Tranexamic Acid in Trauma

Introduction

• According to the World Health Organization, 4.4 million people die of trauma per annum; 8% of all deaths worldwide. Acute hemorrhage is the leading cause of death in trauma patients, accounting for 30-40% of trauma fatalities.
• Trauma-induced coagulopathy is a life-threatening condition that significantly contributes to trauma mortality (see OA summary on trauma-induced coagulopathy Link).
• It is a complex interaction of multiple physiological changes (Figure 1).¹
• Hyperfibrinolysis is one of the pathways that contributes to the development of trauma-induced coagulopathy.
• TXA is a synthetic antifibrinolytic agent that stabilizes the fibrin clot and thereby prevents further bleeding. TXA has been widely used in trauma patients to decrease mortality and improve survival.

Fibrinolysis and TXA

• In the setting of vascular injury, the coagulation cascade is activated, forming a cross-linked fibrin clot to control hemorrhage.
• Clot formation is usually carefully balanced with clot degradation. During recovery, tissue plasminogen activator cleaves plasminogen to plasmin (the active form), which binds to and degrades fibrin clots into fibrin degradation products. This process is called fibrinolysis.
• Excessive plasmin formation can result in hyperfibrinolysis, which increases the risk of bleeding. In the acute phase of trauma, systemic hypoperfusion is often associated with hyperfibrinolysis.
• On the other hand, hypofibrinolysis (fibrinolysis shutdown) has also been observed in severely injured patients, although the exact mechanism remains unclear. Fibrinolytic shutdown contributes to end-organ failure due to microvascular occlusion.
• Animal experiments suggest that shock evokes systemic hyperfibrinolysis, whereas tissue injury (thoracotomy, laparotomy, bowel crush, and femur fracture) may provoke fibrinolysis shutdown.
• TXA is a synthetic derivative of lysine. It reversibly and competitively binds to the lysine-binding site on plasminogen, thereby preventing cleavage to plasmin and fibrin binding, stabilizing the existing fibrin clot, preventing further bleeding, and avoiding hyperfibrinolysis.
• TXA was originally approved by the United States Food and Drug Administration for use in patients with hemophilia for tooth extractions and menorrhagia. It is an off-patent, generic, and cheap medication. Currently, TXA has wide off-label use in patients with severe bleeding (such as in major surgery or in postpartum hemorrhage) or when hyperfibrinolysis is suspected, including in acute trauma.
• Fibrinolysis is a rapid, dynamic process, and viscoelastic testing may provide some guidance to the administration of TXA. However, the data for TXA use in trauma advocates for early administration, and this benefit may be lost if there is a delay to run viscoelastic tests.

Pharmacokinetics of TXA^2,3

TXA can be administered via intravenous (IV), intramuscular (IM), oral, or topical routes.

Clinical Use in General Trauma: Pertinent Trials

Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2); (Lancet) – 2010: PubMed

• A randomized, double-blinded, placebo-controlled trial, 274 hospitals in 40 countries, 20,207 adult civilian trauma patients.
• Carried out to see if TXA decreased all-cause mortality in bleeding trauma patients.
• TXA group: loading dose of 1 g of TXA over 10 min, followed by an IV infusion of 1 g over 8 hours.
• Placebo group: 0.9% saline.
• Primary outcome: death in hospital within 4 weeks of injury.
• Conclusion: Early TXA administration (within 3 hours) can safely reduce the risk of 28-day mortality due to bleeding in adult trauma patients without significant harm. The absolute risk reduction in mortality was small.
• This trial recommended early TXA administration in bleeding adult trauma patients.
• Problems: The majority of patients were from low- and middle-income countries with limited healthcare resources. Patients were often not severely injured, only 17% with severe
• TBI, 68% with mild TBI, and all causes mortality was 15%; only about 5% died of bleeding. Whilst this study showed a clear mortality benefit, many felt that many of the patients were not severely injured, did not have massive hemorrhage, and the trauma management in low- and middle-income countries did not represent the advanced trauma services available in high income countries. There was a potential for increased mortality if TXA was administered after the 3-hour point from injury.

Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study; (Arch Surg) – 2012: PubMed

• A retrospective observational cohort study in a UK military hospital at Camp Bastion, southern Afghanistan; 896 patients with combat injury received at least 1 unit of packed red blood cells (293 received TXA, 603 did not receive TXA).
• Carried out to see if TXA decreased mortality in combat casualties.
• TXA administration: IV bolus of 1 g within 1 hour of injury, repeated if managing clinician felt there was an indication.
• Outcome: 24 hours, 48 hours, and in-hospital mortality.
• Conclusion: The combination of TXA administration and blood-based resuscitation had an absolute mortality benefit in patients with severe injury and hemorrhage, especially in patients who received massive transfusions. TXA was independently associated with better survival and less coagulopathy in these patients.
• This study recommended TXA as a resuscitation strategy following severe combat injury and hemorrhage.
• Problems: single-center, retrospective analysis focusing on combat injuries in a young, male-preponderant population.

