Tranexamic Acid for Acute Bleeding in Severely Traumatized Patients

Mortality, Neurological Outcomes, and Thromboembolic Risk

Background: The optimal use of tranexamic acid (TXA) in trauma care is a matter of intense discussion, particularly with respect to its indications, dosage, temporal window, and thromboembolic adverse effects.

Methods: This review is based on publications retrieved by a selective literature search on the indications, effects, mechanism of action, and side effects of TXA (January 2022 to December 2025). Three randomized, controlled trials (RCTs), three observational studies, eight secondary analyses, and 16 meta-analyses were evaluated.

Results: TXA administration lowers the mortality of severely traumatized patients (e.g., with a relative risk [RR] of 0.73 [0.56;0.96]). The currently available evidence is inconsistent, and many of the effects found in published studies lie within the range of random fluctuation. The reduction of mortality depends on TXA administration at the earliest possible time in the first 90 minutes after trauma (this temporal window is more important than the question of pre- vs. in-hospital administration), as well as on the nature of the injury, particularly in patients with hemorrhagic shock. Among patients with isolated traumatic brain injury, no consistent effect on mortality has been shown, but there may be an effect on the progression of intracranial bleeding. Multiple studies point to a thromboembolic risk, which is dose-dependent, with a marked rise at 4 g (hazard ratio [HR] 5.33, 95% confidence interval [1.94;14.63]). In patients without shock, the reported absolute risk difference for mortality ranges from −5% to +5%, and that for thromboembolic adverse events from −0.2% to +4%.

Conclusion: For trauma patients with life-threatening hemorrhage, especially those in hemorrhagic shock, it is recommended that TXA be given as early as possible (before arrival in the hospital) in a single dose of 1–2 g (15–30 mg/kg body weight [BW]). When this is done, the benefit appears to be greater than the thromboembolic risk.

Cite this as: Lier H, Maegele M, Hossfeld B: Tranexamic acid for acute bleeding in severely traumatized patients: Mortality, neurological outcomes, and thromboembolic risk. Dtsch Arztebl Int 2026; 123: 333–8. DOI: 10.3238/arztebl.m2026.0046

The Trauma Register of the German Society for Trauma Surgery (TraumaRegister DGU®) includes 28 184 patients nationwide for the year 2024. Of these, 22.2% had a pre-existing clotting disorder, 20.6% were receiving hemostatic drug therapy, while only 14.3% received tranexamic acid (TXA). Furthermore, only 45% of those trauma patients who were transfused were given TXA before hospital admission (e1). Following publication of the randomized controlled trial (RCT) CRASH-2, acute care of patients with traumatic injury is now unimaginable without the use of TXA (e2). In that RCT, 20 211 trauma patients had received either placebo or a 1 g loading dose of TXA followed by another 1 g over eight hours within eight hours of injury. All-cause mortality was reduced by an absolute 1.5% (TXA 14.5% versus placebo 16.0%; relative risk [RR] 0.91; 95% confidence interval: [0.85; 0.97]). The risk of death due to bleeding was also reduced by 0.8% (4.9% versus 5.7%; RR 0.85 [0.76; 0.96]). The CRASH-3 trial demonstrated an absolute reduction of head injury-related death in patients with traumatic brain injury (TBI) by 1.3% (18.5% versus 19.8%; RR 0.94 [0.86; 1.02]) (e3). Despite these major trials and subsequent smaller investigations, the optimal use of TXA remains a matter of intense discussion—especially with respect to indications, dosage, temporal window, and thromboembolic risk (TE). The present article summarizes the available evidence on the use of TXA for acute bleeding in severely injured patients, taking into account the literature published since the last update of the AWMF (Association of Scientific Medical Societies in Germany) clinical practice guideline “Polytrauma/Treatment of the Severely Injured Patient” (e4).

Methods

The present review article is based on publications retrieved by a selective literature search using search strategies with various combinations of relevant search terms (“trauma/traumatic”, “bleeding/hemorrhage”, “coagulopathy”, “management”, “tranexamic acid/TXA”, “outcome”, “mortality”, “transfusion”) in the databases MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), and Epistemonikos covering the period from January 2022 to December 2025. The literature search was specifically limited to the period since completion of the literature search for the previous AWMF clinical practice guideline, “Polytrauma/Treatment of the Severely Injured Patient” (e4). After removal of duplicates, 79 articles were reviewed in full text. The analysis of thromboembolic events focused on the following aspects:

• indication
• mechanism of action
• use
• benefits and risks.

Thirty publications with different study designs were included: three RCTs (1, 2, 3), three observational studies (4, 5, 6), eight secondary analyses (7, 8, 9, 10, 11, 12, 13, 14), and 16 meta-analyses (15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) (eTable). Relevant older evidence was also taken into account for specific questions.

