Efficacy and safety analysis of tranexamic acid in patients with hemorrhage and exsanguination

Efficacy and safety analysis of tranexamic acid in patients with hemorrhage and exsanguination | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Efficacy and safety analysis of tranexamic acid in patients with hemorrhage and exsanguination Canan AKMAN, Asli Bahar UCAR, Ozlem INCI, Burak AKIN, Busra ERDEM, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9646001/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Introduction: Tranexamic acid (TXA) belongs to the hemostatic agents that are used in cases of trauma, surgical interventions, or spontaneous bleeding. The use of TXA has recently been reintroduced, especially in trauma patients. These agents act at various steps of primary and secondary hemostasis, promoting clot formation, reducing blood loss, and improving patient outcomes. This narrative review examines the current use of TXA and highlights the major pros and cons of the agent in the trauma setting. Methods A narrative synthesis of literature review was performed using Medline, CINAHL, Web of Science, and Scopus using relevant keywords ("tranexamic acid", "hemorrhage", "hemorrhagic shock", "exsanguination", "hemostasis", "adverse effects") for publications between January 2000 and March 2026. Consecutive trials in English between 2010 and 2026 investigating the indications, adverse effects, contraindications, and use of tranexamic acid were screened. Case reports, editorials, experimental studies (animal models), and expert opinions were not used for the analysis. Results Although the findings differ from each other in hospital and prehospital use, the use of TXA early after primary traumatic injury has a favorable effect on bleeding deaths. Severe and moderate injuries benefit from TXA use to the same extent. Patients from extreme ages, obese patients, and those using specific drugs are worth studying separately. Conclusion Treatment with hemostatic agents such as TXA saves lives in bleeding events, especially following major trauma. Robust data advocates administration of the agent as soon as possible, when available, in 90 minutes. Safety and efficacy profiles of TXA offer a viable choice for exsanguinating victims of trauma when administered at an early phase after the primary injury. Hemostasis trauma bleeding hemorrhage hemorrhagic shock tranexamic acid Figures Figure 1 I. Introduction: Shock and tranexamic acid (TXA) Blood loss or hemorrhage is the most common trigger of shock in victims of trauma. The cornerstones of liquid replacement have not changed over the past few decades. Crystalloid solutions are infused primarily as initial therapy to expand the volume and prevent cellular hypoxia. Those who are not hemodynamically stable and have class III-IV bleeding are treated with blood and products, while operative therapy is organized quickly. Contemporary management of traumatic hemorrhagic shock focuses on damage control resuscitation, focusing on minimizing blood loss, provision of hemostasis, and permissive hypotension. The approach known as `permissive or controlled hypotension` is advocated as a temporary measure before blood loss is completely controlled and is devised to minimize bleeding by keeping the patient at acceptable hypotensive values. First developed in the 1960s in Japan, TXA is a precursor of the enzyme named plasmin, which acts to break down clots in the organism, and is reversibly bound to the plasminogen, leading to the reduction of the fibrinolytic effects of plasmin ( 1 ). TXA is a synthetic analogue of lysine, via competitive inhibition of its receptors on plasminogen and, in turn, blocks conversion to plasmin, preventing fibrin degradation, known as the antifibrinolytic effect ( 2 ). Pharmaceutically, it is produced as 1000 mg/10 mL ampoule forms for intravenous use and 650 mg tablets for oral administration. Following ingestion, it reaches peak blood levels in around three hours. Around 95% is excreted in the urine. The half-life of the oral (tablet) form is 11 hours, and the half-life of the IV (ampoule) form is 2 hours ( 3 ). It has been recommended by the United States Food and Drug Administration (FDA) for two indications: patients with hemophilia undergoing a tooth extraction and female patients with idiopathic menorrhagia. Some other studies revealed various situations in which its use is recommended ( 3 , 4 ). Authors of the CRASH-2 trial advocated that TXA is very cost efficient in high-, middle- and low-income countries ( 5 ). This narrative review was designed to examine the contemporary use of TXA and highlights the major pros and cons of the agent in the trauma setting. II. Methods A narrative synthesis of literature review was performed using Medline, CINAHL, Web of Science, and Scopus using relevant keywords ("tranexamic acid", "hemorrhage", "hemorrhagic shock", "exsanguination", "hemostasis", "adverse effects") for publications between January 2010 and March 2026. Consecutive trials in English investigating the indications, adverse effects, contraindications, and use of tranexamic acid were screened. Cochrane systematic reviews, meta-analyses, and high-quality randomised controlled trials published between 2010 and 2026 were prioritised. Case reports, editorials, experimental studies (animal models), and expert opinions were not used for the analysis. The extracted data and evidence were collated narratively, presented in tabular format, and allocated to subsections in the results. Systematic review and meta-analytic procedures, such as PRISMA guidelines, were not followed. III. Use of TXA in patients with exsanguinating or major bleeding The agent has been reported to be effective in reducing short-term (28-day) mortality, if used within the first three hours after trauma in patients with hemorrhagic shock following blunt trauma ( 6 , 7 ). The multinational, multicentered randomized, placebo-controlled study, CRASH–2, assessed the effect of antifibrinolytic therapy with TXA on death and transfusion ( 4 ). The study included adult trauma patients with severe bleeding who had hypotension (systolic blood pressure 110 bpm) within 8 hours of the injury. The findings demonstrated that 1 g of TXA is infused in the first 10 minutes and 1g in 8 hours reduced the risk of all-cause mortality from 16% to 14.5%, compared with the conservative treatment group. Risk of bleeding-related deaths decreased from 5.7% to 4.9%. Research data show that TXA improves survival when administered within 3 hours after injury to patients with severe bleeding ( 8 ). Current sources of trauma literature recommend the use of TXA with a 1g bolus, followed by 1 gr 8 hours of infusion, or a single dose of 2 g, bolus in trauma patients, starting no later than 3 hours after trauma ( 7 ). In a well-designed randomized study, Ageron et al. indicated that the use of TXA in the first hour following injury had the highest impact, in both severely and non-severely injured patients ( 9 ). The agent was associated with a significantly increase in survival in the first day of bleeding (OR = 1.22, 95% CI 1.11–1.34; p < .01). A small randomized controlled clinical trial showed that TXA is associated with lower use of blood production and reduced length of hospital stay ( 10 ), A pooled meta-analytic study indicated that combined topical with intravenous TXA can decrease the need for transfusion (RR = 0.34, 95% CI: 0.23–0.50, P < 0.001) ( 11 ). IV TXA alone, or combined topical use with TXA, decreased the total blood loss and subsequent need for transfusion when compared to only topical use, without increasing the incidence of DVT. More recently, the CRASH-3 study demonstrated that TXA diminished the mortality risk and disability in those with intracranial hemorrhages and Glasgow Coma Scale scores above 3 and reactive pupillae ( 12 ). It is recommended to be administered via the IV route in the first 3 hours following trauma in the guidelines comprised in the Advanced Trauma Life Support (ATLS) ( 13 ). Indications, doses, and application times for TXA are given in Table 1 . Although it is known as an antifibrinolytic agent, it does not have a procoagulant effect ( 4 , 8 ). Literature data, including the CRASH-3 trial, advocated the use of TXA after orthopaedic injuries ( 12 , 14 , 15 ). Massive transfusion protocols necessitate adjunctive pharmacotherapy, including supplementation with IV calcium and administration of TXA, when indicated ( 16 ). III.A. Use of TXA in traumatic brain injury (TBI) For victims of moderate or severe TBI who present within 3 hours of injury, IV administration of TXA, either a single 2-g dose or a 1-g dose over 10 minutes followed by IV infusion of 1 g over 8 hours, is safe and may decrease mortality. The administration of TXA might be reasonable for other subgroups, such as severe TBI with bilateral reactive pupils and mild TBI with intracranial bleeding, but the benefit remains uncertain. A meta-analytic study demonstrated decreased death rate (RR 0.92 [0.88, 0.97], p = 0.002; I2: 0%) and lower hemorrhagic expansion, attributed to systemic administration of TXA in