Study of Tranexamic Acid during Air Medical Prehospital Transport Trial for Trauma Patients at Risk of Hemorrhage (STAAMP Trial); (JAMA Surg) – 2020: PubMed

• A pragmatic, phase 3, multicenter (4 US level 1 trauma centers), double-blind, placebo-controlled, superiority randomized clinical trial; 903 injured adult patients at risk of hemorrhage (447 with TXA, 456 in placebo).
• Carried out to see if prehospital administration of TXA was feasible (given that CRASH 2 had shown that early TXA was beneficial, but delayed administration increased mortality)
• TXA group: 1 g bolus IV over 10 minutes enroute to the hospital within 2 h of injury (phase A), then 1 g bolus over 10 minutes in the hospital (phase B), and 1 g infusion over 8 hours (phase C).
• Outcome: 30-day all-cause mortality.
• Conclusion: No difference in 30-day mortality between the TXA group and the placebo group when administered within 2 hours of injury. However, when TXA was administered within 1 hour of injury, 30-day mortality was lower, thereby once again highlighting the potential requirement for early medication delivery post-injury.
• This study suggested prehospital administration of TXA is safe during air or ground transport.
• Problems: The trial was terminated early due to financial constraints and was underpowered to assess the primary outcome. This trial was conducted in the USA, a high-income country. Patients were not severely injured, as the median Injury Severity Score was 11 in the placebo group and 13 in the TXA group.

The Immunologic Effect of Early Intravenous Two and Four Gram Bolus Dosing of Tranexamic Acid Compared to Placebo in Patients With Severe Traumatic Bleeding (TAMPITI); (Front Immunol) – 2020: PubMed

• A single-center (Washington University, St Louis), double-blinded, randomized controlled trial; a total of 150 adult patients with primarily penetrating traumatic injuries received a 2 g or 4 g bolus of TXA vs placebo (normal saline) within 2 hours of injury.
• Undertaken, TXA was thought to provide beneficial immunomodulatory effects in trauma and to minimize fibrinolysis.
• Primary Outcome: reduction in monocyte activation.
• Conclusion: high-dose TXA has minimal impact on immune and hemostatic profiles in these trauma patients; however, there was a dose-dependent increase in risk of venous thromboembolism.
• Problems: single-center study, small sample size, high-income country.

Prehospital Tranexamic Acid for Severe Trauma (PATCH study); (N Engl J Med) 2023: PubMed

• An international, randomized, double-blind, placebo-controlled study, 1310 patients with major trauma in Australia, New Zealand, and Germany (661 with TXA, 646 with placebo)
• Carried out to see if TXA was beneficial in high-income modern trauma systems (as compared to the patients involved in CRASH 2)
• TXA group: 1 g bolus before hospital admission, followed by a 1 g infusion over 8 hours after arrival at the hospital; Placebo group: normal saline.
• Outcome: survival with a favorable functional outcome at 6 months after injury
• Conclusion: no improvement in 6-month functional outcomes in patients receiving TXA; however, lower 28-day mortality in the TXA group. No significant adverse effects.
• Problems: This trial was conducted in advanced trauma systems in high-income countries. Compared to the CRASH-2 study, the sample size was relatively small. 13% loss to follow-up. The study was praised for examining functional outcomes, not just survival.  But maybe 6 months is too short a follow-up period in trauma to show long-term clinical improvement.

Overall Conclusions from TXA Trials in General Trauma

• Early administration of TXA (within 3 hours of injury) reduces early mortality from bleeding without significant risk. While there is a theoretical risk of administering TXA during fibrinolytic shutdown, multiple agencies advocate early administration rather than waiting to perform viscoelastic tests to rule out fibrinolytic shutdown or to confirm hyperfibrinolysis.
• TXA can be successfully administered in the prehospital environment.
• Data on long-term survival with favorable outcomes are unclear.

