J Acute Care Surg Search

CLOSE


J Acute Care Surg > Volume 13(3); 2023 > Article
Kim: Tranexamic Acid in Trauma Management: A Review of Evidence

Abstract

Hemorrhage is the leading cause of death in trauma patients and trauma induced coagulopathy (TIC) is a major contributor to bleeding mortality. TIC has a diverse pathophysiology triggered by injury and hypoperfusion, including platelet dysfunction, endotheliopathy, fibrinogen or thrombin abnormalities, and dysregulated fibrinolysis. Early fluid resuscitation, appropriate blood transfusion, and definitive control of bleeding are essential components of initial management for TIC. Additionally, tranexamic acid (TXA), an antifibrinolytic agent, has emerged as a potential adjunctive therapy following the 2010 landmark trial that demonstrated the benefit of early administration of TXA in reducing trauma patient mortality (CRASH-2). This review provides an analysis of the current literature on the use of TXA in trauma patients. It critically evaluates the evidence on the effect of TXA on TIC and other clinical outcomes, emphasizing the time-sensitive nature of TXA administration and the variation of its effect depending on the severity and location of injury. It also discusses the optimal dosage, timing, and safety of TXA, as well as the challenges and limitations of existing studies. Furthermore, it highlights the importance of individualized treatment approaches based on the fibrinolysis status of TIC and the value of goal-directed therapy guided by viscoelastic hemostatic assays for the appropriate use of TXA.

Introduction

Hemorrhage is the leading cause of early mortality in cases of major trauma [1], with coagulation abnormality manifesting in approximately 25% of patients with severe trauma, and higher mortality in patients with the coagulopathy [2].
The cornerstone of initial management includes early fluid resuscitation, prompt and appropriate blood transfusion, and definitive control of bleeding. Following the “Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage” (CRASH)-2 study and the CRASH-3 study, the administration of tranexamic acid (TXA) has emerged as a potential adjunctive strategy to standard resuscitation measures for trauma induced coagulopathy (TIC) and hemorrhagic shock [3,4]. However, despite its widespread application, the current understanding of TXA still remains limited, particularly regarding its therapeutic efficacy, indications for use, safety dosage, organ-specific effects (such as renal) and potential side effects. While its effectiveness in various scenarios such as pre-surgery or nontraumatic bleeding has been explored, many aspects remain to be elucidated. In addition, many recent studies have shown the existence of a fibrinolysis phenotype, which provides an important theoretical background for the more accurate, effective, and safe use of TXA as an antifibrinolytic agent [5]. This review aimed to shed light on the evidence supporting TXA use across diverse clinical conditions and environments, including trauma. Particularly, the review examined the judicious use of TXA in relation to the clinical phenotype of coagulopathy as revealed through recent studies with viscoelastic assays.

Discussion

1. TIC

1.1. Historical research

Acute trauma coagulopathy, now called TIC, has emerged as a concern. It was reported in 2003 that significant coagulopathy occurred in 25% of severely injured patients, regardless of volume resuscitation [2]. This acute coagulopathy of trauma was associated with systemic hypoperfusion, that is hemorrhagic shock, and was characterized by anticoagulation and hyperfibrinolysis [6].
Out of a Trans-Agency Coagulopathy in Trauma Workshop in April 2010 this meeting presented a consensus that the term “trauma induced coagulopathy” would be employed to describe commonly what was previously referred to as acute traumatic coagulopathy [7].

1.2. Epidemiology

In several studies, the incidence of TIC has been reported to be about 24–40% in severe trauma patients [811]. In general, children develop TIC later and less frequently than adults, and older people are more vulnerable to TIC [12,13].

1.3. Pathophysiology

The underlying pathophysiological mechanisms are complex and remain poorly elucidated. However, it is known that acute coagulopathy in severe trauma patients is caused by the combined effects of tissue damage and hypoperfusion, that is, injury and hemorrhagic shock [14]. Subsequent to the initial injury and hypoperfusion, a cascade of biochemical and humoral responses are triggered, both locally at the site of injury and systemically throughout the body. Pathophysiological bases of these responses can be summarized as endothelial cell dysfunction and platelet dysfunction, i.e., dysfunction of cell-based hemostasis, fibrinogen depletion, and dysregulated fibrinolysis [7,15,16]. Within this mechanism, primary fibrinolysis dysfunction provides a physiological plausibility for the administration of hyperfibrinolytic agents in the initial treatment of TIC in patients with hemorrhagic shock, just as the CRASH-2 trial provided clinical relevance [17].

2. Mechanism of action and pharmacokinetics of TXA

TXA (trans-4-aminomethyl cyclohexane carboxylic acid) is a synthetic lysine analogue made by Japanese physiologist, Utako Okamoto in 1962 [18]. TXA exhibits antifibrinolytic function by interfering with the action of the plasminogen activator by reversibly binding to the lysine binding site of plasminogen thereby blocking interactions with fibrin and subsequent clot breakdown and stabilizing a previously formed clot [19]. In addition, TXA also exhibits secondary effects by inhibiting plasmin. TXA improves platelet function and inhibits plasmin-induced platelet activation which facilitates clot stabilization [20].
Plasmin is also a known activator of inflammatory cells, cytokines, and immune mediators and produces proinflammatory effects by binding to and activating monocytes, neutrophils, platelets, and endothelial cells, and releasing lipid mediators and cytokines [21]. So, TXA may attenuate the intense inflammatory response by inhibiting plasminogen or plasmin-mediated inflammation [22]. This anti-inflammatory effect of TXA may also result in a reduction in multiple organ failure (MOF) in severely injured patients [23].
The pharmacokinetics of TXA in a healthy adult reveals its peak concentration by 60 minutes following intravenous (IV) administration and has a half-life of approximately 2 hours. An antifibrinolytic dosage remains in serum and tissue for up to 8 and 17 hours, respectively [24].
Furthermore, it is crucial to consider the alterations in pharmacokinetics depending on the administration route of TXA and its subsequent impact on efficacy. Intravenous administration of TXA is predominantly employed in clinical settings for severe trauma patients presenting with shock and coagulopathy. However, intramuscular (IM) administration is also considered, particularly during prehospital stages or in an Emergency Room where IV access may not be readily available. This method provides a rapid delivery solution in urgent situations. Several animal studies and trials involving normal adult participants have reported no significant difference between IM and IV administration in terms of dosage and time required to achieve effective blood concentrations [25,26]. Therefore, based on these findings, it can be inferred that IM administration is a viable alternative under certain circumstances [27]. However, the pharmacokinetics of this drug in trauma patients may be different to that observed in normal adults, and the clinically appropriate therapeutic dose for patients with severe trauma or hemorrhagic shock has not yet been clearly established.