victims of TBI and hemorrhagic expansion (p = 0.002 and p = 0.03, respectively) ( 17 ). Table 1 Indications for use, doses, and forms of administration of tranexamic acid. Indication Dosing and route of administration Timing Caesarean section 1 gr iv 10 min before skin incision Hip fracture op 15 mg/kg iv Upon skin incision Knee arthroplasty 10–15 mg/kg iv Before deflating the first tourniquet Cervical conization 1 gr iv Periprocedural Heart surgery 50 mg/kg iv Perioperative Spinal surgery 2 gr iv 30 min before skin incision, and lasting for 20 min Dental extraction in hemophiliacs 10 mg/kg iv Just before procedure Heavy menstrual bleeding 1300 mg p.o. Perimenstrual (for 5 days) Dental procedures in patients using OACs 4.8% solution mouthwash Pre-and perioperative Bleeding (shocky) in trauma 1 gr TXA in 100 mL saline (max twice) In the first 3 hours after trauma Epistaxis Nasal tampon Continuous, until complete cessation of bleeding (per physician’s order). III.B. Dose studies The potential mortality benefit of high-dose IV TXA (≥ 2 g or ≥ 30 mg/kg in a single infusion) was investigated by a meta-analytic study in the trauma setting ( 18 ). The authors reported that high-dose IV TXA probably reduces the need for transfusion without a significant effect on blood loss, and an uncertain effect on the rates of thromboembolism and fatality. These findings were supported by many perioperative studies. In cardiac surgery, high-dose infusion of TXA reduced the rate of reoperation (OR: 1.70, 95%CI: [1.03, 2.80]) and the requirement of fresh frozen plasma (FFP) (OR: 1.33, 95% CI: [1.01, 1.74]) ( 19 ). IV. Timing and usage principles of TXA Research suggested an advantage of death rates with TXA treatment after bleeding ( 20 ). Patients with serious bleeding after trauma are to be administered 1 g of TXA IV over 10 min in the first 3 hours, and an infusion of 1 g of TXA over 8 hours ( 21 ). On the other hand, some trials showed that infusion of TXA after three hours` window can increase fatality rates ( 22 ). However, TXA is still a viable alternative when hyperfibrinolysis is present, as demonstrated by viscoelastic tests after three hours, suggesting trauma-induced coagulopathy ( 21 ). Pediatric studies adopted weight-based regimens of TXA for severely injured children, such as 15 mg/kg bolus dose, followed by 2 mg/kg/h infusion over 8 h, or 30 mg/kg bolus dose, followed by 4 mg/kg/h infusion over 8 h ( 23 ). Recent reports also advocated its usage concurrent with REBOA, which was found to be safe in porcine studies ( 24 ). V. Prehospital treatment with TXA In accord with a recent study on the timing of onset of TXA in trauma patients, starting after the 90th minute when the first 28 days significantly reduced mortality was found not to reduce mortality by 90 days ( 25 ). In light of this study, it is likely that in the future the timing of starting treatment of TXA in trauma patients with hemorrhagic shock will shift to 90th minutes and start to be used in the prehospital period. Another study showed that prehospital TXA is linked with a marked 28-day survival benefit and lower need for blood transfusion in the first day and verified a dose-response relationship ( 26 ). The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study evaluated the safety and efficacy of TXA use in the civilian prehospital setting and reduced mortality was reported at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3%, respectively, OR = 0.41 with 95% CI = 0.21 to 0.8) ( 27 ). This mortality difference was greatest in severely injured patients with ISS > 15 (6% vs 14.5% for TXA and control, respectively, OR = 0.37 with 95% CI [0.17 to 0.8]). Prehospital administration of TXA appears to be associated with decreased use of red blood cell transfusion compared with placebo in patients with isolated traumatic brain injury ( 28 ). Cost-effectiveness of the agent is remarkable, especially considering the availability and use in the global shortage of blood ( 29 ). In the recent study by Hsu et al. prehospital blood (RBC + FFP, RBC, and FFP) and non-blood (intravenous crystalloids + dextran and TXA) resuscitation strategies were associated with comparable nonsignificant effects on early and late mortality ( 30 ). However, use of TXA in the prehospital aeromedical setting have produced conflicting results. Prehospital administration of TXA during aeromedical transport did not improve survival compared with ED administration ( 31 ). Currently available data on prehospital administration of comparisons of red blood cells, FFP, IV crystalloids, and TXA in the resuscitation of hemorrhagic shock remains inconclusive. Battlefield conditions are also in the context of prehospital interventions. A study on battle injuries in Afghanistan revealed that higher proportions of patients receiving TXA versus patients not receiving TXA received hemostatic dressings, pressure dressings, and tourniquet placement ( 32 ). Conversely, the proportion of patients receiving IV fluids was higher in the no-TXA group. The authors pointed out that a significant proportion of the patients did not receive TXA due to low adherence to the relevant guidelines, reducing the quality of care in this specific population. Recent publications emphasize that modern approaches, including permissive hypotension, should be revisited in the presence of TXA, and diastolic blood pressure is critical for coronary perfusion, and in turn the cardiac output responsible for cerebral blood flow ( 33 ). On the other hand, the retrospective analysis in French Army Health Service between 2016 and 2020 reported a remarkable underuse of TXA (almost 20%) and highlighted the need for optimising the clinical guidelines to instruct prehospital practitioners in administering TXA to casualties that will require blood products ( 34 ). In brief, TXA is found to be very effective and safe to use in the prehospital setting, and its use is clinically and economically feasible ( 35 ). VI. Coagulopathy of trauma resuscitation IV use of TXA has been recommended in patients with severe bleeding secondary to trauma, who often need multiple transfusions or who have suspected hyperfibrinolysis. In multiple trauma, TXA is a valuable choice, as it can potentially mitigate the effects of hyperfibrinolysis, which occurs in 2–34% of multiple trauma victims and is linked with an increased risk of mortality ( 36 ). The phenomenon called `pathologic hyperfibrinolysis` is the coagulopathic state which occurs after serious injury. This condition will block clot formation and contribute to uncontrolled bleeding. Fibrinolysis is triggered when tPA is bound to plasminogen, activating plasmin. TXA binds to plasminogen, blocking its binding to fibrin and inhibiting fibrinolysis. In patients with bleeding and a fibrinogen level of ≤ 1.5 g/l, the administration of fibrinogen concentrate should be 4 g or 30–60 mg/kg ( 5 , 37 ). Hyperfibrinolysis and coagulopathy are potential etiologies of continued bleeding and lack of response to resuscitation. TXA prevents plasmin from binding to fibrin, thus reducing fibrinolysis and stabilizing a fibrin clot. Figure 1 illustrates the mechanism of action for TXA. When administered within 3 hours of injury, TXA has demonstrated a decrease in mortality in specific high-risk hypotensive bleeding populations. Local pharmacy protocols determine dosing. Clinically, both a 1 g TXA bolus within 3 hours from injury followed by a second 1 g infusion over 8 hours, or a single dose of 2 g, have been safe and efficacious. TXA is not recommended to be administered beyond 3 hours from the time of injury unless hyperfibrinolysis is present. A study included patients with admission hyperfibrinolysis (Ly30 > 3%) on thromboelastography and reported that patients who received TXA had a lower 6-hour mortality rate (34% vs. 13%, p = 0.04) and higher 24-hour transfusion of FFP (15 vs. 10 units, p = 0.03) compared with those not receiving TXA ( 38 ). In brief, TXA can be used safely and effectively to stop hemorrhage due to trauma. Future studies will highlight the potential applications, optimal dosage, and routes of administration of TXA in different clinical situations, such as traumatic brain and spine injury. VII. Use of TXA in surgical procedures TXA was found to be the most frequently prescribed hemostatic agent in 'bleeding disorders of unknown cause` for both minor and major surgery (79% and 86%), dental extractions, and childbirth (both 93%) ( 39 ). Many studies focused on the effects of TXA on bleeding cessation, use of blood products, length of stay in hospital, wound healing, and procedure-related complications. A prospective observational cohort study on patients undergoing laparoscopic sleeve gastrectomy revealed that TXA (1 g IV administered preoperatively) may not significantly impact major bleeding complications but reduced minor hemorrhagic events ( 40 ). Patil et al. recently reported that Botroclot, TXA, and chitosan demonstrated the most rapid hemostatic effect in minor oral surgeries ( 41 ). A retrospective cohort trial by Darras et al. reported that topical application of the agent in a dose