Skip to main content
Download PDF

The efficacy of tranexamic acid treatment with different time and doses for traumatic brain injury: a systematic review and meta-analysis

Thrombosis Journal volume 20, Article number: 79 (2022) Cite this article

Abstract

Objective

Tranexamic acid (TXA) plays a significant role in the treatment of traumatic diseases. However, its effectiveness in patients with traumatic brain injury (TBI) seems to be contradictory, according to the recent publication of several meta-analyses. We aimed to determine the efficacy of TXA treatment at different times and doses for TBI treatment.

Methods

PubMed, MEDLINE, EMBASE, Cochrane Library, and Google Scholar were searched for randomized controlled trials that compared TXA and a placebo in adults and adolescents (≥ 15 years of age) with TBI up to January 31, 2022. Two authors independently abstracted the data and assessed the quality of evidence.

Results

Of the identified 673 studies, 13 involving 18,675 patients met our inclusion criteria. TXA had no effect on mortality (risk ratio (RR) 0.99; 95% confidence interval (CI) 0.92–1.06), adverse events (RR 0.93, 95% Cl 0.76–1.14), severe TBI (Glasgow Coma Scale score from 3 to 8) (RR 0.99, 95% Cl 0.94–1.05), unfavorable Glasgow Outcome Scale (GOS < 4) (RR 0.96, 95% Cl 0.82–1.11), neurosurgical intervention (RR 1.11, 95% Cl 0.89–1.38), or rebleeding (RR 0.97, 95% Cl 0.82–1.16). TXA might reduce the mean hemorrhage volume on subsequent imaging (standardized mean difference, -0.35; 95% CI [-0.62, -0.08]).

Conclusion

TXA at different times and doses was associated with reduced mean bleeding but not with mortality, adverse events, neurosurgical intervention, and rebleeding. More research data is needed on different detection indexes and levels of TXA in patients with TBI, as compared to those not receiving TXA; although the prognostic outcome for all harm outcomes was not affected, the potential for harm was not ruled out.

Trial registration

The review protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (CRD42022300484).

Background

Traumatic brain injury (TBI) is an organic injury of brain tissue caused by external violence [1]. More than 50 million people worldwide suffer from TBI every year, and approximately half of the world's population may suffer from TBI once or more in their lifetime [2]. The annual incidence rate of TBI in Europe ranges from 47.3/10 million to 849/10 million, with a mortality of 3.3/10 million to 28.1/10 million [3]. The high mortality rate associated with TBI may be closely related to its complex pathophysiology.

TBI includes initial head trauma via an external force that results in mechanical damage to brain tissue, and subsequent biochemical cascades such as apoptosis, mitochondrial dysfunction, cortical spreading depression, and microvascular thrombosis [4]. As a result, nerve damage in differing proportions inevitably occurs, with various resultant clinical courses occurring during this process, including intracranial hematoma, brain tissue contusion, and cerebral ischemia [5]. In particular, intracranial hematoma in half of the patients increases after hospital admission, which increases the difficulty of surgical removal and leads to high mortality and disability [6].

Currently, the treatment of TBI mainly involves hyperosmolar therapy, seizure prophylaxis, medically induced comatose state, invasive intracranial monitoring, and radical decompressive surgical interventions as a last resort [7]. These methods, except for surgical interventions, may achieve symptom relief in a short time but do not address the prognosis of TBI. Therefore, research on the treatment of this disease is required, especially regarding hemostatic drugs designed to protect against long-term damage from TBI.

Recently, tranexamic acid (TXA), a synthetic lysine derivative, was shown to play important roles in the treatment of traumatic diseases [8]. TXA exerts its hemostatic function by competitively occupying the lysine binding site of plasminogen, thereby blocking its interaction with fibrin and subsequent clot breakdown [9]. Extensive trials conducted in patients with severe trauma with massive bleeding using TXA have demonstrated that survival increased when TXA was administered early after an accident compared with a placebo [10]. However, the role of TXA in patients with TBI or intracranial bleeding remains controversial [11]. After the recent systematic review and meta-analysis, which included 5 multi-site RCTs and 8 single-site RCTs (The specific information of the RCT is shown in Table 1) [12], we performed this meta-analysis of all related articles to examine the effectas of TXA in TBI patients..

Table 1 Baseline characteristics of included studies
Full size table

Methods

This systematic review and meta-analysis was conducted based on the Cochrane Handbook for Systematic Reviews of Interventions [23] and the “Preferred Reporting Items for Systematic Reviews and Meta-Analysis” recommendations [24]. Two investigators independently searched for articles, extracted the data, and assessed the quality of the included studies.

Search strategy

PubMed, MEDLINE, EMBASE, Cochrane Library, and Google Scholar were searched for RCTs that compared TXA and a placebo in adults and adolescents (≥ 15 years of age) with TBI, up to January 31, 2022. With the assistance of an expert medical librarian, we developed a search strategy, including three search terms: "tranexamic acid,” "traumatic brain injury" and "randomized controlled trial" (appendix 1–1). We also searched the proceedings of emergency medicine, hematology, trauma, neurology, and neurosurgery conferences to identify relevant abstracts.

