Tranexamic Acid (TXA)

Tranexamic acid is a synthetic form of lysine, an amino acid. It is classified as an “anti-fibrinolytic” which means it is a  pro-coagulant. It binds to receptors on plasmin preventing it from breaking down fibrin clots. Tranexamic acid was originally discovered in 1962 and is currently on the World Health Organization’s list of Essential Medicines. 

The drug has been studied in many settings for the prevention or treatment of hemorrhage. The uses most relevant to Emergency Medicine (EM) include traumatic hemorrhage, gynecological hemorrhage, and epistaxis, which are summarized below. However, dosing and references have been included, by specialty, for the other indications that have been studied. Please note that the vast majority of these indications are not currently approved by the US Food and Drug Administration (FDA).


Evidence in EM

Trauma:

Crash-2 (1); RCT, 274 hospitals, 40 countries, 20,000 patients with all forms of trauma and significant hemorrhage, TXA v. Placebo.

  • mortality relative risk reduction of 9% (absolute reduction 1.5%)
  • death from hemorrhage relative risk reduction 15% (absolute reduction 0.8%, NNT 125)
  • no difference in vascular occlusion (thrombosis) rates.
  • IV Loading dose: 1,000 mg over 10 minutes, followed by 1,000 mg over the next 8 hours.

Analysis of Crash-2 data (2)

  • If TXA given within 1 hour, relative risk reduction of death from hemorrhage 32% (absolute reduction 2.4%, NNT 41 )
  • If TXA given between 1-3 hours, relative risk reduction of death from hemorrhage 21% (absolute reduction 1.25% NNT 80)
  • After 3 hours, mortality increased in the TXA group relative risk increased 44% (absolute increase 1.3%, NNH 77)

2015 Cochrane Review (12) reached the same conclusions.

A German pre-hospital study (3) retrospectively evaluated trauma patients administered TXA pre-hospital with a matched cohort. 258 patients each group.

  • TXA treatment population received less pRBCs in the ED (not statistically sig., small study)
  • 24 hour mortality relative risk reduction 53% (absolute risk reduction 6.6%, NNT 15.1)
  • However, overall hospital mortality was similar. (Small study)

There are numerous studies involving use of TXA in pre-hospital military patients. A 2015 lengthy literature review was published in the Journal of Trauma and Acute Care Surgery (4).

Gynecology:

WOMAN trial (16); RCT, 193 hospitals, 21 countries, 20,060 women with diagnosis of post-partum hemorrhage after vaginal or c-section birth

  • death from hemorrhage, relative risk reduction 21% (absolute risk reduction 0.4%, NNT 250)
  • If TXA given within 3 hours of birth, death relative risk reduction 30% (absolute risk reduction 0.5%, NNT 200)
  • If TXA given after 3 hours of birth, no change between two groups.
  • TXA did not change hysterectomy rate.
  • TXA reduced laparotomy to control bleeding, relative risk reduction 39% (absolute risk reduction 0.5%, NNT 200)

Combined:

Hemorrhage and treatment delay effect from the Lancet (17) An analysis of CRASH-2 and WOMAN trials concluded:

  • Surgical from bleeding is better with TXA
  • Effects dramatically fall in a non-linear fashion, the longer the delay in TXA administration, with no effect between 135-180 min.
  • Estimated that treatment benefit decreased by 10% for every 15 minute delay.

Epistaxis:

Epistaxis treatment using injectable form of TXA topically (18).

  • 500 mg in 5 ml of TXA soaked into a cotton pledget was superior to anterior nasal packing.(absolute risk reduction 40%, NNT 2.5).
  • Small study, 216 patients.

Dosing

FDA Approved,Oral

  • Menorrhagia: brandname Lysteda, 1300mg PO TID during menses, max 5 days.*
  • Hereditary angioedema: brandname Lysteda, 0.5-3g /day divided QD-TID, max 1g/dose*

FDA Approved, IV

  • Dental bleeding prophylaxis in hemophilia, given with factor replacement: 10mg/kg IV TID-QID x up to 8 days. [Alternate: IV: 10 mg /kg as a single dose 2 hours prior to procedure (in conjunction with Factor VIII and IX); following procedure, administer oral tranexamic acid for 6 to 8 days]

Off Label Dosing

Cardiac Surgery

  • Prevention of perioperative bleeding associated with cardiac surgery:
  • IV: Loading dose of 30 mg/kg over 30 minutes prior to incision, followed by 16 mg/kg/hour until sternal closure; additional 2 mg/kg to cardiopulmonary bypass circuit (Fergusson 2008)

or

  • Loading dose of 10 mg/kg over 20 minutes prior to surgery followed by 2 mg/kg/hour for 2 hours after completion; add dose of 50 mg for a 2.5 L cardiopulmonary bypass circuit; adjustment for renal insufficiency (Nuttall 2008)

or

  • Loading dose of 10-15 mg/kg over 10 to 15 minutes, then 1 to 1.5 mg/kg/hour.  2 to 2.5 mg/kg to cardiopulmonary bypass circuit;but amounts vary (Gravlee 2008).