of 1–2 mg/mL did not result in an enhanced risk for complications in wound healing in patients who had undergone facelift procedures ( 42 ). VIII. TXA use in special situations Findings of a recent meta-analysis suggest that TXA significantly reduces rebleeding in patients, particularly in upper gastrointestinal bleeding (UGIB) and reduces need for surgical intervention ( 43 ). The authors also reported a significant reduction in mortality, particularly in certain sub-groups. The role of TXA in lower gastrointestinal bleeding (LGIB) is complex, with diverse findings and methodological considerations ( 44 ). Dosage adjustment should be considered in patients with renal insufficiency and low glomerular filtration rate. TXA has been studied in pregnancy as an adjunct for patients undergoing vaginal or cesarean delivery as well as for postpartum hemorrhage, with favorable or mixed results. The agent`s pregnancy category is B, and it crosses the placenta ( 3 ). It is considered safe for the fetus in the setting of trauma with significant bleeding, though it is currently unknown if the use of tranexamic acid in the pregnant trauma patient reduces mortality. The decisions on the use of antifibrinolytics (including TXA) and the Prothrombin Complex Concentrate (PCC) and other hemostatic agents are given on a case-by-case basis. TXA is passed in very low amounts to breastmilk, with studies showing no adverse effects in infants at maternal doses up to 4 g daily. Despite earlier caution from international panels, clinical use in breastfeeding women, such as 3 g daily for bleeding disorders, has been well tolerated ( 45 ). The agent is beneficial in minimizing blood loss, reduction of the need for transfusion, and improving survival rate in pediatric injuries and resultant blood loss ( 46 ). Future studies will enlighten details of age-specific treatments, and long-term safety profiles. Use in epistaxis In 2019, Akkan ark., in a study they performed showed that TXA administered with tampon in patients with epistaxis was as effective as the nasal buffer with Merocel ( 47 ). In research on patients with epistaxis who used aspirin or clopidogrel, topical TXA suggested that there is an appropriate treatment option to stop bleeding, reduce recurrent bleeding, and minimize hospital stay ( 48 ). Hosseinialhashemi et al reported that topical TXA may be associated with a lower rate of frontal nasal buffering and shorter stay in the ED ( 49 ). Indications, doses and application times for TXA are given in Table 1 (Table 1 ). IX. Contraindications for TXA administration include known allergy, intracranial bleeding, color vision deficiency, subarachnoid hemorrhage, previously documented venous or arterial thrombosis or embolism at the time of evaluation. TXA is also contraindicated if longer than 3 hours have passed since the traumatic injury. TXA must be specifically avoided in patients with hemophilia B who receive PCC because it increases the risk of thromboembolism ( 50 ). TXA involves the inhibition of gamma-aminobutyric acid and glycine receptors in the central nervous system, which can lead to neuronal hyperexcitability and subsequent seizures. For this reason, it is not recommended in patients with intracranial bleeding (ICH) ( 51 ). Side effects and safety profile of TXA : X. Side effects and safety profile of TXA Adverse effects of the agent include seizures, headache, back pain, abdominal pain, vomiting, diarrhea, weakness, thromboembolism, deep venous thromboses, anaphylactic reactions, impaired color vision, and other ophthalmological disorders. Seizures may occur due to accidental intrathecal administration ( 52 ). Topical application was associated with minor adverse effects such as nausea and diarrhea, dysgeusia in a Cochrane review and meta-analysis ( 53 ). Although concerns have recently increased over the risk of thromboembolic events soaring due to this agent, meta-analytic studies demonstrated that there may be no effect of TXA in up to 30 days ( 54 ). A meta-analysis of 7 studies (including > 30.000 patients) showed that the rate for vascular occlusive events (p = 0.09), and its deep vein thrombosis subgroup (p = 0.23), pulmonary embolism subgroup (p = 1), stroke subgroup (p = 0.38), and myocardial infarction subgroup (p = 0.15) were similar in TXA and placebo groups ( 17 ). Furthermore, TXA was associated with slightly lower vascular occlusive events in this study (RR 0.85 [0.73, 0.99], p = 0.04; I 2 : 4%). Substantial literature data have recently showed that TXA can be safely used, while no augmented risk of thromboembolic events after infusion of TXA in the injured patients ( 55 ). There was no definitive evidence that its use is associated with thromboembolic events ( 43 ). Khan et al. found that thrombotic complications were not different between patients with admission hyperfibrinolysis treated with or without TXA (p = 0.98) ( 38 ). On the other hand, patients receiving TXA had higher rates of venous thromboembolic events (8.1% in prehospital and 18.5% in ED) than the overall trauma population (2.1%, P < 0.001) ( 31 ). Therefore, the safety profile is more favorable for hospital use. Subglottic thrombus formation has been attributed to administration of nebulized TXA for postoperative hemoptysis following CO 2 laser wedge excision of subglottic stenosis ( 56 ). XI.Comparison of TXA with Prothrombin complex concentrates (PCC): Although this agent was developed as a source of factor IX to be used to treat hemophilia B1, PCCs are concentrated in pathogen-reduced, lyophilized, vitamin K-dependent coagulation factors (VKDCF) in the last few decades ( 57 ). The agent is a derivative of the cryoprecipitate supernatant of FFP pools using ion exchange chromatography ( 58 ). Two different forms contain three (FII, IX, and X) or four factors (FII, VII, IX, and X) at a concentration around 25 times greater than plasma ( 57 , 59 ). PCC replaces VKDCF without risk of volume overload and rapidly reverses warfarin anticoagulation ( 60 , 61 ). The decisions on the use of antifibrinolytics (TXA) and the Prothrombin Complex Concentrate (PCC) and other hemostatic agents should be individualized and given on a case-by-case basis. XII. Conclusions Several large, well-designed studies have pointed out that TXA is viewed an efficacious medication to stop traumatic hemorrhage. Although it was thought that TXA administration is beneficial only in the severely injured, broad based and well-designed studies demonstrated that early treatment with TXA improves survival in both severely and non-severely injured trauma patients. There are conflicting findings on long-term outcomes in severely injured trauma patients who developed hyperfibrinolysis. To achieve the best possible outcomes, the literature supports the use of a loading dose of 1 g of TXA, followed by a 1 g infusion over 8 h, given by IV administration within a 3-h window period of traumatic injury. Safety analysis of broad population-based studies indicated that the agent has a favorable profile. TXA can be used safely and effectively to stop hemorrhage due to trauma. Many reports showed that TXA administration was not associated with thrombotic complications. Emergency practitioners should be informed about its use, and necessary measures should be taken to ensure its expedient availability. Declarations Author Contribution C.A., B.E., A.B.U., and O.K. wrote the main manuscript text, and G.Y. and M.U. prepared the figure. All authors reviewed the manuscript. References -Franchini M, Focosi D, Mannucci PM (2024) Tranexamic Acid: An Evergreen Hemostatic Agent. Semin Thromb Hemost 50(5):733–738. 10.1055/s-0044-1779632. Epub 2024 Feb 9. 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J Am Coll Surg 241(1):7–15. 10.1097/XCS.0000000000001401 -Thompson AA, Misra S, Ayasa L, Kumar N, Eichbaum Q, Raykar N (2026) The critical role of tranexamic acid for bleeding patients. Vox Sang 121(3):222–227. 10.1111/vox.70156 -Hsu CW, Hung WK, Chilinda ZB et al (2026 Feb) Comparative efficacy of prehospital resuscitation strategies on mortality for patients with major trauma: a network meta-analysis. Eur J Emerg Med 9. 10.1097/MEJ.0000000000001315 -Boudreau RM, Deshpande KK, Day GM, Hinckley WR, Harger N, Pritts TA, Makley AT, Goodman MD (2019) Prehospital Tranexamic Acid Administration During Aeromedical Transport After Injury. J Surg Res 233:132–138. 10.1016/j.jss.2018.07.074 -Schauer SG, April MD, Naylor JF et al (2017) Fall;17(3):55–58 Prehospital Administration of Tranexamic Acid by Ground Forces in Afghanistan: The Prehospital Trauma Registry Experience. J Spec Oper Med. 10.55460/7U98-J4HL -Carden R, Horner D (2025) Is it time to reframe resuscitation in trauma? Emerg Med J 42(2):132–133. 10.1136/emermed-2024-214422 -Pinna T, Py N, Aigle L, Travers S, Pasquier P, Cazes N (2024) Retrospective analysis of tranexamic acid administration in French war-wounded between October 2016 and September 2020. BMJ Mil Health 170(e2):e79–e84. 10.1136/military-2022-002321 -Stansfield R, Morris D, Jesulola E (2020) The Use of Tranexamic Acid (TXA) for the Management of Hemorrhage in Trauma Patients in the Prehospital Environment: Literature Review and Descriptive Analysis of Principal Themes. Shock 53(3):277–283. 