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) 24 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 HAuthor
Hartmut Weiler PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH 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