Table

Included meta-analyses of RCTs on survival, neurological outcome, and thromboembolic risk*1

Trauma-induced coagulopathy

Cellular hypoxia and hypoperfusion secondary to massive tissue destruction result in the release of tissue plasminogen activator (tPA) from the endothelium. This enzyme activates plasminogen, which, after conversion to plasmin, promotes accelerated fibrin breakdown. Furthermore, the physiological inhibition of tPA by plasminogen activator inhibitor-1 (PAI-1) no longer occurs. The result of endothelial activation is the phenomenon known as the endotheliopathy of trauma, which can cause marked hyperfibrinolysis and is exacerbated by the “lethal triad” of hypothermia, acidosis, and coagulopathy. A distinction is made between different fibrinolytic phenotypes using specific viscoelastic test profiles (Box 1). Whereas in hyperfibrinolysis the blood clot is dissolved too rapidly and to an excessive degree, the opposite is the case with hypofibrinolysis and fibrinolysis shutdown. Patients with hyperfibrinolysis are more severely injured than those with the other two phenotypes and often suffer from impaired perfusion, with markedly increased mortality (e5, e6, e7, e8).

Box 1

Physiological responses to severe traumatic injury*1

Mechanism of action of tranexamic acid

TXA is a synthetic lysine analog that competitively blocks the lysine-binding sites of plasminogen, thereby inhibiting the fibrin-dependent activation of tPA. Further examples of antifibrinolytics are aprotinin and epsilon aminocaproic acid. Box 2 provides a brief pharmacokinetic overview of TXA (e9, e10). There are no studies available that have specifically defined the pharmacokinetic profile of TXA or the plasma concentrations required for therapeutic efficacy in patients with multiple injuries (e11). Despite the reported elimination half-life of two to three hours, plasma concentrations were still detected after 42 to 96 hours and remained sufficient to inhibit fibrinolysis (e12, e13).

Box 2

Brief pharmacokinetic overview of TXA*

CRASH-2 identified an absolute reduction in all-cause mortality of 1.5% with TXA, with a number needed to treat [NNT] of 67, and a reduction in bleeding-related mortality of 0.8% (NNT 125) (e2). CRASH-3 found a reduction in head injury-related mortality of 1.3% (NNT 77) (e3). The analyses included in the present review, which employed different methodological approaches, reported – sometimes in subgroup analyses – an absolute reduction in mortality of

• up to 1% (15, 17)
• up to 2% (7, 11, 13, 20, 21, 22, 24, 28)
• up to 3% (7, 19, 25)
• up to 5% (2, 14).

Some of the included studies reported either unchanged (1, 3, 28) or even increased (1, 3, 5, 13, 17) mortality, mostly as a trend and without statistical significance (Table). TXA reduces mortality most markedly in the subgroup of patients with massive bleeding and shock. Thus, in the STAAMP trial, mortality among severely injured patients with a systolic blood pressure (SBP) of 70 mm Hg or less was 17% lower in those treated with TXA than in those without TXA (18.5% versus 35.5%, NNT 6) (e14). In the Cal-PAT trial, mortality among severely injured patients who received ≤10 units of total blood products was 14.7% lower with TXA (8.5% versus 23.2 %, NNT 7) (e15), and in the CRASH-2 trial mortality among those with an SBP ≤75 mm Hg was 4.5% lower (30.6% versus 35.1%, NNT 22) (e2). In the military MATTERs trial, overall mortality was 6.5% lower in the TXA group (17.4% versus 23.9%, NNT 15) and 13.7% among patients receiving massive transfusion (14.4% versus 28.1%, NNT 7) (e16). Since 2015, TXA has been recommended for use in the civilian setting only for severely injured patients in shock (e17). According to the current Clinical Practice Guideline, TXA is indicated for “patients with life-threatening hemorrhage and/or in shock and in those with confirmed hyperfibrinolysis” (e4). TXA reverses hyperfibrinolysis, prolongs fibrinolysis suppression, and reduces early mortality (e5, e18). TXA is harmful in patients without hyperfibrinolysis (e19). TXA alone will not control severe hemorrhage when administered to treat patients with massive bleeding (e20, e21). A coagulation-independent effect, such as a reduction in the release of syndecan, has been suggested (e22).

