Antithrombin for severe burns: a systematic review and meta-analysis

Antithrombin for severe burns: a systematic review and meta-analysis | 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 Research Article Antithrombin for severe burns: a systematic review and meta-analysis Yuki Itagaki, Mineji Hayakawa, Yuki Takahashi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6895071/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Anticoagulation therapies may reduce the rate of mortality associated with severe burns. However, only a few high-quality randomized controlled trials have been conducted in this regard, and clinical recommendations are lacking. In this study, we aimed to evaluate the effectiveness and safety of antithrombin-based interventions for severe burns. Main body of the abstract : We systematically reviewed and examined randomized controlled trials and observational studies on antithrombin administration for severe burns. Control groups were administered standard therapy or a placebo. The primary outcome was in-hospital mortality. We assessed the studies using the Cochrane risk-of-bias tool and the Grading of Recommendations Assessment, Development, and Evaluation approach. Two randomized controlled trials and one observational study were included. In the randomized controlled trials, antithrombin administration did not affect overall mortality (low certainty of evidence). However, antithrombin administration resulted in a significant reduction in 28-day mortality rate among patients with overt disseminated intravascular coagulation in one of these trials (high certainty of evidence). In the observational study, antithrombin administration resulted in a significant reduction in 28-day mortality rate (moderate certainty of evidence). Conclusions : Although antithrombin does not affect overall mortality, it may be effective in patients with overt disseminated intravascular coagulation. Given the limited number of available studies, further research and accumulation of high-quality evidence are warranted. antithrombin disseminated intravascular coagulation mortality thrombosis wound healing Figures Figure 1 Figure 2 Figure 3 Background Burns cause approximately 180,000 deaths globally each year [ 1 ]. Severe burns are associated with systemic coagulopathy, which leads to disseminated intravascular coagulation (DIC), organ dysfunction, worsening of the burn site [ 2 , 3 ], and increased mortality [ 4 – 6 ]. The activation of coagulation in patients with burns may be attributed to direct vascular endothelial injury and hypoperfusion [ 7 ]. Burns usually lead to distributive shock, which exacerbates the zone of stasis and ischemia at the burn site, which is potentially salvageable [ 8 ]. A rapid depletion of antithrombin (AT) level has been identified as a factor in the activation of coagulation caused by burns [ 4 ]. Furthermore, AT depletion is positively associated with the total burn surface area (TBSA), inhalation injury, mortality, and hospital stay [ 9 ]. Thus, AT supplementation may be an important therapeutic strategy to mitigate the activation of coagulation in patients with severe burns [ 10 ]. In a pilot study, Lavrentieva et al. revealed that AT administration for patients in the acute phase of burn injury reduced the 28-day mortality rate [ 6 ]. A nationwide database study in Japan with propensity score matching also demonstrated the reduction in 28-day in-hospital mortality rate following AT administration [ 10 ]. Furthermore, AT administration reportedly decreases the number of ventilation days and meshed autograft healing time [ 11 ]. Although the abovementioned studies suggest the potential effectiveness of AT supplementation therapy for severe burns, no systematic reviews have been conducted and no clinical guidelines support its use. Consequently, evidence supporting clinical recommendations remains inadequate [ 3 , 10 ]. Therefore, a comprehensive synthesis of the available evidence on AT-based interventions for patients with severe burns is necessary. We planned a systematic review and meta-analysis aimed at evaluating the effectiveness and safety of AT-based interventions for severe burns. Materials and Methods Protocol registration The study protocol was pre-registered on the Open Science Framework on June 5, 2024 (blinded for peer review). We conducted this systematic review and meta-analysis in accordance with the PRISMA guidelines for systematic reviews and meta-analyses [ 12 ]. Database search To identify relevant studies, a comprehensive search of the following electronic databases was performed: MEDLINE (PubMed), Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Additionally, reference lists of relevant articles were reviewed to identify more studies. Detailed search strategies are provided in the Additional files (Appendices 1–4). Types of studies We included both randomized controlled trials (RCTs) and observational studies published until June 12, 2024 that met our criteria. Studies without clear reporting on population, treatment, or outcomes of