Tranexamic Acid or TXA is a drug administered for a variety of reasons.  In Japan, women can by 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 antifibrinolytic in trauma patients, it had been used for several years in the Role III hospitals in Afghanistan.  It was added to the Tactical Combat Casualty Care (TCCC) guidelines by the Committee on TCCC in 2011.

TXA is a synthetic derivative of the amino acid lysine, it inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. 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.

TXA
CRASH-2 Lancet 2010 Wu AJP 2015, Cap Blood 2017 Marcos-Contreras Blood 2017.

You may be asking, why would there we be breaking down clots immediately after a traumatic event and bleeding.  This is due to the phenomenon called trauma induced coagulopathy (TIC) and acute traumatic coagulopathy (ATC).  Both ATC and TIC are convoluted and still not completely understood.

40560_2016_196_Fig1_HTML
Kushimoto et al. Journal of Intensive Care (2017) 5:6 https://jintensivecare.biomedcentral.com/track/pdf/10.1186/s40560-016-0196-6?site=jintensivecare.biomedcentral.com

What is known, is there are many players. We know that fibrinogen is being consumed 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 even claim activate protein C is the primary driver.

ATC articles and review:

https://jintensivecare.biomedcentral.com/track/pdf/10.1186/s40560-016-0196-6?site=jintensivecare.biomedcentral.com

https://www.ncbi.nlm.nih.gov/pubmed/28333829

TXA comes is supplied in 1 gram in a 10 mL ampule or vial.   The TCCC guidelines state the following for administration:

“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 reason for the 10 minute infusion is because of a few issues of hypotension 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°.

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
  • SAH
  • 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 in 40 countries and had a lot of patients, that number is 20211 patients.  The primary outcome measured was death at 4 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).

MATTERs was a retrospective, observational trial that compared TXA administration with non-TXA administration in combat casualties receiving at least 1unit blood.  They also evaluated a subset of patients receiving a massive transfusion.  They had 896 consecutive patients with combat wound, of which 293 received TXA.  Their findings in the TXA group demonstrated a lower unadjusted mortality (17.4% vs. 23.9%; P=0.3); benefit greater in patients receiving MT (14.4% vs. 28.1%; P=.04)  They said that TXA independently associated with survival (OR=7.7228; CI 3.016-17.322).

However, not everyone is convinced. There are physicians and scientists who are not so sure TXA is beneficial to everyone and in some cases, maybe harmful. Why does this happen?  It may have to do with certain types of gene expression and/or the injury pattern.  They are recommending to hold off on TXA until you can better identify who might benefit.  This is determined in the emergency room.  It is known, that 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, the best we can hope for is TXA is beneficial to most and at least not harmful to those where it is not beneficial.  From a subjective and hopeful standpoint, it is cheap and easy to administer and hope it can help save more lives in combat.  However, the jury is still out on TXA and its overall benefit in trauma patients.