Therapeutic time window for tranexamic acid

The optimal time for administering TXA appears to be within 90 minutes of injury. The CRASH-2 and CRASH-3 trials demonstrated a time-dependent effect of TXA, with a benefit when administered within three hours of injury and harm associated with later administration (e2, e3). A secondary analysis of CRASH-2 further narrowed the time window to within one hour of injury. This resulted in an absolute reduction in death due to bleeding by 2.4% (RR 0.68 [0.57; 0.82]; NNT 41), but an absolute increase by 1.3% when administered more than three hours after injury (RR 1.44 [1.12; 1.84]; number needed to harm [NNH] 76) (e23). Combined data from the CRASH-2 and WOMAN trials showed a 10% decline in the effectiveness of TXA for every 15-minute delay in TXA administration (e24). According to a reanalysis of data from CRASH-2 and CRASH-3 (n = 28 448), the relative risk reduction, irrespective of age and blood pressure, was greatest when TXA was administered within two hours of injury (24-hour mortality: RR 0.73 [0.64; 0.84]). Risk reduction declines rapidly beyond this time window. The greatest absolute risk reduction (24-hour mortality: –2.3 %) was observed in patients with a low blood pressure and a low Glasgow Coma Scale score when TXA was administered immediately after injury (13). Another analysis of this data showed that the beneficial effect on 24-hour mortality was greatest when administered within the first hour after injury (≤1 hour: OR 1.27 [1.03; 1.56]; 1–3 hours: OR 124 [105; 146]; >3 hours: OR 1.14 [0.90; 1.45]) (7). A systematic review article involving five RCTs evaluating prehospital TXA use found a clinically relevant reduction in 24-hour mortality in favor of TXA, corresponding to eight fewer deaths per 1000 TXA administrations; the effect was slightly smaller for 30-day mortality (Table) (18). A meta-analysis of three RCTs on prehospital TXA administration found lower risks of 24-hour and 28-day mortality, with no improvement in neurological outcomes (Table) (19). According to seven RCTs (n = 32 832), prehospital administration of TXA reduced the relative risk of death by 22% compared with placebo and by 9% with in-hospital administration (Table) (21). Another meta-analysis (2 RCTs, 9 cohorts; n = 1259) demonstrated a reduction in 24-hour mortality in all three analyses: in the overall analysis (OR 0.82 [0.71; 0.94]), in the analysis restricted to RCTs (OR 0.71 [0.52; 0.96]), and in the analysis restricted to cohort studies (OR 0.85 [0.72; 0.99]) (24). The results for 28-day mortality were not consistent (24). The PATCH-Trauma trial (n = 1310) found no difference in functional outcomes six months after injury between patients who did and those who did not receive prehospital TXA, although mortality was lower (2). In absolute terms, for every 100 patients treated with TXA, four extra patients were alive at six months; however, four extra patients were also classified as having suffered severe disability. A subgroup analysis of the prehospital STAAMP trial confirmed that the greatest survival benefit was achieved when TXA was administered within one hour of injury in severely injured patients with shock (18.5% versus 35.5%; RR 0.52 [0.34; 0.80]) (e14). A secondary analysis of the PATCH-Trauma trial (2) showed a reduction in the risk of death within 28 days after administration of TXA within 90 minutes (17% versus 25%; adjusted relative risk [aRR] 0.64 [0.50; 0.82]) (Figure 1) (14). In a secondary analysis of two trials (STAAMP, PAMPer) (e14, e25), the reduction in mortality at 24 hours was more pronounced after prehospital TXA administration (adjusted odds ratio [aOR] 0.42 [0.21; 0.83]) than after in-hospital administration (aOR 0,58 [0,19; 1,75]) (9). Furthermore, every one-minute delay was associated with an increase in the 24-hour mortality risk by 1.5% and a 2% increase in the 30-day mortality risk (9). In a secondary analysis (n = 1744) of the STAAMP (e14) and ROC-TXA trials (e26), the 28-day mortality risk was reduced after prehospital administration (adjusted hazard ratio [aHR] 0.72 [0.54; 0.96]) (11). Given the current evidence on the optimal time window for TXA administration, prehospital administration appears most appropriate and is largely consistent with common practice. For patients in shock, early administration within 90 minutes of injury – with timing being more important than location (e27) – enables targeted inhibition of the underlying pathophysiological mechanism (e21, e28).

Figure 1

Effect of the time from injury to administration of TXA or placebo on 28-day mortality. An RR below 1 (thick grey line) indicates a benefit of TXA. (14) Licensed under the CC-BY 4.0 license, https://creativecommons.org/licenses/by/4.0 (Ali A et al.)

Dosage of tranexamic acid

The current recommendation is a single 1–2 g dose of TXA given at the earliest possible time (see the eResults section for supporting evidence).

Tranexamic acid in traumatic brain injury

The CRASH-3 trial investigated the effect of TXA in patients with traumatic brain injury (TBI). Altogether, more than 9000 patients were randomized and treated within three hours of injury in the placebo-controlled trial (e3). After exclusion of patients with a GCS score of three or less or bilateral unreactive pupils, the risk of head injury-related death was 12.5% in the TXA group versus 14% in the placebo group (RR 0.89 [0.80; 1.00]). The risk was reduced with TXA in patients with mild-to-moderate TBI (RR 0.78 [0.64–0.95]) but not in patients with severe TBI (RR 0.99 [0.91–1.07]). The following specific parameters of coagulation function were examined in patients with isolated TBI:

