Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 7, Issue 1, Pages 102-110Publisher
WILEY
DOI: 10.1111/j.1538-7836.2008.03213.x
Keywords
antithrombin; factor V Leiden; fibrinogen; thrombin; thrombosis
Categories
Funding
- NIH [R01 HL-70627]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL070627] Funding Source: NIH RePORTER
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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.
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