OBJECTIVES
Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to decrease mortality rates associated with post-haemorrhage acute coagulopathy of trauma (ACT). By assessing how the timing and dosage of TXA administration impacts on mortality rates pertaining to both intra- and extracranial bleeds, correct measures may be taken to integrate the treatment into emergency (including pre-hospital) protocol. A cautionary review of  TXA’s potential side effects was completed, also evaluating potential outcomes of TXA use in patients not experiencing ACT. 

RESULTS
Optimal effects correspond to a loading dose of 10mg/kg, with subsequent infusions of 1mg/kg/hr. Higher doses do not result in increased efficacy and have been associated with convulsive seizures, linked to the structural similarities between TXA and γ-aminobutyric acid. TXA infusions less than 3 hours post-injury reduce mortality rates, significantly so when delivered less than 1 hour after the trauma. Mortality rates increase when TXA is delayed for 3 or more hours. TXA administration to patients not experiencing ACT does not lead to increased development of thromboembolic events. TXA administration is found to be cost effective based on GDP per capita per disability-adjusted life year. 

CONCLUSIONS
Early treatment (<1 hour post-injury) with TXA results in the greatest reduction in deaths caused by bleeding in patients who are or may be at risk of becoming hyperfibrinolytic. It is logical to assume that early infusion (<1 hour post-injury) of TXA into severely haemorrhaging patients at risk of hyperfibrinolysis will result in reduced in mortality rates.

Introduction

Globally, trauma results in 5.8 million fatalities, accounting for 10% of world deaths. Haemorrhage is responsible for up to 40% of in-hospital trauma-induced deaths, establishing bleeding and its subsequent consequences as the major cause of avoidable death within this category [1].  Coagulopathies are present in the majority of significant haemorrhage cases, induced by clotting factor depletion as a result of haemodilution. These deleterious events result in an impaired platelet and thrombin function and reduced fibrinogen availability [2].

Primary fibrinolysis can result in the development of Acute Coagulopathy of Trauma (ACT). ACT is diagnosed in up to 40% of patients with tissue hypoperfusion and there is a high association between trauma-induced hyperfibrinolytic activity and death (70-100%) [2]. Therefore, it is plausible that the treatment of ACT with antifibrinolytic medications, such as tranexamic acid (TXA) would impact significantly on mortality rates [2]. This review will discuss the modern use of TXA in the treatment of haemorrhage within the trauma environment. Emphasis will be placed on overall relative decreases in mortality rates, timing and dosages of infusions, documented side-effects and overall cost-effectiveness of the drug on an international scale. 
 

Biological Activity of Tranexamic AciD
 

Under normal physiological conditions, plasmin is activated by the endothelium, kallikrein-mediated plasmin activation and the release of tissue plasminogen activator (tPA). These mechanisms are modulated by tissue- and urokinase-type plasminogen activators. Conversely, inhibition is integral for haemostatic balance, a process modulated by multiple inhibitors such as thrombin-activatable fibrinolysis inhibitor, α2-antiplasmin and plasminogen activator inhibitor 1 [3]. However, extensive tissue trauma may shift the equilibrium between plasmin activation and inhibition, resulting in hyperfibrinolysis that contributes significantly to haemorrhage and acute coagulopathy of trauma [3].

Synthesized in the liver, the proenzyme plasminogen, is converted into active form plasmin by tissue plasminogen activator. Plasminogen is folded into protruding circular structures called kringles, which house the lysine-binding sites for fibrin attachment. Fibrin binds both plasminogen and tPA, localising plasmin activation to the injured region. Plasmin is a serine protease that lyses the fibrin into degradation products, sequentially exposes more lysine residues to activate more plasminogen, thus accelerating the fibrinolytic process [4].

