A 32-year-old male presented to the Emergency Department (ED) with two self-inflicted stab wounds to the abdomen. He had used a knife with a 6-inch blade which had been recovered by the ambulance crew. Prior to arrival in the ED he had been cold, clammy and sweating profusely with a blood pressure initially of 85/40 mmHg. On examination he looked unwell and had two wounds in the right upper quadrant of his abdomen. There is minimal external haemorrhage and a dressing has been applied. He has considerable pain on palpation of his abdomen.
A Computed Tomography (CT) scan of the abdomen is arranged and whilst waiting it was suggested that the should patient receive 1g Intra Venous (IV) tranexamic acid (TXA).
Major trauma is a considerable health burden internationally and is the leading cause of death amongst those under 40 years old in the developed world (American College of Surgeons Committee on Trauma 2012). In England there are over 20,000 cases of major trauma per annum which results in 5,400 deaths (National Audit Office 2010). Of those deaths, 40% occur due to uncontrolled haemorrhage (Curry et al 2011).
Haemorrhage (and subsequent shock) is the cause of acute traumatic coagulopathy (ATC), which is found in approximately 25% of trauma patients and is associated with a 5-fold increase in mortality (Brohi et al 2003). A key element of ATC is the activation of fibrinolytic pathways leading to hyperfibrinolysis (Brohi et al 2008).
As part of the normal extrinsic clotting cascade, once the damaged subendothelium is exposed to blood containing aggregated platelets (with upregulated GPIIb/IIIa receptors), a stable clot is formed through a number of mechanisms:
- factor Xa converts prothrombin to thrombin
- fibrinogen converted to fibrin
- fibrin converted to stabilised fibrin by factor XIIIa
Fibrinolysis (the physiological mechanism by which clots are dissolved and vessels are kept patent) is activated at the same time as clot formation (Tengborn et al 2015). This process occurs when Tissue Plasminogen Activators (tPA) convert inactive plasminogen to plasmin, which is a proteolytic enzyme that degrades fibrin (Levy 2010). It is thought that both secretion and synthesis of tPA is increased by the tissue damage caused in trauma, resulting in the hyperfibrinolysis (Tengborn et al 2015).
TXA exerts an antifibrinolytic effect by acting as a lysine analogue, which inhibits the binding of lysine to the binding-sites on plasminogen molecules. This inhibits the activation of the enzyme plasminogen, resulting in decreased activation of plasmin and therefore reduced fibrinolysis and blood loss (Pusateri et al 2013).
Prior to its consideration for use in trauma, TXA had previously been shown to reduce need for blood transfusion by 33% in those undergoing elective surgery (Zufferey et al 2006). The CRASH-2 trial (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2) was published in 2010 and was the first large randomised controlled trial (RCT) examining TXA use specifically in traumatically injured patients. The similar haemostatic responses to trauma and surgery, led the authors to believe TXA could potentially reduce mortality (CRASH-2 trial collaborators 2010). They enrolled 20,000 patients from over 40 countries and randomised over 10,000 patients in each group to receive either, 1g TXA IV over 10 minutes then 1g over 8 hours, or a matching placebo.
The study demonstrated an all cause reduction in mortality from 16% in the placebo group to 14.5% in the TXA group (relative risk 0.91, 95% confidence intervals 0.85-0.97, p=0.0035). This represents a number needed to treat of 68 (i.e. there will be one additional survivor for every 68 patients treated). The risk of death specifically due to bleeding was reduced from 5.7% to 4.9% (relative risk 0.85, 95% confidence interval 0.76-0.96, p=0.0077).
This treatment effect was only present if TXA was administered within 3 hours of the time of injury therefore authors concluded after this time there was no benefit to administration.
The CRASH-2 trial has a number of strengths including its size, methodology (placebo controlled, randomised controlled trial), generalisability (over 40 countries around the world) and absence of any pharmaceutical company bias, as TXA is off-label meaning the entire treatment can be provided for £3 (Joint Formulary Committee 2016).