Study selection

We included all English literature on RCTs on the treatment of TBI with TXA and performed a meta-analysis. Our inclusion criteria were as follows: (1) studies conducted in patients with TBI receiving any dose of TXA. 2) Patients with any type of intracranial hemorrhage secondary to TBI. The exclusion criteria were as follows: 1) preclinical study; 2) The research type was repeated reports or published studies such as case reports, reviews, or literature without control, focusing on surgical methods, surgical techniques, and imported instruments; 3) study with nonclinical patients such as animals, corpses, or specimens; 4) non-English-language publications; and 5) repetitive studies.

Data extraction and quality assessment

Two authors independently abstracted the data and assessed the quality of evidence. We extracted the following information from the included studies [13,14,15,16,17,18,19,20,21,22, 25,26,27]: study author and year of study, study design, demographic data, age and sex of the participants, details of the intervention, and risk of bias. We extracted the results of the included studies as follows: mortality, severe TBI (Glasgow Coma Scale score from 3 to 8), unfavorable Glasgow Outcome Scale (GOS < 4), neurosurgical intervention, mean hemorrhage volume, the number of patients with rebleeding, adverse events including vascular occlusive events, pulmonary embolism, deep vein thrombosis, neurological complications (including stroke and seizure), gastrointestinal bleeding, myocardial infarction, infectious complications, and renal failure. The Cochrane risk of bias assessment tool (Cochrane Collaboration) was used to assess the quality of the included trials and rate the level of evidence.

Statistical analysis

We used RevMan 5.3 software provided by the Cochrane Collaboration Network for meta-analysis, and Stata 16.0 software for Harbord’s test and Egger’s test. Dichotomous data were measured using risk ratios (RR) and 95% confidence interval (CI). In this analysis, because the average blood loss units in some studies was inconsistent with that in other studies, continuous variables were measured using standardized mean difference (SMD) and 95% Cl. Heterogeneity among the included studies was examined using the chi-square and I2 tests. When there was statistical homogeneity among the results (P ≥ 0.1, I2 < 50%), the fixed-effects model was used to continue the meta-analysis. If there was statistical heterogeneity among the research results (P < 0.1, I2 > 50%), the random-effects model was used for the meta-analysis. We did not construct funnel plots to assess publication bias, as these were inaccurate when fewer than 10 trials were included in the analysis. Publication bias of the included studies was analyzed using Harbord’s test and Egger’s test.

Result

Literature search

Based on the results of the search strategy results, 1782 relevant articles were screened. After excluding duplicated articles and those that met the exclusion criteria described in Sect. 2.2, 673 articles remained. After reading the title and abstract according to the inclusion criteria, 547 articles were excluded, yielding 126 studies. The full text of these articles was assessed, leading to the exclusion of another 113 studies, resulting in 13 studies with 18,675 patients, which were included in the analysis [13,14,15,16,17,18,19,20,21,22, 25,26,27]. The baseline characteristics of the included studies are summarized in Table 1. A flowchart of the literature search strategy is presented in Fig. 1.

Fig. 1
figure 1

Flow diagram of study selection process for systematic review

Full size image

Description of included studies

Thirteen articles were included, including eight single-site RCTs [15,16,17,18,19,20, 26, 27] and five multi-site RCTs [13, 14, 21, 22, 25]. The minimum age of the participants was greater than 15 years, which included both adults and adolescents. The timing of TXA administration varied among studies, with five trials in which the post-traumatic registration time was less than 3 h [13, 15, 17, 19, 25], seven trials in which the post-traumatic registration time was more than 3 h [14, 16, 18, 19, 21, 26, 27], and one article that did not clearly explain the registration time. In the included trials, the TXA dose was mostly similar, and the most common regimen was a loading dose of 1 g, followed by a maintenance dose of 1 g over 8 h [13,14,15,16,17,18,19,20,21,22, 25,26,27]. However, one trial used a loading dose of 2 g followed by a maintenance dose of 2 g over 8 h [13]. The risk of bias was lower in eight articles and higher in five articles and is shown in Fig. 2. The regression-based Harbord’s and Egger’s tests were not statistically significant for all outcomes (Table 2). Since the mean hemorrhage volume is continuous data, Harbord’s test could not be utilized. Gastrointestinal bleeding (n = 2), myocardial infarction (n = 2), infection complications (n = 2), and renal failure (n = 1) were included in the less relevant articles; therefore, they were not tested.

Fig. 2
figure 2

Risk of bias assessment. A. Authors' judgments about each risk of bias item for each included study. B. Authors' judgments about each risk of bias item presented as percentages across all included studies

Full size image
Table 2 The risk of bias of studies
Full size table

Prognostic outcome

Ten articles [13, 15,16,17,18,19,20,21,22, 25, 26] reported the mortality of patients with TBI treated with TXA or a placebo. Meta-analysis showed that TXA was not associated with reduced mortality (RR 0.99; 95% CI 0.92–1.06, Fig. 3), adverse events (RR 0.93, 95% Cl 0.76–1.14, Fig. 4), severe TBI (Glasgow Coma Scale score from 3 to 8) (RR 0.99, 95% Cl 0.94–1.05, Fig. 5), unfavorable Glasgow Outcome Scale (GOS < 4) (RR: 0.96, 95% Cl: 0.82–1.11, Fig. 6), neurosurgical intervention (RR 1.11, 95% Cl 0.89–1.38, Fig. 7), or the number instances of rebleeding (RR 0.97, 95% Cl 0.82–1.16, Fig. 8). Our meta-analysis showed that TXA may reduce mean hemorrhage volume in TBI patients on subsequent imaging (SMD -0.35; 95% CI [-0.62, -0.08], Fig. 9). Two articles [17, 19] showed that TXA was a protective factor for mean hemorrhage volume, and three [16, 20, 21] showed that TXA was not associated with mean hemorrhage volume.