Tranexamic acid, a synthetic derivative and analogue of lysine, is an antifibrinolytic drug given to competitively inhibit the conversion of plasminogen to active plasmin, by obstructing the lysine-binding sites on the inactive form. TXA, like ε-aminocaproic acid (another lysine analogue) interrupts the binding of plasminogen to fibrin, an interaction necessary for activation [1-4]. Tranexamic acid has been in use since the early 1960s in treating haemophilia, and is widely used in orthopaedic and cardiac surgery. However, extensive use in the trauma population was sparked only recently by the Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage (CRASH) -2 study, released in 2010 [5].
 

CRASH-2 Trial
 

The CRASH-2 trial investigated the effects of TXA on mortality rate, vascular occlusion and requirement for blood transfusion in trauma patients with significant haemorrhage [5]. 20,211 adult trauma patients were recruited across 274 hospitals. Those experiencing, or at risk of experiencing, significant haemorrhage were assigned randomly to either a TXA-receiving group or a placebo-receiving group. Patient assignment was completed within 8 hours of injury. Patients with a definite indication or definite contraindication for the use of TXA were excluded. The primary outcome of the study was death within 4 weeks of haemorrhage. The study concluded that TXA administration significantly reduced all-cause mortality (14.5%) compared to placebo (16%). The risk of death due to exsanguination was also lower in the TXA-group (4.9%, versus 5.7% in the control patients) [5].
 

i.    Dose: 
The dose of TXA used in this trial was based on the use of this drug in surgery, where the loading doses varied from 2.5-100mg/kg [6]. However, studies indicate that the dose size had no significant impact on blood loss or blood transfusion requirements. For CRASH 2 trial patients weighing from below 50 to in excess of 100kg, an initial loading dose of 10mg/kg, with subsequent infusions of 1mg/kg/h  rendered the plasma concentration sufficiently high to inhibit fibrinolysis, with no additional inferred haemostatic advantage when a higher dose is administrated [7,8] .
 

ii.    Timing: 
Although TXA infusions were received within 8 hours post injury, significant discrepancies in survival rates were observed depending on the timing of administration. TXA infusions delivered within 1 hour, or between 1-3 hours, following injury resulted in significantly reduced mortality rates due to exsanguination vs placebo (5.3% vs 7.7% and 4.8% vs 6.1% respectively). The mortality rates reversed when TXA was administered greater than 3 hours post injury (4.4% vs 3.1%) [5].
The severity of fibrinolysis can be assessed by measurement of D-dimers, protein fragments from fibrin degradation. The higher the concentration of D-dimers, the greater the severity of injury, as shown by Brohi et al. from samples that were extracted from patients at the time of hospital admission, with a median pre-hospital time of 28 minutes [9]. This early increase in fibrinolysis appears to promote exsanguination, increasing the risk of death. Therefore, early administration of an antifibrinolytic drug would be most suitable. This theory is reinforced by the CRASH-2 study that indicated delivery of TXA is most effective less than 1 hour post injury [5].

The increased death rates associated with infusion 3 hours or longer post-trauma were surprising. It may be explained by the pro-thrombotic disseminated intravascular coagulation that can develop in the late stages of trauma [10]. Disseminated intravascular coagulation involves fibrin formation and coagulation, though as time progresses, the coagulation proteins are rapidly consumed and so can become exhausted, causing late bleeding. The CRASH-2 time frame of less than 8 hours was instated in order to avoid delivering an antifibrinolytic drug in this late stage of haemorrhage. It must be considered that the development of a pro-thrombotic state occurred sooner than initially anticipated in some patients [11]. Furthermore, the risk of existing acidosis or hypothermia increases with later hospital arrival. These other systemic factors may play a role in the interaction of TXA and the blood proteins. More research needs to be carried out with regards to the mechanism of TXA action when infused 3-8 hours post trauma [11].
 