interest, as well as animal studies and non-English publications, were excluded. Study population Patients admitted with severe burns, as defined by TBSA or the burn index, were included. Those with only inhalation injuries were excluded. Intervention and control The intervention assessed was intravenous administration of AT. Control groups received either standard care or a placebo. Outcomes The primary outcome was all-cause mortality. The secondary outcomes were the Sequential Organ Failure Assessment (SOFA) score, occurrence of complications such as multiple organ failure or sepsis, wound-healing time, and ventilator-free days. The wound-healing time was defined as the number of days from grafting to the point at which interstices closed and 90% of the wound re-epithelialized without further grafting. Study selection References were stored, and duplicates were removed using EndNote (Thomson Reuters). Two reviewers (YI and YT) independently screened titles and abstracts of the retrieved studies using Rayyan software to identify studies meeting the inclusion criteria. Disagreements on study eligibility were resolved by a third reviewer (MH). Data extraction A standardized form was used for data extraction, covering the study setting, population details, participant characteristics, intervention and control specifics, methodology, outcomes, and bias-risk assessments. Data were independently extracted by two reviewers (YI and YT), with discrepancies resolved by a third reviewer (MH). Risk-of-bias assessment Two reviewers (YI and YT) independently evaluated the risk of bias and quality of each study, with disagreements resolved by a third reviewer (MH). The revised Cochrane RoB2 tool was used for RCTs, assessing factors such as random sequence generation, allocation concealment, and outcome reporting [ 13 ]. For observational studies, the ROBINS-I tool was applied [ 14 ]. Data summary and synthesis A meta-analysis was performed when data from multiple trials were available, following the Cochrane Handbook for Systematic Reviews guidelines. Binary outcomes are reported as risk or odds ratios with 95% confidence intervals, while continuous outcomes, such as intensive care unit stay duration, are reported as mean difference with 95% confidence interval [ 15 ]. All statistical analyses, including the assessment of risk of bias within and/or across studies, were performed using Review Manager, Version 5.4. (The Cochrane Collaboration 2019, The Nordic Cochrane Centre) [ 16 ]. The level of statistical significance was set at P 50% indicated significant heterogeneity) [ 17 ]. Clinical heterogeneity was considered when deciding whether to perform quantitative synthesis or sensitivity analysis. Strength of evidence Two reviewers (YI and YT) assessed the evidence strength for each outcome using the GRADE approach, categorizing evidence quality as high, moderate, low, or very low [ 18 ]. Results Study selection After removing duplicates, a total of 631 records were identified through the literature search. Of these, nine full-text articles were reviewed for eligibility, and two RCTs, along with one observational study, were included in the qualitative synthesis (see Fig. 1 for the PRISMA flowchart) [ 6 , 10 , 11 , 19 ]. Insert Fig. 1 about here Two RCTs by Kowal-Vern et al. (2000 and 2001) were included based on different reported outcomes. Owing to the potential overlap in patient outcomes, these RCTs were treated as a single study in the review. Only the 2001 study reported mortality outcomes and was therefore included in the meta-analysis. The 2000 study was used for qualitative synthesis in the outcome of time to wound-healing (Additional Files). The observational study, in which a Japanese national database and propensity score matching were utilized, provided further insights. Table 1 ( Characteristics of the included studies) summarizes the characteristics of all included studies. (Insert Table 1 about here) In the RCTs, the mean TBSA in both groups exceeded 40%, and AT administration was initiated within 3 days of the burn. Although the TBSA was unavailable in the observational study, the burn index was approximately 40. The secondary outcomes were analyzed in the RCTs and observational study, but none of the outcomes overlapped among the studies. Therefore, we did not create a forest plot for these. Table 1 Characteristics of the included studies First author Year Study type Region Intervention Experimental group (Patients number) Control group (Patients number) Age Mean (SD) Severity of burn injury Inhalational injury, n (%) AT administration dose Initiation and duration of AT administration Primary outcome Kowal-Vern A 2000 Open pilot study USA AT 8 8 AT 4 (21) Control 30 (12) TBSA(%) AT 40 ± 18 Control45 ± 21 AT 4 (50%) Control 2 (25%) {175-baseline AT level} x body weight (kg)/1.4 started within 24 hours after the burn injury continued every 8 hours for 72 hours for a total of 9 infusions Coagulation laboratory tests Kowal-Vern A 2001 Open pilot study USA AT 9 23 AT 44 (20) Control 43 (14) TBSA(%) AT 42 ± 