ENT

  • Epistaxis treatment using injectable form of TXA topically (18). 500 mg in 5 ml of TXA soaked into a cotton pledget was superior to anterior nasal packing.(absolute risk reduction 40%, NNT 2.5). Small study, 216 patients.

Hereditary angioedema (HAE):

  • Treatment of acute HAE attack: Oral, IV: 25 mg/kg/dose (maximum single dose: 1,000 mg) every 3 to 4 hours (maximum: 75 mg/kg/day)  or 1,000 mg 4 times daily for 48 hours (9)

Maxillofacial Surgery

  • Orthognathic (jaw) surgery, blood loss reduction: IV: 20 mg/kg over 15 minutes prior to incision (10)

Neurosurgery

  • Intracranial hemorrhage associated with thrombolytics (plasminogen-activator) (eg, alteplase, reteplase, or tenecteplase): IV: 10 to 15 mg/kg over 20 minutes (as an alternative to cryoprecipitate); check fibrinogen levels after administration, if fibrinogen <150 mg/dL, cryoprecipitate is recommended (8).
  • Spinal fusion, prevention of perioperative bleeding: IV: 2,000 mg over 20 minutes prior to incision followed by 100 mg/hour during surgery and for 5 hours postoperatively (Elwatidy 2008) or 10 mg/kg prior to incision followed by 1 mg/kg/hour for the remainder of the surgery; discontinue at time of wound closure (Wong 2008)

Orthopedics

  • Total knee arthroplasty (bilateral), perioperative blood loss reduction:
    • Three-dose regimen: 10 mg/kg administered as a slow IV infusion 30 minutes before tourniquet deflation for the first operation, 30 minutes before tourniquet deflation for the second operation, and 3 hours after commencement of the second dose (11).
    • Two-dose regimen: 10 or 15 mg/kg administered over 10 minutes before deflation of the first tourniquet, with the second dose administered 3 hours after the first dose (MacGillivray 2011).
  • Total knee arthroplasty (unilateral), perioperative blood loss reduction:
    • Intra- and postoperative regimen: 10 mg/kg at least 10 to 30 minutes prior to tourniquet release (deflation) and 10 mg/kg at 3 hours after the first dose (13; 14; 15). Instead of the second dose, a postoperative infusion may be administered at 1 mg/kg/hour for 6 hours (13).
    • Pre- and intraoperative regimen: 10 mg/kg at least 20 minutes or immediately before tourniquet inflation and repeated at least 15 minutes prior to deflation or immediately after release of tourniquet (Lozano 2008; 15).
    • Pre-, intra-, and postoperative regimen: 10 mg/kg at least 20 minutes before tourniquet inflation, repeated at least 15 minutes prior to deflation and postoperatively at 3 hours after the second dose (15).
  • Total hip replacement surgery, blood conservation: 10 to 15 mg/kg IV (or 1,000 mg) administered over 5 to 10 minutes immediately before the operation or 15 minutes before skin incision; the preoperative dose may be followed by 10 mg/kg administered 3 to 12 hours after the operation. Postoperative doses ranged from a 10 mg/kg IV bolus (or 1,000 mg) to a 1 mg/kg/hour infusion over 10 hours (Gandhi 2013; Oremus 2014).
  • Hip fracture reduction of pRBC transfusion: IV: 15 mg/kg administered at the time of skin incision followed by a second dose (15 mg/kg) 3 hours later (6)(7) Small studies. No significant increase in thrombosis. Promising for reduciton in transfusion.

OB/Gyn

  • C-section blood loss reduction: IV: 1,000 mg over 5 minutes at least 10 minutes prior to skin incision (5)
  • Cervical conization, post-operative bleeding:
    • IV/Oral: Intra- and postoperative regimen: 1 g IV infusion during procedure followed by oral therapy 1 g 3 times daily for 14 days, beginning the day after procedure (Grunsdell 1984).
    • Oral: Postoperative regimen: 1500 mg every 8 hours beginning the evening following the procedure and continuing for 12 days (Rybo 1972).
  • Postpartum hemorrhage: 1,000 mg IV over 10 minutes given within 3 hours of vaginal birth or cesarean section; if bleeding continues after 30 minutes or stops and restarts within 24 hours after the first dose, a second dose of 1,000 mg may be given (16).