3. Timing of administration of TXA

While the optimal TXA administration (timing and duration) in trauma patients remains undetermined, the CRASH-2 study significantly contributed to our understanding of this issue. This landmark randomized placebo-controlled trial of the effect of TXA on mortality in 20,211 trauma patients showed TXA safely reduced the risk of death in trauma patients who were bleeding, without definitive risk of thromboembolic adverse effects [3]. This survival benefit is only evident in patients in who were treated within 3 hours of their injury [heart rate (HR) ≤ 3 hours = 0.78, 0.68–0.90; HR > 3 hours = 1.02, 0.76–1.36]. Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60–0.86) [28]. The results suggest that TXA should be given as soon as possible after injury to trauma patients who are bleeding, and that its use should be avoided beyond 3 hours post injury. A study by Ggayet-Ageron et al [29] reinforced the significance of early TXA administration as their results indicated that survival benefits decreased by 10% for every 15-minute delay beyond the initial 0–3-hour window. This led many treament guidelines based on an evidence-based consensus approach which included the recommendation that TXA be administered as soon as possible and within 3 hours of injury [30].
The positive outcomes associated with timely TXA administration extend beyond trauma cases. Similar benefits have been observed in the context of postpartum hemorrhage [31], suggesting that the importance of administration timing may be a general principle in managing critical bleeding scenarios.
The evidence, primarily drawn from the CRASH-2 trial and subsequent research, consistently supports the early initiation of TXA treatment, ideally within 1 hour of injury. These findings have profound implications for the clinical management of trauma patients, underlining the life-saving potential of timely TXA intervention and inevitably led to interest and research into the prehospital use of this drug.

4. TXA: prehospital use

The results of research on the early administration and effectiveness of TXA were ultimately related to the interest in the effect of the prehospital use for trauma patients. Stein et al [32] reported the results of the prospective, multicenter, observational study of the assessment for the benefit effect of on-scene IV administration of TXA in 2018. In a prospective, multicenter observational study comparing trauma patients who received prehospital TXA with a control group (without TXA), it was observed that early TXA administration led to clot stabilization, reduced fibrinolytic activity, and a significant decrease in production of fibrin degradation products (D-dimer). Specifically, viscoelastic tests showed that maximum clot firmness (MCF) did not change from on-scene to the Emergency Department in the TXA group, while MCF reduced in the control group. This study indicates that prehospital TXA administration plays a crucial role in enhancing coagulation and minimizing fibrinolysis in trauma patients [32].
A multicenter randomized clinical trial on the effects of prehospital use of TXA on approximately 900 injured patients in 2021 [“Study of Tranexamic Acid During Air Medical Prehospital Transport” (STAAMP) trial] showed significantly lower 30-day mortality in the subgroup of the patients administered within 1 hour after injury (4.6% vs 7.6%; p < 0.002) and with severe shock (18.5% vs 35.5%; p < 0.003) [33].
However, in a study on prehospital TXA administration in 1,827 traumatic brain injury (TBI) patients conducted in the Netherlands, 30-day mortality was poor in the TXA administered group for severe isolated TBI patients (OR, 4.49; 95% CI, 1.57–12.87; p = 0.005) [34] and Rowell et al [35] also reported results that did not support effects of prehospital TXA administration on patients with severe traumatic brain injury.
In a recent randomized controlled trial (RCT), “Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage-Trauma” (PATCH trial) on the effect of the pre-hospital use of TXA on survival benefit among 1,310 adults with major trauma and suspected trauma-induced coagulopathy, prehospital administration of TXA followed by infusion over 8 hours did not result in better patient survival or favorable functional outcome at 6 months compared with the placebo [36]. Research on the prehospital use of TXA has produced a variety of results, indicating that a consensus on its effects has not yet been established.

5. TXA: use for non-trauma patients

Considerable research on the effects of TXA on bleeding, mortality, and the occurrence of several types of thromboembolic events has been conducted not only in trauma patients but also in various non injury related clinical situations where bleeding occurs such as post operative bleeding, postpartum hemorrhage, nontraumatic gastrointestinal bleeding, and nontraumatic cerebral hemorrhage. A randomized study in 2017 on the effectiveness of TXA administration in 4,662 cardiac surgery patients did not show mortality benefit (relative risk, 0.92; 95% CI 0.81–1.05; p = 0.22), but a reduction in the amount of transfused blood products, and occurrence of postoperative hemorrhagic complications was observed [37]. A randomized trial on the usefulness of TXA on major bleeding and the occurrence of complications among 9,535 patients undergoing noncardiac surgery showed the incidence of the major bleeding outcome was significantly lower with TXA than the placebo [38]. A small, randomized trial on the preoperative administration of TXA in aortic aneurysm surgery reported that preoperative TXA did not reduce intraoperative blood loss or blood transfusion but may reduce postoperative blood loss without increasing adverse effects. However, it should be taken into account that the dose of TXA used in this study was lower than the dose in other general studies (loading dose of 500 mg and a continuous infusion of 250 mg/h) [39].
For the orthopedic surgery, TXA formulations were superior to the placebo in terms of decreasing blood loss and risk of transfusion after total knee arthroplasty surgery [40].
Two well-designed RCTs analyzed the effects of TXA on postpartum hemorrhage outcomes [31,41]. In a RCT by Ducloy-Bouthors et al [41], the effectiveness of 4 g TXA on postpartum hemorrhage was evaluated. The trial included 144 women with postpartum hemorrhage of more than 800 cc, who were randomly assigned to receive either 4 g TXA or a placebo. The results showed that the TXA group had significantly lower blood loss within the first 6 hours of treatment than the control group (median 173 mL vs 221 mL, p = 0.041) [41]. The WOMAN trial published in 2017, a large-scale RCT, investigated the effect of TXA administration on postpartum hemorrhage [31]. The trial enrolled 20,000 women with postpartum hemorrhage and randomly assigned them to receive either 1 gm of TXA or a placebo. The results showed that TXA significantly reduced the risk of death due to bleeding (1.5% vs 1.9%, p = 0.045) although it did not affect the overall mortality rate [31].
In conclusion, TXA is a promising hemostatic agent that has been shown to reduce bleeding and mortality in various nontraumatic clinical situations such as cardiac, noncardiac, orthopedic, and obstetric surgeries. However, the optimal dose, timing, and duration of TXA administration remains unclear and requires further investigation. Additionally, the safety and efficacy of TXA in nontraumatic cerebral and gastrointestinal hemorrhages, needs to be established by performing large-scale randomized trials, because the benefits in terms of mortality and VTE incidence stability need to be elucidated [42].

