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

• Published in: Journal of thrombosis and haemostasis Vol. 19; no. 2; pp. 470 - 477
• Main Authors: Morla, Shravan, Deguchi, Hiroshi, Griffin, John H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-02-2021
• Subjects: Anticoagulants; Anticoagulants - pharmacology; Antithrombin; Antithrombins; Cardiac muscle; Cardiac Myosins; Clotting; Coagulation factor Xa; Factor Xa; Glycosaminoglycans; Heparan sulfate; Heparin; Humans; Molecular weight; Musculoskeletal system; Myosin; Polysaccharides; Proteinase inhibitors; Skeletal muscle; Skeletal Muscle Myosins; Thrombin; Trauma; heparin; antithrombin; myosin; thrombin; factor Xa
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.15169

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.