Weaknesses have also been suggested by some authors who feel the large numbers of patients from the developing world (without mature trauma systems) may have limited the applicability of the findings to UK practice (Binz et al 2015). It is also widely felt that laboratory analysis of clotting factors (e.g. fibrinogen) throughout the trial would have been valuable when interpreting the findings and determining the value of treatment (Binz et al 2015).
Despite these points, the use of TXA (as per the CRASH-2 trial) has been recommended by the National Institution for Heath and Clinical Excellence (NICE) in their major trauma guidance published in 2016. It is recommended that 1g is given IV over 10 minutes followed by a further 1g over 8 hours in an infusion. With a number needed to treat of 68, this represents the potential to save 80 lives per annum in the UK.
There has been a large randomised placebo-controlled trial which has demonstrated improved mortality when TXA is given in haemorrhagic shock (CRASH-2 trial collaborators 2010). Whilst the overall mortality benefit might be small, is comes with minimal increase in overall cost and no change to thromboembolic risk. NICE guidance published in 2016 has reflected this research and advocates TXA administration for those with suspected non-compressible haemorrhage resulting in hypovolaemic shock.
Clinicians with the potential for exposure to traumatically injured patients should be aware of the mechanism of action, indications and evidence base for TXA. This will allow appropriate, timely administration and improved mortality rates, in those presenting to the ED within 3 hours who have ongoing suspected haemorrhage due to trauma.
Note – this was written before the recent WOMAN trial was published looking at TXA in postpartum haemorrhage. If you are looking for a review of this paper then I’d thoroughly recommend the review by the fantastic team at thebottomline.org. It also features in June’s “papers of the month” over at TheResusRoom – have a listen if you get chance!
American College of Surgeons Committee on Trauma. (2012) Advanced Trauma Life Support. Student Course Manual (9th Edition). American College of Surgeons. United States of America
Brohi, K., Cohen, M. J., Ganter, M. T., Schultz, M. J., Levi, M., Mackersie, R. C & Pittet, J. F. (2008) Acute coagulopathy of trauma: hypoperfusion induces systemic antigoagulation and hyperfibrinolysis. Journal of Trauma. Volume 65, pp1211-17.
Brohi, K., Singh, J., Heron, M & Coats, T. (2003) Acute traumatic coagulopathy. The Journal of Trauma. Volume 54, pp1127-30.
CRASH-2 trial collaborators. (2010) Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. The Lancet. Volume 376, number 9734, pp23-32.
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Joint Formulary Committee. (2016) British National Formulary. 72nd Edition. London. BMJ Group and Pharmaceutical Press.
Levy, J. H. (2010) Antifibrinolytic therapy: new data and new concepts. The Lancet. Volume 376, pp3-4.
National Audit Office. (2010) Major trauma care in England. Stationary Office Limited. London.
National Institute for Health and Clinical Excellence. (2016) Major trauma: assessment and initial management (NICE guideline NG39). Available from: https://www.nice.org.uk/guidance/ng39 (last accessed 21/12/16).
Pusateri, A. E., Weiskopf, R. B., Bebarta, V., Butler, F., Cestero, R. F., Chaudry, I. H., Deal, V., Dorlac, W. C., Gerhardt, R. T., Given, M. B., Hansen, D. R., Hoots, W. K., Klein, H. G., Macdonald, V. W., Mattox, K. L., Michael, R. A., Mogford, J., Montcalm-Smith, E. A., Miemeyer, D. M., Prusaczyk, W. K., Rappold, J. F., Rassmussen, T., Rentas, F., Ross, J., Thompson, C., Tucker, L. D & The US DoD Haemorrhage and Resuscitation Research and Development Steering Committee. (2013) Tranexamic acid and trauma: Current status and knowledge gaps with recommended research priorities. Shock. Volume 39, number 2, pp121-26.
Tengborn, L., Blomback, M & Berntop, E. (2015) Tranexamic acid – an old drug still going strong and making a revival. Thrombosis Research. Volume 135, pp231-242.
Zufferey, P., Merquiol, F., Laporte, S., Decousus, H., Mismetti, P., Auboyer, C., Samama, C. M & Molliex, S. (2006) Do antifibrinolytics reduce allogenic blood transfusion in orthopaedic surgery? Anaesthesiology. Volume 105, number 5, pp1034-46.