In this murine model of trauma and shock, we showed that short duration of shock is associated with hypocoagulability compared to longer duration of shock.
This is in line with previous research showing that hypocoagulability is present as early as minutes after traumatic injury.2, 16 Both the severity of tissue injury as well as the presence of shock worsens TIC.2 Acidosis impairs fibrin polymerisation and clot strength in vitro and in vivo.17, 18 Furthermore, shock and hypoperfusion are major contributors for the release of tissue plasminogen activator (tPA), converting plasminogen into plasmin, resulting in hyperfibrinolysis after trauma.19, 20 In our model, mean values of maximum lysis and D-dimer levels did not significantly differ between groups. This could be explained by the different fibrinolytic system in mice compared to humans (i.e. shorter tPA half-life, clots are more resistant to endogenous breakdown).21
Our main finding, that persistence of shock reduces hypocoagulablity, was contrary to our hypothesis and may seem counterintuitive, since hypoperfusion and acidosis, the driving forces behind the hypocoagulable state, are still present. However, studies also show that minimal amounts of coagulation factors are required for relatively normal thrombin generation.22 In fact, it is not uncommon that thrombin generation is increased after trauma.10 In addition, endothelial dysfunction, increasing presence of circulating procoagulant platelets and exhaustion of anti-coagulant pathways may explain the shift we observe in TIC characteristics.11, 23, 24 The observed effect could also be inflammation-induced, as pro-inflammatory pathways are tightly linked with hypercoagulability and thrombosis.25, 26
Our results add to the existing literature by showing that a reduction in hypocoagulability can occur early after trauma and is influenced by shock duration. Of note, the increased clotting amplitude after 90 minutes of shock was driven by endogenous responses, as animals did not receive treatment.
Our findings of the effect of shock duration on TIC characteristics may have several implications. Our results underline the rationale of early aggressive treatment of TIC, as shown in trials investing early transfusion of blood components, as well as tranexamic acid.27, 28 With persistence of shock, targeting dysfunctional platelets and immunomodulation may convey benefits for the severely injured trauma patient. However, these aspects of trauma-induced shock and coagulopathy need further explorations.
There are limitations to this study. Our model of traumatic shock consists of traumatic injury in combination with controlled blood withdraw. Although our abdominal trauma results in bleeding, it is unlikely that mice continue to bleed excessively during the shock period. This means that after the blood withdraws a relatively stable state ensues, which differs somewhat form the trauma patient with uncontrolled bleeding. Also, since more mice died after 90min shock compared to 30min shock, survival bias might explain part of the observed effect. Lastly, we have not dissected the precise mechanistic coagulation pathways explaining the difference in maximum clot firmness in the ROTEM. We can therefore only speculate about the mechanisms.
In conclusion, hypocoagulability is part of early endogenous TIC and alters with prolonged shock duration. More research is needed to unravel the mechanisms behind this compensation in order to develop more targeted treatments for trauma-induced shock.