6. TXA: use in trauma

The CRASH-2 study, despite its limitations, is often regarded as the pioneering study that sparked this discourse. This trial, which showed a 14.5% reduction in 28-day mortality in the TXA group compared to 16% in the placebo group, has impacted TXA use in trauma patients [3]. After this study, the advantages and disadvantages of TXA use in trauma patients have been thoroughly explored.
While the study conducted by Morrison et al in 2012, was retrospective in nature, it nonetheless offered valuable insights into the efficacy of TXA administration [43]. The findings underscore key considerations in identifying individuals who would most benefit from TXA treatment. In this comparative analysis of 896 combat injury patients with or without the administration of TXA, the researchers reported a significant correlation between the use of TXA and survival rates. The odds ratio was remarkable 7.228 [95% CI (3.016–17.322)]. Furthermore, the incidence of coagulation disorders was notably influenced by TXA usage. This association was stronger in the group of patients who underwent massive transfusion. Therefore, TXA administration should be considered in addition to blood transfusions group as part of a resuscitation strategy following severe injury and hemorrhage.
In the “Military Application of Tranexamic Acid in Trauma Emergency Resuscitation” (MATTERs)-2 study of the effects of TXA and cryoprecipitate on mortality in a larger group of patients than in the MATTERs study, the mortality benefit was greatest in patients who received both TXA and cryoprecipitate [44]. This may mean an additional effect of fibrin on the antifibrinolytic function of TXA, or another synergic effect of TXA and fibrin, but more research is needed.
Cole et al [23] reported a significant association of TXA administration with a reduction in all-cause mortality and MOF in injured patients with shock, and the result of the MATTERs study revealed the most severely injured group benefited the most from the administration of the TXA. These are consistent with the results of subgroup analysis by systolic blood pressure (≤ 75 mmHg, 76–89 mmHg, and > 89 mmHg) in the CRASH-2 study.
However, studies on the benefits of TXA in traumatic brain injury are slightly different. The CRASH-3 trial [4] published in 2019, was a randomized, placebo-controlled trial conducted in 175 hospitals across 29 countries. This trial aimed to assess the effect of TXA treatment within 3 hours of injury in the 12,737 patients with isolated traumatic brain injury who had a GCS of 12 or lower and no major extracranial bleeding. Among them, blind randomization was performed resulting in patients who received TXA [6,406 (50.3%) or the placebo 6,331 (49.7%)], of whom 9,202 (72.2%) patients were treated within 3 hours of injury. This study did not show statistically meaningful differences in the head injury-related death between 2 groups [18.5% in the TXA group versus 19.8% in the placebo group; RR 0.94 (95% CI 0.86–1.02)]. However, this study did show that the effect of TXA varied depending on the degree of brain injury. The risk of head injury-related death reduced with TXA treatment in patients with mild-to-moderate head injury [RR 0.78 (95% CI 0.64–0.95)] but did not in patients with severe head injury [0.99 (95% CI 0.91–1.07)]. In addition, early treatment with TXA was more effective than later treatment in patients with mild to moderate head injury (p = 0.005) but time to treatment had no obvious effect in severe head injury group (p = 0.73). The risk of vascular occlusive events [RR 0.98 (95% CI 0.74–1.28)] and the risk of seizure [1.09 (95% CI 0.90–1.33)] were similar in the TXA and placebo groups. If we recall the results of subgroup analysis in the CRASH-2 study, the results of the CRASH-3 study effect of TXA according to the severity of brain damage were consistent with each other. Furthermore, the finding that early TXA administration was more effective than late administration for survival was also consistent with the results of CRASH-2 [3,4]. In addition to the CRASH-3 study [3], several studies on the effect of TXA in TBI patient groups showed similar results.
In a nested study of more than 200 patients who enrolled in the CRASH-2 study, the authors reaffirmed the results of the CRASH-2 study in the hemorrhagic TBI patient group [45]. Treatment with TXA was associated with a 7% reduction in all-cause mortality, a 5.6% reduction in head injury-related mortality, and a 13.3% reduction in overall poor outcomes. The trial team reported a 7% reduction in all-cause mortality, a 5.6% reduction in head injury-related mortality, and a 13.3% reduction in overall poor outcomes with TXA, and showed a high probability of decreased hemorrhage growth, intracranial mass effect, and new hemorrhage development when compared with matched controls.
Rowell et al [35], in a post hoc study of the CRASH-3 study [4], compared the effects of 1 g and 2 g TXA groups in the pre-hospital setting for patients with mild to moderate TBI. No difference in 28-day mortality and neurological outcome was observed. However, a trend in mortality reduction was observed in the group administered 2 gm of TXA, but seizure risk also increased. This study provides us with important information regarding the appropriate dosage of TXA for TBI patients.
However, not all studies supported the results of the CRASH-2 study in patients with nontraumatic brain hemorrhage, especially aneurysmal subarachnoid hemorrhage, and short-term antifibrinolytic therapy with TXA reduced the risk of rebleeding but did not improve clinical outcome [46].
In conclusion, TXA is an effective hemostatic agent that has been shown to reduce mortality and bleeding in trauma patients, especially when administered early, and in patients with shock or requiring massive transfusion. However, the effect of TXA may vary depending on the severity and location of injury such as traumatic brain injury. Further research is needed to determine the optimal dose, timing, and duration of TXA administration, as well as the safety, and efficacy of TXA in different types of injuries.

