Tranexamic acid (TXA) is an antifibrinolytic agent used to prevent traumatic exsanguination (1). It was first introduced to clinical practice for the management of patients with bleeding disorders, especially adapted to reduce bleeding in hemophiliacs undergoing oral surgical interventions (2). More recently, research work has conveyed its effectiveness in the reduction of fatal traumatic hemorrhage when used within 3 h of injury onset, especially in individuals aged 18 years and above (1, 3–10). Exsanguination due to traumatic injury occurs primarily due to the development of coagulopathy which occurs as a result of extensive tissue injury (11). The high degree of endothelial damage which results from extensive tissue injury then leads to increased sympathoadrenal activity and resultant exposure of a significant proportion of subendothelial tissue factor (TF) to plasma protease factor VIIa, activating factor IX and X (12, 13). FVa and FXa combine to form prothrombinase, triggering the rapid conversion of prothrombin to thrombin (11, 12). Normally, in the event of endothelial damage which accompanies tissue injury, platelets adhere to exposed collagen, and this activation causes platelets to release other procoagulant factors such as thromboxane A2 and adenosine diphosphate (ADP)(14). Thromboxane A2 is a factor responsible for facilitating further platelet aggregation and formation of a platelet plug, whereas ADP interacts with platelets to stimulate fibrinogen deposition (14). TF simultaneously triggers the initiation phase of coagulation, binding factor VIIa, and activating factor IX and X at the site of injury (14, 15). Factor Xa activates thrombin in the amplification stage, activating platelets through platelet protease-activated receptor (PAR)-4 (12, 15). This interaction results in the expression of procoagulant phospholipids on the platelet membrane, shape change, and activation of glycoprotein IIb/IIIa receptors (15). This process triggers factor XIII activation, thus initiating the propagation and stabilization phases of coagulation (14). This creates a strong and stable fibrin clot, which is incorporated into the platelet plug to solidify it and to arrest the ensuing bleeding from the tissue injury (3). Simultaneously, the fibrinolytic system is activated to control the size of the clot formed (14). Plasminogen is activated by tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) to form plasmin (14). Plasmin enzymatically dissolves fibrin, forming fibrin degradation products, thus breaking up the clot (14) (for more details and illustrations on the coagulation pathways, see Refs. (16, 17)).
In the case of trauma-related extensive tissue injury, the procoagulant factors and platelets may be completely consumed and the ability of the body to form strong, stable clots is somewhat altered and a coagulopathy may ensue (11). As previously described by Brohi et al., the widespread activation of anticoagulant and fibrinolytic pathways may be responsible for inducing an “early endogenous coagulopathy” in trauma patients (18, 19). However, in the late stages (usually in the course of resuscitation), the consumption of procoagulant factors and platelets underscores the ensuing “consumptive coagulopathy” (11). In extreme cases, disseminated intravascular coagulation (DIC) may ultimately result (as part of late stage consumptive coagulopathy), causing systemic activation of coagulation pathways (11). Fibrin clots develop systemically, leading to organ failure development and further consumption of platelets and coagulation factors (11). Significant endothelial activation also triggers hyperfibrinolysis (11). Excessive amounts of tPA is released from damaged endothelial cells, leading to excessive degradation of clots and clinically significant bleeding, which may be fatal if not addressed quickly and adequately (11).
TXA exerts its action on the coagulation process by blockade of plasminogen binding to fibrin (Fig. 1). More precisely, TXA binds to a “lysine binding site” of plasminogen (or plasmin), thereby preventing the attachment of plasminogen (or plasmin) to fibrin at this site. Normally, the binding of plasminogen (or plasmin) to fibrin facilitates the breakdown of fibrin (i.e., clot dissolution); thus, by preventing the attachment of plasminogen (or plasmin) to fibrin, TXA ultimately prevents fibrinolysis and reduces traumatic hemorrhage (1, 20). Therefore, TXA may be well suited for the management of traumatic hemorrhage in the prehospital setting, where paramedics and ambulance officers are the first attendants to patients with severe traumatic hemorrhage. Interestingly, ambulance services in some developed countries (e.g., Queensland Australia, South West England, La Crosse, and Nova Scotia) have already adopted the use of TXA for the management of prehospital traumatic hemorrhage (21–23). Queensland Ambulance Service utilizes TXA in their traumatic hypovolaemic shock Clinical Practice Guidelines (CPG) where TXA is considered in the event of uncontrolled hemorrhage (21). The ambulance service of Nova Scotia also recommends TXA to control life-threatening hemorrhage as a result of traumatic injury (22). However, for some unknown reasons, some ambulance services are reluctant to include TXA in their CPGs. Although as with other pharmacological agents used in the prehospital settings, it may be that the consideration of cost, safety of use, side effects of the drugs, personnel training, and ease of administration may influence the decision of such ambulance services to exclude TXA in their CPG for the prehospital management of traumatic hemorrhage.
