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

Abstract

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. 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. 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. 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.