7. Dosage of TXA in trauma patients

The TXA dose currently administered to trauma patients or used in research was the empirical dose based on the CRASH-2 trial (1 g/IV for 15 minutes and 1 g/IV over 8 hours). In this trial, the dosage decision was relatively simple and was based on the 2007 Cochrane review paper [47]. However, there is still much debate as to the appropriate TXA treatment dose.
The antifibrinolytic effect of TXA primarily results from the inhibition of hyperfibrinolysis induced by tissue plasminogen activator (tPA). This is achieved through binding to lysine-binding sites on plasmin and plasminogen, thereby preventing the degradation of fibrin molecules. In keeping with the antifibrinolytic function of TXA, a plasma concentration of 10 μg/mL or 100 μg/mL TXA were required to reach 80% and 98% inhibition, respectively [48].
According to another in vitro study, a concentration of 31 μg/ mL TXA was required to fully inhibit tPA-induced fibrinolysis [49].
There was an experimental study on the appropriate concentration of TXA in the blood to achieve antifibrinolytic function in trauma patients with hyperfibrinolysis. TXA was administered at a median time of 43 minutes after trauma and the plasma TXA level measured was 28.7 [21.5–38.5 (8.7–89.0)] μg/mL on arrival at hospital, which was 57 [43–70 (20–148)] minutes after pre-hospital administration of the drug. It was reported that 20% of the trauma patients who received TXA (1 g) at the scene within 1 hour of injury, had suboptimal levels of TXA with concentrations below 20 μg/mL in 20% of the patients [50]. Therefore, the administered dose of TXA in the CRASH-2 trial, 1 g IV bolus followed by additional administration of 1 g over 8 hours, may be judged to be somewhat appropriate.
However, apart from these research results, as shown in Table 1 [3,4,23,31,5154], There are many other studies on effective TXA administration doses according to various situations, and most of these studies seem to be based on empirical decisions or borrowing doses used in existing clinical studies. Dowd et al [55] reported that a dosage of 2 g of TXA administered over 8 hours was effective in the group of non-trauma patients undergoing cardiopulmonary bypass surgery. And another non-trauma, cardiac surgery study indicated an increase in neurotoxicity when the TXA dosage more than twice that in the CRASH-2 trial was administered [56].
While it is plausible to hypothesize that high doses of TXA may induce adverse effects, there is limited research addressing the threshold dose at which these effects occur. Consequently, further studies are needed to determine the optimal dosage of TXA to consider the potential for adverse events, such as seizures, and thrombotic incidents, particularly when administering high doses.

8. Fibrinolysis phenotype in TIC and TXA

In 2014, Moore et al [57] reported that there was a spectrum for fibrinolysis status in groups with TIC [58]. Trauma patients with injury and shock can be divided into 3 phenotypes, including hyperfibrinolysis HF, fibrinolysis shutdown (SD), and physiological fibrinolysis status group, depending on the fibrinolysis status [57,58]. These observations continue to raise the question as to whether TXA should be used selectively following injury based on the degree of shock. The existence of distinct phenotypes based on the fibrinolysis status of injured patients suggests that the effectiveness of TXA, an antifibrinolytic agent, may vary. It is hypothesized that TXA would be particularly beneficial for patients exhibiting HF, while potentially exacerbating adverse effects in the SD group. This hypothesis has been tested and accepted by subsequent studies.
In a study on the effect of TXA administration in trauma patients with injury and shock (3 phenotypes) where each group was confirmed using TEG analysis, it was reported that fibrin clot strength increased in the HF group, but not in the SD or physiological fibrinolysis group, which was predicable based on the mechanism of action of TXA [59].
In addition, Khan et al [54] investigated the effects of TXA on mortality, transfusion volume, hemostasis, rebleeding, and thrombosis complication in 680 severely injured patients and observed that the administration of TXA increased 6-hour survival in patients with HF. In addition, Meizoso et al [60] reported patients who received TXA were at increased risk of fibrinolysis shutdown SD compared with patients who did not receive TXA.
Moreover, fibrinolytic phenotypes can change over time after injury. Robert et al [61] highlighted these temporal changes in the 3 phenotypes within 24 hours following injury and demonstrated that HF patients initially exhibiting a higher frequency of phenotypes may transition to other types such as SD or physiologic fibrinolysis phenotype within 24 hours. Furthermore, the study revealed that the persistence of the SD phenotype for more than 24 hours was associated with increased mortality.
Coats et al [62] investigated the plasma level of tPA and plasminogen activator inhibitor type 1 (PAI-1) in major trauma patients and illustrated an inverse relationship in the temporal changes of median tPA and PAI-1 concentrations. Initially, elevated tPA levels rapidly declined, while initial PAI-1 levels exhibited a gradual increase. The results of this study suggest the presence of a natural antifibrinolytic system that lags by several hours behind the natural profibrinolytics. These findings support early administration of TXA, to address the poor outcomes associated with delayed administration of TXA use as observed in the previous study [3].

9. Adverse effects of TXA

When considering the use of TXA for the bleeding patients, the risk of adverse events must also be considered. TXA is usually well tolerated and generally considered safe at the empirical dosage. However, TXA can provoke several adverse effects including nausea, diarrhea, drug eruption, renal injury, seizure, and several thromboembolic events like deep vein thrombosis, cerebrovascular infarction, myocardial infarction, and pulmonary embolism. Most of these are mild or subtle, but some can be fatal. In the context of these potentially fatal side effects, there is a scarcity of research findings concerning the dosage, route of administration, and circumstances related to the risk of occurrence. This highlights the need for further investigation to ensure safe and effective use of TXA. The incidence of thrombotic events among bleeding patients who receive TXA is not fully known even though many clinical studies have been performed to date.
The authors of the CRASH-2 study reported no difference in the rate of vascular occlusive events between groups [PE 72 (0.7%) for the TXA group vs. 71 (0.7%) for the control group; DVT 40 (0.4%) for the TXA group vs. 41 (0.4%) for the control group] or risk of stroke [57 (0.6%) for the TXA group vs. 66 (0.5%) for the control group], but in this report the number of these events was small, and no standard diagnostic method was presented. The MATTERs study, where TXA was used in the military, documented no difference in thromboembolic events between groups [43]. In the STAAMP trial [33], an RCT on the effects of prehospital use of TXA in injured patients with hemorrhagic shock, the incidence of deep vein thrombosis, and pulmonary embolism was 2.7:1.5% (p = 0.83) and 2.9%:1.5% (p = 0.78) in the TXA and placebo groups, respectively, and there was no significant difference between the 2 groups.
In the international, multicenter, randomized trial on the effect of TXA on the thromboembolic events in patients with gastrointestinal bleeding (HALT-IT), the incidence of arterial thromboembolic events (myocardial infarction or stroke) in the TXA treated group was similar to the control group, and the venous thromboembolic events (DVT or pulmonary embolism) occurred significantly more frequently than in the control group [42]. However, it should be taken into consideration that the TXA dose in this study was slightly higher than the 24-hour dose compared with the CRASH-2 trial, and this result helped to decide the safe dosage of TXA.
A recent systematic review involving 216 trials and a total of 12,550 people, determined that there was no association between TXA and risk for total thromboembolism [risk difference = 0.001 (95%); CI −0.001–0.002; p = 0.49] including deep vein thrombosis, pulmonary embolism, myocardial infarction or ischemia, and cerebral infarction or ischemia [63].
However, some studies have shown that the administration of TXA in trauma patients is an independent risk factor for the venous thromboembolism [6467].
In addition, a recently published meta-analysis review including 234 studies, reported seizures increased in patients receiving more than 2 g/day of TXA [3.05 (1.01–9.20)] [68]. Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011) indicating a high dose of TXA use should be avoided because there may be dose-dependent increase in the risk of seizures [68].

