Thrombosis risk modification in transgenic mice containing the human fibrinogen thrombin-binding gamma' chain sequence. J Thromb Haemost 2009 Jan;7(1):102-10
Date
11/06/2008Pubmed ID
18983496DOI
10.1111/j.1538-7836.2008.03213.xScopus ID
2-s2.0-57749203814 (requires institutional sign-in at Scopus site) 26 CitationsAbstract
BACKGROUND AND OBJECTIVES: Thrombin binding activity in murine fibrin (Antithrombin I) is restricted to its E domains inasmuch as murine gamma' chains (mu-gamma') do not bind thrombin. This feature prompted us to produce a 'gain-of-function' transgenic mouse in which the wild-type (WT) C-terminal mu-gamma' chain fibrinogen sequence had been replaced with the C-terminal thrombin-binding human gamma' sequence.
RESULTS: This procedure resulted in a murine fibrinogen species containing chimeric hu-gamma' chains (hu-gamma' fibrinogen). As anticipated, thrombin bound to WT fibrin at a single class of sites, whereas thrombin binding to heterodimeric hu-gamma'-containing fibrin was increased, reflecting its content of hu-gamma' chains. In an electrolytically-induced femoral vein thrombosis injury model, we found no differences in the volume of thrombus generation between WT and heterozygous hu-gamma' mice. However, heterozygous factor (F) V Leiden (FVL(+/-)) mice developed greater thrombus volumes than did WT controls (P < 0.01). In doubly heterozygous FVL(+/-), hu-gamma' mice, thrombus formation was reduced to WT levels (P < 0.05).
CONCLUSIONS: Murine hu-gamma' fibrinogen down-regulates venous thrombosis in the presence of another known thrombosis risk factor, FV Leiden. This finding indicates that hu-gamma' chain-containing fibrinogen is a thrombosis risk modifier.
Author List
Mosesson MW, Cooley BC, Hernandez I, Diorio JP, Weiler HMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
Factor V
Fibrinogen
Humans
Mice
Mice, Transgenic
Platelet Aggregation Inhibitors
Recombinant Fusion Proteins
Risk
Thrombin
Thrombosis
