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

作者：Woosuk S. Hur, Tomohiro Kawano, Jean-Marie Mwiza, David S. Paul, Robert H. Lee, Emily G. Clark, Emma G. Bouck, Ananya Dutta, Can Cai, Stephen R. Baker, Martin Guthold, Nigel Mackman, Pierre Mangin, Alisa S. Wolberg, Wolfgang Bergmeier, Matthew J. Flick · 发表于：Blood · 年份：2023 · DOI：10.1182/blood.2023020805 · 被引用次数：21 · 研究领域：Venous Thromboembolism Diagnosis and Management、Blood properties and coagulation、Diagnosis and Treatment of Venous Diseases

ABSTRACT: 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 FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/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 FgaWT/WT, FgaWT/EK, and FgaEK/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, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for...