Antifibrinolytics: Tranexamic acid in trauma

Cover photo.

US Army DUSTOFF (medevac) Blackhawks (right) on the flight line at sunset at a forward operating base in southern Afghanistan, December 2010. Courtesy of Dr Simon Hendel.

In the immediate aftermath of the Second World War, Utako Okamoto, Japanese doctor and physiologist, began work with her husband, Shosuke Okamoto, in a small haematology laboratory in Keio Medical School, Tokyo.^1,2 Short of research funding, they resorted to using their own blood as testing material. They were seeking a treatment for post-partum haemorrhage, then a leading cause of death in Japan. As the enzyme plasmin was known to be responsible for fibrin breakdown and the subsequent dissolution of clots, they were looking for a substance that would counteract plasmin or its precursor, plasminogen. After investigating a number of amino acids, they determined that lysine was a potent plasminogen inhibitor. By modifying the molecule, they created the first lysine analogue antifibrinolytic—epsilon amino caproic acid (EACA)—in 1952.

EACA was soon being applied clinically in many scenarios, used as an adjunct in the treatment of leukaemia, cirrhosis and various congenital blood disorders, as well as for bleeding post-cardiopulmonary bypass.^3,4 For the Okamotos though, the search continued. Large doses of EACA were required for clinical efficacy and they felt something more potent was possible and needed. In 1962, they described a new lysine analogue, 1-(aminomethyl)-cyclohexane-4-carboxylic acid (AMCHA) which existed in two isomers. ⁵ Two years later, they concluded the trans-form had far greater potency than EACA; ⁶ a discovery made simultaneously at the Kabi pharmaceutical laboratories in Stockholm. ⁷ Trans-AMCHA subsequently became known as tranexamic acid (TXA).

Clinical trials then began, particularly in areas where EACA was already proving effective. TXA was found to be useful in patients with congenital bleeding disorders for the management of superficial haemorrhage, like nose bleeds and menstruation. ⁸ Meanwhile, in the operating theatre, aprotinin, a serine protease inhibitor, remained the drug of choice for cardiopulmonary bypass, and the most studied anti-fibrinolytic. ⁹ But as the intricacies of coagulation became better understood, researchers began to address the issue of ‘non-surgical bleeding’—perioperative blood loss associated with disorders of haemostasis outside the cardiac theatres. Alongside studies of aprotinin, more work appeared on TXA with a 1991 review concluding ‘The mechanisms of aprotinin and tranexamic acid suggest we may be underestimating the importance of perioperative activation of fibrinolysis’. ¹⁰ Ten years later, TXA had been shown to be effective in ‘reducing postoperative blood losses and transfusion requirements in a number of types of surgery’. ¹¹ It was also noted that it may have ‘cost and tolerability advantages over aprotinin in patients undergoing cardiac surgery with CPB (cardiopulmonary bypass)’.

Two significant studies then dramatically changed the landscape for tranexamic acid. The first was the 2008 publication of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART), which raised concerns about the safety of aprotinin.^9,12 Despite many subsequent reviews questioning the results of this trial, aprotinin largely disappeared from clinical use, leaving TXA as the only viable alternative in many situations. Then, two years later, the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2), a large multicentre, randomised trial of early TXA administration in bleeding trauma patients, demonstrated that TXA administered in hospital within 3 hours of injury reduced 28-day mortality among patients with suspected bleeding. ¹³

CRASH-2 was largely conducted in countries without advanced regional trauma management and while many questions were raised about its general applicability, it led to a rapid increase in the use of intravenous TXA in the treatment of traumatic haemorrhage. Specifically, as TXA had been shown to be beneficial if administered early, organisations began investigating whether TXA should be given prior to arrival in hospital, a process that often required protocolised delivery by ancillary medical personnel.

Trauma protocols were already well advanced in military organisations. Experience in the wars in Iraq and Afghanistan had led to the development of the Joint Theater Trauma System, a collaboration between the United States Army, Navy and Airforce, first established in 2004. This became the Joint Trauma System (JTS) in 2016. The JTS collects and analyses data, aiming to provide optimal care to combat victims and ‘save lives with data’. ¹⁴ From the outset they developed advanced resuscitation protocols for haemorrhagic shock, focused on the appropriate and timely delivery of blood and blood products—in addition to highly developed first aid protocols.

Initially, as there were no hard data on TXA use in trauma, it was used at the discretion of the treating military surgeons or anaesthetists. While encouraged by the publication of CRASH-2, military doctors quickly realised that combat trauma was generally far more severe than that reported in the study. Accordingly, a retrospective study was conducted on patients treated at Camp Bastion, southern Afghanistan in 2009 and 2010. This suggested a survival benefit at 30 days in the patients given TXA which was much greater than that seen in CRASH-2. The investigators attributed this to the higher level of trauma in the military study and recommended ‘early administration of TXA following severe wartime vascular disruption with haemorrhage should be implemented into clinical practice’. ¹⁵ TXA was then incorporated into the JTS clinical practice guidelines for damage control resuscitation. ¹⁶ The latest review of the JTS guideline (June 2023) increased the initial dose from 1 g to 2 g. ¹⁶

Military conflicts can be even more challenging when they are de-centralised. Since 2013, the French military has been involved in several ‘light footprint operations’, such as mentoring in Somalia, supporting elections in the Democratic Republic of Congo and providing training in Mali.^17,18 Operations such as these provide particular challenges for medical personnel as troops are often spread across vast areas with limited possibilities for retrieval. This has led to prolonged field care of casualties and the need for robust protocols for resuscitation, blood transfusion and drug delivery. TXA has been incorporated into these protocols as part of a sophisticated prolonged pre-hospital trauma response.

TXA can be administered by many routes, and the intramuscular route has obvious advantages for pre-hospital delivery. Currently, the only commercial formulation provides 1 g of TXA in 20 ml, which makes the intramuscular route impractical. An autoinjector for concentrated intramuscular TXA was first proposed by Canadian forces medical personal in 2011. ¹⁹ Despite intensive funding campaigns by military organisations, development has been slow, with the first report of animal testing appearing just recently. ²⁰ This prototype autoinjector delivers 1 g of TXA in 2 ml.

The challenges of the recent conflict in Ukraine have led to even more novel suggestions. ²¹ Most casualties on the Ukraine front are taking at least 6 hours to get to a treatment point, and often up to 24 hours. Intravenous access is not a treatment priority in these circumstances and, in the absence of intramuscular TXA, some French military medical personnel have suggested oral TXA may be a better solution. Oral TXA has delayed onset, around 66 minutes, and has been successfully used in elective orthopaedic surgery. It is also used in heavy menstrual bleeding with no increase in thrombotic complications. The authors noted that this might not be the case with dehydrated, tired combatants, but postulated that prophylactic oral TXA might be useful for medical personnel entering into dangerous circumstances who may not get TXA if injured, as there would be no one to administer it. As there is currently no scientific evidence to support prophylactic use, they noted that these were personal opinions and not reflective of the armed services to which they belong. ²¹

While military organisations have the structure and incentives to drive protocolised medicine, protocols have increasingly become part of trauma care in civilian life. Many ambulance services incorporated pre-hospital TXA into their protocols following the publication of CRASH-2.^17,22 This swift incorporation of TXA into trauma protocols has been questioned by many, especially as it was driven by data largely from one large study, a study which left many questions unanswered. ²³ Subsequent large prospective studies, such as CRASH-3 and the PATCH trial have addressed some of these issues but have not diminished the enthusiasm for pre-hospital TXA in the management of trauma.^24,25

As predicted by the Okamotos, TXA has also found a place in the treatment of post-partum haemorrhage (PPH), a condition that accounts for around 100,000 maternal deaths each year, 99% of them in low and middle income countries. Shosuke Okamoto died in 2004 but Utako lived until 2016, long enough to see TXA included in the World Health Organization (WHO) guidelines for PPH in 2012. ²⁶ Subsequently the WOMAN trial, published in 2017, demonstrated a reduction in death rates from PPH and need for laparotomy to control bleeding in patients given TXA early in their treatment. The WHO guidelines were subsequently modified to reflect this evidence. ²⁷

Tranexamic acid is now well embedded in protocols and guidelines throughout hospitals, and there are calls for greater usage. ²⁸ Questions remain about its optimal use in trauma but, while research continues, more novel delivery methods may be just on the horizon.