An elevated plasma
fibrinogen level is a risk factor for thrombotic
cardiovascular disease, but which of
fibrinogen's functions is responsible for the increased risk is unknown. To define better the contribution of
fibrinogen to large vessel
thrombus formation, we studied
carotid artery thrombosis in wild-type mice, mice lacking
fibrinogen (fbg-/-), mice treated with 7E9 (a blocking antibody to the
fibrinogen gamma-chain C-terminus), and mice expressing a mutant
fibrinogen (gamma delta 5) that lacks the gamma-chain platelet-binding motif QADGV. In control mice,
thrombus formation resulted in occlusion in 8 +/- 2 minutes (mean +/- SD). In fbg-/- mice, thrombi grew to large sizes, but then they abruptly embolized, confirming previous observations by others in an arteriolar
thrombus model. In contrast, mice treated with 7E9 and gamma delta 5 mice developed only small, nonoclusive mural thrombi and embolization was limited. These findings reveal that a
fibrinogen antibody, 7E9, or a
fibrinogen mutant retaining clotting function, can limit
thrombus formation more effectively than the complete absence of
fibrinogen. We hypothesize that the smaller thrombi in these animals result from the ability of
fibrin to bind and sequester
thrombin and/or the ability of the altered
fibrinogen molecules, which cannot recruit platelets, to bind to and passivate the surface.