Tranexamic Acid and Systemic Complement Activation in Traumatic Brain Injury Patients.
Journal of the American College of Surgeons · 2025-08-29 · Randomised trial
Abstract
INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of trauma-related death. A pre-hospital 2-gram 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. METHODS: 40 adult trauma patients with imaging-confirmed TBI, randomized to TXA (2-gram bolus) or placebo in a pre-hospital trial. Plasma was analyzed at presentation (ED), 6 hours, and 24 hours. Complement activation and regulatory markers, coagulation/fibrinolysis parameters, and plasmin generation were assessed using complement multiplex, ELISA, and clinical laboratory testing. Pairwise comparisons were made using ANOVA with significance set at p<0.05. RESULTS: Patients were mostly male (85%) and white (72.5%), with a median age of 36.5 years. TXA significantly reduced sC5b-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 LY30 showed no differences. CONCLUSIONS: A pre-hospital 2-gram TXA bolus appears to significantly reduce complement activation and preserve Factor H, a key complement regulatory protein, suggesting TXA's benefit may involve complement modulation. TXA reduced D-dimer, a downstream product of plasmin activation, indicating complement modulation could be due to a plasmin-mediated process. Further studies are needed to determine if this mechanism is plasmin-mediated and applicable to other dosing regimens and non-TBI trauma populations.