Fig. 3
figure 3

Forest plot comparing TXA and placebo for the outcome of all-cause mortality

Full size image
Fig. 4
figure 4

Forest plot comparing TXA and placebo for all adverse events

Full size image
Fig. 5
figure 5

Forest plot comparing TXA and placebo for severe TBI (Glasgow Coma Scale) score from 3 to 8)

Full size image
Fig. 6
figure 6

Forest plot comparing TXA and placebo for the unfavorable Glasgow Outcome Scale (GOS < 4)

Full size image
Fig. 7
figure 7

Forest plot comparing TXA and placebo for the need of neurosurgical intervention

Full size image
Fig. 8
figure 8

Forest plot comparing TXA and placebo for the number people of Rebleeding

Full size image
Fig. 9
figure 9

Forest plot comparing TXA and placebo for mean hemorrhage volume

Full size image

Safety

We found similar rates of adverse events [13, 15, 18, 21, 25, 27] between those receiving and those not receiving TXA (RR 0.93, 95% Cl 0.76–1.14). We conducted an in-depth analysis to understand the impact of TXA on different adverse events (Fig. 10). Pooled results demonstrated no increased risk of vascular occlusive events (RR 1.05, 95% CI 0.83–1.33), pulmonary emboli (RR 1.19, 0.46–3.10), deep vein thrombosis (RR 0.94, 95% CI 0.57–1.55), neurological complications (RR 0.97, 95% CI 0.70–1.30), gastrointestinal bleeding (RR 0.66, 95% Cl 0.40–1.11), myocardial infarction (RR 0.96 95% Cl 0.52–1.77), infectious complications (RR 0.98, 95% Cl 0.87–1.11), or renal failure (RR 1.18, 95% Cl 0.88–1.57) in patients receiving TXA, as compared to those not receiving TXA, although confidence intervals for all harm outcomes were wide, and did not rule out the potential for harm.

Fig. 10
figure 10

Forest plot comparing TXA and placebo for adverse events of various causes

Full size image

Sensitivity and subgroup analysis

We performed a subgroup analysis of the study design (multi- or single-site RCT), enrollment time after trauma (< 3 h or > 3 h), and TXA dose (2 g TXA bolus followed by placebo infusion or 1 g TXA bolus followed by 1 g TXA maintenance). Table 3 presents the results of the analysis. None of the subgroup analyses showed differences in estimates or conclusions for any of the outcomes of interest appendix 1–2).

Table 3 Subgroup Analysis of TXA and placebo
Full size table

We divided the study design into single-site RCT [15,16,17,18,19,20, 26, 27] and multi-site RCT [13, 14, 21, 22, 25]. TXA had no effect on mortality (RR 0.99, 95% Cl 0.79–1.24, P 0.90), adverse events (RR 0.91, 95% Cl 0.73–1.13, P 0.38), neurosurgical intervention (RR 1.01, 95% Cl 0.61–1.55, P 0.96), rebleeding (RR 0.81, 95% Cl 0.59–1.10, P 0.17), or mean hemorrhage volume (RR -0.08, 95% Cl [-0.32, 0.16], P 0.52) in multi-site RCTs. TXA had no effect on mortality (RR 1.03, 95% Cl 0.73–1.43, P 0.88), adverse events (RR 1.07, 95% Cl 0.39–2.88, P 0.90), neurosurgical intervention (RR 1.15, 95% Cl 0.89–1.48, P 0.29), rebleeding (RR 1.65, 95% Cl 0.94–2.89, P 0.88), or mean hemorrhage volume (RR -0.46, 95% Cl [-0.72, 0.20], P 0.0005) in single-site RCTs.

We observed the effect of TXA on prognosis according to the enrollment time after trauma. When the enrollment time after trauma was less than 3 h [13, 15, 17, 19, 25], TXA had no effect on mortality (RR 0.94, 95% Cl 0.87–1.02, P 0.15), adverse events (RR 0.91, 95% Cl 0.77–1.08, P 0.28), neurosurgical intervention (RR 1.18, 95% Cl 0.89–1.55, P 0.24), or rebleeding (RR 0.91, 95% Cl 0.75–1.10, P = 0.34), but reduced mean hemorrhage volume (RR -0.50, 95% Cl [-0.94, -0.05], P 0.03). When enrollment time after trauma was greater than 3 h [14, 16, 18, 20, 21, 26, 27], TXA had no effect on mortality (RR 0.76, 95% Cl 0.51–1.11, P 0.15), adverse events (RR 2.45, 95% Cl 0.92–6.52, P 0.07), neurosurgical intervention (RR 1.00, 95% Cl 0.70–1.44, P 0.99), rebleeding (RR 1.14, 95% Cl 0.65–2.20, P 0.34), or mean hemorrhage volume (RR -0.33, 95% Cl [-0.65, 0.00], P 0.05).

