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Tranexamic Acid (TXA): Drug Whys

A comprehensive examination of TXA, the support for its prehospital use, and off-label administration of TXA by EMS for trauma patients with major hemorrhage


Generic Name: tranexamic acid (multiple generics available)
Common Brand Name: Cyklokapron® (Pfizer – U.S.)
Class: antifibrinolytic agent, antihemophilic agent, hemostatic agent, lysine analog

Treatment uses

Tranexamic acid (TXA) is given intravenously to prevent or reduce bleeding and reduce the need for transfusion during and after tooth extraction in patients with hemophilia. It is also given orally to treat cyclic heavy menstrual bleeding.

TXA is used off-label (without approval by the U.S. Food and Drug Administration), most often intravenously for a variety of conditions including prevention or reduction of blood loss during hip, knee, cardiac, facial, and spinal surgery as well as cesarean section and trauma. Used orally off-label for hereditary angioedema (HAE), to reduce blood loss during and after prostate surgery, and traumatic hyphema (bleeding in the anterior chamber of the eye). TXA is also used to prevent hemorrhage during extracorporeal membrane oxygenation (ECMO) therapy.  

Some surgeons use TXA soaked sponges in the surgical field to reduce diffuse bleeding. An oral solution can be used (also off-label) to prevent bleeding in anticoagulated patients undergoing dental procedures.

The significant interest in TXA by prehospital providers is its use to combat major hemorrhage in trauma patients. Many EMS protocols have recently added TXA for this off-label indication.

TXA dosing and administration

The recommended oral dose of TXA for cyclic heavy menstrual bleeding is 1300 milligrams three times daily for up to five days during monthly menses. For tooth extraction in patients with hemophilia, 10 milligrams per kilogram is recommended intravenously immediately before surgery (combined, of course, with appropriate blood clotting factor replacement) and followed by a 10 milligram per kilogram dose three to four times daily for two to eight days. The recommendation for traumatic hyphema is 25 milligrams per kilogram orally for five to seven days. HAE recommendations include 75 milligrams per kilogram each day orally divided into two to three doses for five days before and two days after each attack or inciting event/procedure. Long-term HAE prophylaxis recommendations call for 650 milligrams orally two to three times daily, titrated down as attacks decrease. Acute HAE can be treated with intravenous TXA, recommended at 25 milligrams per kilogram, up to 1 gram, every three to four hours. A 4.8 percent solution is used as an oral rinse in anticoagulated patients undergoing dental procedures with a 10 mL rinse for 2 minutes then spit out, repeated four times daily for two days after the procedure. Of note, patients should not eat or drink for one hour after using the oral rinse.  

Intravenous TXA dosing recommendations vary tremendously between surgical procedures and between published dosing regimens. There are literally dozens of clinical trials yielding widely different dosing recommendations in cardiac surgery, the procedure that has probably seen the greatest TXA utilization. The most widely used cardiac surgery IV dosing for children calls for a TXA loading dose of 100 milligrams per kilogram with another 100 milligrams per kilogram added to the cardiopulmonary bypass circuit (heart-lung machine) and an infusion of 10 milligrams per kilogram per hour for the duration of surgery. In adult cardiac surgery cases, 30 milligrams per kilogram IV TXA is the typical load, followed by 16 milligrams per kilogram per hour infusion until chest closure, with 2 milligrams per kilogram added into the bypass circuit. Orthopedic surgery recommendations vary between 10 and 15 milligrams per kilogram at the start of the procedure, repeated 3 hours later. The TXA infusion rate should not exceed 1.5 milligrams per kilogram per minute or a maximum of 100 milligrams per minute. Injections above 50 milligrams per minute can cause dizziness and/or hypotension. In general, IV TXA doses are diluted in 50 to 250 mL of fluid and infused over 5 to 30 minutes to prevent hypotension.

IV recommendations for trauma-associated hemorrhage are more consistent with a loading dose of 1000 milligrams administered over 10 minutes, followed by 1000 milligrams infused over the subsequent 8 hours. These recommendations came from the CRASH-2 clinical trial that serves as the basis for many current EMS protocols for administering TXA.

