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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 988-995
The factor XIII V34L polymorphism accelerates thrombin
activation of factor XIII and affects cross-linked fibrin structure
Robert A. S. Ariëns,
Helen Philippou,
Chandrasekaran Nagaswami,
John W. Weisel,
David
A. Lane, and
Peter J. Grant
From the Unit of Molecular Vascular Medicine, University of Leeds
School of Medicine, Leeds, UK; Department of Haematology, Imperial
College School of Medicine, Charing Cross Hospital Campus, London, UK;
and Department of Cell and Developmental Biology, University of
Pennsylvania School of Medicine, Philadelphia, PA.
Factor XIII on activation by thrombin cross-links fibrin. A common
polymorphism Val to Leu at position 34 in the FXIII A subunit is under
investigation as a risk determinant of thrombosis. Because Val34Leu is
close to the thrombin cleavage site, the hypothesis that it would alter
the function of FXIII was tested. Analysis of FXIII subunit proteolysis
by thrombin using sodium dodecyl sulfate-polyacrylamide gel
electrophoresis and high-performance liquid chromatography showed that
FXIII 34Leu was cleaved by thrombin more rapidly and by lower doses
than 34Val. Mass spectrometry of isolated activation peptides confirmed
the predicted single methyl group difference and demonstrated that the
thrombin cleavage site is unaltered by Val34Leu. Kinetic analysis of
activation peptide release demonstrated that the catalytic
efficiency
(kcat/Km) of thrombin
was 0.5 for FXIII 34Leu and 0.2 (µmol/L) 1 × sec1 for 34Val. Presence of fibrin
increased the catalytic efficiency to 4.8 and 2.2 (µmol/L)1 × sec1,
respectively. Although the 34Leu peptide was released at a similar rate
as fibrinopeptide A, the 34Val peptide was released more slowly than
fibrinopeptide A but more quickly than fibrinopeptide B generation.
Cross-linking of  - and  -chains appeared earlier when fibrin was
incubated with FXIII 34Leu than with 34Val. Fully activated 34Leu and
34Val FXIII showed similar cross-linking activity. Analysis of fibrin
clots prepared using plasma from FXIII 34Leu subjects by turbidity and
permeability measurements showed reduced fiber mass/length ratio and
porosity compared to 34Val. The structural differences were confirmed
by electron microscopy. These results demonstrate that Val34Leu
accelerates activation of FXIII by thrombin and consequently affects
the structure of the cross-linked fibrin clot.
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