• thrombin-antithrombin III complexes as markers of fibrin production
• D-dimer as a marker of hyperfibrinolysis, and
• plasminogen activator inhibitor-1 (PAI-1) for impaired fibrinolysis (e36)

The plasma levels of all three parameters of patients in the group with poor outcome were elevated from arrival until seven days after injury (each p <0.001). There was considerable overlap evident in the time courses of the plasma levels, whereas isolated hyperfibrinolysis was detectable only early after injury and then only for a short period. Injured patients with TBI more commonly developed a fibrinolysis shutdown phenotype. (e37, e38). The timing of TXA administration appears to be even more crucial in patients with TBI (Table) (15). These are probably the reasons why meta-analyses have so far failed to show consistently positive effects of TXA in patients with TBI (13 RCTs, n = 18 675, and 11 studies, n = 1299; Table) (15, 22). Most meta-analyses show no improvement in neurological outcomes after administration of TXA (17, 20, 27, 28, e39, e40, e41). In many of the study groups examined, the upper confidence interval limit for the RR exceeded the null value of one. That means the RR was not statistically significant, and TXA had a beneficial effect in only a small number of patients. A meta-analysis (n = 15 015) demonstrated a beneficial effect on 28-day mortality among patients with a GCS score above  9 (RR 0.71 [0.60; 0.85]; risk difference − 1% [−0.8; +2.9]), not among those with a GCS score of nine or less, however (30). The prehospital 2 g bolus dose was associated with a marked survival benefit, particularly in CT-positive patients with TBI, compared with the standard dose (12). A benefit in neurofunctional outcome was evident in injured patients with an initial GCS score of less than 9 (RR 1.22 [0.89; 1.68]) (2). A secondary analysis excluding patients with unreactive pupils at baseline showed lower rates of progressive hemorrhage and the development of new hemorrhages over time (aRR 0.80 [0.66; 0.98]) (e42). Given the poor neurological outcome and the absence of a sustained reduction in mortality, many authors do not recommend routine TXA administration for intracranial hemorrhage (Table) (3, 16, 22, 28) or are explicitly against it (e43). In patients with isolated TBI and GCS scores ≤12, and especially those with bilaterally preserved pupillary reaction, prospective data and several recent meta-analyses, including subgroup analyses, indicate a possible survival benefit and reduced hemorrhage expansion (12, 20, 22, 30, e3, e26, e41). The administration of TXA may therefore be considered in these patients.

Tranexamic acid and the risk of developing thromboembolism

Although the safety profile of TXA is repeatedly emphasized, the risk of thromboembolism remains (Table) (8). The CRASH-2 trial (e2) with 20 211 participants reported a surprisingly low number of 369 thromboembolic complications (TXA: 168 = 1.7% versus NaCl: 201 = 2.0%). The authors assumed that complications were under-reported and that the incidence of TE was underestimated, so they did not rule out an increased risk of TE (e2, e44). In 2015, the study by Cole et al. led to TXA being recommended only for severely injured patients in the civilian setting who had a fourfold higher absolute rate of TE (2% versus 8%, p <0.01) (e17). Similarly, the CRASH-2 and CRASH-3 trials do not rule out an increased rate of TE, in addition to the possibility of under-reporting. There, the confidence intervals included the null value of 1; for example, in CRASH-2 (e2), the RR for “death due to vascular occlusion” was 0.69 [0.44; 1.07] and the RR for “any vascular occlusive event” was 0.84 [0.68; 1.02]. In the CRASH-3 trial (e3), the corresponding parameters for “vascular occlusive events” were RR 1.13 [0.80; 1.59] after TXA administration within 3 hours of injury, RR 0.77 [0.49; 1.21] after TXA more than three hours after injury, and RR 0.98 [0.74; 1.28]) overall. The analyses included in the present article (using various methodologies) report an increased risk of thromboembolism (4, 6, 8, 23, 24, 26), with confidence intervals either above 1 (1, 2, 11, 14, 15, 17, 19, 20, 25, 26, 28, 29) or at least including 1 (7, 21, 22). This would seem inconsistent with the statement that there was no evidence of thromboembolic complications (e45, e46). A secondary analysis of the multi-center, double-blind RCT “Prehospital TXA for TBI” (e26) found a higher rate of deep vein thrombosis (DVT) after late prehospital administration (<45 minutes: 0.8% versus ≥45 minutes: 3.4%, p = 0.021) (e47). In a retrospective observational study of severely injured military personnel, there was an approximately ninefold increase in the rate of pulmonary embolism (2.7% versus 0.3%) and an approximately twelvefold increase in the rate of DVT (2.4% versus 0.2 %) among patients who received TXA (e16). The TAMPITI trial (8) found a dose-dependent risk of thromboembolic complications. In comparison with placebo, the adjusted hazard ratio was 3.20 [1.12; 9.11] for 2 g TXA and 5.33 [1.94; 14.63] for 4 g TXA. An analysis of the TraumaRegister DGU® (n = 37 342) also demonstrated a dose-dependent rise in the risk of TE complications (one dose: aOR 1.56 [1.35; 1.81]; two doses: aOR 1.79 [1.43; 2.24]) (6). For injuries in the age group of 18- to 40-year-olds, there was a 1.65-fold increased risk of developing DVT and a 2.48-fold increased risk of pulmonary embolism after TXA (4). The risk of TE in patients with TBI was also increased when TXA was administered more than eight hours after injury. A similar increase was observed when treatment was continued for more than one day (Table) (26). A meta-analysis (n = 11 259) showed an approximately 20% relative increase in TE risk after prehospital TXA administration compared with no TXA administration (8.1% versus 6.7%; OR 1.22 [1.03; 1.44]). The increase in this risk was more pronounced in the RCTs (16.3% versus 12.7%; OR 1.33 [1.04; 1.70]) than in the cohort studies (5.3% versus 4.7%; OR 1.13 [0.90; 1.42]) (24). A meta-analysis of almost two million trauma cases found a 2.84-fold increase in the risk of VTE associated with TXA administration (23). Systematic screening for thromboembolic events was not reported in most publications; where such screening was performed, the incidence of TE was about twice as high (23, e48). Even for non-traumatic indications, the use of TXA is currently the subject of critical debate due to the risk of TE (e49). Overall, in patients without shock, the studies listed here report absolute risk differences for mortality ranging from −5% to 5% (5), and for thromboembolic adverse events from −0.2% to +4% (14). Since positive and negative effects occur with similar frequency, a careful assessment of potential benefits and potentially increased risk of TE is recommended for each patient before TXA administration (25, e50).

