Introduction

  • Trauma is the leading cause of death in individuals up to 45 years old and the fourth leading cause of death overall for all ages.
  • Uncontrolled hemorrhage is the leading cause of early mortality in major trauma.
  • Trauma-associated hemorrhagic death occurs as an effect of uncontrolled bleeding and trauma-induced coagulopathy.
  • Tranexamic acid is an antifibrinolytic medication that works by forming a reversible complex that displaces plasminogen from fibrin, resulting in inhibition of fibrinolysis.
  • Tranexamic acid is readily available, simple to administer, and relatively inexpensive, with minimal side effects.

Clinical Detail

Pharmacology

ParameterTranexamic Acid
Dose
  • Loading dose: 1 g over 10 minutes, started within 3 hours of injury
    • 2 g via slow IV push*
  • Maintenance: 1 g over the next 8 hours as a continuous infusion
Administration
  • Loading dose: administer undiluted
  • Max rate: 100 mg/minute
  • For continuous IV infusions: dilute with compatible solutions and administer at a rate not to exceed 100 mg/minute
PK/PD
  • Distribution: Vd (IV) 9 to 12 L
  • Protein binding: ~3%, primarily to plasminogen
  • Half-life elimination: ~2 hours
  • Excretion: urine (>95% as unchanged drug)
Adverse EffectsHypersensitivity reactions, ocular effects, seizures and myoclonus, thromboembolic effects, abdominal pain, headache, back pain

*Emerging data from pre-hospital and military use.

Evidence

Overview of Evidence

Author, yearDesign / sample sizeIntervention & comparisonOutcome
Morrison, 2012Observational (n=896)TXA 1 g bolus + repeat prn vs placeboAll-cause mortality overall within 48 hours and in-hospital mortality significantly reduced with TXA
Roberts, 2013Randomized, placebo-controlled (n=20,211)TXA 1 g bolus + 1 g over 8 hours vs placeboAll-cause mortality at 28 days was significantly reduced by TXA. Treatment within 1 hour and 1–3 hours from injury significantly reduced the risk of death due to bleeding.
Sprigg, 2018Randomized, placebo-controlled (n=2325)TXA 1 g bolus + 1 g over 8 h infusion vs placeboPatients in the tranexamic acid group experienced a reduction in early deaths and serious adverse events, but not long-term functional status.
Roberts, 2019Randomized, placebo-controlled (n=12,737)TXA 1 g bolus + 1 g over 8 hours vs placeboTreatment within 3 h of injury reduced head injury-related death.
Rowell, 2020Double-blinded, randomized (n=966)TXA 1 g bolus + 1 g 8-hour infusion vs 2 g bolus + placebo infusion vs placebo bolus + placebo infusionNo statistically significant difference in 28-day mortality, favorable neurologic function, 6-month disability rating score, or progression of intracranial hemorrhage.
Roberts, 2020Randomized, placebo-controlled (n=12,009)TXA 1 g + 3 g infusion vs placeboNo significant difference in death due to bleeding within 5 days.
Bossers, 2021Prospective observational cohort (n=1827)Pre-hospital TXA vs no TXA in patients with TBINo association between TXA and mortality was found at 30 days. TXA was associated with increased mortality in patients with isolated TBI.
Guyette, 2021Double-blind, placebo-controlled, randomized (n=927)TXA 1 g bolus only vs TXA 1 g + 1 g infusion vs TXA 1 g bolus + 1 g bolus + 1 g infusion vs placebo bolus + placebo infusionPrehospital administration of tranexamic acid compared with placebo did not result in a lower rate of 30-day mortality in this population. No differences were found in 24-hour mortality or in-hospital mortality.
Mahmood, 2021Randomized, placebo-controlled (n=1767)TXA 1 g bolus + 1 g vs placeboNo evidence that TXA prevents IPH (intraparenchymal hemorrhage) expansion.
Gruen, 2023Double-blind, randomized, placebo-controlled (n=1310)TXA 1 g bolus prior + infusion vs matched placeboNo difference in survival with a favorable functional outcome at 6 months. No difference in 6-month mortality.

Conclusions

  • Tranexamic acid has been studied in pre-hospital, hospital, and combat settings in patients who have sustained a traumatic injury.
  • Efficacy of tranexamic acid was demonstrated in some of the studies above, while other studies failed to show a significant difference in outcomes.
  • Dosing of tranexamic acid varied significantly across the above studies; however, one dosing regimen has been widely adopted.
  • Tranexamic acid has minimal adverse effects, is relatively inexpensive, and is readily available in many settings.

References

  1. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg. 2014;260(1):13-21. doi:10.1097/SLA.0000000000000600
  2. Callcut RA, Kornblith LZ, Conroy AS, et al. The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg. 2019;86(5):864-870. doi:10.1097/TA.0000000000002205
  3. Latif RK, Clifford SP, Baker JA, et al. Traumatic hemorrhage and chain of survival. Scand J Trauma Resusc Emerg Med. 2023;31(1):25. doi:10.1186/s13049-023-01088-8
  4. Hijazi N, Abu Fanne R, Abramovitch R, et al. Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice. Blood. 2015;125(16):2558-2567. doi:10.1182/blood-2014-08-588442
  5. Cai J, Ribkoff J, Olson S, et al. The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients. Eur J Haematol. 2020;104(2):79-87. doi:10.1111/ejh.13348
  6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113-119. doi:10.1001/archsurg.2011.287
  7. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17(10):1-79. doi:10.3310/hta17100
  8. Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107-2115. doi:10.1016/S0140-6736(18)31033-X
  9. CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019;394(10210):1713-1723. doi:10.1016/S0140-6736(19)32233-0
  10. Micromedex [Electronic version]. Greenwood Village, CO: Truven Health Analytics. Retrieved January 17, 2021, from http://www.micromedexsolutions.com/
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