Pediatric data on tranexamic acid are limited; most published evidence involves use of TXA for tooth extraction. The limited studies suggest that adult (weight based) TXA dosing can be used for pediatric patients.  

Oral TXA can be taken without regards to food. Patients should be cautioned not to chew, crush or split sustained release (SR) TXA tablets.

In patients with severe renal impairment, dose reductions are necessary. Recommendations are based on serum creatinine and depend on the indication. In patients with liver disease, no dosage adjustments are necessary.

The numbers of patients aged 65 and over included in TXA studies has not been sufficient to determine whether there are age related differences in response to TXA. As with other medications, dosing in older patients should begin at the lower end of recommended ranges. TXA is substantially excreted by the kidneys later and elderly patients are more likely to have decreased renal function so it is particularly important to monitor renal function in older patients receiving TXA.

Overdoses of TXA have been reported. Symptoms are likely to include dizziness, headache, nausea, vomiting, diarrhea, orthostasis and hypotension. Thromboembolic (clotting) events can also occur. Overdose treatment is largely supportive although anticoagulant therapy should be considered in cases of thrombosis.

Pharmacology, pharmacokinetics and stability

Following oral administration, about 50 percent of tranexamic acid is absorbed from the gut, reaching peak plasma drug levels in three hours. Intravenous administration results in peak levels within minutes. The average half-life (time needed for half the active drug to be eliminated from the body) is two hours following intravenous administration and up to 12 hours following oral administration.

Nearly 95 percent of tranexamic acid is excreted unchanged in urine. TXA does pass through to the placenta, cross the blood-brain barrier, diffuse into joint fluid and pass through to semen. Tranexamic acid is secreted in breast milk at concentrations approximately one hundredth of maternal serum levels. At therapeutic doses, there is not likely to be antifibrinolytic effects on the nursing infant. Caution should still be exercised.  

Use of TXA during pregnancy requires a careful risk-benefit analysis. TXA levels in cord blood are similar to maternal concentrations. Adverse events were not observed in animal TXA reproductive studies.  

TXA is competitive inhibitor of plasminogen activation (inhibiting the activation of plasminogen to plasmin) and, at high doses, it noncompetitively blocks plasmin. In other words, TXA inhibits fibrin clots from being dissolved or degraded in the body by plasmin. If you recall, the clotting cascade which helps to control hemorrhage leads to fibrin formation that helps to attract clotting factors and strengthen platelet plugs.  

Obviously, the body needs an “off” switch for this process so that clotting does not continue indefinitely. Plasmin plays a major role in halting the clotting process. Normally, bleeding should be controlled by the time plasmin begins its fibrinolytic work. If it is not, the consequences can be significant. As early as 1794, pathologists noted that the last blood exiting from fatal gunshot wounds did not clot. The role of antifibrinolytics, like tranexamic acid, is to temporarily halt clot breakdown until bleeding can be surgically controlled and the patient adequately resuscitated.

Relevant clinical trials

CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage), published in 2010 provided much of the current inertia for TXA use in trauma. CRASH-2 studied a 20,211 trauma patients in 274 hospitals across 40 countries. When TXA was given within the first hour from time of injury, death due to hemorrhage reduced by one third. When give between one and three hours from injury, death rates dropped by one fifth.

Curiously, when given beyond the third hour, there was a 40 percent increase in hemorrhagic deaths. There were no differences in stroke, DVT (deep venous thrombosis) or PE (pulmonary embolism) between the two groups. The number needed to treat to save one life (NNT) was a rather high 67, considering the whole cohort (only half of which actually required blood transfusion). TXA also did not affect the transfusions actually needed between the two groups. Some of the findings, coupled with the study design, wide variability in trauma care between countries, many of them poor and underdeveloped, raise numerous questions and concerns about the study design and data collection. Regardless, the mere size of the study certainly suggested that TXA might have a prehospital role in reducing hemorrhagic mortality in trauma patients.

