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Nearly 25 years ago, antifibrinolytic therapy — ε-aminocaproic acid or tranexamic acid (TXA) — was considered a preferred hemostatic intervention because of high-quality evidence, which reported that it is useful for primary menorrhagia and upper gastrointestinal bleeding or dental extractions in patients with coagulation disorders. Lower-grade evidence encouraged its use for bleeding associated with thrombocytopenia.1 A fifth of a century later, the same author celebrated “the never ending success story of tranexamic acid” in contributing to blood management by listing additional evidence-based indications: preventing bleeding in major orthopedic surgery and after parturition as well as reducing bleeding associated with trauma, traumatic brain injury, vaginal delivery, and cesarian section.2 These benefits come at little cost, as there appears to be no predictable increase in arterial or venous thromboses when it is used in the described doses and schedules.2,3
There are, however, only two FDA-approved indications for TXA: 1) parenteral TXA for patients with hemophilia to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction; and 2) TXA tablets for the treatment of cyclic heavy menstrual bleeding in females of reproductive potential. Yet, TXA is routinely used for many other provoked and spontaneous bleeding disorders. A 2021 “illustrated review” describes 12 evidence-based indications for using TXA: postpartum hemorrhage, trauma-associated hemorrhage, cardiac surgery, traumatic brain injury, heavy menstrual bleeding, intracerebral hemorrhage, hemoptysis, orthopedic surgery, von Willebrand disease, topical surgery, epistaxis, and hereditary hemorrhagic telangiectasia.4 This review also confronts the thrombotic risk and concludes that “in the absence of patient-specific factors (eg, history of thrombosis or cirrhosis), evidence suggests that there is no reason to avoid tranexamic acid in medical or surgical patients for fear of thrombosis.”
In 2022, the researchers introduced several important narratives into the story of TXA. Some are elucidating, some appear disappointing, and some appear exciting. None are uninteresting, leading one to keep looking forward to what’s next. And there will be plenty, as over 500 clinical trials examining TXA are currently registered at ClinicalTrials.gov.
TXA is used off-label for patients with cerebral bleeding because there is evidence that it decreases bleeding from traumatic brain injury5 and reduces early deaths after acute intracerebral hemorrhage (although there is no improved functional outcome after 6 months).6 Its use in subarachnoid hemorrhage (SAH) is discouraged by an FDA label warning that cerebral edema and cerebral infarction may be caused by its use in these patients. This concern may be overstated, however, as two papers published in 2022 demonstrated no TXA-induced cerebral ischemic events or other intracranial or extracranial thromboses associated with TXA use. The TICH-2 study involved 96 patients with acute spontaneous intracerebral hemorrhage who were given a TXA 1-g bolus followed by 1 g per 8 hours by infusion,7 and the ULTRA study involved 480 patients with SAH who were given a TXA 1-g bolus followed by 1 g per 8 hours infusion over 24 hours. Of note, the latter study failed to show that TXA improved clinical outcomes 6 months after SAH, although the rate of re-bleeding before aneurysm treatment was reduced from 14% to 10%.8 So, while the routine use of TXA for SAH appears unlikely, studies to identify patients with SAH who could derive a clinical benefit from its attenuation of aneurysmal re-bleeding should go forward with fewer concerns about TXA toxicity.
The use of TXA in thrombocytopenic disorders remains uncertain. A Cochrane review published in 2016 concluded that evidence was insufficient to determine its benefits, risks, and side effects.9 New data in the A-TREAT study began to clarify each of these outcomes using TXA 1300 mg orally or 1000 mg IV administered three times per day for a mean period of approximately 14 days to 337 patients with hematological malignancies and platelet counts below 30,000 per µL. TXA, in comparison with placebo, showed no significant difference in the 30-day frequency of WHO grade 2 bleeding, the number of platelet transfusions required, thromboses, or adverse effects.10 The only significant difference was that TXA increased the rate of central venous-catheter occlusions (16.6% vs 6.7%). This study, while useful, fails to clarify the therapeutic index of TXA in those patients most likely to suffer bleeding from disease or chemotherapy-induced thrombocytopenia: outpatients with more severe thrombocytopenia for whom prophylactic platelet transfusions could be difficult or impractical or those who are platelet transfusion refractory. Retrospective data indicate that these patients derive a significant clinical benefit — decreased platelet transfusions and WHO grade 3 and 4 bleeding — when treated with antifibrinolytic therapy.11,12 Until proven otherwise, therefore, I will continue to recommend TXA 650 to 1300 mg orally three times daily to patients with signs of impaired hemostasis owing to severe thrombocytopenia (at least grade CTCAE grade 4 <25,000/µL) for whom platelet transfusions are unavailable or not working.