10.1097/SHK.0000000000001389 -Napolitano LM, Cohen MJ, Cotton BA, Schreiber MA, Moore EE (2013) Tranexamic acid in trauma: how should we use it? J Trauma Acute Care Surg 74(6):1575–1586. 10.1097/TA.0b013e318292cc54 -Advanced Trauma Life Support eleventh edition Copyright© 2025 American College of Surgeons 633 N. Saint Clair Street -Khan M, Jehan F, Bulger EM, PROPPR Study Group et al (2018) Severely injured trauma patients with admission hyperfibrinolysis: Is there a role of tranexamic acid? Findings from the PROPPR trial. J Trauma Acute Care Surg 85(5):851–857. 10.1097/TA.0000000000002022 -Mussert CMA, Monard ALL, van Duijl TT et al (2025) BDUC-iN study group. Current Practice Regarding Bleeding Disorders of Unknown Cause in the Netherlands: A National Survey. Haemophilia 31(4):752–760. 10.1111/hae.70065 -Dalkılıç MS, Şişik A, Gençtürk M, Yılmaz M, Erdem H, Parmar C (2025) The Effect of Prophylactic Intraoperative Tranexamic Acid Use on Bleeding After Laparoscopic Sleeve Gastrectomy With Omentopexy: A Prospective Cohort Study. Surg Innov 32(5):409–416. 10.1177/15533506251344055 -Patil K, Goyal JN, Dudhe S et al (2025) Comparative Evaluation of Local Hemostatic Agents in Minor Oral Surgical Procedures: A Randomized Clinical Trial. Cureus 17(6):e85754. 10.7759/cureus.85754 -Darras O, Janssen PL, Fraiman E, Reategui A, Zins JE Local Tranexamic Acid in Facelift Surgery Is Not Associated With Wound Healing Complications: A Matched, Single-Surgeon Cohort Study. Aesthet Surg J 2025 Jul 4:sjaf130. 10.1093/asj/sjaf130 -Calderon Martinez E, Briceño Silva GD, Sanchez Cruz C et al (2025) Tranexamic acid as treatment for acute gastrointestinal bleeding: A comprehensive systematic review and meta-analysis. Indian J Gastroenterol 44(3):311–329. 10.1007/s12664-025-01749-9 -Khalid S, Saghira M, Saad S et al (2024) Efficacy and Safety of Tranexamic Acid in the Management of Gastrointestinal Bleeding: A Systematic Review. Cureus 16(12):e76086. 10.7759/cureus.76086 -Drugs (2006) and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; Tranexamic Acid. 2025 Jun 15. PMID: 30000793 -Alsabri M, Aziz MM, Fahmy K et al (2026) Tranexamic Acid in Pediatric Care: A Comprehensive Overview. J Pediatr Pharmacol Ther 31(1):18–29. 10.5863/JPPT-25-00027 -Akkan S, Çorbacıoğlu ŞK, Aytar H et al (2019) Evaluating Effectiveness of Nasal Compression With Tranexamic Acid Compared With Simple Nasal Compression and Merocel Packing: A Randomized Controlled Trial. Ann Emerg Med 74(1):72–78. 10.1016/j.annemergmed.2019.03.030 -Amini K, Arabzadeh A, Jahed S et al (2020) Topical Tranexamic Acid versus Phenylephrine-lidocaine for the Treatment of Anterior Epistaxis in Patients Taking Aspirin or Clopidogrel; a Randomized Clinical Trial. Arch Acad Emerg Med 19(1):9. 10.22037/aaem.v9i1.875 -Hosseinialhashemi M, Jahangiri R, Faramarzi A et al (2022) Intranasal Topical Application of Tranexamic Acid in Atraumatic Anterior Epistaxis: A Double-Blind Randomized Clinical Trial. Ann Emerg Med 80(3):182–188. 10.1016/j.annemergmed.2022.04.010 -WOMAN Trial Collaborators (2017) 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. ;389(10084):2105–2116. doi: 10.1016/S0140-6736(17)30638-4. Epub 2017 Apr 26. Erratum in: Lancet. 2017;389(10084):2104. 10.1016/S0140-6736(17)31220-5 -Law ZK, England TJ, Mistri AK et al (2020) Incidence and predictors of early seizures in intracerebral haemorrhage and the effect of tranexamic acid. Eur Stroke J 5(2):123–129. 10.1177/2396987320901391 -Lecker I, Wang DS, Whissell PD et al (2016) Tranexamic acid-associated seizures: Causes and treatment. Ann Neurol 79(1):18–26. 10.1002/ana.24558 -Joseph J, Martinez-Devesa P, Bellorini J, Burton MJ (2018) Tranexamic acid for patients with nasal haemorrhage (epistaxis). Cochrane Database Syst Rev 12(12):CD004328. 10.1002/14651858.CD004328.pub3 -Beverly A, Ong G, Kimber C et al (2023) Drugs to reduce bleeding and transfusion in major open vascular or endovascular surgery: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2(2):CD013649. 10.1002/14651858.CD013649.pub2 -Thomas HM, Kahf H, Bush B, Nahmias J, Lim PK (2025) Use of tranexamic acid in trauma surgical specialties: a narrative review. World J Emerg Surg 20(1):76. 10.1186/s13017-025-00649-9 -Awadallah A, Armstrong M, Aden A, Weidermann J, Bayan SL, Ekbom DC (2024) Life-Threatening Subglottic Thrombus Formation after Administration of Nebulized Tranexamic Acid. Laryngoscope 134(3):1356–1358. 10.1002/lary.30973 -Nesek Adam V, Bošan-Kilibarda I, PROTHROMBIN COMPLEX CONCENTRATE IN, EMERGENCY DEPARTMENT (2022) Acta Clin Croat 61(Suppl 1):53–58. 10.20471/acc.2022.61.s1.09 -Baskaran J, Lopez RA, Cassagnol M, Prothrombin Complex C (2024) Oct 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 30969538 -Tanaka KA, Shettar S, Vandyck K, Shea SM, Abuelkasem E (2021) Roles of Four-Factor Prothrombin Complex Concentrate in the Management of Critical Bleeding. Transfus Med Rev 35(4):96–103. 10.1016/j.tmrv.2021.06.007 -Sarode R, Milling TJ Jr, Refaai MA et al (2013) Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 128(11):1234–1243. 10.1161/CIRCULATIONAHA.113.002283 -Refaai MA, Goldstein JN (2025) Four-Factor Prothrombin Complex Concentrate vs Plasma in Patients on Vitamin K Antagonists with Gastrointestinal Bleeding or Needing a Gastrointestinal Procedure: A Retrospective Analysis of 2 Randomized Controlled Trials. J Am Coll Emerg Physicians Open 6(3):100142. 10.1016/j.acepjo.2025.100142 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9646001","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":637239080,"identity":"c97a4a67-12be-4dbb-af0d-33523e380b5c","order_by":0,"name":"Canan AKMAN","email":"","orcid":"","institution":"Canakkale Onsekiz Mart Universitesi Tip Fakultesi Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Canan","middleName":"","lastName":"AKMAN","suffix":""},{"id":637239082,"identity":"ba48df45-600e-47de-b076-c985937746b9","order_by":1,"name":"Asli Bahar UCAR","email":"","orcid":"","institution":"Marmara Üniversitesi Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Asli","middleName":"Bahar","lastName":"UCAR","suffix":""},{"id":637239084,"identity":"c7681e5e-ecf5-4c42-b0ff-37ca4447c5b2","order_by":2,"name":"Ozlem INCI","email":"","orcid":"","institution":"Ege Üniversitesi Tıp Fakültesi Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Ozlem","middleName":"","lastName":"INCI","suffix":""},{"id":637239086,"identity":"ac82371f-1e4a-4620-ac48-89adac3d807d","order_by":3,"name":"Burak AKIN","email":"","orcid":"","institution":"Bağcılar Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Burak","middleName":"","lastName":"AKIN","suffix":""},{"id":637239087,"identity":"fba46955-228d-48ac-9c26-4a6322d302b2","order_by":4,"name":"Busra ERDEM","email":"","orcid":"","institution":"Şişli Etfal Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Busra","middleName":"","lastName":"ERDEM","suffix":""},{"id":637239088,"identity":"c6838631-239b-44f0-afcd-026c45218d39","order_by":5,"name":"Gokhan YILMAZ","email":"","orcid":"","institution":"Konya Eğitim ve Araştırma Hastanesi","correspondingAuthor":false,"prefix":"","firstName":"Gokhan","middleName":"","lastName":"YILMAZ","suffix":""},{"id":637239089,"identity":"e46317c5-1d4f-4df3-ba49-41eaec7c51df","order_by":6,"name":"Furkan Cagri OGUZLAR","email":"","orcid":"","institution":"Süleyman Demirel University","correspondingAuthor":false,"prefix":"","firstName":"Furkan","middleName":"Cagri","lastName":"OGUZLAR","suffix":""},{"id":637239090,"identity":"3c954fa4-3834-4663-9fbd-436d0384654e","order_by":7,"name":"Ozgur KARCIOGLU","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYDACHhBhwMDAx8B8AMiSkCFeCxsDWwJICw+RWhhAWngMkPm4AT/P4WcffhTY2LVJ5Hx+daPGgoeB/fDRDfi0SPa2Gc/sMUhLbpPI3WadcwzoMJ60tBv4tBicZzBmZjA4nMwG1GKcwwbUIsFjRkAL+2eolpxnxjn/iNFytgdsix1QC/Pj3DYitEj2nClmBPolgY3nmRlzbp8EDxshv/DzpG9m+PHHxp6fPfnx55xvdXL87IeP4dUCA4kNwKiRALHYiFEOAvZAzPyBWNWjYBSMglEwsgAA0GM+bCog7l8AAAAASUVORK5CYII=","orcid":"","institution":"İstanbul Eğitim ve Araştırma Hastanesi","correspondingAuthor":true,"prefix":"","firstName":"Ozgur","middleName":"","lastName":"KARCIOGLU","suffix":""}],"badges":[],"createdAt":"2026-05-07 18:39:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9646001/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9646001/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108979945,"identity":"75982a3a-011a-494f-9c2f-f141ab5001ae","added_by":"auto","created_at":"2026-05-11 12:02:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1164515,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe mechanism of action of tranexamic acid, when used in the setting of bleeding in the multiple trauma setting.