Activated protein C anticoagulant activity is enhanced by skeletal muscle myosin

Heeb, Mary J.; Fernández, José A.; Yamashita, Atsuki; McDowell, Olivia R.; Guo, Zihan; Mosnier, Laurent O.; Deguchi, Hiroshi; Griffin, John H.

doi:10.3324/haematol.2019.242982

Cited by 6 publications

(20 citation statements)

References 15 publications

(24 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[73][74][75][76][77][78][79][80] Multiple mechanism(s) for TIC have been suggested, but much remains to be clarified and translation of this knowledge to the clinic remains highly challenging. As a consequence of traumatic injury, exposure of blood to SkM, including SkM released into the circulation, 18 could possibly augment the ability of blood to generate excessive thrombin or to manifest excess activities of the APC anticoagulant system, 15 or to modify fibrinolysis by extensive activation of TAFI. 16 Our pilot study showed the different…”

Section: Skm and Thrombin Generation In Acute Trauma Induced Coagulmentioning

confidence: 99%

“…Kinetic studies indicate that the potency for SkM and CM preparations to enhance prothrombin activation is generally comparable to that of procoagulant phospholipid vesicles (Table 1). SkM preparations contain very low levels of phosphatidylserine, 15 raising the question of whether myosin‐bound phospholipids may contribute to enhance SkM’s or CM’s procoagulant activity…”

Section: Myosin Structure and Nomenclaturementioning

confidence: 99%

“…Multiple mechanism(s) for TIC have been suggested, but much remains to be clarified and translation of this knowledge to the clinic remains highly challenging. As a consequence of traumatic injury, exposure of blood to SkM, including SkM released into the circulation, 18 could possibly augment the ability of blood to generate excessive thrombin or to manifest excess activities of the APC anticoagulant system, 15 or to modify fibrinolysis by extensive activation of TAFI 16 . Our pilot study showed the different sensitivity of anti‐myosin blocking antibodies neutralizing SkM’s procoagulant activity between trauma patient's plasma and control plasma, 14 suggesting that myosin derived from trauma may contribute to plasma thrombin generation.…”

Section: Clinical Associations Of Skm and CM With Pathobiology Relatementioning

confidence: 99%

See 2 more Smart Citations

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

Deguchi

Morla

Griffin

2021

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

Striated muscle myosins can promote prothrombin activation by FXa or FVa inactivation by APC. Cardiac myosin and skeletal muscle myosin are pro‐hemostatic in murine tail cut bleeding models. Infused cardiac myosin exacerbates myocardial injury caused by myocardial ischemia reperfusion. Skeletal muscle myosin isoforms that circulate in human plasma can be grouped into 3 phenotypes. Abstract Two striated muscle myosins, namely skeletal muscle myosin (SkM) and cardiac myosin (CM), may potentially contribute to physiologic mechanisms for regulation of thrombosis and hemostasis. Thrombin is generated from activation of prothrombin by the prothrombinase (IIase) complex comprising factor Xa, factor Va, and Ca++ ions located on surfaces where these factors are assembled. We discovered that SkM and CM, which are abundant motor proteins in skeletal and cardiac muscles, can provide a surface for thrombin generation by the prothrombinase complex without any apparent requirement for phosphatidylserine or lipids. These myosins can also provide a surface that supports the inactivation of factor Va by activated protein C/protein S, resulting in negative feedback downregulation of thrombin generation. Although the physiologic significance of these reactions remains to be established for humans, substantive insights may be gleaned from murine studies. In mice, exogenously infused SkM and CM can promote hemostasis as they are capable of reducing tail cut bleeding. In a murine myocardial ischemia‐reperfusion injury model, exogenously infused CM exacerbates myocardial infarction damage. Studies of human plasmas show that SkM antigen isoforms of different MWs circulate in human plasma, and they can be used to identify three plasma SkM phenotypes. A pilot clinical study showed that one SkM isoform pattern appeared to be linked to isolated pulmonary embolism. These discoveries enable multiple preclinical and clinical studies of SkM and CM, which should provide novel mechanistic insights with potential translational relevance for the roles of CM and SkM in the pathobiology of hemostasis and thrombosis.

