The Molecular Basis of Blood Coagulation Review

Blood coagulation is a host defense system that assists in maintaining the integrity of the closed, high-pressure mammalian circulatory system after blood vessel injury. After initiation of clotting, the sequential activation of cer- tain plasma proenzymes to their enzyme forms proceeds through either the intrinsic or extrinsic pathway of blood coagulation (Figure 1A) (Davie and Fiatnoff, 1964; Mac- Farlane, 1964). These plasma glycoproteins, including factor XII, factor XI, factor IX, factor X, factor VII, and pro- thrombin, are zymogens of serine proteases. As a family, these proteins bear marked structural and functional ho- mology to the digestive proteases trypsin and chymotryp- sin. They are each converted from an inactive form to an active enzyme by limited proteolysis of one or two peptide bonds. However, most of the blood clotting enzymes are effective on a physiologic time scale only when assem- bled in complexes on membrane surfaces with protein cofactors such as factor VIII and factor V. Calcium ions have a critical role in that many of the component reac- tions in blood coagulation are either Ca2+-dependent or require Caz+ for the interaction of proteins with mem- brane surfaces. Clot formation occurs when fibrinogen is converted by thrombin to fibrin, the structural protein that assembles into the fibrin polymer. The clot, formed after tissue injury, is composed of activated platelets and fibrin. The clot mechanically impedes the flow blood from injured vessel and minimizes blood loss from the wound. Once a stable clot has formed, wound healing ensues. The clot is gradually dissolved by enzymes of the fibrinolytic system. Blood coagulation may be initiated through either the in- trinsic pathway, where all of the protein components are present in blood, or the extrinsic pathway, where the cell- membrane protein tissue factor plays a critical role. Initia- tion of the intrinsic pathway of blood coagulation involves the activation of factor XII to factor Xlla (see Figure lA), a reaction that is promoted by certain surfaces such as glass or collagen. Although kallikrein is capable of factor XII activation, particular protease involved in factor activation physiologically is unknown. The collagen that becomes exposed in the subendothelium after vessel damage may provide the negatively charged surface re- quired for this reaction in vivo. Factor Xlla, with high mo- lecular weight kininogen (HMWK) as cofactor, converts factor Xl to its activated form, Xla. In the presence of Ca2+, factor Xla activates IX to IXa. Factor IXa, in complex with factor Villa on membrane surfaces, catalyzes the activation of factor X to factor Xa. Factor Xa activates prothrombin to thrombin in the presence of Ca2+ and factor Va bound to membrane surfaces. Throm- bin converts fibrinogen to fibrin by cleavage of two peptide bonds, thereby releasing two small amino-terminal pep- tides, fibrinopeptide A and fibrinopeptide B. Although the intrinsic pathway is clearly important in the clotting of blood in vitro, its physiologic importance has been challenged by the absence of bleeding problems in patients deficient in factor XII, prekallikrein, and HMWK. Therefore the intrinsic pathway is not likely to be of impor- tance to normal blood coagulation. The role of factor Xl is