17 Control 44 ± 18 AT 4 (44%) Control 12 (52%) {175-baseline AT level} x body weight (kg)/1.4 started within 24 hours after the burn injury continued every 8 hours for 72 hours for a total of 9 infusions Mortality Lavrentieva A 2008 RCT Greece AT 15 15 AT 37.1 (13.6) Control 44.1 (21.5) TBSA(%) AT 43.3 ± 21.4 Control 44.4 ± 22.4 AT 4 (26.6%) Control 5 (31.3%) {150-baseline AT level} x body weight (kg)/1.4 started from the first post-burn day continued for the next three consecutive days 28day mortality Tagami T 2017 propensity score-matched analysis Japan AT 103 103 AT61.6(21.8) Control 63.6(21.3) Burn Index AT37.1(22.1) Control 38.5 (23.9) AT 1 (1%) Control 1(1%) NA NA 28day mortality Antithrombin; AT, Total burn surface area; TBSA, Randomized clinical trial; RCT Primary outcome Overall mortality For two RCTs, AT had no significant effect on overall mortality (see Fig. 2 a). With moderate bias risks, limited event numbers, and confidence intervals spanning 1, the certainty of this evidence was determined to be very low. Twenty-eight-day mortality among patients with overt DIC A subgroup analysis based on overt DIC criteria revealed that AT administration significantly reduced 28-day mortality rate in one RCT (see Fig. 2 b). Although the event number remained below the optimal information size, the evidence certainty was high. Twenty-eight-day mortality (observational study) Data from the observational study indicated a significant reduction in 28-day mortality rate with AT administration (see Fig. 2 c). The certainty of this evidence was deemed moderate, given the limited event number. Insert Fig. 2 about here Secondary outcomes Ventilator-free days The number of ventilator-free days was assessed only in the observational study [ 10 ]. In that study, AT administration significantly increased the number of ventilator-free days (mean difference: 3.8, 95% confidence interval: 0.29–7.31). Thrombotic events The rate of thrombotic events were also analyzed only in the observational study [ 10 ]. In that study, AT did not significantly affect thrombotic event rates (odds ratio: 0.33, 95% CI: 0.01–8.20).. Wound-healing time According to the observational study, AT significantly reduced wound-healing time in several regions of the body, including the head and neck, back, and hands [ 11 ]. However, AT showed no effect on wound-healing times in other areas, such as the chest, upper extremities, and lower extremities. Owing to the limited number of RCTs and the use of propensity score matching in the observational study, sensitivity analyses were not performed. Additionally, outcomes such as the SOFA score and complications were not consistently reported across studies. The risk-of-bias assessment is summarized in Fig. 3 , and all the meta-analysis results are summarized in Table 2 (Summary of findings: Antithrombin versus placebo for burn injury). Insert Table 2, and Fig. 3 about here Discussion In the RCTs included in this systematic review and meta-analysis, AT had no effect on overall mortality. However, AT significantly reduced the 28-day mortality rate in the overt-DIC subgroup in one RCT and the observational study. To our knowledge, this is the first comprehensive systematic review and meta-analysis on the effectiveness of AT administration for severe burns. However, as for the secondary outcomes, we could synthesize the data. Although AT administration did not reduce the overall mortality among patients with severe burns, it did in the subgroup of patients with overt DIC, which is induced by systemic activation of coagulation in patients with severe burns. This finding suggests that AT administration may have survival benefits in this patient population, similar to the effects of anticoagulation therapy among patients with sepsis [ 20 ]. In the early post-burn period, activation of coagulation induces an elevation in the proportion of thrombin/AT complexes and a decrease in the level of AT in the blood [ 6 ]. Thus, activation of coagulation in patients with severe burns is the main causative factor for overt DIC, explaining why AT administration may be advantageous in patients with burns and overt DIC. Although effective data synthesis was not achieved, the wound-healing time was shortened in the AT group in one RCT. One possible pathophysiological explanation is that AT may contribute to salvaging the zone of stasis, potentially preventing it from progressing to necrosis by decreasing the number of microthrombi and increasing the vascularity of the grafting bed, thus facilitating better graft placement [ 8 , 11 ]. However, additional evidence is required to draw definitive conclusions. Burns and inhalation injuries lead to intrapulmonary activation of coagulation [ 21 ]. Such activation increases the risk of thrombosis and impairs normal fibrinolysis, further complicating the respiratory function of patients with severe burns. Thus, AT administration may reduce the number of ventilator days in such patients by mitigating coagulation disturbances and improving pulmonary outcomes. Further research is