Tranexamic Acid in the treatment of Intracranial Haemorrhage

The efficacy of TXA for intracranial haemorrhage is also of clinical significance in the trauma environment [15]. The size of a traumatic intracranial haemorrhage is proportional to the risk of death and disability, irrespective of location [16-18]. The CRASH-2 trial suggested that if the intracranial bleeding could be reduced, the outcome of the patient may improve. After a physical trauma to the parenchyma, thromboplastin is released into the blood stream in high concentrations, disturbing the coagulation process. Furthermore, due to the damage of the cerebral endothelium, activation of clotting cascades and platelets ensues, resulting in an intravascular thrombosis and a reduction in coagulation factors [19,20]. TXA allows for the maintenance of mature fibrin and uninterrupted coagulation. It is theorized that TXA reduces secondary brain injury through two main mechanisms; firstly, by limiting fibrinolysis (and thus intracranial haematoma enlargement) and secondly, through the reduction in perilesional oedema by inhibiting the effect of tissue plasminogen activator [19]. Two high quality clinical trials [15,21] demonstrated a decrease in intracranial haematoma in the TXA cohort, deduced on the basis of total volumetric growth, new areas of haemorrhage and the presence of the mass effect [5,15]. An improved mortality rate was also seen in patients who received TXA relative to the placebo cohort. Though the individual studies’ results are statistically insignificant, a meta-analysis reveal a statistically significant reduction in haemorrhage progression following the administration of TXA in patients with traumatic brain injuries [19].
 

Integration of Tranexamic Acid into the Pre-hospital Scene: Military and Civilian Settings    
 

Based on the research presented above, haemostatic resuscitation should begin at the earliest possible opportunity. Intervention in the pre-hospital setting presents the best chance for a positive prognosis [28]. The possibility of the administration of TXA in the pre-hospital field has been discussed at length by the WHO. Studies, many of them military based, support its pre-hospital use. The British military incorporated TXA into their formal clinical practice guidelines in 2010, [24] while 2012 saw the US military incorporate TXA use into the guidelines for tactical combat casual care [25].

The MATTERs Military study indicated that TXA use yielded an absolute reduction in mortality of 6.5% [24,25] overshadowing the more subtle 1.5% reduction demonstrated in the CRASH-2 trial [5] .The MATTERs study also revealed a 13.7% absolute reduction in mortality in the portion of the TXA cohort who required a massive blood infusion (greater than 10 units) relative to the non-TXA cohort who required the same transfusion volume [24]. These findings suggest an increased benefit of TXA in those more seriously injured. In 2014, TXA was been introduced in the Irish pre-hospital protocol, 3 years after the NHS commenced paramedic administration of the anti-haemorrhagic agent. Further systematic review of the benefit of pre-hospital TXA infusions in the civilian setting remains to be done [26].

TXA can be reliably stored in emergency vehicles, such as ambulances and medical helicopters. A recent study [27] demonstrated that TXA remains stable for up to 12 weeks, and can be exposed to temperatures ranging from -20 to 50 degrees Celsius without functional compromise. This functionality was determined based on the ability of TXA to completely inhibit streptokinase-induce fibrinolysis in platelet-poor plasma, as determined by D-dimer and thromboelastography evaluations [27]. The storage properties of TXA would facilitate early pre-hospital infusions for haemorrhaging patients.  
 

Side Effects

Seizures following Tranexamic Acid Administration: 
Following cardiac surgery where TXA has been administered, a high number of postoperative convulsive seizures have been documented, corresponding to TXA doses that are 2-10 fold higher than those administered in the CRASH-2 trial [5]. These seizures led to an increased rate of neurological complications. A possible mechanism for TXA-induced seizures is the structural similarity of TXA and γ-aminobutyric acid as a potential cause of neurotoxicity [5]. In the adult brain, γ-aminobutyric acid (GABA), an inhibitory neurotransmitter, plays a fundamental role in the organisation of electrical conductance patterns and the prevention of seizure-like activity [22]. The actions of antagonists against the GABA type A receptors will result in epileptic activity. Temporal lobe epilepsy is stimulated substantially by the neuronal excitability of the basolateral nucleus of the amygdala. In a 2014 study, it has been shown that TXA impairs GABA type A-mediated synaptic transmission in the murine amygdala, in a dose-dependent fashion [23]. TXA administration at doses in the region of 100 mg/kg has an indicated increased risk of seizures, [6,7] conveying the importance of a fixed initial dose in trauma. The incidence in dose-dependent seizure occurrence in the trauma situation has not yet been examined, [11] but is advised considering the listing of TXA in the WHO’s list of essential medicines and thus, its global-wide use [15].