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9646001/v1/2e5627d4610a72bf20c60209.png"},{"id":108982170,"identity":"6d07b262-338e-49b7-8d66-8be8a81821c6","added_by":"auto","created_at":"2026-05-11 12:23:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1410659,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9646001/v1/2d054d27-a61a-4ab6-a96c-62dcfd32ea0a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety analysis of tranexamic acid in patients with hemorrhage and exsanguination","fulltext":[{"header":"I. Introduction: Shock and tranexamic acid (TXA)","content":"\u003cp\u003eBlood loss or hemorrhage is the most common trigger of shock in victims of trauma. The cornerstones of liquid replacement have not changed over the past few decades. Crystalloid solutions are infused primarily as initial therapy to expand the volume and prevent cellular hypoxia. Those who are not hemodynamically stable and have class III-IV bleeding are treated with blood and products, while operative therapy is organized quickly. Contemporary management of traumatic hemorrhagic shock focuses on damage control resuscitation, focusing on minimizing blood loss, provision of hemostasis, and permissive hypotension. The approach known as `permissive or controlled hypotension` is advocated as a temporary measure before blood loss is completely controlled and is devised to minimize bleeding by keeping the patient at acceptable hypotensive values.\u003c/p\u003e \u003cp\u003eFirst developed in the 1960s in Japan, TXA is a precursor of the enzyme named plasmin, which acts to break down clots in the organism, and is reversibly bound to the plasminogen, leading to the reduction of the fibrinolytic effects of plasmin (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). TXA is a synthetic analogue of lysine, via competitive inhibition of its receptors on plasminogen and, in turn, blocks conversion to plasmin, preventing fibrin degradation, known as the antifibrinolytic effect (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePharmaceutically, it is produced as 1000 mg/10 mL ampoule forms for intravenous use and 650 mg tablets for oral administration. Following ingestion, it reaches peak blood levels in around three hours. Around 95% is excreted in the urine. The half-life of the oral (tablet) form is 11 hours, and the half-life of the IV (ampoule) form is 2 hours (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). It has been recommended by the United States Food and Drug Administration (FDA) for two indications: patients with hemophilia undergoing a tooth extraction and female patients with idiopathic menorrhagia. Some other studies revealed various situations in which its use is recommended (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Authors of the CRASH-2 trial advocated that TXA is very cost efficient in high-, middle- and low-income countries (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This narrative review was designed to examine the contemporary use of TXA and highlights the major pros and cons of the agent in the trauma setting.\u003c/p\u003e "},{"header":"II. Methods","content":"\u003cp\u003eA narrative synthesis of literature review was performed using Medline, CINAHL, Web of Science, and Scopus using relevant keywords (\"tranexamic acid\", \"hemorrhage\", \"hemorrhagic shock\", \"exsanguination\", \"hemostasis\", \"adverse effects\") for publications between January 2010 and March 2026. Consecutive trials in English investigating the indications, adverse effects, contraindications, and use of tranexamic acid were screened. Cochrane systematic reviews, meta-analyses, and high-quality randomised controlled trials published between 2010 and 2026 were prioritised. Case reports, editorials, experimental studies (animal models), and expert opinions were not used for the analysis. The extracted data and evidence were collated narratively, presented in tabular format, and allocated to subsections in the results. Systematic review and meta-analytic procedures, such as PRISMA guidelines, were not followed.\u003c/p\u003e\n"},{"header":"III. Use of TXA in patients with exsanguinating or major bleeding","content":"\u003cp\u003eThe agent has been reported to be effective in reducing short-term (28-day) mortality, if used within the first three hours after trauma in patients with hemorrhagic shock following blunt trauma (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). The multinational, multicentered randomized, placebo-controlled study, CRASH\u0026ndash;2, assessed the effect of antifibrinolytic therapy with TXA on death and transfusion (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). The study included adult trauma patients with severe bleeding who had hypotension (systolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;90 mmHg) and tachycardia (heart rate\u0026thinsp;\u0026gt;\u0026thinsp;110 bpm) within 8 hours of the injury. The findings demonstrated that 1 g of TXA is infused in the first 10 minutes and 1g in 8 hours reduced the risk of all-cause mortality from 16% to 14.5%, compared with the conservative treatment group. Risk of bleeding-related deaths decreased from 5.7% to 4.9%. Research data show that TXA improves survival when administered within 3 hours after injury to patients with severe bleeding (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). Current sources of trauma literature recommend the use of TXA with a 1g bolus, followed by 1 gr 8 hours of infusion, or a single dose of 2 g, bolus in trauma patients, starting no later than 3 hours after trauma (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). In a well-designed randomized study, Ageron et al. indicated that the use of TXA in the first hour following injury had the highest impact, in both severely and non-severely injured patients (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). The agent was associated with a significantly increase in survival in the first day of bleeding (OR\u0026thinsp;=\u0026thinsp;1.22, 95% CI 1.11\u0026ndash;1.34; p \u0026lt; .01). A small randomized controlled clinical trial showed that TXA is associated with lower use of blood production and reduced length of hospital stay (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e),\u003c/p\u003e\n\u003cp\u003eA pooled meta-analytic study indicated that combined topical with intravenous TXA can decrease the need for transfusion (RR\u0026thinsp;=\u0026thinsp;0.34, 95% CI: 0.23\u0026ndash;0.50, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e). IV TXA alone, or combined topical use with TXA, decreased the total blood loss and subsequent need for transfusion when compared to only topical use, without increasing the incidence of DVT.\u003c/p\u003e\n\u003cp\u003eMore recently, the CRASH-3 study demonstrated that TXA diminished the mortality risk and disability in those with intracranial hemorrhages and Glasgow Coma Scale scores above 3 and reactive pupillae (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e). It is recommended to be administered via the IV route in the first 3 hours following trauma in the guidelines comprised in the Advanced Trauma Life Support (ATLS) (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). Indications, doses, and application times for TXA are given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Although it is known as an antifibrinolytic agent, it does not have a procoagulant effect (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). Literature data, including the CRASH-3 trial, advocated the use of TXA after orthopaedic injuries (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e). Massive transfusion protocols necessitate adjunctive pharmacotherapy, including supplementation with IV calcium and administration of TXA, when indicated (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIII.A. Use of TXA in traumatic brain injury (TBI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor victims of moderate or severe TBI who present within 3 hours of injury, IV administration of TXA, either a single 2-g dose or a 1-g dose over 10 minutes followed by IV infusion of 1 g over 8 hours, is safe and may decrease mortality. The administration of TXA might be reasonable for other subgroups, such as severe TBI with bilateral reactive pupils and mild TBI with intracranial bleeding, but the benefit remains uncertain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e meta-analytic study demonstrated decreased death rate (RR 0.92 [0.88, 0.97], p\u0026thinsp;=\u0026thinsp;0.002; I2: 0%) and lower hemorrhagic expansion, attributed to systemic administration of TXA in victims of TBI and hemorrhagic expansion (p\u0026thinsp;=\u0026thinsp;0.002 and p\u0026thinsp;=\u0026thinsp;0.03, respectively) (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003e\u003cstrong\u003eIndications for use, doses, and forms of administration of tranexamic acid.