Tissue factor release following traumatic brain injury drives thrombin generation

Background: Traumatic brain injury (TBI) results in neurovascular damage that initiates intrinsic mechanisms of hypercoagulation, which can contribute to the development of life-threatening complications, such as coagulopathy and delayed thrombosis. Clinical studies have hypothesized that tissue factor (TF) induces hypercoagulability after TBI; however, none have directly shown this relationship. Objectives: In the current study, we took a stepwise approach to understand what factors are driving thrombin generation following experimental TBI. Methods: We employed the contusion-producing controlled cortical impact (CCI) model and the diffuse closed head injury (CHI) model to investigate these mechanisms as a function of injury severity and modality. Whole blood was collected at 6 hours and 24 hours after injury, and platelet-poor plasma was used to measure thrombin generation and extracellular vesicle (EV) TF. Results: We found that plasma thrombin generation, dependent on TF present in the plasma, was greater in CCI-injured animals compared to sham at both 6 hours (120.4 +/- 36.9 vs 0.0 +/- 0.0 nM*min endogenous thrombin potential) and 24 hours (131.0 +/- 34.0 vs 32.1 +/- 20.6 nM*min) after injury. This was accompanied by a significant increase in EV TF at 24 hours (328.6 +/- 62.1 vs 167.7 +/- 20.8 fM) after CCI. Further, EV TF is also increased at 6 hours (126.6 +/- 17.1 vs 63.3 +/- 14.4 fM) but not 24 hours following CHI. Conclusion: TF-mediated thrombin generation is time-dependent after injury and TF increases resolve earlier following CHI as compared to CCI. Taken together, these data support a TF-mediated pathway of thrombin generation after TBI and pinpoint TF as a major player in TBI-induced coagulopathy.