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Published on: February 2, 2018
Thrombosis risk modification in transgenic mice containing the human fibrinogen thrombin-binding gamma' chain
M W Mosesson1, B C Cooley, I Hernandez
1Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201-2178, USA. michael.mosesson@bcw.edu
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.
