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

Shravan Morla, Hiroshi Deguchi, John H Griffin

Journal of thrombosis and haemostasis : JTH 2021 Feb

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Heparin enhances the ability of the plasma protease inhibitor, antithrombin, to neutralize coagulation factor Xa and thrombin. Skeletal muscle myosin binds unfractionated heparin. The aim of this study was to investigate the influence of myosin binding to heparin on antithrombin's anticoagulant activity. 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. 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. © 2020 International Society on Thrombosis and Haemostasis.

Citation

Shravan Morla, Hiroshi Deguchi, John H Griffin. Skeletal muscle myosin and cardiac myosin attenuate heparin's antithrombin-dependent anticoagulant activity. Journal of thrombosis and haemostasis : JTH. 2021 Feb;19(2):470-477