A number of studies have been conducted on the use of TXA in the prehospital environment and common themes regarding the use of this pharmacological agent include effectiveness, dosages, route of administration, time of administration, safety/side effects, cost implication, personnel training, and ease of administration (1, 4–9, 24–26). However, as with most other therapeutic pharmacological agents, the findings from these studies vary considerably with significant inconsistencies. For instance, as reported by Robert et al., a major side effect of TXA use is thromboembolic events causing exsanguination, occurring when TXA is administered more than 3 h postinjury (7). There was no statistically significant difference between the experimental and control group in thromboembolic events when TXA was administered within 3 h (7, 25). Also, some studies showed TXA is effective for the management of traumatic hemorrhage, whereas others either showed a null finding when TXA is compared with other pharmacological agents, or a poorer outcome (25, 26). Thus, it is expedient that a holistic review of the literature and a descriptive analysis of the principal themes regarding the use of TXA in the prehospital environment for the management of trauma-related hemorrhage are conducted, hence the purpose of this review. This review may serve as a useful resource for decision-making process by ambulance services who are considering the inclusion or exclusion of TXA for the management of traumatic hemorrhage in the prehospital setting.
An extensive literature search of PubMed and EBSCO databases was conducted using a combination of the following words: tranexamic acid, prehospital, hemorrhage, trauma, mortality, ambulance, and paramedics. This yielded 40 full text journal articles (abstracts or supplemental materials were excluded). From these published works, studies which did not investigate the use of TXA (e.g., study protocols, commentaries, overviews, and letters to the editor) were excluded. Also, published works based on secondary analysis and interpretation of primary data were excluded. In addition, the exclusion criteria also included studies which did not use TXA as an antifibrinolytic agent, studies which examined the use of TXA in nontrauma-related conditions (e.g., obstetrics and gynaecology hemorrhage), and studies on TXA in in-hospital settings (see Fig. 2). From this process, only 14 full text journals met the final inclusion criteria for the purpose of this descriptive analysis. These published works were thoroughly analyzed for the purpose of identifying the principal themes regarding the use of TXA in the prehospital environment for the management of hemorrhage, and from these identified themes, further extensive reviews were performed in an attempt to understand and establish the evidence in support or against the use of the TXA in the prehospital environment for the management of trauma-related hemorrhage.
From the extensive review of the 14 full text journal articles which investigated the use of the TXA in the prehospital environment for the management of trauma-related hemorrhage, the following themes were identified:
- 1. Dose of TXA administration
- 2. Route of TXA administration
- 3. Optimal window of TXA administration
- 4. Safety of TXA use
- 5. Clinical effectiveness of TXA application
- 6. Feasibility of TXA use in the prehospital setting
The summary of the results of this comprehensive review as per the identified or recognized themes is presented in Table 1.
DESCRIPTIVE ANALYSIS OF THE PRINCIPAL THEMES
Dose of TXA administration
Majority of the clinical trials within this review recommended a “one-size-fits-all” dosing regimen for TXA administration in the management of bleeding trauma patients in the prehospital setting, that is, a loading dose of 1 g, followed by a 1-g infusion over 8 h (7, 25, 27–32). A similar regimen was adopted by Lawson et al.; they administered a first dose at 0.15 mg/kg, to a maximum of 1 g, followed by a 1-g infusion over 8 h (33). Two studies did not administer the 8-h infusion dose in the prehospital environment, rather a second dose of TXA was administered only if the trauma patient remained on scene over 3-h duration (27, 31). However, from clinical practice and research, a fixed dose may be more appropriate in an emergency situation. This is particularly important because the use of maximum single dosage have been suggested as a means of reducing errors associated with inaccurate weight estimation and dosage calculations (7, 34).
