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Adv Exp Med Biol. 2001;489:31-43.

Factor V: Dr. Jeckyll and Mr. Hyde.

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Department of Chemistry, Cleveland State University, OH 44115, USA.


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.

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