IXa and VIIIa activate factor X. Activation of factor XII after binding to negatively charged surfaces can also initiate the intrinsic pathway. Via this route, activated factor XII cleaves factor XI, generating factor XIa. Factor XIa can act as an alternate activator of factor IX. Extrinsic and intrinsic clotting cascades converge in the activation of factor X to factor Xa. Activated factor X (Xa) catalyzes the conversion of prothrombin (factor II) to thrombin (factor IIa). This conversion depends on the presence of activated factor V, which is factor Va. Thrombin, in turn, converts fibrinogen to fibrin, an essential building block for stable clot formation. Thrombin also activates factor XIII, which, in turn, crosslinks fibrin monomers and thereby stabilizes the fibrin clot.
To avoid uncontrolled thrombosis in response to tissue damage or alternate activation of the coagulation cascade, a number of antithrombotic control mechanisms are activated in conjunction with clot formation (Fig. 33.2). Important to this discussion are antithrombin (formerly antithrombin III), protein C, and protein S. Proteins C and S are vitamin K–dependent factors that are activated upon clot formation. Activation is initiated by complexes of thrombomodulin and thrombin at sites of endothelial damage. Complexes of activated protein C and S inactivate factors Va and VIIIa, thereby inhibiting their associated procoagulant activities. Antithrombin is a serine protease inhibitor that binds irreversibly to serine proteases. Proteases that bind antithrombin include factors IXa, Xa, XIa, and XIIa. Antithrombin also accelerates dissociation of factor VIIa/tissue factor complexes, thereby inhibiting intrinsic and extrinsic clotting pathways at their points of initiation. Finally, as its name suggests, antithrombin binds (FDPs, FSPs)
Figure 33.2 Physiologic mechanisms that counteract the clotting cascade. The procoagulant cascade is inhibited by several physiologic mechanisms. The balance between pro-and antithrombotic pathways determines the state of coagulability. Antithrombotic mechanisms include the action of antithrombin (AT) and of proteins C and S. The sites of inhibition by these substances are depicted by an “X.” Plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) indirectly inactivate plasmin. Plasmin plays an important role in the dissolution of coagulated blood. For all coagulation factors, the subscript letter “a” denotes the activated form of the factor. FSP, fibrin split products; FDP, fibrin degradation products.
to and inhibits thrombin (factor IIa). Fibrinolysis also acts to delimit uncontrolled coagulation (Fig. 33.3). Mechanisms for fibrinolysis include cleavage of the fibrin clot by plasmin and the formation of fibrin degradation products (FDPs; or fibrin split products [FSPs]). Plasmin activity is, in turn, controlled by plasminogen activator inhibitors (e.g., PAI-1).
Prothrombotic changes associated with pregnancy include increases in the amounts and/or activities of factors in the clotting cascade and decreases in those counteracting clotting.