Va134Leu polymorphism of plasma factor XIII: biochemistry and epidemiologyin familial thrombophilia

Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protectiv e effect against occlusive arterial diseases and venous thrombosis; however , its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concen tration of FXIII of different Val34Leu genotypes are identical, which sugge sts that there is no difference in the rate of synthesis and externalizatio n of wild-type and mutant FXIII-A, In contrast, the release of AP by thromb in from the Leu34 allele proceeded significantly faster than from its wild- type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombi n than between the Val34 variant and thrombin, In agreement with these find ings, the activation ol: mutant plasma FXIII by thrombin was faster and req uired less thrombin than that of the wild-type variant. Full thrombin activ ation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly the mean specifi c FXIII activity in the plasma wa's the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allel e hardly could be associated with its presumed protective effect against ve nous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia. (Blood, 2000;96:2479-2486) (C) 2000 by The American Society of Hematology.