Tranexamic Acid and Systemic Complement Activation in Patients with Traumatic Brain Injury

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of trauma-related death. A prehospital 2-g bolus of tranexamic acid (TXA) has shown mortality benefit but no reduction in brain bleed size on cross-sectional imaging, suggesting an alternative mechanism may explain its effect. Plasmin activates complement proteins C3 and C5, and complement activation is linked to worse outcomes in animal TBI models. STUDY DESIGN: A total of 40 adult trauma patients with imaging-confirmed TBI were randomly assigned to the TXA (2-g bolus) group or the placebo group in a prehospital trial. Plasma was analyzed at presentation (emergency department [ED]), 6 hours, and 24 hours. Complement activation and regulatory markers, coagulation or fibrinolysis parameters, and plasmin generation were assessed using complement multiplex assays, ELISA, and clinical laboratory testing. Pairwise comparisons were made using ANOVA, with significance set at a p value of <0.05. RESULTS: Patients were mostly men (85%) and of White race (72.5%), with a median age of 36.5 years. TXA significantly reduced soluble C5b-9 levels at ED arrival (191.5 ± 143.4 ng/mL TXA vs 333.9 ± 404.4 ng/mL placebo, p = 0.04) and C5a at 24 hours. Factor H levels were higher in the TXA group at ED arrival (226.2 ± 103.6 ng/mL TXA vs 186.0 ± 38.0 ng/mL placebo, p = 0.03). D-dimer levels were significantly lower in the TXA group at 6 hours (4.8 ± 5.1 µg/mL TXA vs 8.4 ± 7.5 µg/mL placebo, p = 0.04). Plasmin-antiplasmin levels and thromboelastography lysis at 30 minutes showed no differences. CONCLUSIONS: A prehospital 2-g TXA bolus appears to significantly reduce complement activation and preserve Factor H, a key complement regulatory protein, suggesting benefit of TXA may involve complement modulation. TXA reduced D-dimer, a downstream product of plasmin activation, indicating that complement modulation could be due to a plasmin-mediated process. Further studies are needed to determine whether this mechanism is plasmin-mediated and applicable to other dosing regimens and non-TBI trauma populations.