10. Value and limitations of the CRASH-2 trial

The CRASH-2 trial [3] was a large scale, international, multicenter randomized placebo-controlled trial on the effect of TXA use on mortality, vascular occlusive event, and transfusion in the adult trauma patients. This trial enrolled 20,211 injured adults with significant bleeding or shock. All-cause 28-day mortality was reportedly 1,463 (14.5%) in patients who received TXA, and 1,613 (16.0%) in patients who received the placebo [RR 0.91 (95% CI 0.85–0.97; p = 0.0035)]. There was no difference in the rate of vascular occlusive events between groups. In this subgroup analysis for the effectiveness of the TXA, the most beneficial subgroup was use within 3 hours from injury in the patients with the most severe shock (SBP ≤ 75 mmHg). This result of subgroup analysis has provided many implications regarding the effectiveness of TXA use in trauma patients.
The relationship between TXA administration time and mortality benefit in trauma patients can be interpreted by considering fibrinolysis phenotype. Considering the basic pharmacological action of TXA, an antifibrinolytic agent, which shows an effective beneficial effect on patients with hyperfibrinolytic status, and the results of several studies showing that the hyperfibrinolytic phenotype is more common in cases of severe damage or shock, or in the early stages of injury [61,69], the result of subgroup analysis of CRASH-2, regarding the timing of TXA administration, are fully appropriate and have implications. However, despite the insight that the CRASH-2 trial gives us, it should be interpreted with several caveats in mind. That is, there is no consideration of the international differences in trauma systems, prehospital infrastructure, and resources between participating countries, and no data regarding the effect of pre-hospital interventions, no formal stratification of severity of injury, and not all patients were severely injured. In addition, the CRASH studies lack assessment of fibrinolysis or coagulation.

11. Goal directed treatment of TIC and use of TXA

TIC appears in various clinical manifestations after injury, ranging from hypocoagulability to hypercoagulability, and this is explained by a complex mechanism involving the cell-based hemostasis concept including platelet function, endothelial cell dysfunction, and dysregulation of fibrinolysis. Clinically, a quick and accurate evaluation of the function and amount of coagulation factors, and the fibrinolysis status of a patient with coagulopathy is crucial in selecting the appropriate blood component, and deciding whether to administer TXA.
However, the plasma-based conventional coagulation test has many weaknesses in determining these various blood coagulation and fibrinolysis conditions. On the contrary, the viscoelastic hemostatic assay (VHA), like thromboelastography (TEG) or rotational thromboelastography (ROTEM), can provide better information about the coagulability status as a result of dysfunction of the platelet or deletion of some coagulation factors. In particular, it is superior in determining the state of fibrinolysis [70]. In a study that compared 2 diagnostic methods, TEG data was clinically superior to the results from 5 conventional coagulation tests. In addition, TEG identified patients early that had an increased risk of requiring RBC, plasma and platelet transfusions, and fibrinolysis, and it was reported that TEG can replace the conventional coagulation tests [71]. Many researchers have explored the threshold values of several parameters of VHA, which has better sensitivity and specificity for TIC diagnosis compared with the conventional tests [72].
In addition, to VHA, research on the fibrinolysis phenotype of patients with TIC is emerging that supports individualized goal-directed resuscitation after injury [73,74].
Gonzalez et al [75] reported that resuscitation of severe trauma patients using a goal-directed, TEG-guided massive transfusion protocol resulted in significant survival benefit compared with the preemptive strategy using conventional coagulation assays (CCA) 19.6%, 36.4%, respectively (p = 0.049). Recently, VHA guided hemostatic resuscitation for severely injured patients was associated with better results than using CCA in terms of survival, massive transfusion, and volume of the transfusion [76].
“The European guideline on management of major bleeding and coagulopathy following trauma: 6th edition” revised in 2019 recommended resuscitation measures using goal-directed strategy guided by standard laboratory coagulation values and/ or viscoelastic measures (VEM) [30].
While research on the superiority of goal-directed resuscitation based on VHA has primarily focused on survival rates and transfusion volumes, there is a notable lack of information guiding the use of TXA. This highlights a critical gap in our understanding that warrants further investigation [77].
The state of fibrinolysis can be determined by measuring LY30 in TEG (the percentage reduction in the area under the curve at 30 minutes after maximal amplitude) and Li30 in ROTEM [the residual clot firmness at 30 minutes after clotting time (CT)] [7]. It appears that a certain degree of consensus has been reached regarding the range of measurement values for each fibrinolysis phenotype. That is that HF is LY30 ≥ 3% and Li30 is > 15%, physiological fibrinolysis is LY30 0.9–3% and Li30 5–15%, and fibrinolysis SD is LY30 < 0.9% and Li30 < 5% [5,7].
These measurements theoretically inform us about the most appropriate indication of TXA for the coagulopathy. Moore et al [7] advocated that TXA should only be used if patients have VHA evidence of hyperfibrinolysis. In the prehospital setting, TXA use should be used prudently in severely injured patients with shock, based on the belief that shock is the main driver of fibrinolytic dysregulation.

Conclusion

TXA has emerged as a crucial hemostatic agent in the management of trauma patients, demonstrating a reduction in mortality and bleeding, particularly when administered early, and in patients with shock or requiring massive transfusion. However, the effects of TXA can vary depending on the severity of the injury and its location, such as in cases of brain injury.
The use of VHA for assessing the fibrinolysis status of TIC has been highlighted as a valuable tool for guiding the appropriate use of TXA. This approach allows for individualized treatment strategies that can optimize patient outcomes.
However, it is important to note that in cases of severe hemorrhagic shock, the patient’s physiology and clinical presentation may be more critical than waiting for the results from VHA or conventional coagulation assays in guiding initial resuscitation strategies, including the administration of TXA.
While significant strides have been made in understanding the role and application of TXA in trauma management, further research is needed to fully elucidate its optimal dosage, timing, safety, and efficacy across different types of injuries. This underscores the need for ongoing investigation into this therapeutic agent within the context of comprehensive, patient-centered trauma care.