Outcome if TXA Administered to a Patient Not Experiencing ACT: 
Direct indication for the use of TXA would rely on a known history of fibrinolytic drug use or lab evidence of hyperfibrinolysis, such as accumulations of D-dimers or degradation products of fibrinogen.  The incidence of hyperfibrinolysis in acute coagulopathy ranges from 2%-34% [2].

However, the locational constraints in the early treatment of haemorrhage rarely facilitate full-scale hyperfibrinolytic investigations, the absolute need for which would completely exclude a pre-hospital infusion of TXA. Fortunately, the CRASH-2 study administered TXA to haemorrhaging patients at risk of ACT and indicated that there was no difference in the development of thromboembolic events in the TXA group relative to the placebo group. Furthermore, there was a decrease in the incidence of myocardial infarctions in the TXA cohort.5 This data would suggest that there were minimal adverse effects recorded in patients of the TXA cohort who were not hyperfibrinolytic, providing treatment was administered less than 3 hours post injury. 
 

Cost-Effectiveness of Tranexamic Acid
 

Cost-effectiveness analysis has shown that the administration of TXA to bleeding trauma patients is financially viable in low, middle and high income settings TXA administration was found to cost $48, $66 and $64 per life-year saved in Tanzania, India and UK respectively [29].  The WHO declares medical intervention to be very cost effective if treatment costs amount to less than the GDP per capita per Disability-Adjusted Life Year averted [30]. In lower income countries, GDP per capita can range from $380 to $1,035. In middle and high income countries GDP per capita ranges from $977 to $12,615 to greater than $12,616 respectively [31]. Evidently, TXA proves very cost effective in all 3 of the studied environments. 
 

Conclusions

The primary delay in the firm implementation of TXA into emergency medicine is related to confusion about the category of patients who should receive it [2]. However, from the available research, there is a proven reduction in mortality in TXA-receiving patients relative to non-TXA receiving patients suffering from significant haemorrhage (systolic blood pressure < 90 mmHg, Heart rate 100 bpm), where TXA is administered less than 3 hours post-injury. [5] Under these circumstances, the WHO may consider advising the use of transexamic acid in both hospital and pre-clinical settings, based on the reduction in mortality and the cost-effectiveness (cost of LY saved relative to the loss in Disability Adjusted Life Years) of said treatment [2,5,29,30].