Evidence supports the use of TXA for decreasing blood loss in heart and orthopedic surgery, and we now have evidence that it can be useful in other non-cardiac surgery, including general, vascular, urologic, spinal, gynecologic, thoracic, and plastic surgery.13 The POISE-3 trial enrolled over 9000 patients randomized to receive parenteral TXA 1000 mg or placebo pre-incision and at closure. TXA reduced the composite endpoint of life-threatening bleeding, major bleeding, and bleeding into a critical organ by approximately 25%, and this reduction in hemorrhage was associated with a reduced quantity of blood products. The primary safety outcome of the composite of myocardial injury, non-hemorrhagic stroke, peripheral arterial thrombosis, or symptomatic proximal deep venous thrombosis differed very little between TXA (14.2%) and placebo (13.9%), although noninferiority was not established.13 A 2022 systematic review of patients receiving abdominal or pelvic surgery buttresses these conclusions by providing additional evidence that TXA decreased surgical bleeding, the magnitude of postoperative anemia, and the need for red cell transfusions without any increase in the risk of venous thromboembolism.14 Taken together, these and previous data1,2,4 support the cautious use of TXA in many different surgical procedures. Caution should be exercised mainly for patients with active atherothrombotic disease; but, for these as well as all other patients, there must be recognition that TXA, by decreasing bleeding and anemia, will predictably improve postoperative morbidity, postoperative mortality, and blood-product utilization — three very beneficial outcomes heavily weighted towards affirming its generally favorable therapeutic index.15
- Mannucci PM. Hemostatic drugs. N Engl J Med. 1998;339(4):245-253.
- Franchini M, Mannucci PM. The never ending success story of tranexamic acid in acquired bleeding. Haematologica. 2020;105(5):1201-1205.
- Ross J, Al-Shahi Salman R. The frequency of thrombotic events among adults given antifibrinolytic drugs for spontaneous bleeding: systematic review and meta-analysis of observational studies and randomized trials. Curr Drug Saf. 2012;7(1):44-54.
- Relke N, Chornenki NLJ, Sholzberg M. Tranexamic acid evidence and controversies: An illustrated review. Res Pract Thromb Haemost. 2021;5(5):e12546.
- 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.
- 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.
- Pszczolkowski S, Sprigg N, Woodhouse LJ, et al. Effect of Tranexamic Acid Administration on Remote Cerebral Ischemic Lesions in Acute Spontaneous Intracerebral Hemorrhage: A Substudy of a Randomized Clinical Trial. JAMA Neurol. 2022;79(5):468-477.
- Tjerkstra MA, Post R, Germans MR, et al. Tranexamic Acid After Aneurysmal Subarachnoid Hemorrhage: Post-Hoc Analysis of the ULTRA Trial. Neurology. 2022 Oct 20. doi: 10.1212/WNL.0000000000201160. Online ahead of print.
- Estcourt LJ, Desborough M, Brunskill SJ, et al. Antifibrinolytics (lysine analogues) for the prevention of bleeding in people with haematological disorders. Cochrane Database Syst Rev. 2016;3(3):CD009733.
- Gernsheimer TB, Brown SP, Triulzi DJ, et al. Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial. Blood. 2022;140(11):1254-1262.
- Antun AG, Gleason S, Arellano M, et al. Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies. Cancer. 2013;119(21):3784-3787.
- Yang W, Tholpady A, Casteel KN, et al. Platelet-refractoriness and the clinical impact in leukemia population at a metropolitan academic cancer center. Leuk Lymphoma. 2020;61(4):996-998.
- Devereaux PJ, Marcucci M, Painter TW, et al. Tranexamic Acid in Patients Undergoing Noncardiac Surgery. N Engl J Med. 2022;386(21):1986-1997.
- Fowler H, Law J, Tham SM, et al. Impact on blood loss and transfusion rates following administration of tranexamic acid in major oncological abdominal and pelvic surgery: A systematic review and meta-analysis. J Surg Oncol. 2022;126(3):609-621.
- Smilowitz NR, Oberweis BS, Nukala S, et al. Association Between Anemia, Bleeding, and Transfusion with Long-term Mortality Following Noncardiac Surgery. Am J Med. 2016;129(3):315-23.e2.
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