Impact of soluble thrombomodulin and activated protein C on dynamic hemostatic function in trauma: a focus on thrombin generation and clot lysis

Trauma-induced coagulopathy describes a complex set of coagulation changes affecting severely injured patients. The thrombomodulin-protein C axis is believed to be central to the evolution of trauma-induced coagulopathy. Soluble thrombomodulin (sTM) levels are elevated after injury. Our objectives were to explore whether sTM (at concentrations found in patients after injury) plays an important role in trauma-induced coagulopathy, and specifically to evaluate the effects of sTM and activated protein C (APC) on thrombin generation (TG) and clot lysis time (CLT). Plasma from healthy volunteers was spiked with rising concentrations of sTM and APC and the effects on TG and CLT were analyzed. Plasma samples from a cohort of trauma patients were evaluated using TG and CLT, and results correlated to clinical parameters and factor VIII, factor V, APC, sTM and fibrinolytic measures. Increasing sTM concentrations in volunteer plasma led to reductions in endogenous thrombin potential and prolongation of 50% CLT, in a dose-dependent manner. No effect on TG or CLT was seen with rising APC concentrations. In 91 trauma patients, higher sTM values were associated with greater, rather than reduced, endogenous thrombin potential (median 1,483 vs. 1,681 nM/min) and longer 50% CLT (41.9 vs. 54.0 mins). In conclusion, sTM concentrations, across ranges found after trauma, affect both TG and 50% CLT, unlike APC. Despite increased circulating sTM levels, the overriding dynamic coagulation effects seen after injury are: (i) accelerated TG and (ii) increased rates of fibrinolysis. We found no evidence for sTM as the major determinant of the coagulation changes seen in early trauma-induced coagulopathy.