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).
CONCLUSIONS: 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.