tPA is known to play a vital role in fibrinolysis, catalyzing the formation of plasmin from plasminogen, and based on the pharmacodynamics of TXA, a TXA blood concentration of 31 μg/mL is required to “completely” inhibit tPA as revealed by previous in vitro studies (35). However, a minimum concentration of 20 μg/mL of TXA is sufficient to provide clinically significant inhibition of fibrinolysis; thus, this is the expected target concentration whenever TXA is administered (35, 36). The “one-size-fits-all” regimen of 1 g loading dose of TXA will achieve and maintain the minimum concentration of 20 μg/mL for 90 min; thus, additional 1-g infusion of TXA over 8 h will ensure that this minimum concentration is maintained for a longer period, thus achieving inhibition of fibrinolysis, and hence a better outcome for the patient (7, 25, 27–29, 35).
Route of TXA administration
In emergency situations, parenteral administrations of essential medications could be lifesaving, and from the current review, it is not surprising that, from the review of the studies which utilized TXA in prehospital management of trauma-based bleeding, the most common route of TXA administration was intravenous injection (IV) (7, 25, 27–29, 31–33). This was mostly the case for studies carried out in civilian environment (7, 25, 28, 29, 31, 33). However, environment and clinical settings can sometimes influence the decision to deliver a medication via a specified route, for instance, in an emergency military situation, there is often inadequate time to cannulate a traumatic patient who has suffered multiple injuries. For this reason, other routes of administration may be warranted. For TXA administration, one study delivered the drug via an intramuscular route (IM) specifically either by an intramuscular autoinjector (for easy self-administration) or “buddy” administration in one study (30). Although in two other studies which were set in similar battlefield situation, TXA was administered intravenously, suggesting that both IV and IM routes can be considered in emergent situations, most probably dependent on the assessment of the patient and the ease of establishing an IV access (27, 32). Surprisingly, in all these studies, the efficacy of TXA in control of bleeding was not significantly affected by the route of administration as they all reported a reduction in the mortality rate of the patients (27, 30, 32). But as a caution, there is a risk of intravascular formation of excess clot when TXA is delivered via the IV route. This finding was more pronounced in the MATTERs (2012) trial, where the treatment group that had IV TXA experienced an increased rate of formation of deep venous thrombosis (DVT) and pulmonary thromboembolism (PTE), although the sample size was too small to determine direct causation (32). Thus, the IV route seems to be the best route of administration in civilian and military settings (with possible risk of DVT and PTE), whereas IM route should be considered in situations where it is difficult to establish IV access and emergent situations where timed intervention is very critical in patient resuscitation (i.e., military setting).
Optimal window of TXA administration
From this review, many studies illustrated the importance of administering TXA within a 3-h window period of traumatic injury (7, 25, 27–32). The most plausible explanation is based on the mechanism of action of TXA–blockade/prevention of plasminogen binding to fibrin, thus preventing fibrinolysis (1, 20). tPA acting as a potent agent of fibrinolysis is activated following tissue injury and its level reaches a peak concentration about 30 min posttrauma. Similarly, plasminogen/plasmin levels peak at the 1 h mark posttrauma (1). Therefore, TXA acting to block plasminogen (or plasmin) from binding to fibrin is most beneficial when administered within this time period of below 3 h posttraumatic injury (1). Administration over 3 h postinjury has been shown to be associated with high morbidity and mortality (1, 7). Furthermore, 2 h after traumatic injury occurrence, plasminogen activator inhibitor-1 (PAI-1) levels increase in the intravascular compartment, reaching its peak at approximately 3 h (1). PAI-1 is known to inhibit fibrinolysis by inhibiting tPA and uPa, thus causing the shutdown of the fibrinolytic process and resulting to disseminated intravascular coagulation (DIC) (1). The late administration of TXA has been shown to further increase this PAI-1-induced fibrinolytic shutdown, potentially worsening DIC (1). Hence, it is logical and safe to administer TXA before the 3 h window period. This may explain why adverse events were reported in two of the studies reviewed where the timeframe for TXA administration was more than the 3 h posttraumatic injury period. In these studies where a portion of the patients were administered TXA outside this vital treatment window, an increase in the risk of death due to prolonged bleeding was reported (7, 25).
