Impact of Tranexamic Acid on Coagulation and Inflammation in Murine Models of TBI and Hemorrhage

Abstract 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 ELISA cytokine analysis. Soluble P-selectin, a biomarker of platelet activation, and serum neuron specific enolase, a biomarker of cerebral injury, were measured at intervals. Brain homogenates were analyzed for inflammatory changes by Multiplex 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 central memory CD8, effector CD8, B cell, and increased naïve CD4 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 coagulation, inflammation, or biomarker generation in either the TBI or TBI/hemorrhage murine models. Administration of TXA following TBI 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 posttraumat