Clinical Use in TBI

CRASH-3 trial; (Lancet) – 2019: PubMed

• An international, multicenter, randomized, placebo-controlled trial with 12737 adult patients with TBI in 175 hospitals in 29 countries.
• TXA group: 1 g loading dose over 10 min within 3 hours of injury, then infusion of 1 g over 8 hours; Placebo group: normal saline.
• TBI carries a very high morbidity and mortality, and so this trial was carried out to explore whether TXA would decrease bleeding in TBI and therefore improve outcomes.
• Outcome: head injury-related death in hospital within 28 days of injury.
• Conclusion: No significant difference in head injury-related mortality between groups within 28 days of injury, but for patients with mild-moderate TBI, the mortality was lower in the TXA group. The risk of vascular occlusive events and seizure was similar. There was no difference in the hemorrhage progression between the TXA and placebo.
• This trial suggested that TXA is safe in patients with TBI and likely confers an early survival benefit in those with mild-to-moderate TBI. Given that severe TBI has very high morbidity and mortality, the fact that TXA did not improve outcomes in these patients may not be surprising. With respect to risks and benefits, TXA should be administered as soon as possible after injury in TBI.

ROC-TXA trial; (JAMA) – 2020: Link

• A multicenter, double-blinded, randomized clinical trial at 20 trauma centers and 39 emergency medical services agencies in the US and Canada, involving 1280 patients with moderate to severe TBI.
• TXA group 1: out-of-hospital 1g bolus within 2 hours of injury and in-hospital 1g over 8 hours infusion.
• TXA group 2: out-of-hospital 2g bolus within 2 hours of injury and in-hospital placebo infusion.
• Placebo group: placebo bolus and infusion.
• Outcome: favorable neurologic function at 6 months.
• Conclusion: out-of-hospital administration of TXA did not significantly improve 6-month neurologic recovery in patients with moderate or severe TBI, and no statistically significant difference in 28-day mortality between groups. TXA 2 g bolus had a higher seizure incidence (5%).
• Problems: High-income countries, 15% loss to follow-up, and only 3% of TBI cases penetrating. Overall, the study showed that prehospital administration of TXA was feasible, but did not improve functional outcomes.  Once again, this may have been due to the trial targeting severe TBI.

Conclusion for TXA Trials in TBI

• Early administration of TXA 1g bolus (within 2-3 hours of injury) plus 1 g infusion over 8 hours has a survival benefit in patients with mild to moderate TBI, even though no improvement in neurologic function at 6 months with moderate to severe TBI.
• The outcome of severe TBI is very poor, so TXA can be given without severe adverse effects, although no survival benefit in isolated severe TBI has been shown.
• TXA has not shown a reduction in hematoma expansion; therefore, TXA may have mechanisms of action beyond those that minimize fibrinolysis.

Clinical Use in Intracerebral Hemorrhage (ICH)

• TICH-2 study was an international randomized, placebo-controlled trial in 2,325 patients with stroke from ICH at 124 hospital sites in 12 countries.⁴
• Within 8 hours of symptom onset, patients received TXA 1g as an IV bolus, followed by a 1g infusion over 8 hours, or a matching placebo.
• Outcome: functional status at day 90.
• Conclusion: No significant improvement in functional status at day 90 in the TXA group. However, TXA group had a reduction in hematoma expansion, early death and serious adverse events.
• It may be reasonable to administer TXA early in patients with ICH.

Clinical Use in Subarachnoid Hemorrhage (SAH)

• The ULTRA study was a multicenter, prospective, randomized, controlled, open-label trial in 8 treatment centers and 16 referring hospitals in the Netherlands.⁵
• TXA: 1g IV bolus immediately after diagnosis, followed by 1g infusion over 8 hours in SAH patients.
• Outcome: clinical outcome at 6 months.
• Conclusion: TXA administration did not improve clinical outcomes at 6 months. The TXA group had less re-bleeding (10% vs 14%) but higher rates of delayed cerebral ischemia (23% vs 22%), although the difference was not statistically significant.
• Deciding whether to administer TXA must balance the risk of re-bleeding against the risk of delayed cerebral ischemia.

Clinical Use in Pediatric Trauma

• Trauma is a leading cause of death in the pediatric population.
• Overall, the quality of data in pediatric trauma is not as robust as for adult trauma, and the dosing regimen remains unstandardized.
• A recently published systematic review and meta-analysis, including 1 RCT and 9 retrospective cohort studies, found that a 1 g IV loading dose of TXA significantly reduced mortality (OR 0.58; 95 % CI, 0.38–0.89), without a significant increase in thromboembolic events. The weight-based dosing TXA groups did not show survival benefits.⁶
• A marginally higher seizure rate was observed among pediatric patients who received TXA.
• TXA is generally safe in pediatric trauma patients. The Eastern Association for the Surgery of Trauma conditionally recommends TXA, and a joint position statement from NAEMSP, ACEP, and ACS-COT emphasized the need for multidisciplinary decision making and quality improvement programs for pediatric TXA use.

