Tranexamic Acid in Severe Traumatic Hemorrhage

On a sunny afternoon you are dispatched to a high-speed motor vehicle crash. You find an alert, belted driver, 30-something years old, trapped in the cabin with significant intrusion. He has good distal pulses and equal breath sounds, and his initial vital signs are heart rate 118, blood pressure 124/76, respiratory rate 27, and O2 98% on room air. 

The driver is extricated and brought to the ambulance for secondary evaluation. He becomes slightly confused, with a heart rate of 135 and BP of 92/55. After ruling out other time-critical pathologies, you identify that the likely cause of his worsening vital signs is worsening hemorrhagic shock. The solution: rapid transport to an emergency department with a trauma surgeon. En route you wonder if you can do anything else to help this patient.

Few scenarios leave prehospital providers feeling as helpless as watching an initially alert and oriented patient decline from ongoing hemorrhage. Road injury is the 10th-leading cause of death worldwide and one of many mechanisms with a potential for fatal hemorrhage that EMS crews encounter.1Clearly rapid transport is required for the patient with significant hemorrhage. In the meantime only a few treatment strategies exist in the prehospital environment: direct pressure, tourniquet application, and possibly permissive hypotension. 

Could giving a medication to limit blood loss by stopping clot breakdown (fibrinolysis) increase the patient’s chance of survival?

A third of trauma patients suffer from an imbalance between clot formation and breakdown associated with increased mortality known as trauma-induced coagulopathy(TIC).2Hyperfibrinolysis (excessive clot breakdown) is associated with a greater need for massive transfusion and a fourfold increase in mortality.3,4Antifibrinolytic medications have long been hypothesized to limit blood loss and increase survival in bleeding patients. The most widely researched antifibrinolytic medications, aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA), were studied for use in adults undergoing nonurgent surgery.5All three agents were shown to be effective in limiting blood loss without any increase in thrombotic events such as myocardial infarction or stroke. TXA was the most effective overall, with a relative risk for RBC transfusion of 61% compared to placebo.5 

TXA is thought to work by inhibiting both fibrinolysis and systemic inflammation. It blocks binding sites on both plasminogen and its active form, plasmin (also a pro-inflammatory molecule), which prevents them from binding to and cleaving fibrin. Patients given TXA following cardiac surgery have also been shown to have reduced inflammatory markers, which might play a role in preventing downstream effects of organ failure related to systemic inflammation.6

Literature

The two major studies evaluating acute adult trauma TXA use are the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial and the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation study (MATTERs).7,8Both studies saw a significant decrease in 28-day mortality among patients who received TXA. 

CRASH-2 was a multinational randomized and controlled blinded trial of 20,211 adults who sustained traumatic injuries. The TXA group had a statistically significant lower 28-day mortality of 14.5% compared to 16% in the placebo group. MATTERs was a retrospective cohort study evaluating 896 severely injured patients requiring a unit or more of pRBCs within 24 hours from a single military hospital in southern Afghanistan. The TXA group had a lower unadjusted 28-day mortality of 17.4% vs. 23.9%. Among patients requiring massive transfusion (more than 10 units of blood products in 24 hours), the difference was even greater: 14.4% vs. 28.1%. 

Because mortality in trauma was decreased with TXA, further analyses sought to understand which variables could help identify the patients who could benefit most. One potential explanation of the mortality difference between MATTERs and CRASH-2 (where patients randomized to receive TXA got it sometime within 8 hours) is that in the MATTERs study every patient received TXA within an hour of injury, vs. 8 hours in CRASH-2. This suggests there might be a time-dependent benefit. 

Analysis of the CRASH-2 data compared the effect of several variables where bleeding was the primary cause and showed mortality was linked to quickness of administration.9The relative risk of bleeding death for patients receiving TXA within one hour of injury was 68% compared to placebo, 79% if given within 1–3 hours, and 144% (an actual increase in mortality compared to placebo) when given from 3–8 hours. This suggests there may be a window (three hours) beyond which the opportunity to give TXA is missed. 

We’ve accepted that TXA has a place in the operating room and emergency department. It is only reasonable to suppose this time-dependent intervention belongs in the arsenal of prehospital providers. What is now needed now is a prehospital trial of TXA versus placebo in severely injured adult trauma patients.

References

1. World Health Organization. The top 10 causes of death, https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death.

2. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma,2003; 54(6): 1,127–30.

3. Kutcher ME, Cripps MW, McCreery RC, et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma Acute Care Surg,2012; 73(1): 87–93.

4. Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med,2012; 20: 15.

5. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev,2011; (3): 1,886.

6. Jiménez JJ, Iribarren JL, Brouard M, et al. Safety and effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial. J Cardiothorac Surg, 2011; 6: 138.

7. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet, 2010; 376(9,734): 23–32.

8. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg, 2012; 147(2): 113–9.

9. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet, 2011; 377(9,771): 1,096–101.

Gabriel P. Gomez, MD, bio TK.

Hawnwan Philip Moy, MD, is an assistant medical director of the St. Louis City Fire Department and emergency medicine clinical instructor and core faculty in the EMS Section of the Division of Emergency Medicine at Washington University in St. Louis.