Dose Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood Brain Barrier Permeability Following Traumatic Brain Injury: An In-vivo Murine Study

Abstract

Abstract Background. Early post-TBI Tranexamic acid (TXA) may reduce blood-brain-barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose dependent reduction of in vivopenumbral leukocyte (LEU) mobilization, BBB microvascular permeability, and enhanced neuroclinical recovery. Study Design. CD1 male mice (n=40) were randomized to TBI by controlled cortical impact (Injury, I) or sham craniotomy (S), followed by IV bolus of either saline (placebo, P) or TXA (15, 30, or 60mg/kg). At 48h, in-vivo pial intravital microscopy (IVM) visualized live penumbral BBB microvascular LEUs and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test (GNT) scores and animal weight changes at 24 and 48h after injury. Results.I+TXA60 reduced live penumbral LEU rolling compared to I+P (p<0.001) and both lower TXA doses (p=0.017 vs. I+TXA15, p=0.012 vs. I+TXA30). LEU adhesion was infrequent and similar across groups. Only I+TXA60 significantly reduced BBB permeability compared to I+P (p=0.004). All TXA doses improved GNT scores relative to I+P at both 24 and 48h (p<0.001 vs. I+P for all at both time points). Mean 24-hour body weight loss was greatest in I+P (-8.7±1.3%) and lowest in TXA15 (-4.4±1.0%, p=0.051 vs. I+P). Conclusion. Only higher TXA dosing definitively abrogates penumbral LEU mobilization, preserving BBB integrity post-TBI. Some neuroclinical recovery is observed even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to LEU-mediated penumbral cerebrovascular inflammation blunting.