Trauma and
hemorrhagic shock can lead to acute traumatic coagulopathy (ATC) that is not fully reversed by prehospital
resuscitation as simulated with a limited volume of fresh whole blood (FWB) in a rat model.
Tranexamic Acid (TXA) is used as an anti-
fibrinolytic agent to reduce surgical
bleeding if administered prior to or during surgery, and to improve survival in
trauma if given early after
trauma. It is not clear from the existing clinical literature whether TXA has the same mechanism of action in both settings. This study sought to explore the molecular mechanisms of TXA activity in
trauma and determine whether administration of TXA as a supplement to FWB
resuscitation could attenuate the established ATC in a rat model simulating prehospital
resuscitation of
polytrauma and
hemorrhagic shock. In a parallel in-vitro study, the effects on clotting assays of adding
plasmin at varying doses along with either simultaneous addition of TXA or pre-incubation with TXA were measured, and the results suggested that maximum anti-fibrinolytic effect of TXA on
plasmin-induced fibrinolysis required pre-incubation of TXA and
plasmin prior to clot initiation. In the rat model, ATC was induced by
polytrauma followed by 40%
hemorrhage. One hour after
trauma, the rats were resuscitated with FWB collected from donor rats. Vehicle or TXA (10mg/kg) was given as bolus either before
trauma (TXA-BT), or 45min after
trauma prior to
resuscitation (TXA-AT). The TXA-BT group was included to contrast the coagulation effects of TXA when used as it is in elective surgery vs. what is actually feasible in real
trauma patients (TXA-AT group). A single dose of TXA prior to
trauma significantly delayed the onset of ATC from 30min to 120min after
trauma as measured by a rise in prothrombin time (PT). The plasma
d-dimer as well as
plasminogen/
fibrinogen ratio in traumatized liver of TXA-BT were significantly lower as compared to vehicle and TXA-AT. Wet/dry weight ratio and leukocytes infiltration of lungs were significantly decreased only if TXA was administrated later, prior to
resuscitation (TXA-AT). In conclusion: Limited prehospital
trauma resuscitation that includes FWB and TXA may not correct established systemic ATC, but rather may improve overall outcomes of
resuscitation by attenuation of
acute lung injury. By contrast, TXA given prior to
trauma reduced levels of fibrinolysis at the site of tissue injury and circulatory
d-dimer, and delayed development of coagulopathy independent of reduction of
fibrinogen levels following
trauma. These findings highlight the importance of early administration of TXA in
trauma, and suggest that further optimization of dosing protocols in
trauma to exploit TXA's various sites and modes of action may further improve patient outcomes.