Different doses of TXA had no effect on adverse events. TXA [13] had no effect on mortality (RR 0.80, 95% Cl 0.56–1.15, P 0.22), adverse events (RR 1.22, 95% Cl 0.85–1.74, P 0.28), or rebleeding (RR 1.24, 95% Cl 0.91–1.70, P 0.17) in 2 g TXA bolus followed by a placebo infusion. TXA [13,14,15,16,17,18,19,20,21,22, 25,26,27] had no effect on mortality (RR 1.01, 95% Cl 0.82–1.24, P 0.95), adverse events (RR 1.00, 95% Cl 0.92–1.08, P 0.97), or rebleeding (RR 1.00, 95% Cl 0.71–1.41, P 1) in 1 g TXA bolus followed by 1 g TXA maintenance.

Discussion

TBI is a serious threat to human health and has attracted research interest owing to its high mortality rate [28]. However, owing to its complex pathophysiology, the treatment of TBI has posed a problem for clinicians and researchers [29]. Recently, TXA, a drug used to reduce bleeding for various indications, has been shown to play an important role in the treatment of TBI. However, the efficacy of TXA at various times and doses remains unclear. We will discuss the hemostatic effect, mortality, and adverse events in patients with TBI treated with TXA compared with a placebo at different times and doses.

Hemostatic effect of TXA with respect to time and dose

The coagulopathy of TBI generally does not provoke hyperfibrinolysis and can even result in an acute impairment of fibrinolysis, referred to as fibrinolytic shutdown [30]. A previous study demonstrated that delayed TXA for TBI has been shown to enhance fibrinolysis via the urokinase plasminogen activator [31]. However, another study showed that TBI may lead to hyperfibrinolysis under specific conditions [30]. Therefore, coagulopathy associated with extracranial injuries is primarily caused by substantial blood loss (hemorrhagic shock), consumption, hypothermia, and hypoperfusion-induced metabolic acidosis, which can be further propagated by iatrogenic factors, such as fluid resuscitation (hemodilution) [32, 33]. Hyperfibrinolysis appears to be closely associated with lethal hemorrhagic shock and is relatively independent of injury severity, which was corroborated in an animal model where isolated hemorrhagic shock induced tissue plasminogen activator-mediated hyperfibrinolysis, whereas isolated tissue injury reduced fibrinolytic activity [34, 35]. Secondary infection after hemorrhage is also one of the factors that promote death in patients [36]. TXA with antifibrinolytic and anti-inflammatory properties is effective in avoiding the progression of hemorrhage volume and controlling its associated inflammation in traumatized patients.

This meta-analysis demonstrated that TXA had no effect on rebleeding but reduced the mean hemorrhage volume on subsequent imaging. This result is different from those of previous studies, which indicated that TXA can inhibit rebleeding after TBI, and the possible benefits of TXA appear in specific populations [37, 38]. For example, patients with moderate and severe hypertension may achieve a better inhibitory effect on rebleeding using TXA. Due to the lack of data related to blood pressure, we could not analyze it in depth.

Our subgroup analysis showed that the timing and dose of TXA were not risk factors for re-bleeding. The result of mean hemorrhage volume was consistent with the CRASH-2 trial, that is, administration of TXA within 8 h was not associated with the mean bleeding volume (RR -0.33, 95% Cl [-0.65, 0.00], P 0.05) [39]. Our subgroup analysis showed that the timing of TXA administration within 3 h after injury could reduce the mean hemorrhage volume but had no effect beyond 3 h after injury. Therefore, the timing of TXA administration is one of the factors affecting the hemostatic effects.

Mortality after the treatment of TXA with respect to time and dose

This meta-analysis demonstrated that TXA has no obvious effect on mortality. This disagrees with other meta-analyses performed at an earlier stage. Some studies have demonstrated a reduction in mortality with TXA [40]. However, the latest study did not include the latest data and analyzed all patients enrolled in the CRASH-2 trial, including those with TBI and extracranial traumatic injuries [12]. Our conclusions are consistent with those of a recent study. Current perspectives suggest that the efficacy of TXA may depend on the severity of TBI, timing of TXA administration, and severity of extracranial hemorrhage, the advantages of which might be offset by the side effects of TXA [41]. In addition, patients with both impeding exsanguination and associated severe TBI are likely to be deceased prior to arrival at the emergency department, which can lead to selection bias in the process of data collection. Therefore, mortality can be affected by multiple factors.

In this study, we performed a subgroup analysis that included the timing of TXA administration, which did not change the results or conclusions for any of the outcomes of interest. Our results show that TXA had no effect on mortality. This is consistent with some research results [14, 15, 17, 18, 26]. However, this contrasts with the findings of a previous CRASH-3 trial, which claimed that TXA was safe in patients with TBI and that treatment within 3 h of injury reduced head injury-related death [42]. This conflicting result does not mean that administration within 3 h is ineffective for TBI patients because of the confounding effect of hemorrhage growth and TBI severity. Although the mortality of patients with TBI treated with TXA may be affected by multiple factors, the results of many large-scale RCTs, such as CRASH-3, indicated that absolute mortality reduction by TXA was low.