Conclusion

Figure 2 presents an algorithm for the pragmatic use of TXA. In light of recent findings, its broad, uncritical, and unselected use does not appear justified (e21). The optimal dose remains a matter of debate and is probably a single dose of 1 to 2 g for adults. The claim that there is no evidence of thromboembolic complications following TXA administration is no longer tenable.

Figure 2

Algorithm for the pragmatic use of tranexamic acid in patients with (suspected) life-threatening hemorrhage * Patients with severe TBI may also benefit from early administration of TXA (2, 27, e51); the benefit, however, has not been consistently shown across studies GCS, Glasgow Coma Scale; ICH, intracranial hemorrhage; BW, body weight; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury; TXA, tranexamic acid

Conflict of interest statement
HL received lecture fees and reimbursement of travel expenses from AstraZeneca, Bayer Vital, German Red Cross Blood Donation Service West, CSL Behring, Ferring, Mitsubishi Pharma, NovoNordisk, Organon, and Werfen.

MM states that he has received lecture fees and fees for participation in expert panels and advisory boards, as well as financial support for attending conferences from AstraZeneca, Bayer, Biotest, CSL Behring, IL-Werfen/TEM-International, LFB Biomedicaments France, and Portola.

BH received reimbursement of travel expenses and lecture fees from Karl Storz, Weinmann Emergency, and CSL Behring.

Manuscript received on 22 September 2025, revised version accepted on 16 March 2026.

Translated from the original German by Dr. Grahame Larkin.

Corresponding author:
Dr. med. Heiko Lier

References

1. El-Menyar A, Ahmed K, Hakim S, et al.: Efficacy and safety of the second in-hospital dose of tranexamic acid after receiving the prehospital dose: Double-blind randomized controlled clinical trial in a level 1 trauma center. Eur J Trauma Emerg Surg 2022; 48: 3089–99

2. PATCH-Trauma Investigators, ANZICS Clinical Trials Group, Gruen RL, et al.: Prehospital tranexamic acid for severe trauma. N Engl J Med 2023; 389: 127–36

3. Yassi N, Zhao H, Churilov L, et al.: Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): An international, double-blind, randomised, phase 2 trial. Lancet Neurol 2024; 23: 577–87

4. Knudson MM, Moore EE, Kornblith LZ, et al.: Challenging traditional paradigms in posttraumatic pulmonary thromboembolism. JAMA Surg 2022; 157: e216356

5. van Wessem KJP, Jochems D, Leenen LPH: The effect of prehospital tranexamic acid on outcome in polytrauma patients with associated severe brain injury. Eur J Trauma Emerg Surg 2022; 48: 1589–99

6. Bayer J, Kirchner T, Lefering R, Bode L, Schmal H, Wagner FC: Tranexamic acid in multiply injured patients-the independent risk of thromboembolic complications with repeated dosing: Retrospective analysis based on the TraumaRegister DGU®. Scand J Trauma Resusc Emerg Med 2025; 33: 185

7. Ageron FX, Shakur-Still H, Roberts I: Effects of tranexamic acid treatment in severely and non-severely injured trauma patients. Transfusion 2022; 62 Suppl 1: S151–S7

