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Blood, 1 October 2000, Vol. 96, No. 7, pp. 2479-2486
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Val34Leu polymorphism of plasma factor XIII:
biochemistry and epidemiology in familial thrombophilia
István Balogh,
Gabriella Szôke,
Levente Kárpáti,
Ulla Wartiovaara,
Éva Katona,
István Komáromi,
Gizella Haramura,
György Pfliegler,
Hanna Mikkola, and
László Muszbek
From the Department of Clinical Biochemistry and
Molecular Pathology, the Department of Immunology and the 2nd
Department of Medicine, University of Debrecen, Medical and Health
Science Center, Debrecen, Hungary; and the Department of Clinical
Chemistry and Biomedicine, University of Helsinki, Helsinki, Finland.
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 protective 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 concentration of FXIII of
different Val34Leu genotypes are identical, which suggests that there
is no difference in the rate of synthesis and externalization of
wild-type and mutant FXIII-A. In contrast, the release of AP by
thrombin 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 thrombin than between the Val34 variant and
thrombin. In agreement with these findings, the activation of mutant
plasma FXIII by thrombin was faster and required less thrombin than
that of the wild-type variant. Full thrombin activation of purified
plasma FXIII of different genotypes, however, resulted in
identical specific transglutaminase activities. Similarly, the mean
specific FXIII activity in the plasma was the same in the groups with
wild-type, heterozygous, and homozygous variants. Faster activation of
the Leu34 allele hardly could be associated with its presumed
protective effect against venous thrombosis. No such protective effect
was observed in a large group of patients with familial thrombophilia.
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