\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eIndication\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eDosing and route of administration\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTiming\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCaesarean section\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 gr iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 min before skin incision\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHip fracture op\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 mg/kg iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUpon skin incision\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eKnee arthroplasty\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10\u0026ndash;15 mg/kg iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBefore deflating the first tourniquet\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCervical conization\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 gr iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePeriprocedural\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHeart surgery\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50 mg/kg iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePerioperative\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSpinal surgery\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2 gr iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 min before skin incision, and lasting for 20 min\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDental extraction in hemophiliacs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 mg/kg iv\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eJust before procedure\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHeavy menstrual bleeding\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1300 mg p.o.\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePerimenstrual (for 5 days)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDental procedures in patients using OACs\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.8% solution mouthwash\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePre-and perioperative\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBleeding (shocky) in trauma\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 gr TXA in 100 mL saline (max twice)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIn the first 3 hours after trauma\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eEpistaxis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNasal tampon\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eContinuous, until complete cessation of bleeding (per physician\u0026rsquo;s order).\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eIII.B. Dose studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe potential mortality benefit of high-dose IV TXA (\u0026ge;\u0026thinsp;2 g or \u0026ge;\u0026thinsp;30 mg/kg in a single infusion) was investigated by a meta-analytic study in the trauma setting (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e). The authors reported that high-dose IV TXA probably reduces the need for transfusion without a significant effect on blood loss, and an uncertain effect on the rates of thromboembolism and fatality.\u003c/p\u003e\n\u003cp\u003eThese findings were supported by many perioperative studies. In cardiac surgery, high-dose infusion of TXA reduced the rate of reoperation (OR: 1.70, 95%CI: [1.03, 2.80]) and the requirement of fresh frozen plasma (FFP) (OR: 1.33, 95% CI: [1.01, 1.74]) (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e"},{"header":"IV. Timing and usage principles of TXA","content":"\u003cp\u003eResearch suggested an advantage of death rates with TXA treatment after bleeding (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Patients with serious bleeding after trauma are to be administered 1 g of TXA IV over 10 min in the first 3 hours, and an infusion of 1 g of TXA over 8 hours (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOn the other hand, some trials showed that infusion of TXA after three hours` window can increase fatality rates (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). However, TXA is still a viable alternative when hyperfibrinolysis is present, as demonstrated by viscoelastic tests after three hours, suggesting trauma-induced coagulopathy (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePediatric studies adopted weight-based regimens of TXA for severely injured children, such as 15 mg/kg bolus dose, followed by 2 mg/kg/h infusion over 8 h, or 30 mg/kg bolus dose, followed by 4 mg/kg/h infusion over 8 h (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Recent reports also advocated its usage concurrent with REBOA, which was found to be safe in porcine studies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e"},{"header":"V. Prehospital treatment with TXA","content":"\u003cp\u003eIn accord with a recent study on the timing of onset of TXA in trauma patients, starting after the 90th minute when the first 28 days significantly reduced mortality was found not to reduce mortality by 90 days (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In light of this study, it is likely that in the future the timing of starting treatment of TXA in trauma patients with hemorrhagic shock will shift to 90th minutes and start to be used in the prehospital period. Another study showed that prehospital TXA is linked with a marked 28-day survival benefit and lower need for blood transfusion in the first day and verified a dose-response relationship (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe California Prehospital Antifibrinolytic Therapy (Cal-PAT) study evaluated the safety and efficacy of TXA use in the civilian prehospital setting and reduced mortality was reported at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3%, respectively, OR\u0026thinsp;=\u0026thinsp;0.41 with 95% CI\u0026thinsp;=\u0026thinsp;0.21 to 0.8) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). This mortality difference was greatest in severely injured patients with ISS\u0026thinsp;\u0026gt;\u0026thinsp;15 (6% vs 14.5% for TXA and control, respectively, OR\u0026thinsp;=\u0026thinsp;0.37 with 95% CI [0.17 to 0.8]).\u003c/p\u003e \u003cp\u003ePrehospital administration of TXA appears to be associated with decreased use of red blood cell transfusion compared with placebo in patients with isolated traumatic brain injury (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Cost-effectiveness of the agent is remarkable, especially considering the availability and use in the global shortage of blood (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the recent study by Hsu et al. prehospital blood (RBC\u0026thinsp;+\u0026thinsp;FFP, RBC, and FFP) and non-blood (intravenous crystalloids\u0026thinsp;+\u0026thinsp;dextran and TXA) resuscitation strategies were associated with comparable nonsignificant effects on early and late mortality (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). However, use of TXA in the prehospital aeromedical setting have produced conflicting results. Prehospital administration of TXA during aeromedical transport did not improve survival compared with ED administration (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). Currently available data on prehospital administration of comparisons of red blood cells, FFP, IV crystalloids, and TXA in the resuscitation of hemorrhagic shock remains inconclusive.\u003c/p\u003e \u003cp\u003eBattlefield conditions are also in the context of prehospital interventions. A study on battle injuries in Afghanistan revealed that higher proportions of patients receiving TXA versus patients not receiving TXA received hemostatic dressings, pressure dressings, and tourniquet placement (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Conversely, the proportion of patients receiving IV fluids was higher in the no-TXA group. The authors pointed out that a significant proportion of the patients did not receive TXA due to low adherence to the relevant guidelines, reducing the quality of care in this specific population.\u003c/p\u003e \u003cp\u003eRecent publications emphasize that modern approaches, including permissive hypotension, should be revisited in the presence of TXA, and diastolic blood pressure is critical for coronary perfusion, and in turn the cardiac output responsible for cerebral blood flow (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). On the other hand, the retrospective analysis in French Army Health Service between 2016 and 2020 reported a remarkable underuse of TXA (almost 20%) and highlighted the need for optimising the clinical guidelines to instruct prehospital practitioners in administering TXA to casualties that will require blood products (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In brief, TXA is found to be very effective and safe to use in the prehospital setting, and its use is clinically and economically feasible (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e"},{"header":"VI. Coagulopathy of trauma resuscitation","content":"\u003cp\u003eIV use of TXA has been recommended in patients with severe bleeding secondary to trauma, who often need multiple transfusions or who have suspected hyperfibrinolysis. In multiple trauma, TXA is a valuable choice, as it can potentially mitigate the effects of hyperfibrinolysis, which occurs in 2\u0026ndash;34% of multiple trauma victims and is linked with an increased risk of mortality (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe phenomenon called `pathologic hyperfibrinolysis` is the coagulopathic state which occurs after serious injury. This condition will block clot formation and contribute to uncontrolled bleeding. Fibrinolysis is triggered when tPA is bound to plasminogen, activating plasmin. TXA binds to plasminogen, blocking its binding to fibrin and inhibiting fibrinolysis. In patients with bleeding and a fibrinogen level of \u0026le;\u0026thinsp;1.5 g/l, the administration of fibrinogen concentrate should be 4 g or 30\u0026ndash;60 mg/kg (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eHyperfibrinolysis and coagulopathy are potential etiologies of continued bleeding and lack of response to resuscitation. TXA prevents plasmin from binding to fibrin, thus reducing fibrinolysis and stabilizing a fibrin clot.