title: Roles of fibrin α- and γ-chain specific cross-linking by FXIIIa in fibrin structure and function.
abstract: Factor XIII is responsible for the cross-linking of fibrin γ-chains in the early stages of clot formation, whilst α-chain cross-linking occurs at a slower rate. Although γ- and α-chain cross-linking was previously shown to contribute to clot stiffness, the role of cross-linking of both chains in determining clot structure is currently unknown. Therefore, the aim of this study was to determine the role of individual α- and γ-chain cross-linking during clot formation, and its effects on clot structure. We made use of a recombinant fibrinogen (γQ398N/Q399N/K406R), which does not allow for γ-chain cross-linking. In the absence of cross-linking, intact D-D interface was shown to play a potential role in fibre appearance time, clot stiffness and elasticity. Cross-linking of the fibrin α-chain played a role in the thickening of the fibrin fibres over time, and decreased lysis rate in the absence of α2-antiplasmin. We also showed that α-chain cross-linking played a role in the timing of fibre appearance, straightening fibres, increasing clot stiffness and reducing clot deformation. Cross-linking of the γ-chain played a role in fibrin fibre appearance time and fibre density. Our results show that α- and γ-chain cross-linking play independent and specific roles in fibrin clot formation and structure.
authors.forename: Cédric
authors.initials: C
authors.lastname: Duval
authors.forename: Peter
authors.initials: P
authors.lastname: Allan
authors.forename: Simon D A
authors.initials: SD
authors.lastname: Connell
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Ridger
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.affiliation: Robert A. S. Ariëns, Theme Thrombosis, Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health, and Therapeutics, Clarendon Way, University of Leeds, LS2 9NL, UK, Tel.: +44 1133437734, E-mail: R.A.S.Ariens@leeds.ac.uk.
authors.forename: Robert A S
authors.initials: RA
authors.lastname: Ariëns
mesh_terms: D001777:Blood Coagulation / Q000235:genetics; D004548:Elasticity; D026122:Factor XIIIa / Q000378:metabolism*; D005337:Fibrin / Q000737:chemistry / Q000378:metabolism*; D063285:Fibrin Clot Lysis Time; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D005337:Fibrin; D005340:Fibrinogen; D026122:Factor XIIIa
keywords: Fibrinogen; clot structure; factor XIII