8. Spinella PC, Bochicchio K, Thomas KA, et al.: The risk of thromboembolic events with early intravenous 2– and 4-g bolus dosing of tranexamic acid compared to placebo in patients with severe traumatic bleeding: A secondary analysis of a randomized, double-blind, placebo-controlled, single-center trial. Transfusion 2022; 62 Suppl 1: S139–S50

9. Deeb AP, Guyette FX, Daley BJ, et al.: Time to early resuscitative intervention association with mortality in trauma patients at risk for hemorrhage. J Trauma Acute Care Surg 2023; 94: 504–12

10. Gunn F, Stevenson R, Almuwallad A, et al.: A comparative analysis of tranexamic acid dosing strategies in traumatic major hemorrhage. J Trauma Acute Care Surg 2024; 96: 216–24

11. Mazzei M, Donohue JK, Schreiber M, et al.: Prehospital tranexamic acid is associated with a survival benefit without an increase in complications: Results of two harmonized randomized clinical trials. J Trauma Acute Care Surg 2024; 97: 697–702

12. Rowell S, Meier EN, Hoyos Gomez T, et al.: The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial. J Trauma Acute Care Surg 2024; 97: 572–80

13. Osawa I, Goto T, Roberts I: Tranexamic acid for trauma: Optimal timing of administration based on the CRASH-2 and CRASH-3 trials. Br J Surg 2025; 112: znaf079

14. Ali A, Gruen RL, Bernard SA, et al.: Tranexamic acid timing and mortality impact after trauma. Ann Emerg Med 2026; 87: 83–9

15. 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. Thromb J 2022; 20: 79

16. Germans MR, Dronkers WJ, Baharoglu MI, et al.: Antifibrinolytic therapy for aneurysmal subarachnoid hemorrhage: An update of a Cochrane systematic review. Stroke 2023; 54: e91–e2

17. Xiong Y, Guo X, Huang X, et al.: Efficacy and safety of tranexamic acid in intracranial haemorrhage: A meta-analysis. PLoS One 2023; 18: e0282726

18. Biffi A, Porcu G, Castellini G, et al.: Systemic hemostatic agents initiated in trauma patients in the pre-hospital setting: A systematic review. Eur J Trauma Emerg Surg 2023; 49: 1259–70

19. Acharya P, Amin A, Nallamotu S, et al.: Prehospital tranexamic acid in trauma patients: A systematic review and meta-analysis of randomized controlled trials. Front Med (Lausanne) 2023; 10: 1284016

20. Song JX, Wu JX, Zhong H, Chen W, Zheng JC: Therapeutic efficacy of tranexamic acid on traumatic brain injury: A systematic review and meta-analysis. Scand J Trauma Resusc Emerg Med 2024; 32: 18

21. Fouche PF, Stein C, Nichols M, et al.: Tranexamic acid for traumatic injury in the emergency setting: A systematic review and bias-adjusted meta-analysis of randomized controlled trials. Ann Emerg Med 2024; 83: 435–45

22. Zhang M, Liu T: Efficacy and safety of tranexamic acid in acute traumatic brain injury: A meta-analysis of randomized controlled trials. Am J Emerg Med 2024; 80: 35–43

23. Tran A, Fernando SM, Rochwerg B, et al.: Prognostic factors associated with venous thromboembolism following traumatic injury: A systematic review and meta-analysis. J Trauma Acute Care Surg 2024; 97: 471–7

24. Chen HY, Wu LG, Fan CC, Yuan W, Xu WT: Effectiveness and safety of prehospital tranexamic acid in patients with trauma: An updated systematic review and meta-analysis with trial sequential analysis. BMC Emerg Med 2024; 24: 202

25. Li Y, Tian M, Zhong W, Zou J, Duan X, Si H: Prehospital tranexamic acid decreases early mortality in trauma patients: A systematic review and meta-analysis. Front Med (Lausanne) 2025; 12: 1552271

26. Lee S, Kim M, Kwon SM, et al.: Relationship between tranexamic acid use and safety in patients with acute brain injury: A systematic review and meta-analysis of mortality and thromboembolic events. CNS Drugs 2025; 39: 637–50

27. Utsumi S, Kawakami A, Amemiya Y: Optimal dose of tranexamic acid in traumatic brain injury: Systematic review and network meta-analysis of randomized controlled trials. J Trauma Acute Care Surg 2025; 98: 816–23

28. Steiner T, Purrucker JC, Aguiar de Sousa D, et al.: European Stroke Organisation (ESO) and European Association of Neurosurgical Societies (EANS) guideline on stroke due to spontaneous intracerebral haemorrhage. Eur Stroke J 2025; 10: 1007–86

29. Lin YC, Wang TH, Kang YN, Chiu HH: Effect of tranexamic acid on children with traumatic bleeding: A systematic review and meta-analysis. Am J Emerg Med 2025; 97: 65–71

