A 19 year old man experienced a head on collision as the driver of a car. He suffered significant lower limb open fractures, pelvic fractures, lung injuries and a small subarachnoid bleed. Initial management was performed in ED and included oxygen, IV access and fluid, lower limb and spine immobilisation, and analgesia. He underwent a trauma series CT scan, which identified the various injuries given above. At no point was his level of consciousness a concern, and he maintained his own patent airway throughout. He did not show signs of haemodynamic instability or evidence of life threatening haemorrhage. Tranexamic acid (TXA) was not given.
What is the evidence for using tranexamic acid in trauma?
Tranexamic acid (TXA) is a synthetic derivative of the lysine amino acid, and acts by antagonising the lysine binding site on plasminogen molecules. This has the end result of inhibiting fibrinolysis through reduced plasmin formation.
Along with aprotinin, TXA has been greatly studied in the elective surgery setting, especially cardiac surgery (1). Both have been shown to reduce bleeding and the need for blood transfusion, although aprotinin has been withdrawn from sale after concerns about its side effects (specifically thrombotic events and renal failure).
From this, the use of TXA has been further investigated in the context of trauma. This has been motivated by several factors: trauma is second only to HIV/AIDS as the leading cause of death of young adults worldwide; haemorrhage accounts for up to half of traumatic deaths in certain areas; blood transfusion is inherently hazardous and not immediately available in developing regions; and TXA offers a low risk, low cost intervention.
The multi-centre, multi-national CRASH-2 trial (2) aimed to investigate this intervention with in-hospital mortality within 4 weeks as the primary outcome. The relative risk was found to be 0.91 (CI 0.85 – 0.97, p = 0.0035) of death in the TXA group compared to placebo. But, interestingly, there was not a significant difference in transfusion requirement. So, TXA did not stop or clinically reduce the bleeding, but it did reduce mortality. A theory suggested (3) highlights plasmin’s role in inflammation, and the antiinflammatory effect that TXA may therefore have.
Also, the CRASH-2 trial had a very specific administration protocol for TXA: 1g over 10 minutes, followed by a further 1g over 8 hours. This 2-gram loading regime effectively blocks fibrinolysis. Extrapolation to multi-dose regimes is not possible from these data. Pharmacokinetic data4 for TXA demonstrates an elimination half-life of approximately 2 hours, with a 1g IV dose effectively being renally cleared within 8 hours. This would support the practice of administering 1g TDS, but this may not correlate to clinical efficacy. Interestingly, the follow-up analysis (5) to CRASH-2 demonstrated that mortality due to bleeding was only reduced if TXA was given with 3 hours of traumatic injury. Beyond this time limit, mortality actually increased. A possible theory (6) is that TXA prevents initiation of the fibrinolysis cascade, but does not halt it once established. Through an unidentified effect, it may cause harm if given late.
In summary, haemorrhage caused by acute trauma or surgery that will initiate excessive fibrinolysis can be reduced with early tranexamic acid, but late bleeding due to established fibrinolysis, coagulopathies of other causes, or physical vascular pathologies may not benefit. No other supporting evidence relevant to this particular case could be found through searching Medline with related MeSH terms and text words.
1 Henry DA, et al. Anti-fibrinolytic use for minimising perioperative allogenic blood transfusion. Cochrane Database of Systematic Reviews 2011, Issue 3, Art. No.: CD001886. DOI: 10.1002/14651858.CD001886.pub4.
2 The CRASH-2 Trial Collaborators. 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. The Lancet 2010; 376: 23-32. Doi:10.1016/S0140-6736(10)60835-5.
3 Levy J. Antifibrinolytic therapy: new data and new concepts. The Lancet 2010; 376: 3-4. Doi:10.1016/ S0140-6736(10)60939-7.
4 Pilbrant Å, et al. Pharmacokinetics and Bioavailability of Tranexamic Acid. European Journal of Clinical Pharmacology 1981; 20(1): 65-72.
5 The CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. The Lancet 2011; 377: 1096-1101. Doi:10.1016/S0140-6736(11)60278-X.
6 Gruen R, Mitra B. Tranexamic acid for trauma. The Lancet 2011; 377: 1052-1054. Doi:10.1016/S0140-6736(11)60396-6.