Clinical Transfusion

5. Tranexamic acid

Introduction

Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. Three formulas of anti-fibrinolytic drugs are in use: aprotinin, tranexamic acid (TXA) and epsilon aminocaproic acid (EACA). TXA is about eight times more active than its analogue EACA. Aprotinin has proven to be effective in reducing blood transfusions in cardiac surgery, but there are some concerns about its side effects and was withdrawed by the FDA in 2008 [1]. Therefore the most studied anti-fibrinolytic drug for a variety of surgical and medical indications has been TXA. TXA is a synthetic lysine analogue antifibrinolytic agent. It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, by binding to specific sites of both plasminogen and plasmin, a molecule responsible for the degradation of fibrin. TXA has been in clinical use for many years and has important health and economic implications in high, middle, and low income countries. TXA has been available for more than 20 years and was first approved by the US Food and Drug Administration (FDA) in 1986 for short-term use (2 to 8 days) as an injection to reduce or prevent bleeding during tooth extraction in haemophilia patients.

Indications of TXA

Non-cardiac surgery

TXA can be used topical (gauze saturated with TXA) or systemic in oral surgery [15,16]. Whether topical is as effective (or even better) as systemic use of TXA has to be proven. 

Surgery of urinary tracts leads to increasing urokinase challenging hemostasis. A recent meta-analysis investigated the effect of lysine analogues in pelvic surgery including urinary tract surgery (next to gynaecologic procedures) [14]. The study showed a significant reduction of blood loss and blood transfusion during pelvic surgery.  More data will be required to definitively assess adverse events.   

During liver surgery hyperfibrinolysis may exist either due to underlying disease or due to the operation itself for which TXA can be administered. However in end-stage liver disease there is increasing evidence of a prothrombotic tendency [13], warranting care with the administration of TXA.  

Most studies with regard to TXA have been done in total hip and total knee replacement and spinal surgery. Two meta-analyses have been conducted with regard to TXA in  total hip replacement [7,8]. They both showed a statistically significant reduction in intraoperative, postoperative, and total blood loss as well as a significant reduction in allogeneic blood transfusion requirements in the TXA group compared to the control group. A few meta-analysis of use of TXA in unilateral knee replacement have been published recently [9-11]. The use of TXA significantly reduced postoperative drainage, total blood loss, and blood transfusion requirements. VTE as an adverse event of TXA use was addressed both in total hip and knee replacement, but could not be commented upon due to the design of the investigated studies. Furthermore there are discussions whether TXA should be used intravenously, topically or both [11]. A recent meta-analysis of  9 controlled studies of use of TXA in spinal surgery showed reduced blood loss and less transfusion when TXA was used; the studies were not powered to evaluate safety [12]. 

Haematology

Although there is insufficient evidence from large randomized controlled trials [27], for patients with haemophilia, Von Willebrand disease and Glanzmann thrombasthenia TXA is often (topically or systematically) administered  with positive effects.

Trauma

In trauma patients the effect of TXA was studied in the CRASH-2 trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage). All-cause mortality was significantly reduced with TXA (14.5 vs. 16.0%), and the risk of death due to bleeding was also significantly reduced [17]. It should be noted that the study was mostly conducted in non-high income countries. A recent Cochrane analysis showed that TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events [18].  The ongoing CRASH-3 study which is conducted in patients with isolated traumatic brain injury should resolve remaining uncertainties with regard to effect of TXA in those patients [19]. For non-traumatic subarachnoidal bleeding (SAB) the Dutch ULTRA study will assess whether there is effect of adding TXA to standard care of SAB (to prevent recurrent bleeding from the aneurysm) with regard to functional outcome [20].

Cardiac Surgery

Many studies with TXA have been conducted in cardiopulmonary bypass operations. The  optimum dose of TXA has been discussed widely, with regard to anti-fibrinolytic effectivity, prevention of blood loss and side effects  (especially convulsive seizures) [2]. During a consensus meeting it was recommended not to exceed a maximum TXA total dose of 100 mg/kg in patients over 50 years of age undergoing pump surgery in open heart procedures [3]. Recent studies have again addressed this issue [4,5]. For children undergoing cardiac surgery calculations of TXA doses have been studied as well [6].

Bleeding patients who are on Direct Oral Anticoagulants (DOAC)

Tranexamic acid has been recommended for mildly and moderately bleeding patients on DOACs (in addition to local management of bleeding site and withdrawal of drug), although evidence of its effect is low [28]. 

Gynaecology and Obstetrics

The use of TXA has been studied in pregnant women both in post partum haemorrhage and elective caesarian section. A recent meta-analysis on treatments for primary post-partum haemorrhage recommended further studies to assess the effect of TXA [21]. Currently, this is studied in the WOMAN trial (World Maternal Antifibrinolytic Trial), which results are expected soon [22]. A positive effect of TXA on blood loss in elective caesarian section has  been shown in a recent study [23]. For menstruating women TXA can reduce menstrual blood loss and quality of life [24], as well as for women with a congenital bleeding disorder [25]. As for benign and oncological surgery meta-analysis show (some) advantage of TXA use [26].

