Effect of Val34Leu Polymorphism on the Activation of the Coagulation Factor XIII-A

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Abstract
Coagulation factor XIII (FXIII) is a protransglutaminase involved in the last step of the coagulation cascade by stabilising the fibrin clot. Recently, a common variation (FXIII Val34Leu) has been associated with a decreased risk of myocardial infarction and deep venous thrombosis. Val34Leu is critically located near the thrombin activation site of FXIII-A. In this study we investigated its effects on the activation of FXIII. Both recombinant and platelet-derived FXIII Val34Leu variants were shown to be more susceptible to thrombin cleavage than the wild type FXIII. The rate of enzymatic activation of FXIII Val34Leu was found increased, however, the specific activity of fully activated wild type FXIII and the Val34Leu mutant did not differ. During the course of thrombin-induced activation of FXIII fibrin γ-chain dimerisation and α-chain polymerisation developed more rapidly with the Val34Leu mutant. The increased rate of fibrin stabilisation brought about by the Val34Leu FXIII seems to be paradoxically associated with a protective effect against pathological thrombosis. Abbreviations: AP, activation peptide of factor XIII; FXIII, blood coagulation factor XIII; FXIII-A, factor XIII subunit A; FXIII-A’, proteolytically activated subunit A; FXIII-B, factor XIII subunit B; SDS PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis