Tranexamic Acid or TXA is a drug administered for a variety of reasons. In Japan, women can buy it over the counter for heavy menstrual bleeding. It is used for prophylaxis before some knee surgeries to prevent bleeding. In the military, it is used as an anti-fibrinolytic in trauma patients and has been in use for several years at the Role III hospitals in Afghanistan. In 2011, it was added to the Tactical Combat Casualty Care (TCCC) guidelines by the Committee on TCCC for the use for casualties that are expected to receive a blood transfusion.
TXA is a synthetic derivative of the amino acid lysine, it inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. In normal clotting cascade and fibrinolysis (Figure 1), plasminogen is cleaved to plasmin by tissue plasminogen activator (tPA). In turn, plasmin then breaks down fibrin, the insoluble substance that holds clots together. Therefore, by blocking this conversion of plasminogen to plasmin, the formed clot will be maintained.
Due to trauma induced coagulopathy (TIC) and acute traumatic coagulopathy (ATC), there can be increased fibrinolysis in severe trauma (Figure 2). Both ATC and TIC are convoluted and still not completely understood.
There are several factors involved with ATC and TIC. It is known that fibrinogen is being consumed rapidly and if there is no resuscitation, prothrombin drops up to 20%, and thrombin is increased 1.5 times over first 4 hours, and finally, plasmin rises 2.5 times. Some studies support the theory that activated protein C is the primary driver.
ATC articles and review:
The current indications for the use of TXA in TCCC are as follows:
“If a casualty is anticipated to need significant blood transfusion (for example: presents with hemorrhagic shock, one or more major amputations, penetrating torso trauma, or evidence of severe bleeding): Administer 1 gm of tranexamic acid in 100 ml Normal Saline or Lactated Ringer’s as soon as possible but NOT later than 3 hours after injury. When given, TXA should be administered over 10 minutes by IV infusion. Begin the second infusion of 1 gm TXA after initial fluid resuscitation has been completed.”
The reasoning behind the 10 minute infusion, is due the possibility of hypotension if given too rapidly. This was observed and noted during the CRASH-2 study. Some argue that it can be pushed slowly in a 10 mL syringe over a few minutes. TXA should not be administered in the same line as blood or blood products or in a line used for rFVIIa or Penicillin. It should be stored between 15-30 C°or 56-86 F°. TXA is supplied as 1 gram in a 10 mL ampule or vial.
Side effects include:
- Ocular – color vision change, vision loss
- Seizure – probably related to neuronal GABA inhibition
- Renal Impairment
- Ureteral Obstruction – upper tract obstruction may lead to bleeding
The contraindications for TXA:
- Acquired defective color vision
- Active intravascular clotting
- Hypersensitivity to TXA
What do the studies demonstrate?
CRASH-2 was a randomized and prospective study. It took place in 247 hospitals throughout 40 countries, with a large number of patients (N=20,211). The primary outcome measured was death at four weeks with intention to treat. The investigators found, that all causes of mortality decreased by 10% (RR 0.91, 95% CI 0.85-0.97). Furthermore, the risk of death from bleeding decreased by 15% (RR 0.85, 95% CI 0.76-0.96). The data also noted that there was increased mortality when the initial dose of TXA was given past three hours.
MATTERs was a retrospective, observational trial that compared TXA administration with non-TXA administration in combat casualties receiving at least 1 unit blood. They also evaluated a subset of patients receiving a massive transfusion. There were 896 consecutive patients with a combat wound, of which 293 received TXA. Their findings in the TXA group demonstrated a lower unadjusted mortality (17.4% vs. 23.9%; p=0.03); benefit greater in patients receiving MT (14.4% vs. 28.1%; p=0.04) Their conclusion said TXA was independently associated with survival (OR=7.7228; CI 3.016-17.322).
Military use of tranexamic acid in combat trauma: Does it matter? was a much larger retrospective study from Afghanistan over a 3-year, 6-month period from October 1, 2010, to March 31, 2014. It included combat wounded, those admitted to a Role 3, and received at least one unit of blood or blood component. The overall patient population was 3,773. For results purposes, the casualties groups, 1. patients requiring a massive transfusion (N = 784), 2. a propensity score-matched sample (N = 1,030), and 3. NATO members (N=1262). Of those casualties receiving a massive transfusion (HR, 0.84; 95% CI, 0.46–1.56; p = 0.51), the propensity-matched sample (HR, 0.68; 95% CI, 0.27–1.73; p = 0.34), or US/NATO military sample (HR, 0.76; 95% CI, 0.30–1.92; p = 0.48) did not indicate a significant association between TXA administration and mortality. The use of TXA was associated with increased risk of pulmonary embolism in the total sample, massive transfusion sample, and the NATO military sample. TXA was also associated with increased risk of deep vein thrombosis in the total sample and the NATO military sample.
Prehospital Administration of Tranexamic Acid by Ground Forces in Afghanistan: The Prehospital Trauma Registry Experience is the only study from the TCCC perspective. This retrospective review from January 2013 to September 2014, there were 272 patients who met inclusion criteria. Most injuries (97.8%; n = 266) were battle injuries. Of the 111 patients who met criteria to receive prehospital TXA only 51 (18.8%) received TXA, the remaining 221 (81.2%) did not. There was a sub-analysis of four interventions, 1. Hemostatic dressing, 2. Pressure dressing, 3. Tourniquet and 4. IV fluids. Though the numbers were small, there was a significant difference in TXA administration versus not receiving TXA for casualties with hemostatic dressings, pressure dressings, and tourniquet placement. Oddly, the proportion of patients receiving IV fluids was higher among the non-TXA group.
The mechanism of TXA in the trauma has been debated. A sub-analysis of the CRASH-2 trial suggested TXA’s impact is due to anti-fibrinolytic effects, whereas results from the MATTERs trial supported an anti-inflammatory effect mechanism.
There are physicians and scientists who believe TXA may not beneficial to everyone and in some cases, maybe harmful. This issue may have to do with certain types of gene expression and/or the injury pattern. Some studies recommend holding off on TXA administration until they arrive at the hospital and can conduct the proper lab work. As previously mentioned, giving TXA after three hours is harmful, there is no debate about that claim.
For now, TXA will remain a vital part of TCCC. It may have contributed to saving lives in combat since its implementation. Many EMS agencies around the country have implemented similar protocols to TCCC. From a scientific standpoint, it is hopeful, that TXA is beneficial to most and not harmful.