From the Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA (J.Z.-R., H.D., M.S., J.N.O., Z.G., T.W., L.O.M., Z.M.R., J.H.G.).
Department of Biomedical Engineering (J.Z.-R., O.J.T.M.), School of Medicine, Oregon Health & Science University, Portland.
Arterioscler Thromb Vasc Biol. 2020 Apr;40(4):901-913. doi: 10.1161/ATVBAHA.120.313990. Epub 2020 Feb 27.
Cardiac myosin (CM) is structurally similar to skeletal muscle myosin, which has procoagulant activity. Here, we evaluated CM's ex vivo, in vivo, and in vitro activities related to hemostasis and thrombosis. Approach and Results: Perfusion of fresh human blood over CM-coated surfaces caused thrombus formation and fibrin deposition. Addition of CM to blood passing over collagen-coated surfaces enhanced fibrin formation. In a murine ischemia/reperfusion injury model, exogenous CM, when administered intravenously, augmented myocardial infarction and troponin I release. In hemophilia A mice, intravenously administered CM reduced tail-cut-initiated bleeding. These data provide proof of concept for CM's in vivo procoagulant properties. In vitro studies clarified some mechanisms for CM's procoagulant properties. Thrombin generation assays showed that CM, like skeletal muscle myosin, enhanced thrombin generation in human platelet-rich and platelet-poor plasmas and also in mixtures of purified factors Xa, Va, and prothrombin. Binding studies showed that CM, like skeletal muscle myosin, directly binds factor Xa, supporting the concept that the CM surface is a site for prothrombinase assembly. In tPA (tissue-type plasminogen activator)-induced plasma clot lysis assays, CM was antifibrinolytic due to robust CM-dependent thrombin generation that enhanced activation of TAFI (thrombin activatable fibrinolysis inhibitor).
CM in vitro is procoagulant and prothrombotic. CM in vivo can augment myocardial damage and can be prohemostatic in the presence of bleeding. CM's procoagulant and antifibrinolytic activities likely involve, at least in part, its ability to bind factor Xa and enhance thrombin generation. Future work is needed to clarify CM's pathophysiology and its mechanistic influences on hemostasis or thrombosis.
心肌球蛋白（CM）在结构上与骨骼肌肌球蛋白相似，后者具有促凝活性。在此，我们评估了 CM 与止血和血栓形成相关的体外、体内和体外活性。
将新鲜的人血灌注在 CM 涂层表面上会导致血栓形成和纤维蛋白沉积。将 CM 添加到流过胶原蛋白涂层表面的血液中会增强纤维蛋白的形成。在缺血/再灌注损伤模型的小鼠中，静脉内给予外源性 CM 会增加心肌梗死和肌钙蛋白 I 的释放。在血友病 A 小鼠中，静脉内给予 CM 可减少尾巴切割引起的出血。这些数据为 CM 的体内促凝特性提供了概念验证。体外研究阐明了 CM 促凝特性的一些机制。凝血酶生成测定表明，CM 像骨骼肌肌球蛋白一样，增强了富含血小板和血小板少的人血浆以及纯化的因子 Xa、Va 和凝血酶原混合物中的凝血酶生成。结合研究表明，CM 像骨骼肌肌球蛋白一样，直接结合因子 Xa，支持 CM 表面是凝血酶原酶组装位点的概念。在 tPA（组织型纤溶酶原激活物）诱导的血浆凝块溶解测定中，CM 具有抗纤维蛋白溶解作用，因为 CM 依赖性凝血酶生成增强了 TAFI（凝血酶激活的纤溶抑制物）的激活。
CM 在体外具有促凝和促血栓形成作用。CM 在体内可加重心肌损伤，在出血存在的情况下具有促止血作用。CM 的促凝和抗纤维蛋白溶解活性可能至少部分涉及其结合因子 Xa 和增强凝血酶生成的能力。需要进一步的研究来阐明 CM 的病理生理学及其对止血或血栓形成的机制影响。