30. Bian W, Qi M, Ding L, et al.: Is tranexamic acid effective for all traumatic brain injury patients? A severity based systematic review and meta-analysis. Front Pharmacol 2025; 16: 1677936

e1. Deutsche Gesellschaft für Unfallchirurgie (DGU): TraumaRegister DGU Jahresbericht 2025. www.auc-online.de/fileadmin/AUC/Dokumente/Register/TraumaRegister_DGU/TR-DGU-Jahresbericht_2025.pdf (last accessed on 3 February 2026).

e2. CRASH-2 Trial Collaborators, Shakur H, Roberts I, 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: 23–32

e3. CRASH-3 Trial Collaborators, Roberts I, Shakur-Still H, et al.: 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: 1713–23

e4. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.: AWMF-Leitlinie 187–023: S3-Leitlinie Polytrauma/Schwerverletzten-Behandlung. https://register.awmf.org/assets/guidelines/187-023l_S3_Polytrauma-Schwerverletzten-Behandlung_2023-06.pdf (last accessed on 14 February 2023).

e5. Takahashi K, Yamakawa K, Siletz AE, et al.: Hyperfibrinolysis: A crucial phenotypic abnormality of posttraumatic fibrinolytic dysfunction. Res Pract Thromb Haemost 2024; 8: 102568

e6. Chalkias A: Shear stress and endothelial mechanotransduction in trauma patients with hemorrhagic shock: Hidden coagulopathy pathways and novel therapeutic strategies. Int J Mol Sci 2023; 24: 17522

e7. Moore HB, Moore EE, Gonzalez E, 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: 811–7

e8. Moore HB: Fibrinolysis shutdown and hypofibrinolysis are not synonymous terms: The clinical significance of differentiating low fibrinolytic states. Semin Thromb Hemost 2023; 49: 433–43

e9. Rote Liste Fachinformation: Cyklokapron-Injektionslösung (Feb 2025). https://www.fachinfo.de/fi/detail/008797 (last accessed on 12 April 2025).

e10. Grassin-Delyle S, Semeraro M, Lamy E, 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: 465–72

e11. Faraoni D, Fenger-Eriksen C: Dosing of tranexamic acid in trauma. Curr Opin Anaesthesiol 2024; 37: 125–30

e12. Yoshii R, Takahashi Y, Sawa T, Amaya F, Ogawa S: Long duration of action of tranexamic acid after cardiac surgery in a hemodialysis patient: A case report. A A Pract 2023; 17: e01676

e13. Kammerer T, Groene P, Sappel SR, et al.: Functional testing for tranexamic acid duration of action using modified viscoelastometry. Transfus Med Hemother 2021; 48: 109–17

e14. Guyette FX, Brown JB, Zenati MS, 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: 11–20

e15. Neeki MM, Dong F, Toy J, et al.: Tranexamic acid in civilian trauma care in the California prehospital antifibrinolytic therapy study. West J Emerg Med 2018; 19: 977–86

e16. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ: Military application of tranexamic acid in trauma emergency resuscitation (MATTERs) Study. Arch Surg 2012; 147: 113–9

e17. 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: 390–4

e18. 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: 148–61

e19. Moore HB, Moore EE, Huebner BR, et al.: Tranexamic acid is associated with increased mortality in patients with physiological fibrinolysis. J Surg Res 2017; 220: 438–43

e20. Patel PA, Wyrobek JA, Butwick AJ, et al.: Update on applications and limitations of perioperative tranexamic acid. Anesth Analg 2022; 135: 460–73

e21. Barrett WJ, Kaucher KA, Orpet RE, et al.: Tranexamic acid in trauma: A joint position statement and resource document of NAEMSP, ACEP, and ACS-COT. J Trauma Acute Care Surg 2025; 99: 357–63

e22. Gruen DS, Brown JB, Guyette FX, et al.: Prehospital tranexamic acid is associated with a dose-dependent decrease in syndecan-1 after trauma: A secondary analysis of a prospective randomized trial. J Trauma Acute Care Surg 2023; 95: 642–8

e23. CRASH-2 Trial Collaborators, Roberts I, Shakur H, et al.: The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377: 1096–101, 1101.e1–2

e24. Gayet-Ageron A, Prieto-Merino D, Ker K, et al.: Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: A meta-analysis of individual patient-level data from 40 138 bleeding patients. Lancet 2018; 391: 125–32

e25. Sperry JL, Guyette FX, Brown JB, et al.: Prehospital plasma during air medical transport in trauma patients at risk for hemorrhagic shock. N Engl J Med 2018; 379: 315–26

e26. 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: 961–74

e27. Brito AM, Meizoso JP, Costantini TW: Research priorities in tranexamic acid after trauma: Secondary analysis of the National Trauma Research Action Plan. J Trauma Acute Care Surg 2024; 97: 566–71

