Tranexamic acid and aminocaproic acid

"Critically evaluate the use of tranexamic acid" is not a CICM Second Part SAQ at the time of writing (in April 2021), for reasons which may be entirely accidental. Certainly, trainees have been asked questions with much less clinical relevance. It has already appeared as a sub-section in several questions about trauma (Question 16 from the second paper of 2015) resuscitating the bleeding cardiothoracic catastrophe (Question 4 from the first paper of 2001) as well as in the First Part exam (Question 4 from the first paper of 2013). It is therefore only a matter of time before the unblinking alien gaze of the examiners falls upon it. 

Pharmacological properties of tranexamic acid

Without trespassing overmuch into primary exam territory, some sort of brief pharmacological rundown is probably called for here, as otherwise it would feel wrong to keep prescribing something when you don't have a clear idea of what it does. It's not exactly novel or exotic (we've had this stuff since 1962). In brief summary:

Class Serine protease inhibitor
Chemistry Monocarboxylic acid (a synthetic derivative of the amino acid lysine)
Routes of administration IV, nebulised, topical, oral
Absorption 50% absorbed from the GI tract; bioavailability is about 30-35%. Most of it is not metabolised.
Solubility pKa of 10.22; highly water soluble, but minimally fat-soluble
Distribution VOD = 0.18 L/kg; minimally protein bound (3%, all of which is accounted for by its binding to plasminogen). After some loading (eg. several doses over 24-36 hrs), enough of it distributes to the tissues to continue having a sustained antifibrinolytic effect for many hours.
Target receptor Plasminogen
Metabolism Minimally metabolised
Elimination 95% of the dose is excreted unchanged in the kidneys; half-life is 2 hours
Time course of action Relatively short-acting, very rapid onset of effect
Mechanism of action Competitive inhibitor of plasminogen activation (by binding to the 5-lysine site on plasminogen). This inhibts the formation of plasmin and displaces plasminogen from the surface of fibrin.
Clinical effects Prevents the breakdown of fibrin, thus maintaing clot integrity. Numerous other effects (as it also inhibits other proteases), as well as indirect effects via plasminogen inhibition (eg. on complement activation, where by reducing plasmin activity it reduces the consumption of C1 esterase inhibitor)
Single best reference for further information Data sheet from medsafe.govt.nz

Aminocaproic acid (or epsilon-aminocaproic acid) was also available for many years, but was de-adopted because of hideous toxicity, including cardiac arrhythmias, rhabdomyolysis, and clots where one does not wish to have clots. Moreover, tranexamic acid has about 10 times the affinity for plasminogen.

Rationale for the use of tranexamic acid in haemorrhagic shock

  • Haemorrhage, particularly in trauma, is associated with hyperfibrinolysis (Wikkelsø et al, 2011)
  • This is seen in 2-8% of trauma patients, though the true incidence is speculated to be higher, and is associated with increased risk of mortality (Theusinger et al, 2011),
  • The reason for it seems to be the release of tissue plasminogen activator from the numerous damagaed endothelial cells (Schöchl et al, 2012)
  • Tissue plasminogen activator activates plasminogen, which in turn activates plasmin, and plasmin then acts as a fibrinolytic agent, breaking down fibrin into degradation products.
  • Plasminogen activator interacts with plasmin and plasmin interacts with fibrin by binding to lysine residues. Tranexamic and aminocaproic acid are competitive inhibitors of this binding.
  • Ergo, tranexamic acid should act as the antagonist to this process, and should decrease the transfusion requirements and mortality from haemorrhagic shock

Advantages of using tranexamic acid to control haemorrhage

  • It is cheap and widely available
  • It is a relatively safe drug, with few side effects within the usual dose range
  • It has good oral bioavailability
  • It has good shelf stability and can therefore be administered in the prehospital environment

Disadvantages of using tranexamic acid to control haemorrhage

  • The option to administer this stuff orally is not much of an advantage, as in the situations wehere one really needs it, to wait for (sluggish, erratic) absorption would be preposterous.
  • Unfortunately, tranexamic acid tructuraly resembles GABA, but does nothing to excite its receptors. The consequence of this crossreactivity is seizures, although it appears one requires insanely large doses, in the order of 7-10g.
  • There is a theoretical possibility of increased risk of thrombosis, which is still listed among other possible side effects of tranexamic acid. However, there is little evidence to support this.

