Thrombosis risk modification in transgenic mice containing the human fibrinogen thrombin-binding gamma' chain sequence.
OBJECTIVE
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.
Mosesson
M W
MW
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201-2178, USA. michael.mosesson@bcw.edu
Cooley
B C
BC
Hernandez
I
I
Diorio
J P
JP
Weiler
H
H
D000818:Animals; D001665:Binding Sites; D005165:Factor V / Q000235:genetics; D005340:Fibrinogen / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010975:Platelet Aggregation Inhibitors; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012306:Risk; D013917:Thrombin; D013927:Thrombosis / Q000517:prevention & control*
D010975:Platelet Aggregation Inhibitors; D011993:Recombinant Fusion Proteins; C095381:factor V Leiden; C027539:fibrinopeptides gamma; D005165:Factor V; D005340:Fibrinogen; D013917:Thrombin