Clinical Use in Geriatric Trauma

• Trauma-related mortality increases with age, and trauma is a leading cause of morbidity and mortality in the geriatric population.
• Multiple large trials and meta-analyses show TXA reduces mortality and blood loss in geriatric trauma patients, especially in patients on anticoagulant therapy.⁷
• TXA does not increase the risk of clots or harm in elderly patients.

Clinical Use in Epistaxis

• Epistaxis is a common ear, nose, and throat emergency in the emergency department, occurring most frequently in children younger than 10 years and in adults older than 60 years.
• Patients on antiplatelet therapy are at high risk of nose-bleeding without trauma.
• Multiple randomized controlled trials show that topical TXA application (pledget soaked in 5-10ml of 100mg/ml TXA) resulted in faster bleeding control, reduced rebleeding within 1 week, and shorter emergency department length of stay compared with anterior nasal packing alone.⁸
• Topical TXA is particularly beneficial for patients on anticoagulants.

Clinical Use in Other Major Surgeries

• Spine/orthopedic surgeries: please see the OA summary on antifibrinolytics and spine surgery.
• Cardiac surgeries: please see the OA summary on CPB antifibrinolytics.
• Postpartum hemorrhage in obstetric patients: please check OA summary on antifibrinolytics and OA summary on postpartum hemorrhage.

TXA Dosing Regimens

• Adult dose: within 3 hours of injury,
  • IV 1 g bolus in 100 ml of normal saline infusion over 10 minutes, then 1 g infusion over 8 hours, or 0.5 g IM twice with max dose of 2 g.
  • OR 2 g IV or IO slow push bolus if significant TBI or altered mental status.
  • OR 1 g IM if no other access, repeat once as needed in a care-under-fire scenario.⁹
• IM TXA is well tolerated and rapidly absorbed in trauma patients with hemorrhage without significant side effects. Plasma concentration of 10-15 mg/L is sufficient to inhibit fibrinolysis within 10 minutes of administration.
• Military guidelines recommend administering the TXA auto-injector IM as close to the point of injury as possible. The JTCCC guidelines for military combat casualties recommend a 2 g slow IV / IO load as close to the time of injury as possible (up to 3 hours).
• Pediatric dose:
  • If the weight is less than 66 kg, a weight-based, 10-30 mg/kg IV loading dose over 10 minutes (maximum loading dose 2g), then 5-10 mg/kg/hr over 8 hours with target plasma concentrations 20-70 µg/ml.
  • If the weight is more than 66 kg, administer an IV 1g bolus over 10 minutes, followed by a 1g infusion over 8 hours, as per adult dosing.
• Topical dose for epistaxis: 100 mg/ml in 5-10 ml saline, applied to a soaked pledget.
• Topical dose in spine/orthopedic surgery: 1–3 g in 20–100 ml saline irrigation, injected into the wound, soaked into the wound, or soaked with a sponge.¹⁰

Adverse Effects of TXA

• Risk of venous thromboembolic event: no increase in thrombotic complications compared to controls in multiple studies.
• Postoperative seizures in large doses (loading dose of 30 mg/kg with continuous infusion of 15 mg/kg/hr during operation, or total dose of ≥100 mg/kg during cardiopulmonary bypass), rare, but seizure disorders are not a contraindication, and patients should be monitored closely. In the ROC-TXA trial, patients had a 5% seizure risk after the 2 g load, compared to the 1g load followed by 1 g infusion patients (2% risk).  Extra care should be taken in patients with renal impairment.
• Hypersensitivity: rare but severe; symptoms include rash, hives, itching, and swelling of the face/tongue/throat, with difficulty breathing.
• Visual disturbances: in high-dose animal studies, not in humans at standard doses
• Hypotension occurs if the TXA bolus is given too rapidly.
• Gastrointestinal symptoms: nausea, vomiting, diarrhea, abdominal pain.
• Musculoskeletal symptoms: muscle pain, joint pain, and stiffness.
• Others: headache, fever, chills.

Take-Home Messages

• TXA has early survival benefits in adult trauma patients with significant bleeding.
• Early administration (within 3 hours) is most effective.
• General recommended dose: 1g IV bolus within 10 minutes followed by 1g infusion over 8 hours.
• Alternatively, IO or IM may be used if there is no IV access.
• Viscoelastic testing may be useful for monitoring hyperfibrinolysis and fibrinolytic shutdown and for guiding the administration of TXA.
• TXA improves early survival in patients with mild-to-moderate TBI, but not in those with isolated severe TBI.
• Early administration of TXA reduces hematoma expansion in patients with ICH.
• There is a need to balance re-bleeding and delayed cerebral ischemia before giving TXA in patients with SAH.
• TXA is safe in both pediatric and geriatric trauma patients.
• Topical TXA is effective in stopping epistaxis and spine/orthopedic surgeries.