Author(s): Kalafatis M
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Abstract PURPOSE OF REVIEW: Thrombin is necessary for survival and is produced after activation of prothrombin by prothrombinase at the site of a vascular injury. While the enzyme component of prothrombinase alone, factor Xa, bound to a membrane surface can activate prothrombin, incorporation of the cofactor molecule, factor Va, into prothrombinase results in a five orders of magnitude increase in the catalytic efficiency of factor Xa that provides the physiologic pathway for thrombin generation. While the kinetic constants and the identity of peptide bonds cleaved in prothrombin to generate alpha-thrombin have been long established, the peptidyl portions of the factor Va molecule responsible for its interactions with factor Xa, prothrombin, and the lipid surface are still the subject of intense investigation. In this review, we summarize the current state of knowledge with respect to the interactions of the factor Va molecule with the various components of prothrombinase. RECENT FINDINGS: Binding sites for factor Xa have been identified on both the heavy and light chains of factor Va. Two amino acid regions that interact with factor Xa have been delineated on the heavy chain of the cofactor. It has also been demonstrated that the carboxyl-terminal portion of the heavy chain of factor Va contains hirudin-like motifs and appears to be responsible for the interaction of factor Va with prothrombin. This region of the molecule is important for procofactor activation by thrombin as well as cofactor function. Finally, the membrane-binding site of factor Va is contributed by several elements of the light chain and involves both electrostatic and hydrophobic interactions. SUMMARY: The absence or dysfunction of factor Va leads to hemorrhagic diseases while prolonged existence of the active cofactor species is associated with thrombosis. Thus, modulation of the incorporation of factor Va into prothrombinase in vivo by using synthetic peptides that have the potential to impair factor Va binding to any of the components of prothrombinase, will allow for control of the rate of thrombin generation at the site of vascular damage. As a consequence, a systematic definition of the regions of factor Va governing its incorporation within prothrombinase will provide the scaffold for the synthesis of potent anticoagulant molecules that could modulate thrombin formation and suppress excessive clotting in thrombotic individuals.
This article was published in Curr Opin Hematol
and referenced in Journal of Neonatal Biology