Factor VLeiden and thrombophilia.

Abstract

Blood coagulation is initiated after injury to the vasculature and exposure of TF. TF is an integral single-chain glycoprotein that, when exposed to the circulating blood, binds to circulating factor VIIa and initiates the process of blood coagulation. Although the majority of factor VII molecules circulate in plasma as a single-chain, inactive zymogen, ≈2% of them possess a Ser protease active site but have poor catalytic activity.1 2 After binding to TF, the catalytic efficiency of the factor VIIa/TF complex increases by four orders of magnitude, and the enzymatic complex initiates a series of enzymatic reactions that lead to the generation of α-thrombin.2 3 The prothrombin-activating enzyme prothrombinase is composed of the Ser protease factor Xa and cofactor factor Va, associated on the cell membrane.4 Factor Va is required for prothrombinase activity because it serves the dual function as a factor Xa receptor and a factor Xa catalytic effector on the cell surface. Both enzyme and cofactor are derived from plasma precursors by regulatory proteolytic events that involve α-thrombin. These events include activation of factor VIII to factor VIIIa and of factor V to factor Va. α-Thrombin, the major procoagulant enzyme of the blood coagulation cascade, is also paradoxically a major anticoagulant. Once formed, α-thrombin binds to the endothelial cell receptor thrombomodulin and initiates the protein C pathway that leads to the formation of APC. The protein C pathway is composed of the zymogen protein C, thrombomodulin, and the accessory protein, protein S.5 APC downregulates α-thrombin generation by inactivating factors Va and VIIIa and eliminating their participation in the prothrombinase and tenase complexes, respectively. Under physiological conditions, inactivation of factor VIIIa occurs in the absence of APC by dissociation of the A2 domain.6 7 8 Hence, APC is not essential for factor VIIIa inactivation.8 …