Old Drug, New Tricks: Tranexamic Acid Use in the Emergency Department

By Yanmen Yang, PharmD

 

What is tranexamic acid?

Tranexamic acid (TXA) is an antifibrinolytic agent approved by the Food and Drug Administration in December 1996 as an intravenous injection to reduce hemorrhage during tooth extractions and as an oral tablet in November 2009 for heavy menstrual cycles.1,2 Since then, its use has expanded to a number of off-label indications including hemorrhage from trauma, upper gastrointestinal bleeding, and epistaxis. However, TXA is not without its risks; post-marketing reports of thromboembolic events and seizures have occurred.1 Below is a review of the TXA use in the emergency situation and the risks associated with use that clinicians should be aware of.

 

  • TXA is a synthetic lysine amino acid derivative
  • Mechanism of action (see Figures 1 and 2)
    • Diminishes the dissolution of hemostatic fibrin by plasmin
    • Acts as a competitive inhibitor of plasminogen activation and at high concentrations, a noncompetitive inhibitor of plasmin

 

Figure 1. Tranexamic acid binding site on plasminogen and plasmin

 

 

Image from: Nadeau et al. JBJS Rev. 2015 Jun 2;3(6).

 

Figure 2. Tranexamic acid effects on the fibrinolytic pathway

 

Pharmacokinetics1

 

Absorption
  • Bioavailability
    • Intravenous = 100%
    • Topical = < 30% systemic absorption
  •  Onset of action = 5 – 15 minutes
  •  Duration of action = 3 hours
Distribution
  • Vd = 9-12 L, aqueous humor of eye and CSF levels 10% of plasma concentration
  • Protein binding: approximately 3% (primarily to plasminogen)
  • Crosses the placenta with approximately similar concentration in cord blood and maternal blood
Metabolism
  • < 5% metabolized
Excretion
  • Half-life = approximately 2-11 hours
  • Excretion = Urine (95% unchanged)

 

Renal dose adjustments1
Serum Creatinine (mg/dL) Tranexamic acid intravenous dosage
1.36 to 2.86 (120 to 250 umol/L) 10 mg/kg twice daily
2.83 to 5.66 (250 to 500 umol/L) 10 mg/kg daily
>5.66 (>500 umol/L) 10 mg/kg every 48 hours or 5 mg/kg every 24 hours

 

Adverse effects
  • Hypotension and bradycardia (during rapid intravenous injection > 1mL/min)
  • Infusion reaction
  • Allergic dermatitis
  • Gastrointestinal disturbances (nausea, vomiting, diarrhea)
  • Blurred vision
  • Thromboembolic events (e.g. DVT, PE)

 

Trauma-related hemorrhage

The most prominent trial on the use of TXA in acute hemorrhage comes from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial, a large, prospective randomized placebo-controlled trial.3 The investigators assessed the effects of early administration of TXA on the incidence of death, vascular occlusive events, and the need for blood transfusion in trauma patients. This randomized controlled trial enrolled over 20,000 adult trauma patients from 24 hospitals across 40 countries. Patients in the intervention group were given a loading dose of TXA 1g over 10 minutes followed by an infusion of 1g over 8 hours while the placebo group received placebo in the same manner to maintain blinding.

 

The primary outcome was death in hospital within 4 hours of injury. Patients receiving TXA had significantly reduced all-cause mortality compared with the placebo group (14.5% vs. 16.0%, p=0.035), driven by the significantly reduced risk of death due to bleeding (4.9% vs. 5.7%, p=0.007). Of note, TXA administered more than 3 hours after the injury was associated with an increased risk of death by bleeding and may be a limitation for use. The authors concluded there are mortality benefits with use of TXA and it should be considered in trauma-related bleeding.

 

For extra reading, click here for another great TOKC post on TXA in trauma. 

 

Upper gastrointestinal bleeding

After the results of the CRASH-2 trial were published on TXA’s efficacy in reducing the risk of death from traumatic bleeding, it raised the possibility of expanding TXA’s use to other bleeding situations. Studies showed a benefit with use of TXA in dialysis patients with upper gastrointestinal bleeds (UGIB).4 A randomized, controlled trial on peptic ulcer bleeding in children treated with either TXA or epinephrine submucosally during endoscopy found no statistically significant differences in the frequency of blood transfusions or duration of hospitalization.4 While a systematic review by Gluud et al. (2008) suggests a reduction in all-cause mortality with TXA, it is limited by the internal and external validity of the studies included in its review.5 An updated 2014 Cochrane review of the TXA literature on UGIBs appears to show mortality benefits but again states that high-quality randomized controlled trials are needed.6

 

The literature has largely shown inconclusive results on the benefits of TXA in UGIB. In response, the HALT-IT was designed as a randomized, double-blind, placebo-controlled trial to study tranexamic acid and its effects on mortality, morbidity, blood transfusion, surgical intervention, and health status in patients with acute UGIB.7 The HALT-IT trial is currently underway with the end of recruitment planned for May 31, 2017.7 Until the results of the HALT-IT trial are published, the risks versus benefits of patient-specific factors should be taken into consideration when deciding to use TXA for UGIB.

