Fibrin Binding Explains Reduced Circulating Myosin After Trauma

Unraveling Coagulation Dynamics in Trauma

Severe injury frequently triggers trauma-induced coagulopathy, a complex dysregulation of hemostasis that contributes to mortality from both hemorrhage and subsequent thrombosis [1, 2]. While skeletal muscle myosin (SkM) released from damaged tissue is known to promote clot formation and inhibit fibrinolysis, clinicians have observed a paradoxical decrease in circulating SkM levels in trauma patients, even with extensive muscle injury [3, 4, 5]. A recent study sought to resolve this discrepancy by investigating the fate of SkM after it enters the circulation, exploring a potential mechanism that could explain its disappearance and clarify its role in post-trauma coagulation.

Investigating Myosin's Role in Coagulation

Skeletal muscle myosin is understood to have a procoagulant effect, both by promoting the generation of thrombin to form fibrin and by increasing the resistance of those fibrin clots to breakdown. Based on these properties, it has been hypothesized that a large-scale release of SkM from injured tissue would drive systemic hypercoagulation. This hypothesis, however, conflicts with clinical findings of unexpectedly low plasma SkM levels in trauma patients. To address this puzzle, researchers designed a study to track SkM concentrations over time in both humans and a large animal model. They collected plasma from orthopedic trauma patients at two key time points, admission and 6 weeks post-injury, to capture both the acute and recovery phases. These clinical data were supplemented with samples from pigs that underwent experimental muscle injury, allowing for controlled observation of the acute post-injury period. This dual-pronged approach, copyrighted by Wolters Kluwer Health, Inc. in 2026, aimed to systematically characterize the post-traumatic kinetics of SkM.

Clinical and Preclinical Evidence of Myosin Dynamics

The investigation into post-injury muscle protein levels yielded a consistent and counterintuitive pattern in both trauma patients and the animal model. In orthopedic trauma patients, plasma SkM levels were significantly lower at admission compared to the 6-week follow-up. This finding directly contradicts the expectation that acute, severe muscle damage would lead to a spike in circulating SkM. In stark contrast, plasma myoglobin, a well-established biomarker for muscle injury, followed the expected course: myoglobin levels were higher at admission and lower at 6 weeks. This divergent behavior was mirrored in the preclinical model, where pigs with experimental injuries also showed decreased plasma SkM and increased myoglobin at 24 hours post-injury. The opposing kinetics of these two muscle-derived proteins strongly suggested that the reduction in circulating SkM is not due to a lack of release from injured tissue but rather to a specific biological process that actively removes it from the plasma.

Direct Interaction with Fibrin: A Mechanism Uncovered

To identify the mechanism responsible for clearing skeletal muscle myosin (SkM) from circulation, the researchers performed a series of in vitro experiments. They used fluorescence imaging assays, which allow for direct visualization of molecular binding, to test whether SkM interacts with components of a blood clot. The functional consequences of this binding on clot stability were then assessed using turbidimetric assays, which measure clot density, and thromboelastography, a viscoelastic method that provides a comprehensive profile of clot formation, strength, and lysis. The investigation revealed that SkM bound directly to fibrin but, notably, did not bind to its precursor, fibrinogen. This demonstrates a specific affinity for the polymerized, structural component of the clot. The binding was robust, with an apparent dissociation constant (K d) of 0.18 μM, a value indicating a strong interaction. This sequestration was confirmed visually, as fluorescence imaging showed SkM incorporated throughout the fibrin mesh. Critically, this binding event was associated with a corresponding decrease in the level of SkM in the surrounding solution, providing a direct mechanistic explanation for the reduced plasma SkM levels seen in patients.

Impact on Clot Stability and Clinical Implications

The sequestration of skeletal muscle myosin (SkM) into a developing clot does more than simply remove it from circulation; it fundamentally alters the clot's properties. The study demonstrated that the presence of SkM within fibrin clots increased their resistance to fibrinolysis, making them more durable and difficult to break down. This finding provides a powerful, two-part explanation for observations in trauma patients. First, the direct binding of SkM to fibrin accounts for the paradoxically low circulating SkM levels after injury, as the protein is rapidly incorporated into clots at sites of vascular damage. Second, this process helps clarify the role of SkM in trauma-associated coagulopathy. By being drawn into the clot and simultaneously reinforcing it against lysis, SkM may contribute to the hypercoagulable state that can follow initial hemorrhage, potentially increasing risk for deep vein thrombosis or pulmonary embolism. This specific molecular interaction presents SkM as a potential biomarker for assessing thrombotic risk and may represent a future therapeutic target for modulating clot stability in severely injured patients.

References

1. Crispin P, Choi P, Gardiner EE. SkM‐ing information from traumatized tissue. Journal of Thrombosis and Haemostasis. 2022. doi:10.1111/jth.15721

2. Reed CR, Curry N, Juffermans NP, Neal MD. Hemostatic abnormalities after trauma resuscitation: challenges and strategies in caring for the critically injured patient. Annals of Intensive Care. 2025. doi:10.1186/s13613-025-01587-0

3. Coleman JR, Deguchi H, Deguchi TK, Cohen MJ, Moore EE, Griffin JH. Full-length plasma skeletal muscle myosin isoform deficiency is associated with coagulopathy in acutely injured patients.. Journal of thrombosis and haemostasis : JTH. 2022. doi:10.1111/jth.15695

4. Coleman JR, Moore EE, Zilberman‐Rudenko J, et al. Cardiac and Skeletal Muscle Myosin Exert Procoagulant Effects. Shock. 2019. doi:10.1097/shk.0000000000001426

5. Coleman JR, Moore EE, Zilberman-Rudenko J, et al. Cardiac and Skeletal Muscle Myosin Exert Procoagulant Effects.. Shock (Augusta, Ga.). 2019. doi:10.1097/SHK.0000000000001426