The MATTERs study (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) looked back at 896 combat injuries treated in Afghanistan; 296 received TXA and cryoprecipitate (a blood component product). The TXA group had 6.5 percent less mortality despite being more severely injured. They also had a higher incidence of blood clots, specifically DVT and PE but when adjusted for injury severity, this difference disappeared. The NNT was 7. Some of the limitations of MATTERs were its retrospective design, no standard protocol or dosing, no lab testing for fibrinolysis and no data on the timing of TXA administration. The study did speak very strongly to the benefits of TXA in resuscitating severe battlefield injuries with hemorrhage.  

The PATCH (Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage) trial, currently under way in Australia and New Zealand will specifically address some of the civilian and prehospital TXA administration questions and more closely examine long term patient outcomes.

TXA dosage forms, storage, and stability

Tranexamic acid has multiple generic forms in the U.S. Tablets come in 650-milligram strength. Intravenous TXA comes in 100 milligram per mL bottles of 10 mL each (total = 1 gram per vial). Tablets and IV forms of TXA should be stored at room temperature (77°F) with excursions permitted between 59 and 86°F. A diluted mixture may be stored for up to 4 hours at room temperature, according to the manufacturer. IV TXA is compatible with dextrose, saline, electrolytes, amino acid, dextran and heparin solutions. It is incompatible with solutions containing penicillin.

TXA cautions and warnings

TXA crosses the blood-brain barrier, penetrates the eye and results in cerebrospinal fluid concentrations roughly 10 percent of plasma levels. Seizures have been reported from TXA, as have visual defects consisting of color blindness and visual loss. Cardiac surgery studies suggest that moderate to high TXA doses significantly increase the risk of seizures. Visual defects, when reported, occurred in patients treated with TXA for several days or longer.  

Obviously, an antifibrinolytic agent such as TXA can result in clots. Venous and arterial blood clots (thromboembolic events) including DVT, PE and cerebral thrombosis (stroke) have been reported.  

Caution should be exercised when considering TXA for patients with a history of thrombotic events or a familial history of thrombosis. As mentioned previously, dose adjustments are necessary in patients with renal impairment.

Important TXA side effects and interactions

Gastrointestinal side effects are the most commonly reported by patients receiving TXA and occur in 30 percent of people given more than 6 grams daily of TXA.  

Other side effects are relatively rare (less than 1 percent). Dizziness has been reported and is likely dose related or, in the case of intravenous administration, related to the speed of administration.

Currently, there are only a handful of drugs reported to interact with tranexamic acid. Of these, three are worth noting for prehospital and emergency medicine providers. Patients taking estrogens or progestins may have enhanced thrombogenic effects with TXA. Patients taking oral tretinoin, a chemotherapy agent used to treat leukemia may also have enhanced effects from TXA. Note that tretinoin is also used as a topical cream for treatment of acne; it is the systemic (oral) form that interacts with TXA.

Average costs of TXA in the US

Price at the time this article was written for a 100 mg/mL (10 mL) generic tranexamic acid vial for intravenous administration:

  • EMS Service cost: $53.20 each
  • Large Hospital cost: $21.10 each
  • CRASH-2 Study cost: $5.70 each (US dollars) on British National Formulary

References

1. Lexicomp®: Wolters Kluwer Health, Hudson, Ohio (accessed June, 2015).

2. Albany Medical Center Pharmacy, Albany, New York.

3. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE. Tranexamic acid in trauma: How should we use it? J Trauma Acute Care Surg. 2013; 74:1575-1586.

4. Ausset S, Glassberg E. Nadler R, Sunde G, Cap AP, Hoffmann C, Plang S, Sailliol A. Tranexamic acid as a 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:S70-S75.

5. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military application of tranexamic acid in trauma emergency resuscitation (MATTERS) study. Arch Surg. 2012; 147: 113-119.

6. Moore EE, Moore HB, Gonzalez E, Chapman MP, Hansen KC, Sauaia A, Silliman CC, Banerjee A. Postinjury dibrinolysis shutdown: rationale for selective tranexamic acid. J Trauma Acute Care Surg. 2015; 78:S65-S69.

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