\u003c/p\u003e\n\u003cp\u003eFigure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the mechanism of action for TXA. When administered within 3 hours of injury, TXA has demonstrated a decrease in mortality in specific high-risk hypotensive bleeding populations. Local pharmacy protocols determine dosing. Clinically, both a 1 g TXA bolus within 3 hours from injury followed by a second 1 g infusion over 8 hours, or a single dose of 2 g, have been safe and efficacious. TXA is not recommended to be administered beyond 3 hours from the time of injury unless hyperfibrinolysis is present.\u003c/p\u003e\n\u003cp\u003eA study included patients with admission hyperfibrinolysis (Ly30\u0026thinsp;\u0026gt;\u0026thinsp;3%) on thromboelastography and reported that patients who received TXA had a lower 6-hour mortality rate (34% vs. 13%, p\u0026thinsp;=\u0026thinsp;0.04) and higher 24-hour transfusion of FFP (15 vs. 10 units, p\u0026thinsp;=\u0026thinsp;0.03) compared with those not receiving TXA (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). In brief, TXA can be used safely and effectively to stop hemorrhage due to trauma. Future studies will highlight the potential applications, optimal dosage, and routes of administration of TXA in different clinical situations, such as traumatic brain and spine injury.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"VII. Use of TXA in surgical procedures","content":"\u003cp\u003eTXA was found to be the most frequently prescribed hemostatic agent in 'bleeding disorders of unknown cause` for both minor and major surgery (79% and 86%), dental extractions, and childbirth (both 93%) (\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e). Many studies focused on the effects of TXA on bleeding cessation, use of blood products, length of stay in hospital, wound healing, and procedure-related complications. A prospective observational cohort study on patients undergoing laparoscopic sleeve gastrectomy revealed that TXA (1 g IV administered preoperatively) may not significantly impact major bleeding complications but reduced minor hemorrhagic events (\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e). Patil et al. recently reported that Botroclot, TXA, and chitosan demonstrated the most rapid hemostatic effect in minor oral surgeries (\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e). A retrospective cohort trial by Darras et al. reported that topical application of the agent in a dose of 1\u0026ndash;2 mg/mL did not result in an enhanced risk for complications in wound healing in patients who had undergone facelift procedures (\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e).\u003c/p\u003e"},{"header":"VIII. TXA use in special situations","content":"\u003cp\u003eFindings of a recent meta-analysis suggest that TXA significantly reduces rebleeding in patients, particularly in upper gastrointestinal bleeding (UGIB) and reduces need for surgical intervention (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e). The authors also reported a significant reduction in mortality, particularly in certain sub-groups. The role of TXA in lower gastrointestinal bleeding (LGIB) is complex, with diverse findings and methodological considerations (\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e). Dosage adjustment should be considered in patients with renal insufficiency and low glomerular filtration rate.\u003c/p\u003e\n\u003cp\u003eTXA has been studied in pregnancy as an adjunct for patients undergoing vaginal or cesarean delivery as well as for postpartum hemorrhage, with favorable or mixed results. The agent`s pregnancy category is B, and it crosses the placenta (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). It is considered safe for the fetus in the setting of trauma with significant bleeding, though it is currently unknown if the use of tranexamic acid in the pregnant trauma patient reduces mortality. The decisions on the use of antifibrinolytics (including TXA) and the Prothrombin Complex Concentrate (PCC) and other hemostatic agents are given on a case-by-case basis.\u003c/p\u003e\n\u003cp\u003eTXA is passed in very low amounts to breastmilk, with studies showing no adverse effects in infants at maternal doses up to 4 g daily. Despite earlier caution from international panels, clinical use in breastfeeding women, such as 3 g daily for bleeding disorders, has been well tolerated (\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe agent is beneficial in minimizing blood loss, reduction of the need for transfusion, and improving survival rate in pediatric injuries and resultant blood loss (\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e). Future studies will enlighten details of age-specific treatments, and long-term safety profiles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eUse in epistaxis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn 2019, Akkan ark., in a study they performed showed that TXA administered with tampon in patients with epistaxis was as effective as the nasal buffer with Merocel (\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e). In research on patients with epistaxis who used aspirin or clopidogrel, topical TXA suggested that there is an appropriate treatment option to stop bleeding, reduce recurrent bleeding, and minimize hospital stay (\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e). Hosseinialhashemi et al reported that topical TXA may be associated with a lower rate of frontal nasal buffering and shorter stay in the ED (\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e). Indications, doses and application times for TXA are given in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e"},{"header":"IX. Contraindications","content":"\u003cp\u003efor TXA administration include known allergy, intracranial bleeding, color vision deficiency, subarachnoid hemorrhage, previously documented venous or arterial thrombosis or embolism at the time of evaluation. TXA is also contraindicated if longer than 3 hours have passed since the traumatic injury. TXA must be specifically avoided in patients with hemophilia B who receive PCC because it increases the risk of thromboembolism (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e). TXA involves the inhibition of gamma-aminobutyric acid and glycine receptors in the central nervous system, which can lead to neuronal hyperexcitability and subsequent seizures. For this reason, it is not recommended in patients with intracranial bleeding (ICH) (\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSide effects and safety profile of TXA\u003c/strong\u003e:\u003c/p\u003e"},{"header":"X. Side effects and safety profile of TXA","content":"\u003cp\u003eAdverse effects of the agent include seizures, headache, back pain, abdominal pain, vomiting, diarrhea, weakness, thromboembolism, deep venous thromboses, anaphylactic reactions, impaired color vision, and other ophthalmological disorders. Seizures may occur due to accidental intrathecal administration (\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e). Topical application was associated with minor adverse effects such as nausea and diarrhea, dysgeusia in a Cochrane review and meta-analysis (\u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e). Although concerns have recently increased over the risk of thromboembolic events soaring due to this agent, meta-analytic studies demonstrated that there may be no effect of TXA in up to 30 days (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e). A meta-analysis of 7 studies (including\u0026thinsp;\u0026gt;\u0026thinsp;30.000 patients) showed that the rate for vascular occlusive events (p\u0026thinsp;=\u0026thinsp;0.09), and its deep vein thrombosis subgroup (p\u0026thinsp;=\u0026thinsp;0.23), pulmonary embolism subgroup (p\u0026thinsp;=\u0026thinsp;1), stroke subgroup (p\u0026thinsp;=\u0026thinsp;0.38), and myocardial infarction subgroup (p\u0026thinsp;=\u0026thinsp;0.15) were similar in TXA and placebo groups (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e). Furthermore, TXA was associated with slightly lower vascular occlusive events in this study (RR 0.85 [0.73, 0.99], p\u0026thinsp;=\u0026thinsp;0.04; I\u003csup\u003e2\u003c/sup\u003e: 4%). Substantial literature data have recently showed that TXA can be safely used, while no augmented risk of thromboembolic events after infusion of TXA in the injured patients (\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThere was no definitive evidence that its use is associated with thromboembolic events (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e). Khan et al. found that thrombotic complications were not different between patients with admission hyperfibrinolysis treated with or without TXA (p\u0026thinsp;=\u0026thinsp;0.98) (\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e). On the other hand, patients receiving TXA had higher rates of venous thromboembolic events (8.1% in prehospital and 18.5% in ED) than the overall trauma population (2.1%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e). Therefore, the safety profile is more favorable for hospital use.