 

Interested in more EM-critical care of upper GI bleeds? Check out this stellar post from our archives.

 

Epistaxis

Epistaxis is common and estimated to occur in approximately 60% of patients at least once in their lifetime. Approximately 90% of epistaxis episodes are anterior, involving the Kiesselbach’s plexus within the nasal septum. Management of epistaxis in the ED typically starts with holding down firmly on the nasal septum until the bleeding episode subsides. Other measures include the use of vasoconstrictor agents (e.g. phenylephrine or epinephrine), cauterization, and nasal packing.8 Literature on the use of TXA topically in epistaxis is promising and shows good results.

 

A randomized controlled trial of 216 patients that presented to an ED were treated with either nasal packing soaked in a TXA solution (500mg in 5mL) or nasal packing soaked in epinephrine plus lidocaine for 10 minutes followed by repacking with cotton pledglets covered in tetracycline for 3 days.9 Patients who received TXA had a significant reduction in bleeding stop time of 10 minutes or less and were discharged from the ED in 2 hours or less compared with standard treatment. Complications in the ED were not significant between the groups, and the authors concluded the superiority of topical TXA based on the results of this trial. Of note, the investigators of the trial were not blinded to the treatment options and may explain the significantly greater proportion of patients with a history of epistaxis receiving TXA. These patients may exhibit a greater benefit from TXA and impact the results of the studies.9 

 

Risks with using TXA

The use of TXA, however, does not come without its risks. Thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been reported when used for off-label indications.1 Although the incidence of thromboembolic events is reportedly low, it should be taken into consideration prior to administering TXA.10

 

TXA has also been reported in a single case report to cause an extremely low false-negative D-dimer test masking pulmonary embolism. The patient presented to emergency department with 1 week of shortness of breath following TXA for menorrhagia (last dose taken 7 days prior to presentation) and was found to have a D-dimer level of 15 ng/mL (normal range ≤ 230 mg/mL). Pulmonary embolus (PE) was initially eliminated from the differential diagnosis. A CT pulmonary angiogram was eventually performed and the patient was subsequently diagnosed with an extensive bilateral PE.11 TXA can produce a false negative D-dimer due to the inhibitory effects on plasmin activation and fibrin clot dissolution and degradation. Based on this report, it may be prudent not to use D-dimer as the sole test for ruling out PE in a patient who has been treated with TXA.

 

Additionally, TXA carries a seizure risk that appears to increase with administration of high-dose TXA (~80-100 mg/kg total dose), female gender, increased age, and poor overall health.12 Seizures are reported more often when TXA is used post-procedure, particularly following cardiac and trauma surgeries and most often occurs 5-8 hours post-procedure.12 A possible mechanism for TXA-induced seizures may be related to neuronal excitation through inhibitory GABAergic antagonism activity or by TXA-mediated inhibition of glycine receptors of neurons.12,13 Results from animal studies have shown complete and reversible TXA inhibition of tonic glycine current with general anesthetics isoflurane and propofol.12

 

Lastly, an article published recently in April 2017 found neurotoxic effects (e.g. acute disorientation, confused or slurred speech, myoclonus) from TXA in patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) and a thromboembolic complication from TXA in a renal transplant recipient.14 Two of the patients on PD received intravenous TXA for post-operative bleeding (total ~15 mg/kg and ~120 mg/kg) and one patient on PD received oral TXA for post-polypectomy bleeding (total ~135 mg/kg). Of note, neurotoxicity developed after only 1 dose of TXA in one of the patients on PD. The transplant recipient received oral TXA regularly for menorrhagia (~30 mg/kg/day for an unspecified duration). All four patients recovered without sequelae. However, renal dysfunction may have contributed to the development of neurotoxicity and thromboembolic complication, therefore renal doses adjustments should be considered when using TXA these patient populations.