More specifically, Kunze-Szikszay et al. illustrated the importance of administering TXA early in the prehospital environment, as this reduces the level of fibrinogen consumption while improving the functionality of the coagulation system (31). Thus, TXA's effectiveness in improving the prognosis of bleeding trauma patients is well established in the literatures (7, 25, 27–32).
Safety of TXA use
Most studies reported that TXA is a safe drug to apply in the prehospital environment (7, 24, 27, 29, 31–33, 37). No adverse effects were recorded in studies where TXA was administered as an intervention, even when vascular occlusive events such as DVT were considered (24, 27, 31). In fact one study showed that the possible risk associated with the use of TXA is not over and beyond what could have occurred even when TXA was not used (7). These authors showed that there was no difference in the occurrence of vascular occlusive events between the recipients of TXA and the placebo group (7). Thus, TXA is safe to use. However, some authors illustrated an increase in the occurrence of adverse drug effects (majorly vascular occlusive events), following the use of TXA (28, 29, 32, 33, 37). However, it is possible that delayed or lack of thromboprophylactic measures may have contributed to the finding of increased adverse drug effect, as this potential cofounder was not properly accounted for in most studies (28, 29, 32, 33, 37). Furthermore, some authors suggest that the fluid requirements of TXA recipients are generally higher than nonrecipients, most likely due to hypotension resulting from excess blood loss (28, 31). Thus, aggressive fluid administration which is known to be a possible cause of coagulopathies in bleeding hypovolaemic patients may be the true culprit responsible for the vascular occlusive events rather than the direct effect of TXA application (28). In all, TXA application in the prehospital environment is generally safe (7, 24, 27, 29, 31–33, 37).
Clinical effectiveness of TXA application
TXA was shown to effectively control bleeding by prevention or inhibition of the development of coagulopathy (7, 25, 31, 32). It was also shown to significantly reduce the development of multiorgan failure (29, 32). As such, the clinical effectiveness of TXA justifies its use in the management of bleeding patients in the prehospital setting. This message is buttressed by the results of some of the studies reviewed which showed that, when TXA is administered, there is a significant reduction in the mortality rate reported, although one study suggests that TXA was only effective in patients who experience hemorrhagic shock (7, 27, 29, 30, 32, 33).
TXA's effectiveness in the prevention of coagulopathy and multiorgan failure development may be associated with its inherent chemical structure, and by extension, its mechanism of action. TXA is a synthetic derivative of lysine, an amino acid that plays a role in the inhibition of fibrinolysis (38). The enzymatic breakdown of fibrin into fibrin degradation products relies on lysine binding to plasminogen via the tip of its kringle domain (38, 39). This binding facilitates the transformation of plasminogen into its active form, plasmin, which splits fibrin into fibrin degradation products (39). Although plasmin remains bound to fibrin, the molecule is less susceptible to plasmin inhibitors, thus reducing negative feedback and the body's ability to prevent coagulopathy (39). Interestingly, TXA has a higher binding affinity for this domain than lysine; hence, it effectively blocks this interaction and prevents fibrinolysis and consumption of fibrin (38).
In contrast, TXA was shown to be ineffective in two studies (28, 37). In one of these studies, the experimental cohort was reported to possess a higher injury severity score than the control group, as such a higher proportion of deaths were expected in the experimental group (37). Also, about 9% of all study participants had moderate–high probability of mortality outcome; thus, the use of TXA reduced the mortality of patients who were deemed to have “unsurvivable injuries” (37). In the other study, all the patients who were administered TXA were in severe traumatic shock which may explain the poor outcome regarding mortality rates. Although TXA has been previously shown to be effective in reducing mortality rate in patients experiencing hypovolaemic shock, the increased mortality rate in these studies (which reported a high mortality) may be due to the effect of hypotension which may accompany the use of TXA especially when TXA is administered at a faster rate. A previous study observed this adverse effect of hypotension when TXA was administered at a rate faster than 100 mg/min (28, 29). Hypotension as a side effect would further exacerbate the traumatic shock seen in these group of patients, further worsening their prognosis. Thus, hypotension as a side effect of TXA administration should be watched out for whenever TXA is administered, and as a preventive measure, the administration of TXA should be done slowly, at least at a rate less than 100 mg/min (24).
