Abstract Number: PB0137
Meeting: ISTH 2020 Congress
Background: Skeletal muscle myosin (SkM) has procoagulant activities and is structurally very similar to cardiac myosin (CM) which is exposed and released during myocardial infarction.
Aims: We evaluated CM’s procoagulant activities in vitro and in vivo.
Methods: Standard assays included: thrombin generation assays in purified clotting factor mixtures and in human plasma; factor Xa binding to immobilized CM; tail-cut-induced bleeding in acquired hemophilia-A mice; and murine myocardial ischemia-reperfusion injury. The ability of a myosin-based peptide mimicking SkM residues 816-837 (P-816/837) of myosin’s neck region to inhibit CM’s procoagulant activities was studied in vitro and in vivo.
Results: CM, similar to SkM, enhanced thrombin generation in mixtures of purified clotting factors Xa and Va, calcium ions, and prothrombin, and in human platelet-rich and platelet-poor plasmas. Immobilized CM, like SkM, directly bound FXa. These data support the concept that CM’s surface is a site for prothrombinase assembly and thrombin generation. In vivo testing for CM’s procoagulant activities in acquired hemophilia-A mice subjected to tail cutting showed that intravenously-administered CM significantly reduced tail-cut-initiated bleeding. In vivo testing for CM’s activities in a murine myocardial ischemia-reperfusion injury model showed that intravenously-administered CM augmented myocardial injury because CM significantly increased infarct size from 25% to 45% and serum troponin-I level from 54 to 179 ng/mL. Notably, the myosin sequence-based peptide, P-816/837 which binds FXa, inhibited CM’s procoagulant activities in vitro and in vivo.
Conclusions: CM exhibits procoagulant activities in vitro and in vivo, and CM can either promote hemostasis in the context of bleeding or exacerbate thrombosis-related myocardial injury in the context of myocardial ischemia/reperfusion. Remarkably, peptide P-816/837 targets and inhibits CM’s procoagulant activities in vitro and in vivo, and such myosin based peptides may provide myosin-specific anticoagulants for translational research. Research is needed to clarify CM’s pathophysiology and its mechanistic influences on hemostasis or thrombosis.
To cite this abstract in AMA style:Shukla M, Deguchi H, Zilberman-Rudenko J, Oyama Y, Eckle T, Guo Z, Lear S, Shen W, Wyseure T, Mosnier L, Orje J, Ruggeri Z, McCarty O, Griffin J. Cardiac Myosin Promotes Thrombin Generation and Coagulation in vitro and in vivo [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/cardiac-myosin-promotes-thrombin-generation-and-coagulation-in-vitro-and-in-vivo/. Accessed May 6, 2021.
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