Acknowledgment

I acknowledge the significant contributions of Hyerim Lee, RN and Jiwon Kim, RN to this review article. Their diligent efforts in searching, collecting, sorting, and referencing the literature and data have been invaluable. Their dedication and hard work have greatly enhanced the quality of this work. I extend my deepest gratitude for their assistance.

Notes

Conflicts of Interest

The author has no conflicts of interest to declare.

Funding

None.

Ethical Statement

This research did not involve any human or animal experiments.

Data Availability

All relevant data are included in this manuscript.

Table 1
TXA administration dosage in reviewed studies
Year Author [ref] Design No. of patients Dosage of TXA Results
2010 Shakur et al (CRASH-2) [3] Double blind RCT 20,211 1 g IV bolus and subsequent 1 g IV infusion over 8 h TXA was associated with reduced all-cause mortality (14.5% for the TXA group vs 16.0% for the placebo group) and risk of death from bleeding if given in < 3 h (4.9% for TXA vs 5.7% for the placebo). Effect is greater if given in < 1 h.
2011 Ducloy-Bouthors et al [51] Open label RCT 144 4 g over 1 h, then 1 g/h for 6 h Blood loss within the first 6 h of enrollment was significantly lower in the TXA group (173 mL median) compared with the control group (221 mL median) (p = 0.041). TXA was associated with a decreased need for blood transfusion and total volume transfused.
2014 Bennett et al [52] Meta-analysis, retrospective cohort 851 4 to 8 g ranging from 2 to 7 d TXA 1 g intravenous injection followed by additional 1 g if bleeding continues or if bleeding recurs within 24 h.
2015 Cole et al [23] Prospective cohort 160 1 g IV bolus and subsequent 1 g IV infusion over 8 h TXA was associated with reduced multiorgan failure (p = 0.03) and all-cause mortality (p = 0.01) in patients experiencing shock.
2017 (WOMAN Trial) Collaborators [31] Double blind RCT 20,060 1 g intravenous, hemorrhage recurrence within 24 h additional 1 g Rates of bleeding to death were significantly lower in the TXA group (1.5%) compared with the placebo group (1.9%; p = 0.045). Although TXA did not significantly decrease all-cause mortality, it did modestly decrease death from bleeding. Effects were most notable in patients receiving TXA within 3 h.
2018 Boutonnet et al [53] Retrospective cohort 1,476 Not recorded TXA was associated with reduced mortality only in patients with significant hemorrhage (qualified by hemodynamic instability) requiring pRBC transfusion (HR, 0.3; 95% CI, 0.3–0.6 compared with HR, 1.2; 95% CI, 0.8–2.6; p < 0.001).
2018 Khan et al [54] Retrospective cohort 118 Not recorded TXA was associated with improved 6-h survival (13% for TXA vs 34% for no TXA) in patients with hyperfibrinolysis (p = 0.04). There were no reductions in the need for transfusion.
2019 CRASH-3 Trial Collaborators [4] RCT 12,737 1 g IV over 10 min followed by additional 1 g over 8 h The risk of head injury-related death was 18·5% in TXA group versus 19·8% in the placebo group [855 vs 892 events; (HR) 0·94 (95% CI 0·86–1·02)].

CI= confidence interval; HR= hazard ratio; IV= intravenous; RCT = randomized controlled trial; TXA = tranexamic acid.

References

1. Callcut RA, Kornblith LZ, Conroy AS, Robles AJ, Meizoso JP, Namias N, et al. The why and how our trauma patients die: a prospective Multicenter Western Trauma Association study. J Trauma Acute Care Surg 2019;86(5):864–70.
crossref pmid pmc
2. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma 2003;54(6):1127–30.
crossref pmid
3. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, et 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. Lancet 2010;376(9734):23–32.
crossref pmid
4. CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019;394(10210):1713–23.
crossref pmid pmc
5. Rossetto A, Vulliamy P, Lee KM, Brohi K, Davenport R. Temporal transitions in fibrinolysis after trauma: adverse outcome is principally related to late hypofibrinolysis. Anesthesiology 2022;136(1):148–61.
crossref pmid pdf
6. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008;64(5):1211–7. discussion 1217.
crossref pmid
7. Moore EE, Moore HB, Kornblith LZ, Neal MD, Hoffman M, Mutch NJ, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers 2021;7(1):30.
crossref pmid pmc pdf
8. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma 2003;55(1):39–44.
crossref pmid
9. Maegele M, Lefering R, Yucel N, Tjardes T, Rixen D, Paffrath T, et al. Early coagulopathy in multiple injury: an analysis from the German Trauma Registry on 8724 patients. Injury 2007;38(3):298–304.
crossref pmid
10. Cohen MJ, Kutcher M, Redick B, Nelson M, Call M, Knudson MM, et al. Clinical and mechanistic drivers of acute traumatic coagulopathy. J Trauma Acute Care Surg 2013;75(1 Suppl 1):S40–7.
crossref pmid pmc
11. Fröhlich M, Mutschler M, Caspers M, Nienaber U, Jäcker V, Driessen A, et al. Trauma-induced coagulopathy upon emergency room arrival: still a significant problem despite increased awareness and management? Eur J Trauma Emerg Surg 2019;45(1):115–24.
crossref pmid pdf
12. Strumwasser A, Speer AL, Inaba K, Branco BC, Upperman JS, Ford HR, et al. The impact of acute coagulopathy on mortality in pediatric trauma patients. J Trauma Acute Care Surg 2016;81(2):312–8.
crossref pmid
13. Peltan ID, Vande Vusse LK, Maier RV, Watkins TR. An international normalized ratio-based definition of acute traumatic coagulopathy is associated with mortality, venous thromboembolism, and multiple organ failure after injury. Crit Care Med 2015;43(7):1429–38.
crossref pmid pmc
14. Frith D, Goslings JC, Gaarder C, Maegele M, Cohen MJ, Allard S, et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost 2010;8(9):1919–25.
crossref pmid
15. Ho VK, Wong J, Martinez A, Winearls J. Trauma-induced coagulopathy: mechanisms and clinical management. Ann Acad Med Singap 2022;51(1):40–8.
crossref pmid
16. Zanza C, Romenskaya T, Racca F, Rocca E, Piccolella F, Piccioni A, et al. Severe trauma-induced coagulopathy: molecular mechanisms underlying critical illness. Int J Mol Sci 2023;24(8):7118.
crossref pmid pmc
17. Kashuk JL, Moore EE, Sawyer M, Wohlauer M, Pezold M, Barnett C, et al. Primary fibrinolysis is integral in the pathogenesis of the acute coagulopathy of trauma. Ann Surg 2010;252(3):434–42. discussion 443–4.
crossref pmid
18. Watts G. Utako Okamoto. Lancet 2016;387(10035):2286.
crossref pmid
19. Tengborn L, Blombäck M, Berntorp E. Tranexamic acid--an old drug still going strong and making a revival. Thromb Res 2015;135(2):231–42.
crossref pmid
20. Hanley C, Callum J, Jerath A. Tranexamic acid and trauma coagulopathy: where are we now? Br J Anaesth 2021;126(1):12–7.
crossref pmid
21. Medcalf RL. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost 2007;5(Suppl 1):132–42.
crossref pmid
22. Syrovets T, Simmet T. Novel aspects and new roles for the serine protease plasmin. Cell Mol Life Sci 2004;61(7–8):873–85.
crossref pmid pdf
23. Cole E, Davenport R, Willett K, Brohi K. Tranexamic acid use in severely injured civilian patients and the effects on outcomes: a prospective cohort study. Ann Surg 2015;261(2):390–4.
pmid
24. CYKLOKAPRON-tranexamic acid injection, solution Pharmacia and Upjohn Company [Internet].; [cited 2023 Oct 10]. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=556 .

