Abstract 143: Differential Suppression Of Arterial Versus Venous Thrombosis But Preserved Hemostasis In Mice Expressing Fibrinogen That Cannot Support Fibrin Formation

Abstract

Elevated circulating fibrinogen correlates 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. However, the precise contribution of fibrin matrix to occlusive arterial and venous thrombus formation in vivo remains largely undefined. To determine the contribution of fibrinogen versus fibrin to arterial thrombosis, venous thrombosis, and hemostatic potential in vivo , arterial and venous thrombotic challenges as well as hemostatic tests were performed in wildtype ( Fga WT ) and Fga EK mice that express normal levels of fibrinogen “locked” in the monomeric form. In a model arterial thrombosis, a 10% FeCl 3 injury to the carotid artery resulted in similar times to occlusion between Fga WT/WT , Fga WT/EK and Fga EK/EK mice, while Fga -/- mice were completely protected. However, when injured with 5% FeCl 3 , Fga EK/EK mice were partially protected from occlusion but had increased embolic events. These results suggest that fibrinogen can contribute to arterial thrombus formation independent of fibrin formation. Consistently, fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content in Fga WT/WT , Fga WT/EK and Fga EK/EK mice were similar. In an inferior vena cava stasis model of venous thrombosis, Fga EK/EK had near complete protection from thrombus formation. Intriguingly, Fga WT/EK mice also displayed significant reduction in thrombus frequency and mass relative to Fga WT/WT mice. Plasma from Fga WT/EK mice produced prolonged prothrombin and thrombin times with reduced fibrin formation based on turbidity assay. In bleeding models, Fga WT/EK and, Fga EK/EK mice had preserved hemostasis in contrast to Fga -/- mice that presented with significantly impaired hemostasis. These findings show that selective prevention of fibrin polymerization significantly reduces venous thrombosis and suppresses arterial thrombosis based on the severity of injury with minimal disruption to hemostasis. Moreover, the data suggests that administration of non-polymerizable fibrinogen may be a therapeutic strategy against thrombosis.