Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va

Hiroshi Deguchi, Ranjeet K. Sinha, Patrizia Marchese, Zaverio M. Ruggeri, Jevgenia Zilberman-Rudenko, Owen J.T. McCarty, Mitchell J. Cohen, John H. Griffin

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

To test the hypothesis that skeletal muscle myosins can directly influence blood coagulation and thrombosis, ex vivo studies of the effects of myosin on thrombogenesis in fresh human blood were conducted. Addition of myosin to blood augmented the thrombotic responses of human blood flowing over collagen-coated surfaces (300 s-1 shear rate). Perfusion of human blood over myosin-coated surfaces also caused fibrin and platelet deposition, evidencing myosin's thrombogenicity. Myosin markedly enhanced thrombin generation in both platelet-rich plasma and platelet-poor plasma, indicating that myosin promoted thrombin generation in plasma primarily independent of platelets. In purified reaction mixtures composed only of factor Xa, factor Va, prothrombin, and calcium ions, myosin greatly enhanced prothrombinase activity. The Gla domain of factor Xa was not required for myosin's prothrombinase enhancement. When binding of purified clotting factors to immobilizedmyosin wasmonitored using biolayer interferometry, factors Xa and Va each showed favorable binding interactions. Factor Va reduced by 100-fold the apparent Kd of myosin for factor Xa (Kd ~0.48 nM), primarily by reducing koff, indicating formation of a stable ternary complex of myosin:Xa:Va. In studies to assess possible clinical relevance for this discovery, we found that antimyosin antibodies inhibited thrombin generation in acute trauma patient plasmas more than in control plasmas (P = .0004), implying myosin might contribute to acute trauma coagulopathy. Weposit that myosin enhancement of thrombin generation could contribute either to promote hemostasis or to augment thrombosis risk with consequent implications for myosin's possible contributions to pathophysiology in the setting of acute injuries.

Original languageEnglish (US)
Pages (from-to)1870-1878
Number of pages9
JournalBlood
Volume128
Issue number14
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va'. Together they form a unique fingerprint.

  • Cite this

    Deguchi, H., Sinha, R. K., Marchese, P., Ruggeri, Z. M., Zilberman-Rudenko, J., McCarty, O. J. T., Cohen, M. J., & Griffin, J. H. (2016). Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va. Blood, 128(14), 1870-1878. https://doi.org/10.1182/blood-2016-03-707679