25. Spruce MW, Beyer CA, Caples CM, DeSoucy ES, Kashtan HW, Hoareau GL, et al. Pharmacokinetics of tranexamic acid given as an intramuscular injection compared to intravenous infusion in a swine model of ongoing hemorrhage. Shock 2020;53(6):754–60.
crossref pmid
26. Kane Z, Picetti R, Wilby A, Standing JF, Grassin-Delyle S, Roberts I, et al. Physiologically based modelling of tranexamic acid pharmacokinetics following intravenous, intramuscular, sub-cutaneous and oral administration in healthy volunteers. Eur J Pharm Sci 2021;164:105893.
crossref pmid pmc
27. Grassin-Delyle S, Semeraro M, Lamy E, Urien S, Runge I, Foissac F, et al. Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers. Br J Anaesth 2022;128(3):465–72.
crossref pmid
28. Roberts I, Prieto-Merino D, Manno D. Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. Crit Care 2014;18(6):685.
crossref pmid pmc pdf
29. Gayet-Ageron A, Prieto-Merino D, Ker K, Shakur H, Ageron FX, Roberts I; Antifibrinolytic Trials Collaboration. Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40138 bleeding patients. Lancet 2018;391(10116):125–32.
crossref pmid pmc
30. Rossaint R, Afshari A, Bouillon B, Cerny V, Cimpoesu D, Curry N, et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care 2023;27(1):80.
crossref pmid pmc pdf
31. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet 2017;389(10084):2105–16.
crossref pmid pmc
32. Stein P, Studt JD, Albrecht R, Müller S, von Ow D, Fischer S, et al. The impact of prehospital tranexamic acid on blood coagulation in trauma patients. Anesth Analg 2018;126(2):522–9.
crossref pmid
33. Guyette FX, Brown JB, Zenati MS, Early-Young BJ, Adams PW, Eastridge BJ, et al. Tranexamic acid during prehospital transport in patients at risk for hemorrhage after injury: a double-blind, placebo-controlled, randomized clinical trial. JAMA Surg 2020;156(1):11–20.
pmid pmc
34. Bossers SM, Loer SA, Bloemers FW, Den Hartog D, Van Lieshout EMM, Hoogerwerf N, et al. Association between prehospital tranexamic acid administration and outcomes of severe traumatic brain injury. JAMA Neurol 2021;78(3):338–45.
pmid
35. Rowell SE, Meier EN, McKnight B, Kannas D, May S, Sheehan K, et al. Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA 2020;324(10):961–74.
crossref pmid pmc
36. PATCH-Trauma Investigators and the ANZICS Clinical Trials Group, Gruen RL, Mitra B, Bernard SA, McArthur CJ, Burns B, Gantner DC, et al. Prehospital tranexamic acid for severe trauma. N Engl J Med 2023;389(2):127–36.
crossref pmid
37. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med 2017;376(2):136–48.
crossref pmid
38. Devereaux PJ, Marcucci M, Painter TW, Conen D, Lomivorotov V, Sessler DI, et al. Tranexamic acid in patients undergoing noncardiac surgery. N Engl J Med 2022;386(21):1986–97.
pmid
39. Monaco F, Nardelli P, Pasin L, Barucco G, Mattioli C, Di Tomasso N, et al. Tranexamic acid in open aortic aneurysm surgery: a randomised clinical trial. Br J Anaesth 2020;124(1):35–43.
crossref pmid
40. Fillingham YA, Ramkumar DB, Jevsevar DS, Yates AJ, Shores P, Mullen K, et al. The Efficacy of tranexamic acid in total knee arthroplasty: a network meta-analysis. J Arthroplasty 2018;33(10):3090–8e1.
crossref pmid
41. Ducloy-Bouthors AS, Duhamel A, Kipnis E, Tournoys A, Prado-Dupont A, Elkalioubie A, et al. Postpartum haemorrhage related early increase in D-dimers is inhibited by tranexamic acid: haemostasis parameters of a randomized controlled open labelled trial. Br J Anaesth 2016;116(5):641–8.
crossref pmid
42. HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet 2020;395(10241):1927–36.
pmid pmc
43. 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.
crossref pmid
44. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg 2013;148(3):218–25.
crossref pmid
45. Perel P, Al-Shahi Salman R, Kawahara T, Morris Z, Prieto-Merino D, Roberts I, et al. CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury--a nested randomised, placebo-controlled trial. Health Technol Assess 2012;16(13):iii–xii. 1–54.
crossref pdf
46. Baharoglu MI, Germans MR, Rinkel GJ, Algra A, Vermeulen M, van Gijn J, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2013;2013(8):CD001245.
crossref pmid pmc
47. Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007;(4):CD001886.
crossref pmid
48. Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N Y Acad Sci 1968;146(2):642–58.
crossref pmid
49. Hoylaerts M, Lijnen HR, Collen D. Studies on the mechanism of the antifibrinolytic action of tranexamic acid. Biochim Biophys Acta 1981;673(1):75–85.
crossref pmid
50. Grassin-Delyle S, Theusinger OM, Albrecht R, Mueller S, Spahn DR, Urien S, et al. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. Anaesthesia 2018;73(6):719–29.
crossref pmid pdf
51. Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011;15(2):R117.
crossref pmid pmc
52. Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2014;11:CD006640.
crossref pmid pmc
53. Boutonnet M, Abback P, Le Saché F, Harrois A, Follin A, Imbert N, et al. Tranexamic acid in severe trauma patients managed in a mature trauma care system. J Trauma Acute Care Surg 2018;84(6S Suppl 1):S54–62.
crossref pmid
54. Khan M, Jehan F, Bulger EM, O’Keeffe T, Holcomb JB, Wade CE, et al. Severely injured trauma patients with admission hyperfibrinolysis: is there a role of tranexamic acid? Findings from the PROPPR trial. J Trauma Acute Care Surg 2018;85(5):851–7.