Adverse event after the treatment of TXA with respect to time and dose

Thrombotic and neurological complications are the most common adverse events associated with TXA administration because of its antifibrinolytic activity and as a competitive antagonist of γ-aminobutyric acid (GABA) [9]. Coagulation disorders following TBI are associated with a complex interplay between coagulopathy, fibrinolysis, and hypercoagulability. A hypercoagulable state can promote the occurrence of different coagulation complications such as cerebral intravascular microthrombi or systemic disseminated intravascular coagulation. TXA, which blocks lysine-dependent plasmin generation and inhibits the dissolution and degradation of fibrin clots, can alter the delicate balance between coagulation and fibrinolysis and theoretically have detrimental implications for outcomes, resulting in vascular occlusive events, pulmonary embolism, and deep vein thrombosis [43]. TXA may not increase gastrointestinal bleeding during TBI [44]. Moderate to high doses (100 mg/kg/bolus and 10 mg/kg/h, for example) of TXA are potentially associated with neurological complications (seizures, transient ischemic attack, delirium) in adults and children [44,45,46]. TXA competitively inhibits glycine receptors in cortical and spinal cord neurons as well as GABA receptors in cortical and medullary neurons. Both inhibitory pathways of TXA cause an increased excitatory synaptic stimulus, which is theoretically prone to convulsion and stroke [11, 47].

In this meta-analysis, we analyzed various reported adverse events after treatment, including vascular occlusive events, deep vein thrombosis, neurological complications, gastrointestinal bleeding, myocardial infarction, infectious complications, and renal failure. No obvious adverse events related to TXA administration were found. The incidence of these events may be too low to demonstrate significant effects. Nevertheless, the possibility of bias should not be ruled out because the underlying pre-injury diseases of TBI patients were not fully recorded.

Our subgroup analysis showed that the timing of TXA administration was not a factor affecting adverse events. Notably, some researchers believe that the early use of TXA can effectively prevent adverse events [15, 21]. However, the most recent study did not include the latest data [12]. Our conclusions are consistent with those of a recent study. The study design was not a factor affecting the results of adverse events. This indicated that the experiment had low heterogeneity in different regions. The TXA dose was not a factor affecting adverse events. This indicated that different doses of TXA may have the same effect. However, there are few articles on TXA dose. Therefore, there is a risk of publication bias regarding TXA dose. In conclusion, using TXA to treat TBI patients should not be discontinued in clinical practice, solely due to the possibility of adverse events.

As has been mentioned above, this paper is the first study to investigate the efficacy of different time and dose of TXA in the treatment of TBI. There is no universal standard on the most effective dose and time of TXA administration, limiting its routine use in many centers. For TXA dose, the current conventional dose is 1 g TXA bolus followed by 1 g TXA maintenance, but a recent study showed 2 g TXA bolus followed by a placebo infusion [13]. Although different doses did not affect the results, the focus of this direction is a key direction of TXA treatment. For enrollment time of TXA, the traditional view is that enrollment time of TXA within 3 h has less complications [19, 25], but many patients still use TXA within 8 h due to long distance from the hospital or lack of drugs [20, 27]. Therefore, research on the efficacy of different time and dose of TXA in the treatment of TBI may greatly contribute to improving the TXA safety during the TBI treatment. In addition, the results of our meta-analysis showed that limiting the enrollment time of TXA within 3 h may be recommended. Specifically, the result of different time of TXA showed that using of TXA have no associated with all-cause mortality, all adverse events, the need of neurosurgical intervention and the number people of new bleeding. However, when enrollment time after trauma is less than 3 h, TXA can reduce mean blood volume (RR -0.50, 95% Cl [-0.94, -0.05], P 0.03). This shows that early enrollment time of TXA have a certain good effect, but the discover of specific benefits still need more clinical trials.

Limitation

This study is the first to investigate the efficacy of different timings and doses of TXA for the treatment of TBI. We collected data from the latest studies and drew reliable conclusions. TXA at various times and doses was associated with reduced mean bleeding but not with mortality, adverse events, neurosurgical intervention, or rebleeding. However, our study had several limitations. First, the current study lacked the recorded time between injury and TXA delivery, which makes the timing of TXA inaccurate. The risk of publication bias cannot be excluded, even though Harbord’s test and Egger’s test showed P > 0.05. Only a few studies have reported the average time from injury to TXA administration and stratified them; hence, the results will be affected by covariates in the studies.

Conclusion

TXA at different times and doses was associated with reduced mean bleeding but not with mortality, adverse events, neurosurgical intervention, or rebleeding. We need more research data on different detection indexes and levels of TXA in patients with TBI, as compared to those not receiving TXA; although the prognostic outcome for all harm outcomes was not affected, the potential for harm was not ruled out.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

CI:

Confidence interval

GABA:

γ-Aminobutyric acid

GOS:

Glasgow Outcome Scale

SMD:

Standardized mean difference

TXA:

Tranexamic acid

TBI:

Traumatic brain injury

RCT:

Randomized controlled trial

RR:

Risk ratio

References

  1. Najem D, Rennie K, Ribecco-Lutkiewicz M, et al. Traumatic brain injury: classification, models, and markers. Biochem Cell Biol. 2018;96(4):391–406. https://doi.org/10.1139/bcb-2016-0160.

