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

Matthew C Culkin; Priyanka Bele; Anastasia P Georges; Patricia Santos; Grace Niziolek; Lewis J Kaplan; Douglas H Smith; Jose L Pascual

doi:10.1007/s12028-024-01952-0

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

Neurocrit Care. 2024 Mar 5. doi: 10.1007/s12028-024-01952-0. Online ahead of print.

Authors

Matthew C Culkin^{1

2}, Priyanka Bele^{1

2}, Anastasia P Georges^{2

3}, Patricia Santos^{1

2}, Grace Niziolek¹, Lewis J Kaplan¹, Douglas H Smith², Jose L Pascual^{4

5}

Affiliations

¹ Division of Traumatology, Surgical Critical Care and Emergency Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, SICU Administration Office - 5 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, 19104, USA.
² Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Division of Traumatology, Surgical Critical Care and Emergency Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, SICU Administration Office - 5 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA, 19104, USA. jose.pascual@pennmedicine.upenn.edu.
⁵ Center for Brain Injury and Repair, Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jose.pascual@pennmedicine.upenn.edu.

PMID: 38443709
DOI: 10.1007/s12028-024-01952-0

Abstract

Background: Early posttraumatic brain injury (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 vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery.

Methods: CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60 mg/kg). At 48 h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test scores and animal weight changes at 24 h and 48 h after injury.

Results: I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24 h and 48 h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I + TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group.

Conclusions: Only higher TXA dosing definitively abrogates penumbral leukocyte 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 blunting of leukocyte-mediated penumbral cerebrovascular inflammation.

Keywords: Blood–brain barrier; Dosing; Leukocytes; Permeability; TBI; Tranexamic acid.