\u003c/p\u003e\n\u003cp\u003eSubglottic thrombus formation has been attributed to administration of nebulized TXA for postoperative hemoptysis following CO\u003csub\u003e2\u003c/sub\u003e laser wedge excision of subglottic stenosis (\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e).\u003c/p\u003e"},{"header":"XI.Comparison of TXA with Prothrombin complex concentrates (PCC):","content":"\u003cp\u003eAlthough this agent was developed as a source of factor IX to be used to treat hemophilia B1, PCCs are concentrated in pathogen-reduced, lyophilized, vitamin K-dependent coagulation factors (VKDCF) in the last few decades (\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e). The agent is a derivative of the cryoprecipitate supernatant of FFP pools using ion exchange chromatography (\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e). Two different forms contain three (FII, IX, and X) or four factors (FII, VII, IX, and X) at a concentration around 25 times greater than plasma (\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e). PCC replaces VKDCF without risk of volume overload and rapidly reverses warfarin anticoagulation (\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e). The decisions on the use of antifibrinolytics (TXA) and the Prothrombin Complex Concentrate (PCC) and other hemostatic agents should be individualized and given on a case-by-case basis.\u003c/p\u003e"},{"header":"XII. Conclusions","content":"\u003cp\u003eSeveral large, well-designed studies have pointed out that TXA is viewed an efficacious medication to stop traumatic hemorrhage. Although it was thought that TXA administration is beneficial only in the severely injured, broad based and well-designed studies demonstrated that early treatment with TXA improves survival in both severely and non-severely injured trauma patients. There are conflicting findings on long-term outcomes in severely injured trauma patients who developed hyperfibrinolysis. To achieve the best possible outcomes, the literature supports the use of a loading dose of 1 g of TXA, followed by a 1 g infusion over 8 h, given by IV administration within a 3-h window period of traumatic injury.\u003c/p\u003e \u003cp\u003eSafety analysis of broad population-based studies indicated that the agent has a favorable profile. TXA can be used safely and effectively to stop hemorrhage due to trauma. Many reports showed that TXA administration was not associated with thrombotic complications. Emergency practitioners should be informed about its use, and necessary measures should be taken to ensure its expedient availability.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eC.A., B.E., A.B.U., and O.K. wrote the main manuscript text, and G.Y. and M.U. prepared the figure. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e-Franchini M, Focosi D, Mannucci PM (2024) Tranexamic Acid: An Evergreen Hemostatic Agent. Semin Thromb Hemost 50(5):733\u0026ndash;738. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1055/s-0044-1779632.\u003c/span\u003e\u003cspan address=\"10.1055/s-0044-1779632.\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Epub 2024 Feb 9. 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J Am Coll Emerg Physicians Open 6(3):100142. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.acepjo.2025.100142\u003c/span\u003e\u003cspan address=\"10.1016/j.acepjo.2025.100142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Hemostasis, trauma, bleeding, hemorrhage, hemorrhagic shock, tranexamic acid","lastPublishedDoi":"10.21203/rs.3.rs-9646001/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9646001/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e \u003cp\u003eTranexamic acid (TXA) belongs to the hemostatic agents that are used in cases of trauma, surgical interventions, or spontaneous bleeding. The use of TXA has recently been reintroduced, especially in trauma patients. These agents act at various steps of primary and secondary hemostasis, promoting clot formation, reducing blood loss, and improving patient outcomes. This narrative review examines the current use of TXA and highlights the major pros and cons of the agent in the trauma setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA narrative synthesis of literature review was performed using Medline, CINAHL, Web of Science, and Scopus using relevant keywords (\"tranexamic acid\", \"hemorrhage\", \"hemorrhagic shock\", \"exsanguination\", \"hemostasis\", \"adverse effects\") for publications between January 2000 and March 2026. Consecutive trials in English between 2010 and 2026 investigating the indications, adverse effects, contraindications, and use of tranexamic acid were screened. Case reports, editorials, experimental studies (animal models), and expert opinions were not used for the analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAlthough the findings differ from each other in hospital and prehospital use, the use of TXA early after primary traumatic injury has a favorable effect on bleeding deaths. Severe and moderate injuries benefit from TXA use to the same extent. Patients from extreme ages, obese patients, and those using specific drugs are worth studying separately.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eTreatment with hemostatic agents such as TXA saves lives in bleeding events, especially following major trauma. Robust data advocates administration of the agent as soon as possible, when available, in 90 minutes. Safety and efficacy profiles of TXA offer a viable choice for exsanguinating victims of trauma when administered at an early phase after the primary injury.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety analysis of tranexamic acid in patients with hemorrhage and exsanguination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-11 10:58:24","doi":"10.21203/rs.3.rs-9646001/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-18T10:28:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"72858923340455158962510219274125661461","date":"2026-05-18T08:58:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"120521088113219887758650956576308066172","date":"2026-05-17T05:53:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-16T12:32:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"237344271092438657244701811626971419274","date":"2026-05-16T08:09:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308299569134683643480043058391360530293","date":"2026-05-14T09:20:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-05-14T07:42:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-11T22:25:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-11T22:25:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Pharmacology","date":"2026-05-07T18:26:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejcl","sideBox":"Learn more about [European Journal of Clinical Pharmacology](http://link.springer.com/journal/228)","snPcode":"228","submissionUrl":"https://submission.nature.com/new-submission/228/3","title":"European Journal of Clinical Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bbf4765d-2982-4ea2-8e09-52adfe105476","owner":[],"postedDate":"May 11th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-18T10:28:09+00:00","index":43,"fulltext":""},{"type":"reviewerAgreed","content":"72858923340455158962510219274125661461","date":"2026-05-18T08:58:26+00:00","index":42,"fulltext":""},{"type":"reviewerAgreed","content":"120521088113219887758650956576308066172","date":"2026-05-17T05:53:43+00:00","index":40,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-16T12:32:00+00:00","index":39,"fulltext":""},{"type":"reviewerAgreed","content":"237344271092438657244701811626971419274","date":"2026-05-16T08:09:04+00:00","index":36,"fulltext":""},{"type":"reviewerAgreed","content":"308299569134683643480043058391360530293","date":"2026-05-14T09:20:39+00:00","index":32,"fulltext":""},{"type":"reviewersInvited","content":"19","date":"2026-05-14T07:42:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-05-11T22:25:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-05-11T22:25:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Pharmacology","date":"2026-05-07T18:26:08+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-14T08:08:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-11 10:58:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9646001","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9646001","identity":"rs-9646001","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}