Early posttraumatic brain injury tranexamic acid prevents blood-brain barrier hyperpermeability and improves surrogates of neuroclinical recovery

Abstract

BACKGROUND Tranexamic acid (TXA) given early, but not late, after traumatic brain injury (TBI) appears to improve survival. This may be partly related to TXA-driven profibrinolysis and increased leukocyte (LEU)-mediated inflammation when administered late post-injury. We hypothesized that early TXA (1 hour post-TBI), blunts penumbral, blood-brain barrier (BBB) leukocyte-endothelial cell (LEU-EC) interactions and microvascular permeability, in vivo when compared with late administration (24 hours post-TBI) METHODS CD1 male mice (n = 35) were randomized to severe TBI (injury by controlled cortical impact; injury: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy followed by intravenous saline (placebo) at 1 hour, or TXA (30 mg/kg) at 1 hour or 24 hours. At 48 hours, in vivo pial intravital microscopy visualized live penumbral LEU-EC interactions and BBB microvascular fluorescent albumin leakage. Neuroclinical recovery was assessed by the Garcia Neurological Test (motor, sensory, reflex, and balance assessments) and body weight loss recovery at 1 and 2 days after injury. Analysis of variance with Bonferroni correction assessed intergroup differences (p < 0.05). RESULTS One-hour, but not 24-hour, TXA improved Garcia Neurological Test performance on day 1 post-TBI compared with placebo. Both 1 hour and 24 hours TXA similarly improved day 1 weight loss recovery, but only 1 hour TXA significantly improved weight loss recovery on day 2 compared with placebo (p = 0.04). No intergroup differences were found in LEU rolling or adhesion between injured animal groups. Compared with untreated injured animals, only TXA at 1 hour reduced BBB permeability. CONCLUSION Only early post-TBI TXA consistently improves murine neurological recovery. Tranexamic acid preserves BBB integrity but only when administered early. This effect appears independent of LEU-EC interactions and demonstrates a time-sensitive effect that supports only early TXA administration.