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Thrombosis risk modification in transgenic mice containing the human fibrinogen thrombin‐binding γ′ chain sequence

Summary.  Background and objectives: Thrombin binding activity in murine fibrin (Antithrombin I) is restricted to its E domains inasmuch as murine γ′ chains (mu‐γ′) 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‐γ′ chain fibrinogen sequence had been replaced with the C‐terminal thrombin‐binding human γ′ sequence. Results: This procedure resulted in a murine fibrinogen species containing chimeric hu‐γ′ chains (hu‐γ′ fibrinogen). As anticipated, thrombin bound to WT fibrin at a single class of sites, whereas thrombin binding to heterodimeric hu‐γ′‐containing fibrin was increased, reflecting its content of hu‐γ′ 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‐γ′ 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‐γ′ mice, thrombus formation was reduced to WT levels (P < 0.05). Conclusions: Murine hu‐γ′ fibrinogen down‐regulates venous thrombosis in the presence of another known thrombosis risk factor, FV Leiden. This finding indicates that hu‐γ′ chain‐containing fibrinogen is a thrombosis risk modifier.