Effect of Va134Leu polymorphism on the activation of the coagulation factor XIII-A

Coagulation factor XIII (FXIII) is a protransglutaminase involved in the la st 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 criti cally located near the thrombin activation site of FXIII-A. In this study w e 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 activ ation 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 gamma-cha in dimerisation and alpha-chain polymerisation developed more rapidly with the Val34Leu mutant. The increased rate of fibrin stabilisation brought abo ut by the Val34Leu FXIII seems to be paradoxically associated with a protec tive effect against pathological thrombosis.