e28. Vigneshwar NG, Moore EE, Moore HB, et al.: Precision medicine: Clinical tolerance to hyperfibrinolysis differs by shock and injury severity. Ann Surg 2022; 275: e605–e7

e29. Grassin-Delyle S, Theusinger OM, Albrecht R, et al.: Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. Anaesthesia 2018; 73: 719–29

e30. Picetti R, Shakur-Still H, Medcalf RL, Standing JF, Roberts I: What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies. Blood Coagul Fibrinolysis 2019; 30: 1–10

e31. Henry DA, Carless PA, Moxey AJ, et al.: Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2007: CD001886

e32. Hmidan Simsam M, Delorme L, Grimm D, et al.: Efficacy of high dose tranexamic acid (TXA) for hemorrhage: A systematic review and meta-analysis. Injury 2023; 54: 857–70

e33. National Institute for Health and Care Excellence (NICE): NICE guideline NG232. Head injury: assessment and early management. https://www.nice.org.uk/guidance/ng232 (last accessed on 3 February 2024).

e34. Stitt G, Spinella PC, Bochicchio GV, Roberts I, Downes KJ, Zuppa AF: Population pharmacokinetic modelling and simulation of tranexamic acid in adult trauma patients. Br J Clin Pharmacol 2024; 90: 1932–41

e35. Drew B, Auten JD, Cap AP, et al.: The use of tranexamic acid in tactical combat casualty care: TCCC proposed change 20–02. J Spec Oper Med 2020; 20: 36–43

e36. Nakae R, Murai Y, Wada T, et al.: Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury. Sci Rep 2022; 12: 19107

e37. Meizoso JP, Moore HB, Moore EE, et al.: Traumatic brain injury provokes low fibrinolytic activity in severely injured patients. J Trauma Acute Care Surg 2022; 93: 8–12

e38. Favors L, Harrell K, Miles V, et al.: Analysis of fibrinolytic shutdown in trauma patients with traumatic brain injury. Am J Surg 2024; 227: 72–6

e39. Chang Y, Lai PC, Huang CY, et al.: Tranexamic acid in spontaneous intracerebral hemorrhage: A meta-analysis. Eur J Med Res 2025; 30: 133

e40. Imai E, Ito H, Okano H, et al.: Efficacy and safety of tranexamic acid administration for subarachnoid hemorrhage: A systematic review and meta-analysis. Front Neurol 2025; 16: 1617817

e41. Meer MM, Mumtaz M, Farrukh Z, Ahmed B: Efficacy and safety of tranexamic acid in traumatic brain injury: A systematic review and meta-analysis of randomized controlled trials. Cureus 2024; 16: e73781

e42. 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: 270–8

e43. Tjerkstra MA, Post R, Germans MR, et al.: Ultra-early and short-term tranexamic acid treatment in patients with good- and poor-grade aneurysmal subarachnoid hemorrhage. Neurology 2024; 102: e209169

e44. Yeguiayan JM, Rosencher N, Freysz M: Tranexamic acid for trauma. Lancet 2010; 376: 1050; author reply 1050–1

e45. Arznei-telegramm: Tranexamsäure (Cyklokapron u.a.) nach Schädel-Hirn-Trauma. a-t 2019; 50: 92.

e46. Lier H, Maegele M, Shander A: Tranexamic acid for acute hemorrhage: A narrative review of landmark studies and a critical reappraisal of its use over the last decade. Anesth Analg 2019; 129: 1574–84

e47. Brito AMP, Schreiber MA, El Haddi J, Meier EN, Rowell SE: The effects of timing of prehospital tranexamic acid on outcomes after traumatic brain injury: Subanalysis of a randomized controlled trial. J Trauma Acute Care Surg 2023; 94: 86–92

e48. Wirtz MR, Schalkers DV, Goslings JC, Juffermans NP: The impact of blood product ratio and procoagulant therapy on the development of thromboembolic events in severely injured hemorrhaging trauma patients. Transfusion 2020; 60: 1873–82

e49. Polymeris AA, Karwacki GM, Siepen BM, et al.: Tranexamic acid for intracerebral hemorrhage in patients on non-vitamin K antagonist oral anticoagulants (TICH-NOAC): A multicenter, randomized, placebo-controlled, phase 2 trial. Stroke 2023; 54: 2223–34

e50. Tsan SEH, Viknaswaran NL, Cheong CC, et al.: Prophylactic intravenous tranexamic acid and thromboembolism in non-cardiac surgery: A systematic review, meta-analysis and trial sequential analysis. Anaesthesia 2023; 78: 1153–61

e51. Utsumi S, Ohki S, Shime N: Efficacy of tranexamic acid in adult isolated traumatic brain injury: A multicenter retrospective study. Am J Emerg Med 2025; 95: 173–8