warranted to elucidate the mechanisms through which AT exerts its protective effects on the pulmonary system in patients with severe burns. The rate of thrombotic events did not decrease significantly in patients who received AT in our analyses. However, the control groups did not experience a sufficient number of events for a conclusive comparison. Although hemorrhagic events were not investigated in each study, Kowal-Vern et al. reported that AT administration was not accompanied by significant hemorrhagic complications [ 11 ]. Additionally, Tagami et al. reported similar transfusion volumes between the AT and control groups in a national database study [ 10 ]. This study had several limitations. First, each outcome was analyzed in only one or two of the included trials and studies. Thus, data synthesis was limited. The included number of studies was too small to yield sufficient evidence regarding the effectiveness and safety of antithrombin-based treatment for burns. Second, we did not account for unmeasured confounding factors such as other therapies administered for burn injuries, including fluid resuscitation and surgical approaches (e.g., allograft and artificial dermis transplantation). Further well-constructed clinical trials are required to better assess these outcomes in patients with burns. Third, the observed reduction in mortality rate among patients with overt DIC was based on a subgroup analysis from a single RCT with a small cohort. Although clinically intriguing, this finding should be interpreted with caution and regarded as hypothesis-generating rather than conclusive. Finally, two studies by Kowal-Vern et al. (2000 and 2001) were included in our review. Although these studies may have involved overlapping patient populations, they reported different outcomes. Only the 2001 study, which evaluated mortality, was included in the meta-analysis. The 2000 study, which focused on coagulation parameters, was included for qualitative synthesis only to avoid double-counting in the pooled analysis. Conclusions This systematic review and meta-analysis indicate that AT administration has no observable effect on overall mortality among patients with severe burns. However, AT treatment notably decreased 28-day mortality rates in the subgroup of patients experiencing overt DIC, as demonstrated in one RCT and the observational study. Given the limited number of available studies, further research and accumulation of high-quality evidence are warranted. List of abbreviations DIC, disseminated intravascular coagulation AT, antithrombin TBSA, total burn surface area RCT, randomized controlled trial SOFA, Sequential Organ Failure Assessment Declarations Ethics approval and consent to participate Ethics committee approval was not required, we conducted the review and meta-analysis using publicly available data without direct patient involvement. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the Department of Emergency Medicine, Hokkaido University Hospital, Japan. Authors' contributions MH is a guarantor and contributed to the conception of the study. The manuscript protocol was drafted by YI and revised by MH. All authors developed the search strategy performed by YI and MH. YI and YT independently extracted data from the included studies, assessed the risk of bias, and completed the data synthesis. MH arbitrated in cases of disagreement and ensured the absence of errors. All authors have approved the publication of this protocol. YI was responsible for funding acquisition. Acknowledgments We would like to thank Editage (www.editage.com) for English language editing. Authors' information References Rybarczyk MM, Schafer JM, Elm CM, Sarvepalli S, Vaswani PA, Balhara KS, Carlson LC, Jacquet GA: A systematic review of burn injuries in low- and middle-income countries: Epidemiology in the WHO-defined African Region. Afr J Emerg Med 2017, 7(1):30-37. Kowal-Vern A, Orkin BA: Antithrombin in the treatment of burn trauma. World J Crit Care Med 2016, 5(1):17-26. Glas GJ, Levi M, Schultz MJ: Coagulopathy and its management in patients with severe burns. J Thromb Haemost 2016, 14(5):865-874. Lavrentieva A, Kontakiotis T, Bitzani M, Papaioannou-Gaki G, Parlapani A, Thomareis O, Tsotsolis N, Giala MA: Early coagulation disorders after severe burn injury: impact on mortality. Intensive Care Med 2008, 34(4):700-706. Nikolaidou E KD, Kaldoudi E et al. : Coagulation disorders and mortality in burn injury: A systematic review. Annals of Burns and Fire Disasters 2022, XXXV(June). Lavrentieva A KT, Bitzani M, Parlapani A, et al.: The efficacy of antithrombin administration in the acute phase of burn injury. Thromb Haemost 2008, 100(2): 286-290. Lonic D, Heidekrueger PI, Bosselmann T, Niclas Broer P, Gertler R, Wolfgang Martin K, Prantl L, Ninkovic M, Giunta R, Ehrl D: Is major burn injury associated with coagulopathy? The value of thrombelastometry in the detection of coagulopathy in major burn injury: A prospective observational study. Clin Hemorheol Microcirc 2020, 76(2):299-308. Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S: Burn injury. Nat Rev Dis Primers 2020, 6(1):11. Niedermayr M, Schramm W, Kamolz L, Andel D, Römer W, Hoerauf K, Zimpfer M, Andel H: Antithrombin deficiency and its relationship to severe burns. Burns 2007, 33(2):173-178. Tagami T MH, Moroe Y et al.: Antithrombin use and 28-day in-hospital mortality among severe-burn patients：an observational nationwide study. Ann intensive care 2017, 7:18. Kowal-Vern A MV, Walenga JM, Gamelli RL: Antithrombin(H) concentrate infusions are safe and effective in patients with thermal injuries. Journal of Burn Care & Rehabilitation 2000(March/April):115-127. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE et al: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021, 372:n71. Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM et al: RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019, 366:l4898. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I et al: ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016, 355:i4919. Higgins JPT TJ CJ, Cumpston M, et al.: Cochrane Handbook for Systematic Reviews of Interventions version 6.0(updated July 2019). Cochrane. Available from www.training.org/handboo. 2019. Copenhagen: The Nordic Cochrane Centre TCC. Review Manager (RevMan) [Computer program]. Version 5.4. 2019. Huedo-Medina TB S-MJ, Marín-Martínez F, et al.: Assessing heterogeneity in meta-analysis- Q statistic or I2 index? Psychol Methods 2006, 11:193-206. Santesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, Brignardello-Petersen R, Carrasco-Labra A, De Beer H, Hultcrantz M et al: GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol 2020, 119:126-135. Kowal-Vern A WJ, McGill V, Gamelli RL The impact of antithrombin (H) concentrate infusions on pulmonary function in the acute phase of thermal injury. Burns 2001, 27 52-60. Yamakawa K, Umemura Y, Hayakawa M, Kudo D, Sanui M, Takahashi H, Yoshikawa Y, Hamasaki T, Fujimi S, Japan Septic Disseminated Intravascular Coagulation study g: Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. Crit Care 2016, 20(1):229. Hofstra JJ, Vlaar AP, Knape P, Mackie DP, Determann RM, Choi G, van der Poll T, Levi M, Schultz MJ: Pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma. J Trauma 2011, 70(6):1389-1397. Additional Declarations No competing interests reported. Supplementary Files AdditionalFiles.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6895071","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":476258584,"identity":"d9afab96-fbaf-47a3-9132-f54592f9be79","order_by":0,"name":"Yuki Itagaki","email":"","orcid":"","institution":"Hokkaido University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Itagaki","suffix":""},{"id":476258585,"identity":"083add2d-dc6d-4309-9166-69a988fbfae5","order_by":1,"name":"Mineji Hayakawa","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIiWNgGAWjYDACZiCWMLBhbCBVSxopWiDgMAladNt5Dz6wKDgvu729+ekGhhqbaIJazA7zJRtIGNw2nnPmmNkNhmNpuQStMzvMYyYB1JI4QyLB7AZjw2GitJj/kDA4lzhD/vk3orWYAUPsANAWHuJtMQY6LNl4Bk9O2Y0Eovxy/ozhZ4k/drIz2I9vu/GhxoawFhBgloCxEohRDgKMH4hVOQpGwSgYBSMTAABF6j2OByZIMwAAAABJRU5ErkJggg==","orcid":"","institution":"Sapporo City General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Mineji","middleName":"","lastName":"Hayakawa","suffix":""},{"id":476258587,"identity":"f2c88b97-7207-4b17-8619-3ed7c95bcaed","order_by":2,"name":"Yuki Takahashi","email":"","orcid":"","institution":"Hokkaido University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Takahashi","suffix":""}],"badges":[],"createdAt":"2025-06-14 16:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6895071/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6895071/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85825058,"identity":"fde678a9-237f-4c7b-9191-016ab0a19a44","added_by":"auto","created_at":"2025-07-02 07:06:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":27486,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePreferred Reporting Items for \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eSystematic Reviews\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e and Meta-Analyses 2000 flow diagram for new systematic reviews which included searches of databases and registers only\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6895071/v1/03fce8bbe6cb8f95106ccd1f.png"},{"id":85827209,"identity":"2560ced0-7005-4e09-b3dd-d0a48f197956","added_by":"auto","created_at":"2025-07-02 07:22:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":112515,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots for each outcome.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e2a. Overall mortality\u003c/p\u003e\n\u003cp\u003e2b. 28-day mortality in patients with overt DIC\u003c/p\u003e\n\u003cp\u003e2c. 28-day mortality (observational study)\u003c/p\u003e\n\u003cp\u003eBlue square means dichotomous outcomes and green square means continuous outcomes.