    Article  CAS  Google Scholar 

  2. MAAS A I R, MENON D K, ADELSON P D, ANDELIC N, BELL M J, BELLI A, et al; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol, 2017, 16: 987–1048. DOI: https://doi.org/10.1016/S1474-4422(17)30371-X.

  3. BRAZINOVA A, REHORCIKOVA V, TAYLOR M S, BUCKOVA V, MAJDAN M, PSOTA M, et al. Epidemiology of traumatic brain injury in Europe: a living systematic review. J Neurotrauma, 2018 (2018–12–19) [2020–08–21]. https://doi.org/10.1089/neu.2015.4126.DOI: https://doi.org/10.1089/neu.2015.4126.

  4. Khellaf A, Khan DZ, Helmy A. Recent advances in traumatic brain injury. J Neurol. 2019;266(11):2878–89. https://doi.org/10.1007/s00415-019-09541-4.

    Article  Google Scholar 

  5. McGinn MJ, Povlishock JT. Pathophysiology of Traumatic Brain Injury. Neurosurg Clin N Am. 2016;27(4):397–407. https://doi.org/10.1016/j.nec.2016.06.002.

    Article  Google Scholar 

  6. Anderson TN, Hwang J, Munar M, et al. Blood-based biomarkers for prediction of intracranial hemorrhage and outcome in patients with moderate or severe traumatic brain injury. J Trauma Acute Care Surg. 2020;89(1):80–6. https://doi.org/10.1097/TA.0000000000002706.

    Article  CAS  Google Scholar 

  7. Galgano M, Toshkezi G, Qiu X, et al. Traumatic Brain Injury: Current Treatment Strategies and Future Endeavors. Cell Transplant. 2017;26(7):1118–30. https://doi.org/10.1177/0963689717714102.

    Article  Google Scholar 

  8. Maegele M. Prehospital Tranexamic Acid (TXA) in Patients with Traumatic Brain Injury (TBI). Transfus Med Rev. 2021;35(4):87–90. https://doi.org/10.1016/j.tmrv.2021.08.003.

    Article  Google Scholar 

  9. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011;1:D1886. https://doi.org/10.1002/14651858.CD001886.pub3.

    Article  Google Scholar 

  10. Brenner A, Belli A, Chaudhri R, et al. Understanding the neuroprotective effect of tranexamic acid: an exploratory analysis of the CRASH-3 randomised trial. Crit Care. 2020;24(1):560. https://doi.org/10.1186/s13054-020-03243-4.

    Article  Google Scholar 

  11. de Faria JL, Da SBJ, Costa ESL, et al. Tranexamic acid in Neurosurgery: a controversy indication-review. Neurosurg Rev. 2021;44(3):1287–98. https://doi.org/10.1007/s10143-020-01324-0.

    Article  Google Scholar 

  12. Lawati KA, Sharif S, Maqbali SA, et al. Efficacy and safety of tranexamic acid in acute traumatic brain injury: a systematic review and meta-analysis of randomized-controlled trials[J]. Intensive Care Med. 2021;47(1):14–27. https://doi.org/10.1007/s00134-020-06279-w.

    Article  CAS  Google Scholar 

  13. Rowell SE, Meier EN, McKnight B, 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. https://doi.org/10.1001/jama.2020.8958.

    Article  CAS  Google Scholar 

  14. Mahmood A, Needham K, Shakur-Still H, et al. Effect of tranexamic acid on intracranial haemorrhage and infarction in patients with traumatic brain injury: a pre-planned substudy in a sample of CRASH-3 trial patients. Emerg Med J. 2021;38(4):270–8. https://doi.org/10.1136/emermed-2020-210424.

    Article  Google Scholar 

  15. van Wessem K, Jochems D, Leenen L. The effect of prehospital tranexamic acid on outcome in polytrauma patients with associated severe brain injury. Eur J Trauma Emerg Surg. 2021. https://doi.org/10.1007/s00068-021-01827-5.

    Article  Google Scholar 

  16. Mojallal F, Nikooieh M, Hajimaghsoudi M, et al. The effect of intravenous tranexamic acid on preventing the progress of cerebral hemorrhage in patients with brain traumatic injuries compared to placebo: A randomized clinical trial. Med J Islam Repub Iran. 2020;34:107. https://doi.org/10.34171/mjiri.34.107.

    Article  Google Scholar 

  17. Mousavinejad M, Mozafari J, Ilkhchi RB, et al. Intravenous Tranexamic Acid for Brain Contusion with Intraparenchymal Hemorrhage: Randomized, Double-Blind, Placebo-Controlled Trial. Rev Recent Clin Trials. 2020;15(1):70–5. https://doi.org/10.2174/1574887114666191118111826.

