injury. Then hemostasis and thrombosis share threephases:(1) Formation of a loose and temporary platelet aggregateat the site of injury. Platelets bind to collagenat the site of vessel wall injury and are activatedby thrombin (the mechanism of activationof platelets is described below), formed in the coagulationcascade at the same site, or by ADP releasedfrom other activated platelets. Upon activation,platelets change shape and, in thepresence of fibrinogen, aggregate to form the hemostaticplug (in hemostasis) or thrombus (inthrombosis).(2) Formation of a fibrin mesh that binds to theplatelet aggregate, forming a more stable hemostaticplug or thrombus.(3) Partial or complete dissolution of the hemostaticplug or thrombus by plasmin.598There Are Three Types of ThrombiThree types of thrombi or clots are distinguished. Allthree contain fibrin in various proportions.(1) The white thrombus is composed of platelets andfibrin and is relatively poor in erythrocytes. Itforms at the site of an injury or abnormal vesselwall, particularly in areas where blood flow israpid (arteries).(2) The red thrombus consists primarily of red cellsand fibrin. It morphologically resembles the clotformed in a test tube and may form in vivo inareas of retarded blood flow or stasis (eg, veins)with or without vascular injury, or it may form ata site of injury or in an abnormal vessel in conjunctionwith an initiating platelet plug.(3) A third type is a disseminated fibrin deposit invery small blood vessels or capillaries.We shall first describe the coagulation pathway leadingto the formation of fibrin. Then we shall briefly describesome aspects of the involvement of platelets andblood vessel walls in the overall process. This separationof clotting factors and platelets is artificial, since bothplay intimate and often mutually interdependent rolesin hemostasis and thrombosis, but it facilitates descriptionof the overall processes involved.Both Intrinsic & Extrinsic Pathways Resultin the Formation of FibrinTwo pathways lead to fibrin clot formation: the intrinsicand the extrinsic pathways. These pathways are notindependent, as previously thought. However, this artificialdistinction is retained in the following text to facilitatetheir description.Initiation of the fibrin clot in response to tissue injuryis carried out by the extrinsic pathway. How theintrinsic pathway is activated in vivo is unclear, but itinvolves a negatively charged surface. The intrinsic andextrinsic pathways converge in a final common pathwayinvolving the activation of prothrombin to thrombinand the thrombin-catalyzed cleavage of fibrinogento form the fibrin clot. The intrinsic, extrinsic, andfinal common pathways are complex and involve manydifferent proteins (Figure 51–1 and Table 51–1). In