What is the evidence behind TXA in Trauma?

The tissue injury from trauma is far more extensive than that of an elective surgery. Imagine the damage from the blast of an improvised explosive device or the polytrauma after a high-speed car crash compared to the precise incisions of a surgeon’s scalpel in the controlled setting of the operating room. The traumatic injury is uncontrolled, treatment is delayed, and often there is concurrent hypothermia and hypovolemia. The tissue injury in and of itself causes an early endogenous coagulopathy, which at a cellular level is the result of protein C activation, glycocalyx disruption, platelet exhaustion, and fibrinogen depletion. Elective surgery patients are usually kept normotensive and normovolemic through crystalloid and colloid administration. Coagulopathies are rare and generally are secondary to a hemodilutional effect from receiving large volumes of plasma-poor infusions rather than mediated from tissue injury itself^2,7,8,9.

There are no large studies comparing markers of coagulopathy in patients with traumatic vs. atraumatic bleeding. A small (n=40) prospective study looked at anti-thrombin 3 levels in three cohorts of patients.  Group 1 was comprised of elective orthopedic surgeries; their patients did not have a significant decrease in anti-thrombin 3 levels.  Group 2 had moderate-severe orthopedic injuries not requiring blood transfusions and also did not have significant decrease in anti-thrombin 3 levels.  Group 3 patients had severe extremity trauma requiring blood transfusions.  Their anti-thrombin 3 levels dropped significantly and had delayed clotting times, representing a hypercoagulable state¹⁰.

Group 1

Group 2

Group 3

In conclusion, the etiology of traumatic and atraumatic coagulopathies differs however there is overlap. Traumatic coagulopathy etiologies are multifactorial, initially resulting from tissue injury, but further exacerbated by hypovolemia, hemodilution, hypothermia, and acidosis. The early administration of TXA is thought to mitigate the effects of tissue injury as well as blood loss, reducing the severity of the coagulopathy. Atraumatic coagulopathies are primarily secondary to dilution as the tissue injury alone is unlikely to be severe enough to result in a coagulopathy. Both traumatic and atraumatic coagulopathies result in the body’s normal clotting/fibrinolysis mechanism becoming overburdened leading to a consumptive coagulation. Despite the different etiologies of the coagulopathy, there is abundant evidence that TXA is an effective treatment in both.

In the MATTERs study, there were statistically significant increased rates of DVT and PE in the TXA group (2.4% vs. 0.2% increased rate of DVT, 2.4% vs. 0.3% increased rate of PE), however after adjusting for the severity of injury, there was no significant incidence of DVT or PE³. Moreover, previous studies prior to the use of TXA have also shown military trauma cohorts have significantly elevated DVT and PE rates (5% to 26%) as compared to civilian trauma cohorts (0.42%). In a more recent military study, the researchers did a retrospective chart review of combat patients who went on to receive limb reconstruction or flap repair and analyzed the incidents of venothrombolic events and flap-related thrombosis in TXA and non-TXA cohorts. They found no significant difference in thromboembolic events or flap complications between these groups¹¹. In a massive systemic review of 252 RCTs looking at antifibrinolytic drugs (mostly TXA) in elective surgery, there was no significant increase in thromboembolic events¹². These results were mirrored in CRASH-2, where there was no significant difference in fatal or non-fatal thromboembolic events between the TXA and the placebo group³. In conclusion, our best current data suggests TXA doe not increase risk of thromboembolic events.

Part of the elegance of CRASH-2 was that a simple intervention (giving TXA) produced a meaningful survival benefit to patients treated in locations all over the world (excluding the US for liability and insurance reasons), many of which lacked advanced trauma care. Some experts criticize CRASH-2 for having overly broad inclusion criteria (hypotension or tachycardia + clinical judgement) that included many patients who were unlikely to have ATC, no trauma severity index score recorded, and relatively low numbers of patients requiring transfusion or surgery. Despite the potential overrepresentation of lower acuity trauma patients, they were still able to demonstrate that TXA improves mortality in a well- designed and inclusive study. In the MATTERs study, all patients received at least 1 blood transfusion, which implies a sicker population, and may explain their 6.5% absolute mortality reduction compared to 1.5% in CRASH-2. Currently, our best available data comes from these 2 large RCTs.  The evidence for TXA in trauma is compelling, however, the naysayers will say nay until we have an RCT in a patient population and practice setting similar to that of our home institutions.  This brings us to… drum roll…… the PATCH study currently underway in Australia and New Zealand. Stay tuned. Until then, the best currently available data suggests that TXA has minimal side effects while still conferring survival benefits in a broad swath of clinical settings.