Kalafatis M, Mann K G
Department of Chemistry, Cleveland State University, OH 44115, USA.
Adv Exp Med Biol. 2001;489:31-43. doi: 10.1007/978-1-4615-1277-6_3.
The regulation of the delicate balance between the procoagulant and anticoagulant mechanisms is of extreme importance for survival. The procoagulant enzymatic complexes (i.e. prothrombinase, intrinsic tenase and extrinsic tenase) are similar in structure and composed of an enzyme, a cofactor, and the substrate associated on a cell surface in the presence of divalent metal ions. Factor Va and factor VIIIa, which are very similar in structure and function, are required for prothrombinase and intrinsic tenase activities respectively because both cofactors express a dual function in their respective complexes, acting as an enzyme receptor and catalytic effector on the cell surface. The cofactors derive from inactive plasma precursors by regulatory proteolytic events, which involve alpha-thrombin. In general bleeding tendencies are usually associated with defects in the activation of one of the zymogens or the cofactors of the procoagulant complexes. a-Thrombin, participates in its own down-regulation by binding to the endothelial cell receptor thrombomodulin, and initiating the protein C pathway, which in turn leads to the formation of activated protein C (APC). APC is required for efficient neutralization of factor Va cofactor activity which results in the inactivation of the prothrombin-activating complex. This inactivation can only occur in the presence of the appropriate membrane surface. APC down-regulates the prothrombinase complex by cleaving specific peptide bonds on the heavy chain of factor Va which results in the dissociation of the A2 domain of factor Va from the rest of the molecule. Irregularities in the mechanism of inactivation of factor Va by APC, are associated with thrombotic risk, presumably due to sustained prothrombin activation.
促凝和抗凝机制之间微妙平衡的调节对生存至关重要。促凝酶复合物（即凝血酶原酶、内源性X因子酶复合物和外源性X因子酶复合物）结构相似，由一种酶、一种辅因子以及在二价金属离子存在下与细胞表面结合的底物组成。结构和功能非常相似的因子Va和因子VIIIa分别是凝血酶原酶和内源性X因子酶复合物活性所必需的，因为这两种辅因子在各自的复合物中都发挥双重功能，在细胞表面充当酶受体和催化效应物。这些辅因子通过涉及α-凝血酶的调节性蛋白水解事件从无活性的血浆前体衍生而来。一般来说，出血倾向通常与促凝复合物中一种酶原或辅因子激活缺陷有关。α-凝血酶通过与内皮细胞受体血栓调节蛋白结合并启动蛋白C途径来参与自身的下调，这反过来又导致活化蛋白C（APC）的形成。APC是有效中和因子Va辅因子活性所必需的，这会导致凝血酶原激活复合物失活。这种失活只能在适当的膜表面存在时发生。APC通过切割因子Va重链上的特定肽键来下调凝血酶原酶复合物，这导致因子Va的A2结构域与分子其余部分解离。APC使因子Va失活的机制异常与血栓形成风险有关，可能是由于凝血酶原的持续激活。