However, the effectiveness of TXA in reducing mortality rate was unclear in two studies (25, 31). In one study, TXA resulted in a trend of reduction in mortality rate, although this was not statistically significant, and this finding was attributed to insufficient sample size (25). In the other study, it was also reported that insufficient sample size made it difficult to reliably determine the effectiveness of TXA in reducing mortality rate (31). Other potential confounders include the use or lack of use of intravenous fluid and other relevant pharmacological therapy (31).
Feasibility of TXA use in the prehospital setting
From the studies reviewed, the major feasibility concern was about storage of TXA as a medication to be used in the prehospital environment. One study showed that TXA remains viable when stored between −20°C and 50°C for less than 12 weeks (7). TXA was also shown to be stable when stored for up to 12 weeks at temperatures from −20°C to 50°C (35). TXA was shown to continue to inhibit streptokinase-induced fibrinolysis of platelet poor plasma, as determined by thromboelastography, fibrin degradation products, and D-Dimers after 12 weeks’ storage at −20°C to 50°C (40). This conveys that TXA can be easily incorporated into existing kits in the prehospital environment as most medications are stored within this temperature range (40). However, care needs to be taken with TXA stored at −20°C as the possibility of ampoules cracking during defrosting exists; therefore, appropriate precautions such as paraffin-film wrapping should be put in place when using TXA which was stored at −20°C (40).
In addition, some studies illustrated that TXA is a practical and economically viable option in the prehospital setting, including the civilian and military environments (7, 30, 41). In the civilian prehospital setting, TXA was shown to cost between $48 and $64 per life-year saved, making it a highly cost effective and accessible option to ambulance services (7). Thus, the use of TXA in the prehospital management of hemorrhage posttrauma is both clinically and economically feasible and should be considered by the all ambulance services which attend to these group of patients.
The findings of this review and analysis of the principal themes underscore the clinical significance of TXA use in the prehospital management of hemorrhage posttrauma. Precisely, the timely administration of intravenous TXA in the appropriate dose to bleeding patients in the prehospital environment is a safe measure which is able to significantly and effectively reduce morbidity and mortality and facilitate a better health outcome for patients. Also, as highlighted above, the use of TXA in the prehospital setting is both clinically and economically feasible, thus suggesting that quality prehospital care of the bleeding trauma patient can be improved upon in a cost-effective way by the introduction of TXA in the prehospital management of hemorrhage in trauma patients. Therefore, TXA is highly recommended for use in the prehospital environment for the management of trauma-based hemorrhage, and should be considered by ambulance services for inclusion in their treatment protocol and prehospital management of trauma-based hemorrhage.
Although this literature review and descriptive analysis provide detailed information on the characteristics and usefulness of TXA in the prehospital setting, additional information about this important drug (and its use in the prehospital setting especially with control of hemorrhage) may be obtained from a meta-analysis. However, a major challenge to this is that very few studies have investigated the use and effectiveness of TXA in the prehospital setting, and these studies vary in scope and design. Thus, performing a thorough meta-analytic review on this topic may be somewhat challenging. More investigations on the use of TXA in the prehospital are thus required.
Also, further research is required regarding the usage of TXA and possible extension of its use in both pre- and in-hospital setting. The areas warranting additional investigations include routes of administration, weight-based dosages—on how to reduce calculation errors in the prehospital environment, and criteria for the administration of TXA—especially considering whether TXA is appropriate in the presence of normotension and traumatic brain injuries.
From this review, evidence exists in support of TXA use in the management of trauma-based hemorrhage in the prehospital setting. More specifically, the literature supports the use of TXA and the recommended approach is a dose of 1 g (loading dose), followed by 1-g infusion over 8 h, which is given by intravenous administration within a 3-h window period of traumatic injury. TXA has been found to be safe to use in the prehospital setting, and its clinical effectiveness in arresting hemorrhage is also supported by literature, and its use in the prehospital setting is clinically and economically feasible. Therefore, TXA should be considered by all ambulance services which attends to patients with trauma-based hemorrhage in the prehospital environment.
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