 

Take Home Points

    1. Tranexamic acid has shown significant mortality benefits when used for acute hemorrhage in trauma patients in the CRASH-2 trial.
    2. Expansion of TXA use in upper GI bleeds has shown inconclusive results within the literature. Clinical judgment remains of the essence – it may be reasonable to use in massive UGIBs with hemodynamic compromise.
    3. TXA used topically in the ED has shown reductions in bleeding stop time and discharge time from the ED compared with standard treatment.
    4. While thromboembolic events are rarely reported, they remain a risk with TXA therapy.
    5. The inhibitory effect of TXA on plasmin activation may produce false negative D-dimer results and may require additional diagnostic tests and imaging to rule out pulmonary emboli.
    6. Seizures have been reported after TXA use, particularly with higher doses of TXA post-procedure, and may be related to inhibitory GABAergic activity or inhibition of neuronal glycine receptors. As neurotoxicity and thrombotic complications have been reported in patients with impaired renal function, renal dose adjustments should be considered in this patient population.
References
  1. Tranexamic acid [package insert]. Rockford, IL: Mylan Institutional LLC; 2013.
  2. Lysteda [package insert]. Parsippany, NJ: Ferring Pharmaceuticals Inc.; 2013.
  3. 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. 2010;376:23-32.
  4. Sabovic M, Lavre J, Vujkovac. Tranexamic acid is beneficial as adjunctive therapy in treating major upper gastrointestinal bleeding in dialysis patients. Nephrol Dial Transplant. 2003,18:1388-1391.
  5. Gluud LL, Klingenberg SL, Langholz SE. Systematic review: tranexamic acid for upper gastrointestinal bleeding. Ailment Pharmacol Ther. 2008 May; 27(9):752-758.
  6. Bennett C, Klinenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding (review). Cochrane Database of Syst Rev. 2014 Nov 21;(11):CD006640.
  7. Roberts I, Coats T, Edwards P, Gilmore I, Jairath V, Ker K, Manno D, Shakur H, Stanworth S, Veitch A. HALT-IT – tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomized controlled trial. 2014 Nov 19,15:450.
  8. Bertrand D, Eloy P, Rombaux P, Lamarque C, Watelet JB, Collet S. Guidelines to the management of epistaxis. B-ENT. 2005;Suppl 1:27-41; quiz 42-3.
  9. Zahed R, et al. A new and rapid method for epistaxis treatment using injectable form of tranexamic acid topically: a randomized controlled trial. Am J Emerg Med. 2013 Sep;31(9):1389-92.
  10. Ng W, Jerath A, Waswicz M. Tranexamic acid: a clinical review. Anaestheiology Intensive Therapy. 2015;47(4):339-350.
  11. Salam A, King C, Orhan O, Mak V. The great deception: tranexamic acid and extensive pulmonary emboli. BMJ Case Rep. 2013 Jan. pii: bcr2012007808. doi: 10.1136/bcr-2012-007808.
  12. Lecker I, Wang DS, Whissell PD, Avramescu S, Mazer CD, Orser BA. Tranexamic acid-associated seizures: causes and treatment. Ann Neurol. 2016;79:18-26.
  13. Kratzer S, Irl H, Mattusch C, Burge M, Kurz Jorg, Kochs E, Eder M, Rammes G, Haseneder R. Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala. 2014;130:639-49.
  14. Ma TK, Chow KM, Kwan BC, Leung CB, Szeto CC, Li PK. Manifestation of tranexamic acid toxicity in chronic kidney disease and kidney transplant patients: A report of four cases and review of literature. Nephrology (Carlton). 2017 Apr;22(4):316-21.  

 

 

Written by: Yanmen Yang, PharmD

PGY-1 Pharmacy Practice Resident

 

Reviewed by: Teresa Chan, PharmD, BCPS

Edited by: Kylie Birnbaum, MD

The following two tabs change content below.

yyang

PGY-1 Pharmacy Practice Resident

2 comments for “Old Drug, New Tricks: Tranexamic Acid Use in the Emergency Department

  1. edenkim
    April 20, 2017 at 5:59 pm

    What dose of TXA should we be ordering if used for UGIB?

    Is there any evidence for LGIB?

    • Ian deSouza
      April 20, 2017 at 11:20 pm

      From the 2014 Cochrane Review: “Tranexamic acid was administered intravenously in one trial (Barer 1983) and orally in three trials (Cormack 1973; Bergqvist 1980; Hawkey 2001). The remaining trials used intravenous followed by oral administration. The total daily dose of tranexamic acid ranged from 4 to 8 g. Duration of therapy ranged from two to seven days.”

      Stay tuned for the results of the HALT-IT trial:
      http://trialsjournal.biomedcentral.com.newproxy.downstate.edu/articles/10.1186/1745-6215-15-450

      Treatment group will receive 1g bolus and then 3g over 24h.

Leave a Reply

Your email address will not be published.