show abstract

Section: Skm and Thrombin Generation In Acute Trauma Induced Coagulmentioning

confidence: 99%

Section: Myosin Structure and Nomenclaturementioning

confidence: 99%

Section: Clinical Associations Of Skm and CM With Pathobiology Relatementioning

confidence: 99%

See 1 more Smart Citation

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

Deguchi

Morla

Griffin

2021

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

show abstract

“…SkM and CM were shown to exert procoagulant effects by binding factor (F) Xa and FVa, thereby forming a surface for the assembly of the prothrombinase complex 1,6 . In addition, SkM was found to enable negative feedback downregulation of thrombin generation by acting as a cofactor for activated protein C's proteolytic inactivation of FVa 4 . SkM can bind to von Willebrand factor, suggesting another possible procoagulant role by localizing FVIII wherever von Willebrand factor is localized, (eg, on activated platelets) 5 .…”

Section: Introductionmentioning

confidence: 99%

“…Research on the role of some striated muscle myosins, namely skeletal muscle myosin (SkM) and cardiac myosin (CM), in the pathophysiology of blood coagulation is a promising new area. [1][2][3][4][5][6][7][8] Structurally, SkM and CM are similar and exist as dimers of heterotrimers and consist of six polypeptide chains: two heavy chains, and two pairs of two light chains (essential light chain and regulatory light chain). 3, [8][9][10] Recently, SkM rare exomic variations were identified as associated with increased venous thrombosis risk through a rare exomic variant genotyping study.…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle myosin and cardiac myosin attenuate heparin's antithrombin‐dependent anticoagulant activity

Morla

Deguchi

Griffin

2021

Journal of Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

Background Heparin enhances the ability of the plasma protease inhibitor, antithrombin, to neutralize coagulation factor Xa and thrombin. Skeletal muscle myosin binds unfractionated heparin. Objectives The aim of this study was to investigate the influence of myosin binding to heparin on antithrombin's anticoagulant activity. Methods Inhibition of factor Xa and thrombin by antithrombin in the presence of different heparins and skeletal muscle myosin or cardiac myosin was studied by measuring inhibition of each enzyme's chromogenic substrate hydrolysis. Results and Conclusions Skeletal muscle myosin and cardiac myosin neutralized unfractionated heparin's enhancement of antithrombin's inhibition of purified factor Xa and thrombin. Skeletal muscle myosin also reduced the inhibition of factor Xa and thrombin by antithrombin in the presence of heparan sulfate. These two myosins did not protect factor Xa from antithrombin inhibition when tested in the presence of smaller heparins (eg, low molecular weight heparin, heparin pentasaccharide). This chain length dependence for skeletal muscle myosin's ability to reduce heparin's anticoagulant activity might have potential implications for therapy for patients who experience increases in plasma myosin levels (eg, acute trauma patients). In addition to the chain length, the type and extent of sulfation of glycosaminoglycans influenced the ability of skeletal muscle myosin to neutralize the polysaccharide's ability to enhance antithrombin's activity. In summary, these studies show that skeletal muscle myosin and cardiac myosin can influence antithrombin's anticoagulant activity against factor Xa and thrombin, implying that they may significantly influence the hemostatic balance involving bleeding vs clotting.

show abstract

Unresolved hemostasis issues in haemophilia

Sidonio,

Weisel,

Stafford

2024

Haemophilia

View full text Add to dashboard Cite

Despite rapid technological advancement in factor and nonfactor products in the prevention and treatment of bleeding in haemophilia patients, it is imperative that we acknowledge gaps in our understanding of how hemostasis is achieved. The authors will briefly review three unresolved issues in persons with haemophilia (PwH) focusing on the forgotten function that red blood cells play in hemostasis, the critical role of extravascular (outside circulation) FIX in hemostasis in the context of unmodified and extended half‐life FIX products and finally on the role that skeletal muscle myosin plays in prothrombinase assembly and subsequent thrombin generation that could mitigate breakthrough muscle hematomas.

show abstract

Activated protein C anticoagulant activity is enhanced by skeletal muscle myosin

Cited by 6 publications

References 15 publications

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

Novel blood coagulation molecules: Skeletal muscle myosin and cardiac myosin

Skeletal muscle myosin and cardiac myosin attenuate heparin's antithrombin‐dependent anticoagulant activity

Unresolved hemostasis issues in haemophilia

Contact Info

Product

Resources

About