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

Abstract

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.

Full‐length plasma skeletal muscle myosin isoform deficiency is associated with coagulopathy in acutely injured patients

“…Notably, the angle reflects the speed of fibrin accumulation and polymerization corresponding to the thrombin burst phase. 22 Increased level of thrombin activity in whole blood by procoagulant activities of SkM (ie, prothrombinase cofactor and antiheparin/antithrombin activities) [2][3][4][5][6] may be reflected by the TEG angle measurement. Further, patients with a depressed MA <55 mm (n = 36) had a significantly lower median SkM level of 34.0% versus 123.9% in patients with MA ≥55 mm (n = 68) (p = .002) (Table 2).…”

“…1 We have previously identified significant association of full-length skeletal muscle myosin (SkM) molecules with hemostatic capacity, specifically with increasing thrombin generation both in vitro and in vivo. [2][3][4][5][6][7][8][9] SkM is a molecular motor and conventional muscle myosin and is a dimer of heterotrimers, with each trimer containing one heavy chain (HC), one essential light chain, and one regulatory light chain. 6,10 When the tail of the full length of SkM HC (~240 kDa) (defined as full-SkM) is cleaved, smaller fragments, HMM HC (160 kDa) or S1 HC (95 kDa), are generated.…”

“…Thrombin generation is central to the hemostatic balance, and insufficient thrombin generation is linked to bleeding risk 1 . We have previously identified significant association of full‐length skeletal muscle myosin (SkM) molecules with hemostatic capacity, specifically with increasing thrombin generation both in vitro and in vivo 2–9 . SkM is a molecular motor and conventional muscle myosin and is a dimer of heterotrimers, with each trimer containing one heavy chain (HC), one essential light chain, and one regulatory light chain 6,10 .…”