Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis

• Mice expressing nonpolymerizable fibrinogen are protected against venous thrombosis and have suppressed arterial thrombosis.

• Selective prevention of fibrin polymerization had minimal influence on hemostasis.

Elevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using Fga^EK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, Fga^WT/EK and Fga^EK/EK mice were protected from occlusion with 4% ferric chloride (FeCl₃) challenges compared with wild-type (Fga^WT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl₃. In contrast, fibrinogen-deficient (Fga^−/−) mice showed no evidence of occlusion, even with high-concentration FeCl₃ challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in Fga^WT/WT, Fga^WT/EK, and Fga^EK/EK mice, consistent with preserved fibrinogen–platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, Fga^EK/EK mice had near complete protection from thrombus formation. Fga^WT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to Fga^WT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, Fga^WT/EK and Fga^EK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga^−/− mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.