Opthalmology:

  • Traumatic hyphema: Oral: 25 mg/kg administered 3 times daily for 5 to 7 days (Rahmani, 1999; Vangsted, 1983; Varnek, 1980).

Urology

  • Transurethral prostatectomy, blood loss reduction: Oral: 2,000 mg 3 times daily on the operative and first postoperative day (Rannikko 2004)

Trauma

  • Trauma-associated hemorrhage: IV: Loading dose: 1,000 mg over 10 minutes, followed by 1,000 mg over the next 8 hours.

References

  1. Shakur H, Roberts I, Bautista R, et al. 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;376(9734):23-32. https://www.ncbi.nlm.nih.gov/pubmed?term=20554319
  2. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-101, 1101.e1-2. https://www.ncbi.nlm.nih.gov/pubmed?term=21439633
  3. Wafaisade A, Lefering R, Bouillon B, et al. Prehospital administration of tranexamic acid in trauma patients. Crit Care. 2016;20(1):143. https://www.ncbi.nlm.nih.gov/pubmed?term=27176727
  4. Ausset S, Glassberg E, Nadler R, et al. Tranexamic acid as part of remote damage-control resuscitation in the prehospital setting: A critical appraisal of the medical literature and available alternatives. J Trauma Acute Care Surg. 2015;78(6 Suppl 1):S70-5. https://www.ncbi.nlm.nih.gov/pubmed?term=26002268
  5. Gungorduk K, Yıldırım G, Asıcıoğlu O, Gungorduk OC, Sudolmus S, Ark C. Efficacy of intravenous tranexamic acid in reducing blood loss after elective cesarean section: a prospective, randomized, double-blind, placebo-controlled study. Am J Perinatol. 2011;28(3):233-40. https://www.ncbi.nlm.nih.gov/pubmed/20979013
  6. Farrow LS, Smith TO, Ashcroft GP, Myint PK. A systematic review of tranexamic acid in hip fracture surgery. Br J Clin Pharmacol. 2016;82(6):1458-1470. https://www.ncbi.nlm.nih.gov/pubmed/27492116
  7. Zufferey PJ, Miquet M, Quenet S, et al. Tranexamic acid in hip fracture surgery: a randomized controlled trial. Br J Anaesth. 2010;104(1):23-30. https://www.ncbi.nlm.nih.gov/pubmed/19926634
  8. Frontera JA, Lewin JJ, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. https://www.ncbi.nlm.nih.gov/pubmed/26714677
  9. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005;139(3):379-94. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809312/
  10. Choi WS, Irwin MG, Samman N. The effect of tranexamic acid on blood loss during orthognathic surgery: a randomized controlled trial. J Oral Maxillofac Surg. 2009;67(1):125-33. https://www.ncbi.nlm.nih.gov/pubmed/19070758
  11. Weng K, Zhang X, Bi Q, Zhao C. The effectiveness and safety of tranexamic acid in bilateral total knee arthroplasty: A meta-analysis. Medicine (Baltimore). 2016;95(39):e4960. https://www.ncbi.nlm.nih.gov/pubmed/27684841/
  12. Ker K, Roberts I, Shakur H, Coats TJ. Antifibrinolytic drugs for acute traumatic injury. Cochrane Database Syst Rev. 2015;(5):CD004896. https://www.ncbi.nlm.nih.gov/pubmed/?term=25956410
  13. Alvarez JC, Santiveri FX, Ramos I, et al, “Tranexamic Acid Reduces Blood Transfusion in Total Knee Arthroplasty Even When a Blood Conservation Program is Applied,” Transfusion, 2008, 48(3):519-25. https://www.ncbi.nlm.nih.gov/pubmed?term=18067499
  14. Camarasa MA, Ollé G, Serra-Prat M, et al, “Efficacy of Aminocaproic, Tranexamic Acids in the Control of Bleeding During Total Knee Replacement: A Randomized Clinical Trial,” Br J Anaesth, 2006 https://www.ncbi.nlm.nih.gov/pubmed?term=16531440
  15. Maniar RN, Kumar G, Singhi T, Nayak RM, Maniar PR. Most effective regimen of tranexamic acid in knee arthroplasty: a prospective randomized controlled study in 240 patients. Clin Orthop Relat Res. 2012;470(9):2605-2612. https://www.ncbi.nlm.nih.gov/pubmed?term=22419350
  16. 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. 2017;389(10084):2105-2116. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446563/
  17. Gayet-ageron A, Prieto-merino D, Ker K, et al. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet. 2017; http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32455-8/fulltext
  18. Zahed R, Moharamzadeh P, Alizadeharasi S, Ghasemi A, Saeedi M. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013;31(9):1389-92. https://www.ncbi.nlm.nih.gov/pubmed/23911102

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