1. Curry N, Hopewell S, Doree C, Hyde C, Brohi K, Stanworth S. . The acute management of trauma hemorrhage; a systematic review of randomized controlled trials. Critical Care 2011; 15(2):  (accessed 12 October 2014).
2. Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE.. Tranexamic Acid in Trauma: How should we use it? J Trauma Acute Care Surg 2013; 74(6): 1575-1586.
3. Levy JH.. Antifibrinolytic therapy: new data and new concepts. The Lancet 2010; 376(9734): 3-4. (accessed 31 October 2014)
4. Roberts I, Preito-Merino D. Applying results from clinical trials: tranexamic acid in trauma patients. Journal of Intensive Care2014; 2(10): http://www.jintensivecare.com/content/2/1/56 (accessed 20 October 2014).
5. CRASH -2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y etc al. 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 2010; 376(9734): 23-32.
6. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007; 4: CD001886
7. Fiechtner BK, Nuttall GA, Johnson ME, et al. Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg 2001; 92: 1131–36. 
8. Horrow JC, Van Riper DF, Strong MD, Grunewald KE, Parmet JL. The dose-response relationship of tranexamic acid. Anesthesiology 1995; 82: 383–92.
9. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfbrinolysis. J Trauma 2008;64:1211–17
10. Sawamura A, Hayakawa M, Gando S, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res 2009; 1214: 608–13.
11. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. The Lancet 2011; 377(9771): 1096-1101
12. Pasche B, Ouimet H, Francis S, Loscalzo J. Structural changes in platelet glycoprotein IIb/IIIa by plasmin: determinants and functional consequences. Blood 1994; 83: 404–14.
13. Cesarman-Maus G, Hajjar KA. Molecular mechanisms of fibrinolysis. Br J Haematol 2005; 129: 307–21.
14. Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, Tait G, Beattie WS. The risk-benefi t profi le of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg 2010; 110: 21–29.
15. Dewan Y, Komolafe EO, Mejia-Mantilla J, Perel P, Roberts E, Shakur H et al. CRASH-3 - tranexamic acid for the treatment of significant traumatic brain injury: study protocol for an international randomized, double-blind, placebo-controlled trial. Trials 2012; 13. http://www.trialsjournal.com/content/13/1/87 (accessed 31 October 2014).
16. MRC CRASH Trial Collaborators, Perel P, Arnago M, Clayton T, Edwards P, Komolafe E et al. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 2008; 336; http://www.bmj.com/content/336/7641/425.long (accessed )20 October 2014
17. Maas AI, Steyerberg EW, Butcher I, et al. Prognostic value of computerized tomography scan characteristics in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007; 24(2): 303–14.
18. Perel P, Roberts I, Bouamra O, Woodford M, Mooney J, Lecky F. Intracranial bleeding in patients with traumatic brain injury: a prognostic study. BMC Emerg Med 2009, 9(15)
19. Zehtabchi S, Abdel Baki SG, Falzon L, Nishijima DK.. Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. The American Journal of Emergency Medicine2014; 32(9): http://www.ajemjournal.com/article/S0735-6757(14)00674-3/pdf (accessed 1 November 2014).
20. Stein SC, Smith DH. Coagulopathy in Traumatic Brain Injury. Neurocritical Care 2004; 1(4): 479-488.
21. Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, Thinkamrop B, Phuenpathom N, Lumbiganon P. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med 2013; 13; 20-27
22. Freund TF, Buzsáki G: Interneurons of the hippocampus. Hippocampus 1996; 6 (4) :347–470
23. Kratzer S, Irl H, Mattusch C, Burge M, Kurz J, Kocks E et al. Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures? Anesthesiology 2014; 120(3); 639-649
24. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg 2012; 147(2); 113-9
25. Pusateri AE, Weiskopf RB, Bebarta V, Butler F, Cestero RF, Chaudry IH et al. Tranexamic Acid and Trauma: Current Status and Knowledge Gaps With Recommended Research Priorities. Shock; 2013; 39(2); 121-126
26. Schöchl H, Schlimp CJ, Maegele M. Tranexamic acid fibrinogen concentrate and prothrombin complex concentrate: data to support prehospital use? Shock 2014; 41; 44-46
27. De Guzman R, Polykratis IA, Sondeen JL, Darlington DN, Cap AP, Dubick MA. Stability of tranexamic acid after 12-week storage at temperatures from -20 °C  to 50 °C. Prehospital Emergency Care; 2013; 17 (3); 394-400
28. Cap AP, Baer DG, Orman JA, Aden J, Ryan K, Blackbourne LH. Tranexamic Acid for rauma Patients: A critical review of the literature. Journal of Trauma Injury, Infection and Critical Care. 2011; 71(1)
29. Guerriero C, Cairns J, Perel P, Shakur H, Roberts I, et al. Cost-Effectiveness Analysis of Administering Tranexamic Acid to Bleeding Trauma Patients Using Evidence from the CRASH-2 Trial. PLoS ONE 2011 6(5)
30. Commission on Macroeconomics and Health (2001) Macroeconomics and health: investing in health for economic development. Geneva: World Health Organization.
31. The World Bank. New Country Classifications. http://data.worldbank.org/news/new-country-classifications (accessed 30 October 2014)
32. Injuries and violence: the facts. Geneva, World Health Organization, 2010