Hemostasis is the dynamic process of coagulation as it occurs in areas of vascular injury, involving the carefullymodulated interaction of platelets, vascular wall, and pro-coagulant and anticoagulant proteins. After an injury tothe vascular endothelium, subendothelial collagen inducesa conformational change in von Willebrand factor (vWF), an adhesive protein to which platelets bind via their glycoprotein Ib receptor. After adhesion, platelets undergo activation and release numerous intracellular contents, includingadenosine diphosphate (ADP). These activated plateletssubsequently induce aggregation of additional platelets.Simultaneously, tissue factor, collagen, and other matrix proteins in tissue activate the coagulation cascade, leading to theformation of the enzyme thrombin (Fig. 151-1). Thrombincauses further aggregation of platelets, a positive feedbackactivation of factors 5 and 8, the conversion of fibrinogen tofibrin, and the activation of factor 11. A platelet plug forms, and bleeding ceases, usually within 3 to 7 minutes. The generation of thrombin leads to formation of a permanent clot bythe activation of factor 13, which cross-links fibrin, forminga stable thrombus. Finally, contractile elements within theplatelet mediate clot retraction. Thrombin also contributes to the eventual limitation of clot size by binding to the protein thrombomodulin on intact endothelial cells, convertingprotein C into activated protein C. Thrombin contributes to the eventual lysis of the thrombus by activating plasminogento plasmin. All of the hemostatic processes are closely interwoven and occur on biologic surfaces that mediate coagulation by bringing the critical players—platelets, endothelialcells, and subendothelium—into close proximity with pro-and anticoagulant proteins.
Many think of coagulation as having intrinsic and extrinsic pathways, but the reality is that these pathways are closely interactive and do not react independently (Fig. 151-2). For ease of use, all coagulation factors are denoted using Arabic rather than Roman numerals to prevent misreading factor VII (7) as factor VIII (8). In vivo, factor 7 autocatalyzes to form small amounts of factor 7a. When tissue is injured, tissue factor is released and causes a burst of factor 7a generation. Tissue factor, in combination with calcium and factor 7a, activates factor 9 and factor 10. The activation of factor 9 by factor 7a results in eventual generation of thrombin, which feeds back on factor 11, generating factor 11a and accelerating thrombin formation. This process explains why deficiency of factor 8 or factor 9 leads to severe bleeding disorders, whereas deficiency of factor 11 is usually mild, and deficiency of factor 12 is asymptomatic.
A series of inhibitory factors serve to tightly regulate theactivation of coagulation. Antithrombin III inactivates thrombin and factors 10a, 9a, and 11a. The protein C and protein S system inactivates activated factors 5 and 8, whichare cofactors localized in the “tenase” and “prothrombinase” complexes. The tissue factor pathway inhibitor, an anticoagulant protein, limits activation of the coagulation cascade by factor 7a and factor 10a. Fibrinolysis is initiated by the action of tissue plasminogen activator on plasminogen, producing plasmin, the active enzyme thatdegrades fibrin into split products. Fibrinolysis eventually dissolves the clot and allows normal flow to resume.Deficiencies of anticoagulant proteins may predispose tothrombosis.