Mechanistic insights and novel treatments for trauma-induced coagulopathy

Bleeding after trauma is a leading cause of mortality worldwide and is exacerbated by trauma-induced coagulopathy (TIC). Early on, TIC is characterised by platelet dysfunction, coagulation factor depletion and hyperfibrinolysis. Despite its clinical importance, the pathophysiology of TIC is not fully understood, and effective treatment options are limited. Therefore, we aimed to investigate the mechanisms underlying TIC and explore novel treatments using a translational approach.
First, we studied the effect of shock duration on TIC, using a murine trauma model. Next, we reviewed the mechanisms and treatment options for trauma-induced platelet dysfunction. Using an experimental model of trauma and shock, we explored the relationship between high mobility group box 1 (HMGB1) and TIC. We investigated whether inhibition of HMGB1 would improve platelet dysfunction and TIC.
Reduced coagulation factor activity is one of the key features of TIC. Previously it was shown that Factor V activity is most severely depleted. In an international cohort of trauma patients, we explored the relationship between Factor V activity and mortality. Next, we used an in vitro model of TIC to investigate whether supplementing FV(a) would improve coagulation.
TIC with hyperfibrinolysis has the highest mortality when compared to other TIC phenotypes. The mechanisms are however incompletely understood. In the final part of this thesis, we studied the effect of ADAMTS13 degradation in hyperfibrinolytic trauma patients and explored whether ADAMTS13 has a causal role in hyperfibrinolysis. In this study, we combined clinical data from severely injured trauma patients, with a mechanistic in vitro study. These results were further supported in an experimental trauma model, using ADAMTS13 knock-out mice.