Impact of tranexamic acid on coagulation and inflammation in murine models of traumatic brain injury and hemorrhage

Abstract

Background: 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 antifibrinolytic and antiinflammatory 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 10 mg/kg TXA or equivalent volume of saline 10 min 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 rotational 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 measured at intervals. Brain homogenates were analyzed for inflammatory changes by Multiplex enzyme-linked immunosorbent assay, 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. After 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 with saline alone. At 24 hours after TBI, mice given TXA demonstrated lower splenic total cell counts central memory CD8, effector CD8, B cell, and increased naive CD4 cell populations. By contrast, TXA did not affect splenic leukocyte populations after combined TBI/H.

Conclusions: Despite clinical data suggesting a mortality benefit, TXA did not modulate coagulation, inflammation, or biomarker generation in either the TBI or TBI/H murine models. Administration of TXA after 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 posttraumatic immunosuppression and risk of nosocomial infections.