    Article  Google Scholar 

  18. Yutthakasemsunt S, Kittiwatanagul W, Piyavechvirat P, et al. Tranexamic acid for patients with traumatic brain injury: a randomized, double-blinded, placebo-controlled trial. BMC Emerg Med. 2013;13:20. https://doi.org/10.1186/1471-227X-13-20.

    Article  CAS  Google Scholar 

  19. Jokar A, Ahmadi K, Salehi T, et al. The effect of tranexamic acid in traumatic brain injury: A randomized controlled trial. Chin J Traumatol. 2017;20(1):49–51. https://doi.org/10.1016/j.cjtee.2016.02.005.

    Article  Google Scholar 

  20. Ebrahimi P, Mozafari J, Ilkhchi RB, et al. Intravenous Tranexamic Acid for Subdural and Epidural Intracranial Hemorrhage: Randomized, Double-Blind, Placebo-Controlled Trial. Rev Recent Clin Trials. 2019;14(4):286–91. https://doi.org/10.2174/1574887114666190620112829.

    Article  CAS  Google Scholar 

  21. Perel P, Al-Shahi SR, Kawahara T, 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):1–54. https://doi.org/10.3310/hta16130.

    Article  Google Scholar 

  22. Bossers SM, Loer SA, Bloemers FW, et al. Association Between Prehospital Tranexamic Acid Administration and Outcomes of Severe Traumatic Brain Injury. JAMA Neurol. 2021;78(3):338–45. https://doi.org/10.1001/jamaneurol.2020.4596.

    Article  Google Scholar 

  23. Cumpston M, Li T, Page M J, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev, 2019,10:D142.DOI:https://doi.org/10.1002/14651858.ED000142.

  24. Parums DV. Editorial: Review Articles, Systematic Reviews, Meta-Analysis, and the Updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Guidelines. Med Sci Monit. 2021;27: e934475. https://doi.org/10.12659/MSM.934475.

    Article  Google Scholar 

  25. Roberts I, Shakur-Still H, Aeron-Thomas A, et al. Tranexamic acid to reduce head injury death in people with traumatic brain injury: the CRASH-3 international RCT. Health Technol Assess. 2021;25(26):1–76. https://doi.org/10.3310/hta25260.

    Article  Google Scholar 

  26. Fakharian E, Abedzadeh-Kalahroudi M, Atoof F. Effect of Tranexamic Acid on Prevention of Hemorrhagic Mass Growth in Patients with Traumatic Brain Injury. World Neurosurg. 2018;109:e748–53. https://doi.org/10.1016/j.wneu.2017.10.075.

    Article  Google Scholar 

  27. Chakroun-Walha O, Samet A, Jerbi M, et al. Benefits of the tranexamic acid in head trauma with no extracranial bleeding: a prospective follow-up of 180 patients. Eur J Trauma Emerg Surg. 2019;45(4):719–26. https://doi.org/10.1007/s00068-018-0974-z.

    Article  Google Scholar 

  28. Kaur P, Sharma S. Recent Advances in Pathophysiology of Traumatic Brain Injury. Curr Neuropharmacol. 2018;16(8):1224–38. https://doi.org/10.2174/1570159X15666170613083606.

    Article  CAS  Google Scholar 

  29. Jha RM, Kochanek PM, Simard JM. Pathophysiology and treatment of cerebral edema in traumatic brain injury. Neuropharmacology. 2019;145(Pt B):230–46. https://doi.org/10.1016/j.neuropharm.2018.08.004.

    Article  CAS  Google Scholar 

  30. Moore HB, Moore EE, Liras IN, Gonzalez E, Harvin JA, Holcomb JB, Sauaia A, Cotton BA. Acute Fibrinolysis Shutdown after Injury Occurs Frequently and Increases Mortality: A Multicenter Evaluation of 2,540 Severely Injured Patients. J Am Coll Surg. 2016;222(4):347–55. https://doi.org/10.1016/j.jamcollsurg.2016.01.006.

    Article  Google Scholar 

  31. Longstaff C, Locke M. Increased urokinase and consumption of α2 -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay. J Thromb Haemost. 2019;17(1):195–205. https://doi.org/10.1111/jth.14338.

    Article  CAS  Google Scholar 

  32. Chang R, Cardenas JC, Wade CE, Holcomb JB. Advances in the understanding of trauma-induced coagulopathy. Blood. 2016;128(8):1043–9. https://doi.org/10.1182/blood-2016-01-636423.

    Article  CAS  Google Scholar 

  33. MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma. 2003;55(1):39–44. https://doi.org/10.1097/01.TA.0000075338.21177.EF.

    Article  Google Scholar 

  34. Cotton BA, Harvin JA, Kostousouv V, Minei KM, Radwan ZA, Schöchl H, Wade CE, Holcomb JB, Matijevic N. Hyperfibrinolysis at admission is an uncommon but highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care Surg. 2012 Aug;73(2):365–70; discussion 370. DOI:https://doi.org/10.1097/TA.0b013e31825c1234.

  35. Moore HB, Moore EE, Lawson PJ, Gonzalez E, Fragoso M, Morton AP, Gamboni F, Chapman MP, Sauaia A, Banerjee A, Silliman CC. Fibrinolysis shutdown phenotype masks changes in rodent coagulation in tissue injury versus hemorrhagic shock. Surgery. 2015;158(2):386–92. https://doi.org/10.1016/j.surg.2015.04.008.

