M. D. Johnson1, R. Veile1, L. Friend1, H. Goetzman1, T. Pritts1, C. Caldwell1, A. Makley1, M. Goodman1 1University Of Cincinnati,College Of Medicine,Cincinnati, OH, USA
Introduction: Posttraumatic coagulopathy and inflammation can exacerbate secondary cerebral damage after traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown clinically to reduce mortality in hemorrhaging and head injured trauma patients, and has the potential to mitigate secondary brain injury with its reported anti-fibrinolytic and anti-inflammatory properties. We hypothesized that TXA would improve posttraumatic coagulation and inflammation in a murine model of TBI alone and in a combined injury model of TBI and hemorrhage (TBI/H).
Methods: An established murine weight-drop model was used to induce a moderate TBI. Mice were administered intraperitoneal injections of 10mg/kg TXA or equivalent volume of saline 10 minutes after injury. An additional group of mice was subjected to TBI followed by hemorrhagic shock using a pressure-controlled model. TBI/H mice were given intraperitoneal injections of TXA or saline during resuscitation. Blood was collected at intervals after injury to assess coagulation by thromboelastometry (ROTEM®) and inflammation by Multiplex cytokine analysis. Soluble P-selectin, a biomarker of platelet activation, and serum neuron specific enolase, a biomarker of cerebral injury, were also measured at intervals. Brain tissue was analyzed for inflammatory changes by Mutiplex ELISA and splenic tissue was collected for splenic cell population assessment by flow cytometry.
Results: There were no coagulation, serum or cerebral cytokine, P-selectin, or neuron specific enolase differences between mice treated with TXA or saline after TBI. Following the addition of hemorrhagic shock and resuscitation to TBI, TXA administration still did not affect coagulation parameters, systemic or cerebral inflammation, or platelet activation, as compared to saline alone. At 24 hours post-TBI, mice given TXA demonstrated lower splenic total cell counts (93.6 vs. 130.1, TXA vs. saline, p = 0.01), central memory CD8 (0.2 v. 0.3, TXA vs. saline, p = 0.001), effector CD8 (0.04 vs. 0.1, TXA vs. saline, p = 0.006), B cell (48.5 vs. 72.9, TXA vs. saline, p = 0.001), and increased naïve CD4 (14.6 vs. 11.5, TXA vs. saline, p = 0.04) cell populations. By contrast, TXA did not affect splenic leukocyte populations after combined TBI/H
Conclusion: Despite clinical data suggesting a mortality benefit, TXA did not modulate the coagulation effects, inflammatory changes, or biomarker generation in either the TBI or TBI/hemorrhage murine models. Administration of TXA following TBI alone altered splenic leukocyte populations, which may contribute to a change in posttraumatic immune status. Future studies should be done to investigate the role of TXA in the development of posttraumatic immunosuppression and risk of nosocomial infections.