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Blood coagulation takes place in 3 essential phases. The first phase is the activation of a prothrombin activator complex. The second phase is the activation of prothrombin. The third stage is clot formation as a result of fibrinogen cleavage by activated thrombin. The prothrombin activation complex is formed by two pathways each of which results in a different form of the prothrombin activator. The extrinsic mechanism of prothrombin activator formation begins with trauma to vascular walls or extravascular tissues. The damaged tissue releases tissue thromboplastin also known as tissue factor (TF). The formation of a clot by this mechanism usually takes as little as 15 seconds. This cascade is initiated by the activation of factor X by TF and factor VII. Activated factor X combined with factor V, factor VII and TF constitutes the prothrombin activator. Calcium (Ca++) is required for each of these steps. The prothrombin activator in the extrinsic pathway is very similar to the activator in the intrinsic pathway. Antithrombin III inhibits the activity of thrombin and also the step leading to the activation of factor X. Antithrombin III is a hundred to a thousand times more effective when bound by heparin. Protein C is activated by thrombin and with the Protein S cofactor provides a strong negative feedback in this phase of clot formation. (This definition may be outdated - see the DesignNote.)
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