纤维蛋白原
止血
血栓
血栓形成
医学
纤维蛋白
血小板
下腔静脉
内科学
静脉血栓形成
心脏病学
凝血酶
病理
内分泌学
外科
免疫学
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,P Mangin,Alisa S. Wolberg,Wolfgang Bergmeier,Matthew J. Flick
出处
期刊:Blood
[American Society of Hematology]
日期:2023-10-13
卷期号:143 (2): 105-117
被引量:5
标识
DOI:10.1182/blood.2023020805
摘要
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 conferring protection. Notably, FgaWT/EK and FgaEK/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.
科研通智能强力驱动
Strongly Powered by AbleSci AI