DOSING OF TRANEXAMIC ACID

Tranexamic acid (Cyklokapron ®)

  • Intravenous     Solution 100mg/ml, ampul (vial) 5 ml
  • Topical            Solution 50 mg/ml
  • Oral                 Tablet 500 mg (it can be divided into two)

  • Dosing            See reference or this link.  
  • Adverse events (most common):

    • GI upset
    • Allergic reactions
    • Seizures (high doses) 

The effect of tranexamic acid on thromboembolic events and mortality remains uncertain.

  • Contra-indications:

    • Patients with or at elevated risk for thrombosis 
    • Hematuria
    • Fibrinolytic conditions following consumption coagulopathy
    • History of convulsion
    • Renal failure (dose adjustment)
    • Pregnancy (only use at strict conditions)

  1. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. Fergusson DA et al. NEJM 2008; 358: 2319-31.
  2. Tranexamic – an old drug still going strong and making a revival. Tengborn L et al. Thromb Res 2015; 135: 231-242.
  3. Drug, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) 2011. Menkis AH et al. Innovations 2012;7:229–41.
  4. Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. Sharma V et al. Anaesthesia 2012;67:1242–50.
  5. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Sigaut S et al. Anesthesiology 2014; 120: 590-600.
  6. A practical tranexamic acid dosing scheme based on population pharmacokinetics in children undergoing cardiac surgery. Grassin-Delyle S et al. Anesthesiology 2013;118:853–62.
  7. Systematic review and meta-analysis of the use of tranexamic acid in total hip replacement. Sukeik M et al. J Bone Joint Surg 2011; 93:39–46.
  8. Do we really need tranexamic acid in total hip arthroplasty? A meta-analysis of nineteen randomized controlled trials. Zhou XD et al. Arch Orthop Trauma Surg 2013;133:1017–27.
  9. A meta-analysis of the effectiveness and safety of using tranexamic acid in primary unilateral total knee arthroplasty. Tan J et al. J Surg Res 2013;184:880–7.
  10. Is tranexamic acid clinically effective and safe to prevent blood loss in total knee arthroplasty? A meta-analysis of 34 randomized controlled trials. Wu Q et al. Eur J Orth Surg Trauma 2015; 25: 525-41.
  11. One step closer to sparing total blood loss and transfusion rate in total knee arthroplasty: a meta-analysis of different methods of tranexamic acid administration. Shemshaki H et al. Arch Orth Trauma Surg 2015; 135: 573-88.
  12. Systematic review and meta-analysis of perioperative intravenous tranexamic acid use in spinal surgery. Yang B et al. PLoS one 2013; 8: e55436.
  13. Haemostasis and thrombosis in liver disease. Roberts LN et al. Br J Haematol 2010;148:507–21.
  14. The effects of lysine analogs during pelvic surgery: a systematic review and meta-analysis. Breau RH et al. Transf Med Rev 2014;28: 145-55.
  15. Systematic review and meta-analysis of the use of tranexamic acid in tonsillectomy. Chan CC et al. Eur Arch Otorhinolaryngol 2013;270: 735–48.
  16. Effect of tranexamic acid irrigation on perioperative blood loss during orthognathic surgery: a double-blind, randomized controlled clinical trial. Eftekharian H. et al. J Oral Maxillofac Surg 2015; 73: 129-33.
  17. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2) A randomised, place- bo-controlled trial. Williams-Johnson JA et al. West Indian Med J 2010;59:612–24.
  18. Antifibrinolytic drugs for acute traumatic injury. Ker K et al. Cochrane Database Syst Rev 2015;5:CD004896 .
  19. CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Dewan Y et al. http://www.trialsjournal.com/content/13/1/87
  20. Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. Germans MR et al. Trials 2013;14:143.
  21. Treatment forprimary postpartum haemorrhage. Mousa HA et al. Cochrane Database of Systematic Reviews. 2014;2:CD003249.
  22. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Shakur H et al. Trials. 2010;11:40.
  23. Effectiveness of tranexamic acid on blood loss in patients undergoing elective caesarian section: randomized clinical trial. Abdel-Aleem H et al. J Matern-Fetal Neon Med 2013; 26: 1705-9.
  24. Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review. Naoulou B et al. Acta Obstetricia et Gynecologica Scandinavica. 2012;91(5):529-37.
  25. Multisite man- agement study of menorrhagia with abnormal laboratory haemostasis: a prospec- tivecrossover study of intranasal desmopressin and oral tranexamic acid. Kouides PA et al. Br J Haematol 2009;145:212–20.
  26. Interventions to reduce haemorrhage during myomectomy for fibroids. Kongnyuy EJ et al. Cochrane Database of Systematic Reviews. 2014;8:CD005355.
  27. Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery. Coppola A et al. Cochrane Database Syst Rev 2015; 2; CD009961.
  28. How I treat target-specific oral anticoagulant–associated bleeding. Siegal DM et al. Blood 2014: 123(8): 1152-1158.
Sima Zolfaghari

Sima Zolfaghari

author

E-mail
Canada

Marian van Kraaij

Marian van Kraaij

author

E-mail
The Netherlands

Disclaimer

The content of this resource has been developed and reviewed by members of the ISBT Clinical Transfusion Working Party and should be used at the discretion of healthcare professionals utilising this clinical resource. The authors or the International Society of Blood Transfusion cannot accept legal responsibility for the content of this resource.