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 McCarty, Mitchell J. Cohen, John H. Griffin

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 immobilized myosin was monitored 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. We posit 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 - Oct 6 2016

Fingerprint

Factor Va
Skeletal Muscle Myosins
Factor Xa
Prothrombin
Myosins
Chemical activation
Platelets
Blood
Thrombin
Plasmas
Blood Platelets
Thromboplastin
Wounds and Injuries
Thrombosis
Interferometry
Platelet-Rich Plasma
Blood Coagulation Factors
Blood Coagulation

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Deguchi, H., Sinha, R. K., Marchese, P., Ruggeri, Z. M., Zilberman-Rudenko, J., McCarty, O., ... 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

Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va. / Deguchi, Hiroshi; Sinha, Ranjeet K.; Marchese, Patrizia; Ruggeri, Zaverio M.; Zilberman-Rudenko, Jevgenia; McCarty, Owen; Cohen, Mitchell J.; Griffin, John H.

In: Blood, Vol. 128, No. 14, 06.10.2016, p. 1870-1878.

Research output: Contribution to journalArticle

Deguchi, H, Sinha, RK, Marchese, P, Ruggeri, ZM, Zilberman-Rudenko, J, McCarty, O, Cohen, MJ & Griffin, JH 2016, 'Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va', Blood, vol. 128, no. 14, pp. 1870-1878. https://doi.org/10.1182/blood-2016-03-707679
Deguchi, Hiroshi ; Sinha, Ranjeet K. ; Marchese, Patrizia ; Ruggeri, Zaverio M. ; Zilberman-Rudenko, Jevgenia ; McCarty, Owen ; Cohen, Mitchell J. ; Griffin, John H. / Prothrombotic skeletal muscle myosin directly enhances prothrombin activation by binding factors Xa and Va. In: Blood. 2016 ; Vol. 128, No. 14. pp. 1870-1878.
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