    Article  Google Scholar 

  36. Lighvani S, Baik N, Diggs JE, et al. Regulation of macrophage migration by a novel plasminogen receptor Plg-R KT[J]. Blood. 2011;118(20):5622–30. https://doi.org/10.1182/blood-2011-03-344242.

    Article  CAS  Google Scholar 

  37. Currie S, Saleem N, Straiton JA, et al. Imaging assessment of traumatic brain injury. Postgrad Med J. 2016;92(1083):41–50. https://doi.org/10.1136/postgradmedj-2014-133211.

    Article  Google Scholar 

  38. Suri MF, Suarez JI, Rodrigue TC, et al. Effect of treatment of elevated blood pressure on neurological deterioration in patients with acute intracerebral hemorrhage. Neurocrit Care. 2008;9(2):177–82. https://doi.org/10.1007/s12028-008-9106-7.

    Article  Google Scholar 

  39. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013;17(10):1–79. https://doi.org/10.3310/hta17100.

    Article  CAS  Google Scholar 

  40. July J, Pranata R. Tranexamic acid is associated with reduced mortality, hemorrhagic expansion, and vascular occlusive events in traumatic brain injury - meta-analysis of randomized controlled trials[J]. BMC Neurol. 2020;20(1):119. https://doi.org/10.1186/s12883-020-01694-4.

    Article  CAS  Google Scholar 

  41. Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107–15. https://doi.org/10.1016/S0140-6736(18)31033-X.

    Article  CAS  Google Scholar 

  42. 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. https://doi.org/10.1016/S0140-6736(19)32233-0.

    Article  Google Scholar 

  43. Moore EE, Moore HB, Kornblith LZ, et al. Trauma-induced coagulopathy. Nat Rev Dis Primers. 2021;7(1):30. https://doi.org/10.1038/s41572-021-00264-3.

    Article  Google Scholar 

  44. 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. https://doi.org/10.1016/S0140-6736(20)30848-5.

    Article  Google Scholar 

  45. Goobie S. The case for the use of tranexamic acid. Paediatr Anaesth. 2013;23:281–4.

    Google Scholar 

  46. Sponseller PD, Johnson CC, Nami N, Wetzler JA, Frank SM, Goobie SM, Johnson DJ. High-dose versus low-dose tranexamic acid to reduce transfusion requirements in pediatric scoliosis surgery. J Pediatr Orthop. 2016;37:e552–7. https://doi.org/10.1097/BPO.0000000000000820.

    Article  Google Scholar 

  47. Martin K, Breuer T, Gertler R, Hapfelmeier A, Schreiber C, Lange R, Hess J, Wiesner G. Tranexamic acid versus ε-aminocaproic acid: efficacy and safety in paediatric cardiac surgery. Eur J Cardio-thoracic Surg. 2011;39:892–7. https://doi.org/10.1016/j.ejcts.2010.09.041.

    Article  Google Scholar 

Download references

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Funding

National Natural Science Foundation of China (82102506), General Hospital of Western Theater Command Research Project (2021-XZYG-B29, 2021-XZYG-B30) and the Sichuan science and technology innovation seedling project (2022094).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, General Hospital of Western Theater Command (Chengdu Military General Hospital), Chengdu, 610036, China

    Honghao Huang, Mei Xin, Xiqiang Wu, Jian Liu, Wenxin Zhang, Ke Yang & Jinbao Zhang

  2. College of Medicine, Southwest Jiaotong University, Chengdu, 610036, China

    Honghao Huang, Wenxin Zhang & Ke Yang

Authors
  1. Honghao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei Xin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiqiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jian Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenxin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ke Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinbao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Honghao Huang contributed substantially to the conception, design, acquisition, analysis, and interpretation of data for the work; and drafted and revised the work. Mei Xin contributed substantially to the acquisition, analysis, interpretation of data, and revising the intellectual content. Xiqiang Wu made substantial contributions to the interpretation of data and revising the intellectual content. Jian Liu made substantial contributions to the interpretation of data and revising the intellectual content. Wenxin Zhang made substantial contributions to the interpretation of data and revising the intellectual content. Ke Yang and Jinbao Zhang contributed substantially to the conception, design, acquisition, analysis, and interpretation of data for the work; and drafted and revised the work. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ke Yang or Jinbao Zhang.

Ethics declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file1:

Appendix 1-1. search strategy for medline , embase and pubmed. Appendix 1-2. Subgroup analysis (including study design (multisite RCT or single site RCT), Enrollment time after trauma (< 3h or > 3h), and TXA dose (2g TXA bolus followed by a placebo infusion or 1g TXA bolus followed by 1g TXA maintenance)).

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huang, H., Xin, M., Wu, X. et al. The efficacy of tranexamic acid treatment with different time and doses for traumatic brain injury: a systematic review and meta-analysis. Thrombosis J 20, 79 (2022). https://doi.org/10.1186/s12959-022-00440-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12959-022-00440-9

Keywords

Thrombosis Journal

ISSN: 1477-9560

Contact us