Tranexamic Acid

Tranexamic acid is a derivative of lysine that was discovered by Drs Utako and Shosuke Okamoto in Japan
in the late 1950s. It inhibits conversion of plasminogen into plasmin, thus preventing fibrinolysis and some
inflammatory cascades. It was initially proven to be effective in the control of menorrhagia in the late
1960s, and in the 1970s for various other diseases associated with coagulopathy and hemorrhage, including
heredity angioedema. These early successes spurred studies into intra-cranial hemorrhage and intra-vitreal
hemorrhage, on which TXA had limited effect. Further uses included prophylaxis for hemophiliacs prior to
tooth extraction.

Tranexamic acid was further explored for control of massive hemorrhage from upper GI bleeding in the mid
1980s with some benefit in reducing transfusion requirements. In the early 1990s, randomized controlled
trials demonstrated benefit in reducing transfusion requirements during cardiopulmonary bypass.
In the early 2000s, expansion of this benefit in cardiac surgery to trauma patients with hemorrhage was
attempted, as trauma patients with severe injuries are frequently coagulopathic due to acidosis, hypothermia
and dilution from resuscitation.

The largest trial of tranexamic acid was a randomized, placebo-controlled study involving 20,000 patients
thoughout the world: CRASH-2. This trial recruited blunt and penetrating trauma victims presenting within
8 hours of their injury who were believed to be hemorrhaging or at high risk of hemorrhaging. They were
included in the trial if they had no contra-indication to tranexamic acid, and the attending surgeon did not
believe there was a clear indication to give the medicine. The resulting participants were generally young
(75% less than 45 years old) males (84%) with blunt trauma (68%). Of note, 70% of participants were
mildly hypotensive or normotensive (SBP >90) but tachycardic. The vast majority of deaths in this study
occurred within 24 hours of treatment initiation.

The main outcome of the study was decrease in mortality of 2.5% from any cause (14.5% vs 16%), resulting
in a 9% relative reduction in death. This is quite a significant result for any single intervention in the
complicated process of trauma resuscitation. Death from bleeding was similarly decreased from 5.7% to
4.9%, resulting in a 15% relative reduction in death.

Interestingly, only 50% of both groups were transfused. In addition, the median amount transfused was only
6 units for both groups. A possible explanation is that surviving patients in the tranexamic acid group lived
long enough to receive more blood later in resuscitation, and subsequent doses of the drugs were given well
after the initial resuscitation. Though tranexamic acid could be expected to increase thrombotic events, this
was not seen even though trauma patients are generally at high risk for such complications.

A retrospective analysis by a US & UK military hospital in Afghanistan on penetrating trauma requiring
transfusion and operative intervention showed an even larger survival benefit of 17 vs 24% (a 30% relative
benefit) in all studied patients, and remarkable 14% vs 28% (50% relative survival) in patients undergoing
massive transfusion. In the first half of the time period that was reviewed, patients were given TXA upon
discretion of the surgeon. Afterwards, any patient requiring emergency blood transfusion was given TXA.
In general, patients receiving TXA had a higher Injurity Severity Score, lower GCS, high rates of hypotension and taken earlier for operative intervention. Of note, patients in the massive transfusion cohort had no significant difference in amount of blood products transfused. As in CRASH-2, there were no significant increases in thrombosis, DVTs or PEs in the transexamic acid group.

In summary, tranexamic acid is a medication well known to reduce hemorrhage and its resulting
complications in a wide variety of illnesses. Through CRASH-2, a well-designed randomized controlled trial,
some benefit for trauma patients in general has been identified. The limitation of that trial was the low
severity of injury and that only 50% of patients required any transfusion. MATTERs is a retrospective study
that strongly suggests that in severely injured patients with hemorrhage, tranexamic acid can be a life-saving
medication with limited side effects.

Editorial: The Lancet, Volume 379, Issue 9819, Page 867, 10 March 2012
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Thanks to Dr. Abhineet Uppal for this review.