Skeletal muscle myosin promotes coagulation by binding factor XI via its A3 domain and enhancing thrombin-induced factor XI activation

Abstract

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Unresolved hemostasis issues in haemophilia

“…Accumulating evidence demonstrates that SkM is elevated during acute muscle damage and one of the SkM functions is to promote haemostasis by binding FXa and FVa thus enhancing prothrombinase activity and improving thrombin generation without the phospholipid vesicles. 47,48 Furthermore, Flood and colleagues demonstrated that SkM may indirectly escalate thrombin generation by binding VWF via the A1 domain and delivering FVIII to sites of injury. 49 Since emicizumab is not structurally like FVIII, following acute damage to skeletal muscle, it is possible a lack of clotting FVIII could prevent early haemostasis that is required to mitigate a larger muscle bleed.…”

“…SkM is part of a family of motor proteins that seem to play a role in procoagulant activity. Accumulating evidence demonstrates that SkM is elevated during acute muscle damage and one of the SkM functions is to promote haemostasis by binding FXa and FVa thus enhancing prothrombinase activity and improving thrombin generation without the phospholipid vesicles 47,48 . Furthermore, Flood and colleagues demonstrated that SkM may indirectly escalate thrombin generation by binding VWF via the A1 domain and delivering FVIII to sites of injury 49 .…”

Substrates, Cofactors, and Cellular Targets of Coagulation Factor XIa

“…This interaction enhances FXI activation by thrombin, yet not FXI activation by FXIIa. 43 Together, the polyamorous nature of the catalytic signature of FXI may be tied to the unique structure of this serine protease.…”

SkM‐ing information from traumatized tissue

“…Recently, SkM has been reported to possess an intrinsic thrombin activation potential via FXI A3 domain binding. 14 SkM also indirectly promotes coagulation via obligatory phospholipid contamination with tissue factor. 15 Thus, SkM isoforms with potentially distinct affinities for FXI A3, or phospholipids bearing tissue factor, may indeed correlate with some of the variability observed in coagulation following trauma.…”

“…Nonetheless, the possibility of a role of SkM in coagulation and trauma‐induced coagulopathy is intriguing. Recently, SkM has been reported to possess an intrinsic thrombin activation potential via FXI A3 domain binding 14 . SkM also indirectly promotes coagulation via obligatory phospholipid contamination with tissue factor 15 …”