By Christina Creel-Bulos, MD and Enyo Ablordeppey, MD MPH
Anti-fibrinolytics were first introduced by a husband and wife team of Japanese researchers searching for a product that would help prevent maternal mortality associated with postpartum hemorrhage. In the 1960’s, they invented the first anti-fibrinolytic agent, Episilon Aminocaproic Acid (eACA). Initial efforts demonstrated the need for more potent anti-fibrinolytics and lead to the identification of what is now known as Tranexamic Acid (TXA). Initially this was marked as a medication for menorrhagia and bleeding after dental extractions, but further research in the utilization of this medication proved to be significantly astounding!
What is TXA?
TXA was originally described as a chemical able to inhibit the enzymatic breakdown and degradation of fibrin by plasmin. It is an amino acid (lysine) analog that binds to the lysine-binding site on plasminogen; thus preventing the conversion of plasminogen into plasmin and blocking clot breakdown. Although its utilization began in the 1960’s, it was not until 2010 when studies demonstrated a mortality benefit in trauma patients.
TXA has the highest hypothetical benefit during the trauma induced “Lethal Triad” of death, which describes the implications of hypothermia and acidosis on coagulation. It has been cited that for every degree decrease from core temperature, coagulation factor activity decreases by 10%. Acidosis contributes to this triad by reducing Factor Xa, platelet counts, and fibrinogen levels; thus further highlighting the importance of fibrin clot preservation by using an antifibrinolytic such as TXA.
CRASH-2 and MATTERS
In 2010, the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial was released and its findings lead to its inclusion in the World Health Organization (WHO) list of essential medications. This international, randomized control and multi-centered trial enrolled 20,000 trauma patients-cited to be at risk for “significant hemorrhage”- from 274 hospitals and 40 different countries. It cited an absolute risk reduction (ARR) in mortality of 1.5% with a number needed to treat (NNT) of 65. A subgroup analysis further cited a mortality risk reduction (RR) from bleeding at different timelines from initial injury. Risk reductions at less than 1 hour, 1 to 3 hours, and greater than 3 hours were cited at: 0.68, 0.79, and 1.44 respectively with NNT 125. (CRASH 2 collaborators et al, 2010)
The (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study released in 2012 was a retrospective cohort analysis of 896 military trauma patients. A multivariate logistical analysis of a subgroup of patients who met criteria for activation of massive transfusion, demonstrated that TXA was independently associated with reduced mortality with an odds ratio (OR) for survival of 7.23 (Morrison et al, 2012).
TXA for Peripartum Hemorrhage
The release of the World Maternal Antifibrinolytic (WOMAN) trial in 2017 marked increase interest in the utilization of TXA in obstetrical populations to reduced post partum hemorrhage (PPH). This randomized control trial consisting of 20,000 females diagnosed with PPH-after vaginal or cesarean delivery from 193 hospitals across 21 countries and found that death due to bleeding was reduced in patient who received 1g of TXA within three hours of delivery compared with placebo( ARR 0.4% and NNT 267).
Simonazzi et al performed a systemic review and meta-analysis of randomized control trials in 2016 regarding TXA in the peripartium population. Researchers identified 9 trials consisting of 2365 females and noted a significant decrease in: PPH rates, frequency of severe PPH, decrease in post partum blood loss, hemoglobin depreciation, and utilization of medications to increase uterine tone in those who received TXA prior to c-section compared with those who did not. Additionally there was not a significant difference in incidence of thromboembolic events between either group (Simonazzi et al 2016).
Expansion of TXA Utilization
Since these initial studies introducing TXA for traumatic indications, data evaluating expanded utilization of TXA has been cited in gynecological, gastrointestinal, orthopedic and Spinal literature. For example:
Wang et al noted trends towards reduced: total blood loss, transfusion requirements, and duration of surgery (Wang et al, 2017) in patients receiving TXA perioperatively after open myomectomy. Orthopedic surgery literature has additionally begun investigating the utilization of anti-fibrinolytics in their practice. Although additional data is needed, a systematic review of randomized control trials also demonstrated a decrease in transfusion requirements and blood loss in patients undergoing total hip replacement or total knee arthroplasty given TXA without an increased risk in VTE in both study groups (Kagoma et al, 2009). [EA1] Finally, additional research to examine TXA utilization in Traumatic Brain Injury (TBI) patients after a systematic review of TXA utilization in patients with TBI/Intracerebral hemorrhage showed decreased ICH regression in patients receiving TXA but did not statistically change clinical outcomes (Zehtabchi et al, 2014).
As this data and clinical implications continue to be discovered and developed, be on the look out for more exciting discoveries in this realm and keep in mind that TXA is not simply limited to cases with Trauma!
As always….Happy Resuscitating!
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. Lancet. 2010 Jul3;376(9734):23-‐32.
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. Lancet. 2011 Mar 26;377(9771):1096-‐101, 1101.
Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012 Feb;147(2):113-‐9.
Simonazzi G, Bisulli M, Saccone G, Moro E, Marshall A et al. Tranexamic acid for preventing postpartum blood loss after cesarean delivery: a systematic review and meta-analysis of randomized controlled trials. Acta Obstet Gynecol Scand. 2016 Jan;95(1):28-37.
Wang D, Wang L, Wang Y, Lin X. The efficiency and safety of tranexamic acid for reducing blood loss in open myomectomy: A meta-analysis of randomized controlled trials. Medicine. 2017; 96 (23): e7072.
Shakur H, Roberts I, Fawole B, Chaudhri R et al. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet Glob Health. 2018 Feb;6(2):e222-e228. doi: 10.1016/S2214-109X(17)30467-9.
Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009 Mar;123(5):687-96.
Winter SF, Santaguida C, Wong J, Fehlings M. Systemic and Topical Use of Tranexamic Acid in Spinal Surgery: A Systematic Review. Global Spine Journal. 2016; 6 (3): 284-95.
Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK. Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med. 2014 Dec;32(12):1503-9.
Kini RM, Koh CY. Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites. Toxins. 2016; 8(10):284.