Virginia Anesthesia Services LLC Use of Tranexamic Acid in Surgery  - Virginia Anesthesia Services LLC

Use of Tranexamic Acid in Surgery 

Blood loss is one of the most common causes of mortality in both surgical and non-surgical settings. Antifibrinolytics are a class of medications that can be administered in these situations to control blood loss. One of the more common agents, tranexamic acid (TXA), is a synthetic derivative of lysine. The landmark WOMAN study assessed upwards of 20,000 women suffering from postpartum hemorrhage and concluded that TXA significantly reduces death due to bleeding.1 Additionally, a review of 104 randomized clinical trials found TXA reduces blood loss in surgical patients by around 33% compared to placebo, indicating that tranexamic acid has important use in surgery.2  

TXA’s mechanism of action is thought to be in part attributable to its attenuation of the inflammatory response, and therefore, related hemodynamic instability. As an antifibrinolytic, TXA inhibits the dissolution of fibrin clots by non-competitively inhibiting the binding of plasminogen to plasmin. The reduced activation of plasmin, which naturally breaks down fibrin, results in stabilization of the fibrin meshwork produced by homeostasis.3 In a randomized controlled trial of 50 patients undergoing cardiopulmonary bypass surgery, administration of tranexamic acid pre-surgery reduced several biomarkers of inflammation, including the pro-inflammatory cytokine IL-6, fibrin separation products, creatine-kinase, and plasminogen activator inhibitor.4 TXA also interacts positively with desmopressin, an antidiuretic hormone. Alone, desmopressin exerts fibrinolytic action; however, when that activity is abolished by TXA, desmopressin has a positive effect on platelet aggregation, reducing postoperative blood loss.5 

Most patients undergoing surgical treatment for myocardial infarction and other cardiovascular issues receive antifibrinolytic therapy to limit blood loss. Since the 2006 publication of a seminal study that examined the effects of three antifibrinolytic therapies on 4,374 patients undergoing revascularization, the clinical preference of antifibrinolytic has shifted from aprotinin to TXA.6 In this study, aprotinin was associated with a 55% increase in the risk of myocardial infarction or heart failure and a near threefold increase in the risk of stroke or encephalopathy. By contrast, TXA was not associated with any detrimental renal, cardiac, or cerebral events. A second highly cited study, known as the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study, randomly administered TXA and aprotinin to 2,331 high-risk cardiac patients. Aprotinin’s mortality rate was 2% higher than that of TXA, leading the FDA and Health Canada to withdraw aprotinin from clinical use and promote the more widespread adoption of TXA as the antifibrinolytic of choice for cardiac surgery.7,8 

Clinical trials also firmly support the use of tranexamic acid in trauma surgery. The largest RCT to date in this field is CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2), which included over 20,000 adult trauma patients from over 270 hospitals and 40 different countries. The study showed all-cause mortality was significantly reduced in the TXA group compared to the placebo group, as was death due to bleeding.9  

Another surgical field where TXA is used is neurosurgery, where these antifibrinolytics are attractive for preventing blood loss in intracranial hemorrhage (ICH).  After a 2000 study showed TXA treatment in patients suffering from aneurysmal subarachnoid hemorrhage (SAH) reduced risk of re-bleeding but significantly increased risk of ischemic stroke, the authors concluded the routine use of antifibrinolytics like TXA in SAH treatment should be discontinued. However, since then, new strategies using antifibrinolytics for a shorter duration have shown promise of reduced bleeding with fewer adverse effects.8 In a randomized controlled trial of 505 patients with SAH, TXA significantly reduced early re-bleeding and resulted in an 80% reduction in the mortality rate of these early re-bleeders.8,10 Furthermore, since the publication of the CRASH-2 trial, there has been a growing interest in the use of TXA for traumatic ICH, which includes epidural, subdural, and subarachnoid hemorrhage.8  

Some new and interesting areas where TXA administration is being investigated are subdural and subarachnoid hemorrhage, gastrointestinal bleeding, chemotherapy-induced thrombocytopenia, and ruptured abdominal aortic aneurysms.3 Additional prospective studies can confirm the findings of many small and/or retrospective studies, with the goal of demonstrating the safety and efficacy of tranexamic acid use for different types of surgery. For example, some unanswered questions surrounding TXA usage include drug dose regimens that minimize seizure risk and conclusions regarding the thromboembolic risk. Further studies can also better characterize TXA use in novel clinical contexts.  

 
References 

  1. Shakur, Haleema, 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.” The Lancet, vol. 389, no. 10084, May 2017, pp. 2105–16. https://doi.org/10.1016/S0140-6736(17)30638-4  
  1. Ker, K., et al. “Systematic Review, Meta-Analysis and Meta-Regression of the Effect of Tranexamic Acid on Surgical Blood Loss.” British Journal of Surgery, vol. 100, no. 10, Aug. 2013, pp. 1271–79. https://doi.org/10.1002/bjs.9193  
  1. Cai, Johnny, et al. “The Many Roles of Tranexamic Acid: An Overview of the Clinical Indications for TXA in Medical and Surgical Patients.” European Journal of Haematology, vol. 104, no. 2, Feb. 2020, pp. 79–87. https://doi.org/10.1111/ejh.13348  
  1. Jimenez, Juan J., et al. “Tranexamic Acid Attenuates Inflammatory Response in Cardiopulmonary Bypass Surgery through Blockade of Fibrinolysis: A Case Control Study Followed by a Randomized Double-Blind Controlled Trial.” Critical Care, vol. 11, no. 6, Nov. 2007, p. R117. https://doi.org/10.1186/cc6173 
  1. Özal, Ertuğrul, et al. “Does Tranexamic Acid Reduce Desmopressin-Induced Hyperfibrinolysis?” The Journal of Thoracic and Cardiovascular Surgery, vol. 123, no. 3, Mar. 2002, pp. 539–43. https://doi.org/10.1067/mtc.2002.117281  
  1. Mangano, Dennis T., et al. “The Risk Associated with Aprotinin in Cardiac Surgery.” New England Journal of Medicine, vol. 354, no. 4, Jan. 2006, pp. 353–65. https://doi.org/10.1056/NEJMoa051379  
  1. Fergusson, Dean A., et al. “A Comparison of Aprotinin and Lysine Analogues in High-Risk Cardiac Surgery.” New England Journal of Medicine, vol. 358, no. 22, May 2008, pp. 2319–31. https://doi.org/10.1056/NEJMoa0802395  
  1. Ng, William Chuk Kit, et al. “Tranexamic Acid: A Clinical Review.” Anestezjologia Intensywna Terapia, vol. 47, no. 4, Sept. 2015, pp. 339–50. https://doi.org/10.5603/AIT.a2015.0011  
  1. “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.” The Indian Journal of Neurotrauma, vol. 9, no. 1, June 2012, pp. 3–14. https://doi.org/10.1016/j.ijnt.2012.05.001  
  1. Hillman, Jan, et al. “Immediate Administration of Tranexamic Acid and Reduced Incidence of Early Rebleeding After Aneurysmal Subarachnoid Hemorrhage: A Prospective Randomized Study.” Journal of Neurosurgery, vol. 97, no. 4, Oct. 2002, pp. 771–78. https://doi.org/10.3171/jns.2002.97.4.0771