Tranexamic acid bolus plus drip paradoxically increases complement activation: A PATCH trial secondary study.

BACKGROUND

Previous trials have found a modest survival benefit from tranexamic acid (TXA) administration after polytrauma, but the early discrimination of the survival benefit observed suggests that the clinical effect of TXA may be multifactorial, not solely through bleeding reduction. Plasmin is known to directly cleave and activate complement proteins, and TXA can inhibit plasmin generation. We hypothesized that polytrauma patients who received TXA would demonstrate less complement activation compared with placebo controls.

METHODS

Patient plasma was obtained from 53 polytrauma patients enrolled in the Pre-hospital Antifibrinolytics for Traumatic Coagulopathy and Hemorrhage (PATCH) trial of prehospital TXA (1 g bolus plus 1 g drip over 8 hours) versus placebo in the emergency department, at 8 hours, and at 24 hours after admission. Complement activation and regulatory markers were measured via multiplex, and plasmin-antiplasmin levels via enzyme-linked immunosorbent assay. Pairwise comparisons of analytes between TXA and placebo at each time point were performed with significance set at p  < 0.05.

RESULTS

The median age was 41.0 years (interquartile range, 28-57 years), 69.8% were male, the median Injury Severity Score was 38.0 (27.0-50.0), and all included patients were blunt mechanism. At early time points (emergency department and 8 hours), patients who received TXA did not demonstrate a reduction in C3a, C5a, sC5b-9, or plasmin-antiplasmin relative to placebo. At 24 hours, there was a significant increase in both C3a (274.0 vs. 416.6 ng/mL, p  = 0.0024) and C5a (9.4 vs. 11.6 ng/mL, p  = 0.0462) in the TXA group.

CONCLUSION

A 1 g bolus plus 1 g drip of TXA paradoxically increased complement activation at 24 hours in the TXA group. These findings support that TXA is essential in the inflammatory pathway after trauma. The delayed increase in complement may reflect the timing of TXA dosing and the shift to urokinase as the main plasminogen activator at later time points after injury. These results raise important questions about the optimal dosing of TXA in trauma patients. ( J Trauma Acute Care Surg . 2026;100: 747-753. Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.).

LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.