TXA Literature Review

Author: Alexandra Murray, DO PGY1
Mercy St. Vincent Medical Center Emergency Medicine

Originally Published: Modern Resident - December-January 2016

What is tranexamic acid (TXA)?
When the body experiences vascular injury, the hemostatic system tries to maintain circulation by balancing the formation and degradation of blood clots. In response to severe blood loss, this balance is challenged and hyper-fibrinolysis can occur. The conversion of plasminogen to plasmin plays a large role in fibrin binding and degradation. Tranexamic acid is a synthetic derivative of lysine that reversibly blocks binding sites on plasminogen and inhibits fibrinolysis.[1] TXA has been approved by the FDA since 1986 as an antifibrinolytic and has been marketed for menorrhagia (Lysteda) and dental hemorrhage in hemophiliacs (Cyklokapron).[2,3] More recently, TXA has been investigated as a treatment for posttraumatic hemorrhage, postpartum hemorrhage and prevention of surgical blood loss.

CRASH-2 Trial (2010)
The CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage-2) Trial was published in the Lancet in 2010. This double-blinded, randomized, placebo-controlled trial examined 20,211 adult trauma patients in 274 hospitals in 40 countries.[4] The study was designed to assess effects of early administration of TXA (within eight hours of injury) on death, vascular occlusive events and the receipt of blood transfusion in trauma patients. The results showed that all-cause mortality was significantly reduced with TXA (RR 0.91, p=0.0035).[4] The risk of death due to bleeding on Day Zero was also significantly reduced (RR 0.80, p=0.003) with the greatest benefit of TXA administration being within the first hour of injury (RR 0.68, p=0.0001).[4] There was concern that TXA would increase the formation of pathologic blood clots; however, there was no apparent increase in fatal or nonfatal vascular occlusive events between treatment and control groups. Based on the results, the number needed to treat with TXA was 67 patients.[4]

MATTERs Study (2012)
The MATTERs (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) Study was published in Archives of Surgery in 2012 as a retrospective observational cohort study that examined 896 military combat injuries.[5] The study was designed to characterize contemporary use of TXA in combat injury and to assess the effect of its administration on total blood product use, thromboembolic complications and mortality.[5] There was a significant reduction in 48 hour (ARR 7.6%, p=0.004) and in-hospital (ARR 6.5%, p=0.004) all-cause mortality with TXA administration, but not 24 hour all-cause mortality (ARR 2.8%, p=0.20).5 The benefit of TXA was greatest in those patients who received massive transfusion of >10 units PRBC per 24 hours (<24h: ARR 5.2%, p=0.17; <48h: ARR 13.1%, p=0.003; In-hospital: ARR 13.7%, p=0.004).[5] The number of venous thrombotic events in the study was too small to assess any independent risk of TXA for vascular occlusive events. Based on the results, the number needed to treat with TXA was seven patients.[5]

Cochrane Review: Antifibrinolytic Drugs for Acute Traumatic Injury (2015)
In 2015, the Cochrane Collaboration published a review of randomized controlled trials of antifibrinolytic agents (aprotinin, TXA, epsilon-aminocaproic acid and aminomethyl-benzoic acid) to assess the effect of antifibrinolytic drugs in patients with acute traumatic injury.[6] Three trials were included; however, 99% of the data was contributed by the CRASH-2 trial. Two trials (n=20,451) assessed the effect of TXA (CRASH-2 2010, Yutthakasemsunt 2013) and one trial (n=77) assessed aprotinin (McMichan 1982). The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, p=0.002). There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events, need for surgical intervention or receipt of blood transfusion.[6] The authors recommend that TXA should be given as early as possible and within three hours of injury for trauma patients with bleeding. They give no recommendations concerning the effect of TXA in patients with isolated traumatic brain injury; however, there are two ongoing trials that should help guide future management.[6]

References:

1. Okamoto S, et al. Enzyme-controlling medicines: Introduction. Semin Thromb Hemost. 1997;23(6):493-501.
2. Wilton JM. Tranexamic acid: A new option for heavy menstrual bleeding. Nurs Womens Health. 2012 Apr-May;16(2):146-50.
3. Nuvvula S, Gaddam KR, and Kamatham R. Efficacy of tranexamic acid mouthwash as an alternative for factor replacement in gingival bleeding during dental scaling in cases of hemophilia: A randomized clinical trial. Contemp Clin Dent. 2014 Jan;5(1):49-53.
4. 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 randomized, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32.
5. Morrison JJ1, Dubose JJ, Rasmussen TE, and Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) study. Arch Surg. 2012 Feb;147(2):113-9.
6. Ker K, Roberts I, Shakur H, and Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015 May 9;5:CD004896.