Evidence for the use of tranexamic acid to control haemorrhage

One could classify the tranexamic acid trials into two broad categories, "trials that found something" and "trials that did not find any effect".

  • Evidence for a positive effect:
    • CRASH-2 trial: a large study, including numerous prehospital patients, in which tranexamic acid was demonstrated to reduce all-cause mortality in trauma patients. The trial-based dosing regimen was 1g within the first 3 hrs, followed by an infusion of 1g over the following 8 hours. A more detailed dissection of the CRASH-2 trial is performed in the chapter on haemostatic resuscitation. It will suffice to say that it had several problems with methodology, mainly stemming from the patient selection process (some might say that those people weren't real ICU trauma patients).
    • CRASH-3 trial (2019): another large study, this time looking at adults with traumatic brain injury. Again, when given with 3 hours of the injury, the mortality from mild-moderate TBI was reduced (12.5% in the tranexamic acid group versus 14.0% in the placebo group), though not from severe TBI. It also did not have any major adverse effects (so why not give it?).
    • ATACAS trial (Myles et al, 2017) looked at blood loss following cardiac suergery, and demonstrated a substantial improvement in blood product use (roughly half as much blood was transfused into the treatment group). Most interestingly, cardiac tamponade and chest reopening occurred in only 1.4%, vs. 2.8% of the placebo patients. As Dr Begley had kindly pointed out, this trial is also the only trial to demonstrate an increase in the seizure risk (0.7& instead of 0.1%), likely because the trial initially called for 100mg/kg of tranexamic acid (7g for a normal 70kg patient).
  • No evidence for a positive effect:
    • In spontaneous intracranial haemorrhage, the TICH-2 trial (2018) did not find any benefit in any patient-centred outcomes (mortality, functional outcome, etc), though the early deaths decreased from 11% to 9%. Ultimately, by day 90, the groups were the same. A radiologically detectable decrease in the expansion of the haematoma was found, which was clearly not associated with any clinical benefit, and was therefore a purely cosmetic effect. 
    • In the WOMAN trial (Shakur et al, 2017), a statistically significant improvement in the rate of death from postpartum haemorrhage was ultimately manufactured by adding 5000 extra patients to the n. Even following this manoeuvre, the difference in death from haemorrhage was 1.5% vs 1.9%, in favour of tranexamic acid by 0.4% of absolute risk reduction. The number needed to treat are 267. In view of this, one could not classify this as a positive trial while keeping a straight face.
    • In the HALT-IT trial (Roberts et al, 2020), tranexamic acid did not improve outcomes from GI bleeding, and was even thought to cause some increased risk of clotting (0.8% vs 0.4%). This was weird, as they used small conventional doses of tranexamic acid, whereas ATACAS used insanely huge ones and did not demonstrate any increase in the risk of VTE.

"Own practice"

To summarise, the literature is divided as to whether this drug actually saves any lives or not, but there is broad agreement that it is safe in responsible doses, and even in irresponsibly large doses it apprears to have no effect on the risk of thromboembolism. As such, one would be well justified in writing something like "My practice is to continue using tranexamic acid in trauma patients, PPH and during/following cardiac surgery, as the risk appears low."

References

Pilbrant, Å., M. Schannong, and J. Vessman. "Pharmacokinetics and bioavailability of tranexamic acid." European journal of clinical pharmacology 20.1 (1981): 65-72.

Griffin, James D., and Leonard Ellman. "Epsilon-aminocaproic acid (EACA).Seminars in thrombosis and hemostasis. Vol. 5. No. 1. 1978.

Wikkelsø, Anne Juul, et al. "Hyperfibrinolysis as the cause of haemorrhage and increased mortality in trauma patients." Ugeskrift for laeger 173.18 (2011): 1284-1287.

Theusinger, Oliver M., et al. "Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM®) is associated with higher mortality in patients with severe trauma." Anesthesia & Analgesia 113.5 (2011): 1003-1012.

Schöchl, H., et al. "Trauma-associated hyperfibrinolysis." Hämostaseologie 32.01 (2012): 22-27.

CRASH trial collaborators. "Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial." The Lancet 394.10210 (2019): 1713-1723.

Sprigg, Nikola, et al. "Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial." The Lancet 391.10135 (2018): 2107-2115.

Myles, Paul S., et al. "Tranexamic acid in patients undergoing coronary-artery surgery." New England Journal of Medicine 376.2 (2017): 136-148.