crossref pmid pmc
55. Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, et al. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2002;97(2):390–9.
crossref pmid pdf
56. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008;107(6):1783–90.
crossref pmid
57. Moore HB, Moore EE, Gonzalez E, Chapman MP, Chin TL, Silliman CC, et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg 2014;77(6):811–7.
pmid pmc
58. Moore EE, Moore HB, Gonzalez E, Chapman MP, Hansen KC, Sauaia A, et al. Postinjury fibrinolysis shutdown: Rationale for selective tranexamic acid. J Trauma Acute Care Surg 2015;78(6 Suppl 1):S65–9.
pmid pmc
59. Moore HB, Moore EE, Chapman MP, Hansen KC, Cohen MJ, Pieracci FM, et al. Does tranexamic acid improve clot strength in severely injured patients who have elevated fibrin degradation products and low fibrinolytic activity, measured by thrombelastography? J Am Coll Surg 2019;229(1):92–101.
crossref pmid pmc
60. Meizoso JP, Dudaryk R, Mulder MB, Ray JJ, Karcutskie CA, Eidelson SA, et al. Increased risk of fibrinolysis shutdown among severely injured trauma patients receiving tranexamic acid. J Trauma Acute Care Surg 2018;84(3):426–32.
crossref pmid
61. Roberts DJ, Kalkwarf KJ, Moore HB, Cohen MJ, Fox EE, Wade CE, et al. Time course and outcomes associated with transient versus persistent fibrinolytic phenotypes after injury: A nested, prospective, multicenter cohort study. J Trauma Acute Care Surg 2019;86(2):206–13.
crossref pmid
62. Coats TJ, Morsy M. Biological mechanisms and individual variation in fibrinolysis after major trauma. Emerg Med J 2020;37(3):135–40.
crossref pmid
63. Taeuber I, Weibel S, Herrmann E, Neef V, Schlesinger T, Kranke P, et al. Association of intravenous tranexamic acid with thromboembolic events and mortality: a systematic review, meta-analysis, and meta-regression. JAMA Surg 2021;156(6):e210884.
crossref pmid pmc
64. Johnston LR, Rodriguez CJ, Elster EA, Bradley MJ. Evaluation of military use of tranexamic acid and associated thromboembolic events. JAMA Surg 2018;153(2):169–75.
crossref pmid pmc
65. Adair KE, Patrick JD, Kliber EJ, Peterson MN, Holland SR. TXA (tranexamic acid) risk evaluation in combat casualties (TRECC). Trauma Surg Acute Care Open 2020;5(1):e000353.
crossref pmid pmc
66. Howard JT, Stockinger ZT, Cap AP, Bailey JA, Gross KR. Military use of tranexamic acid in combat trauma: Does it matter? J Trauma Acute Care Surg 2017;83(4):579–88.
pmid
67. Myers SP, Kutcher ME, Rosengart MR, Sperry JL, Peitzman AB, Brown JB, et al. Tranexamic acid administration is associated with an increased risk of posttraumatic venous thromboembolism. J Trauma Acute Care Surg 2019;86(1):20–7.
crossref pmid
68. Murao S, Nakata H, Roberts I, Yamakawa K. Effect of tranexamic acid on thrombotic events and seizures in bleeding patients: a systematic review and meta-analysis. Crit Care 2021;25(1):380.
crossref pmid pmc pdf
69. Moore HB, Moore EE. Temporal changes in fibrinolysis following injury. Semin Thromb Hemost 2020;46(2):189–98.
crossref pmid
70. Gratz J, Güting H, Thorn S, Brazinova A, Görlinger K, Schäfer N, et al. Protocolised thromboelastometric-guided haemostatic management in patients with traumatic brain injury: a pilot study. Anaesthesia 2019;74(7):883–90.
crossref pmid pdf
71. Holcomb JB, Minei KM, Scerbo ML, Radwan ZA, Wade CE, Kozar RA, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Ann Surg 2012;256(3):476–86.
pmid
72. Baksaas-Aasen K, Van Dieren S, Balvers K, Juffermans NP, Næss PA, Rourke C, et al. Data-driven development of ROTEM and TEG algorithms for the management of trauma hemorrhage: a prospective observational multicenter study. Ann Surg 2019;270(6):1178–85.
pmid
73. Moore HB, Moore EE, Liras IN, Wade C, Huebner BR, Burlew CC, et al. Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality. Am J Surg 2017;214(6):1041–5.
crossref pmid pmc
74. Chin TL, Moore EE, Moore HB, Gonzalez E, Chapman MP, Stringham JR, et al. A principal component analysis of postinjury viscoelastic assays: clotting factor depletion versus fibrinolysis. Surgery 2014;156(3):570–7.
crossref pmid pmc
75. Gonzalez E, Moore EE, Moore HB, Chapman MP, Chin TL, Ghasabyan A, et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg 2016;263(6):1051–9.
pmid
76. David JS, James A, Orion M, Selves A, Bonnet M, Glasman P, et al. Thromboelastometry-guided haemostatic resuscitation in severely injured patients: a propensity score-matched study. Crit Care 2023;27:141.
crossref pmid pmc pdf
77. 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):1575–86.
pmid
TOOLS
Share :
Facebook Twitter Linked In Google+ Line it
METRICS Graph View
  • 0 Crossref
  •    
  • 1,035 View
  • 81 Download
Related articles in
J Acute Care Surg

Tranexamic Acid in Trauma Management2015 October;5(2)



For JACS
Articles and Issues
For Authors
Editorial and Ethical Policies
Submit Manuscript
Editorial Office
7th Floor, East-Gwan, Asan Medical Center, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea
Tel: +82-10-9040-6245    Fax: +82-50-7993-9018    E-mail: ksacs@ksacs.org                

Copyright © 2024 by Korean Society of Acute Care Surgery.

Developed in M2PI

Close layer
prev next