Control Mechanisms in Thrombin Generation

Thrombin accelerates its own production by activating platelets (and perhaps other cells) to provide coagulant surfaces on which prothrombinase, the enzyme complex that activates prothrombin in plasma and consists of equimolar factor Xa (serine protease) and factor Va (cofactor), assembles in a Ca(2+)-dependent reaction. Thrombin also activates factor V to provide the cofactor for factor Xa in prothrombinase, and factor VIII to provide the cofactor for factor X activation by factor IXa. Even when factor X activation is initiated by tissue factor, efficient propagation of factor X activation is critically dependent on intrinsic tenase (the factor IXa and factor VIIIa enzyme complex). These procoagulant actions of thrombin explain why good antithrombins can inhibit both intrinsic and extrinsic prothrombin activation. Because of the low level of thrombin (1 nM) required to initiate platelet activation and the activation of platelet-bound factor V, only highly efficient antithrombins, such as hirudin, can abrogate platelet-dependent prothrombinase assembly.