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 Blood, 1 August 2007, Vol. 110, No. 3, pp. 902-907.
Prepublished online as a Blood First Edition Paper on April 13, 2007; DOI 10.1182/blood-2007-01-066837.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Functional analysis of fibrin {gamma}-chain cross-linking by activated factor XIII: determination of a cross-linking pattern that maximizes clot stiffness

Kristina F. Standeven1, Angela M. Carter1, Peter J. Grant1, John W. Weisel2, Irina Chernysh2, Leona Masova2, Susan T. Lord3, and Robert A. S. Ariëns1

1 Academic Unit of Molecular Vascular Medicine, Leeds Institute for Genetics Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, United Kingdom; 2 Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia; 3 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill

Activated coagulation factor XIII (FXIIIa) cross-links the {gamma}-chains of fibrin early in clot formation. Cross-linking of the {alpha}-chains occurs more slowly, leading to high molecular weight multimer formations that can also contain {gamma}-chains. To study the contribution of FXIIIa-induced {gamma}-chain cross-linking on fibrin structure and function, we created 2 recombinant fibrinogens ({gamma}Q398N/Q399N/K406R and {gamma}K406R) that modify the {gamma}-chain cross-linking process. In {gamma}K406R, {gamma}-dimer cross-links were absent, but FXIIIa produced a cross-linking pattern similar to that observed in tissue transglutaminase cross-linked fibrin(ogen) with mainly {alpha}-{gamma} cross-links. In Q398N/Q399N/K406R, cross-links with any {gamma}-chain involvement were completely absent, and only {alpha}-chain cross-linking occurred. Upon cross-linking, recombinant normal fibrin yielded a 3.5-fold increase in stiffness, compared with a 2.5-fold increase by {alpha}-chain cross-linking alone ({gamma}Q398N/Q399N/K406R). {gamma}K406R fibrin showed a 1.5-fold increase in stiffness after cross-linking. No major differences in clot morphology, polymerization, and lysis rates were observed, although fiber diameter was slightly lower in cross-linked normal fibrin relative to the variants. Our results show that {gamma}-chain cross-linking contributes significantly to clot stiffness, in particular through {gamma}-dimer formation; {alpha}-{gamma} hybrid cross-links had the smallest impact on clot stiffness.


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