\u003c/p\u003e\n\u003cp\u003eThe Kowal-Vern studies from 2000 and 2001 may share overlapping populations. Only the 2001 study, which reported mortality outcomes, was included in the meta-analysis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6895071/v1/17e267f969518c754983062e.png"},{"id":85826624,"identity":"49bfed3f-1731-43e2-9404-2a125982b89f","added_by":"auto","created_at":"2025-07-02 07:14:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":23505,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe risk of bias assessment by RoB2 and ROBINS-I\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e3a. The risk of bias assessment by the Risk of Bias2 (RoB2)\u003c/p\u003e\n\u003cp\u003e3b. The risk of bias assessment by the Risk Of Bias In Non-randomised Studies – of Interventions (ROBINS-I)\u003c/p\u003e\n\u003cp\u003eD1: Bias arising from the randomization process. D2: Bias due to deviations from intended intervention. D3: Bias due to missing outcome data. D4: Bias in measurement of the outcome. D5: Bias in selection of the reported results\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6895071/v1/c00d04a8b52ff98a39dce935.png"},{"id":87683072,"identity":"4690572c-a8f4-48db-8a48-e7dbfb9cb5f9","added_by":"auto","created_at":"2025-07-28 00:38:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020518,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6895071/v1/777b296b-7be7-4eb8-aed4-beb280effacb.pdf"},{"id":85825057,"identity":"11592a39-ca31-4183-b642-e25aa188aac3","added_by":"auto","created_at":"2025-07-02 07:06:35","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16099,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFiles.docx","url":"https://assets-eu.researchsquare.com/files/rs-6895071/v1/9ec6ce76f1c7dee8e19350ae.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Antithrombin for severe burns: a systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eBurns cause approximately 180,000 deaths globally each year [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Severe burns are associated with systemic coagulopathy, which leads to disseminated intravascular coagulation (DIC), organ dysfunction, worsening of the burn site [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and increased mortality [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The activation of coagulation in patients with burns may be attributed to direct vascular endothelial injury and hypoperfusion [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Burns usually lead to distributive shock, which exacerbates the zone of stasis and ischemia at the burn site, which is potentially salvageable [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA rapid depletion of antithrombin (AT) level has been identified as a factor in the activation of coagulation caused by burns [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, AT depletion is positively associated with the total burn surface area (TBSA), inhalation injury, mortality, and hospital stay [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Thus, AT supplementation may be an important therapeutic strategy to mitigate the activation of coagulation in patients with severe burns [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In a pilot study, Lavrentieva et al. revealed that AT administration for patients in the acute phase of burn injury reduced the 28-day mortality rate [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A nationwide database study in Japan with propensity score matching also demonstrated the reduction in 28-day in-hospital mortality rate following AT administration [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, AT administration reportedly decreases the number of ventilation days and meshed autograft healing time [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough the abovementioned studies suggest the potential effectiveness of AT supplementation therapy for severe burns, no systematic reviews have been conducted and no clinical guidelines support its use. Consequently, evidence supporting clinical recommendations remains inadequate [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Therefore, a comprehensive synthesis of the available evidence on AT-based interventions for patients with severe burns is necessary. We planned a systematic review and meta-analysis aimed at evaluating the effectiveness and safety of AT-based interventions for severe burns.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProtocol registration\u003c/h2\u003e \u003cp\u003eThe study protocol was pre-registered on the Open Science Framework on June 5, 2024 (blinded for peer review). We conducted this systematic review and meta-analysis in accordance with the PRISMA guidelines for systematic reviews and meta-analyses [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDatabase search\u003c/h3\u003e\n\u003cp\u003eTo identify relevant studies, a comprehensive search of the following electronic databases was performed: MEDLINE (PubMed), Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Additionally, reference lists of relevant articles were reviewed to identify more studies. Detailed search strategies are provided in the Additional files (Appendices 1\u0026ndash;4).\u003c/p\u003e\n\u003ch3\u003eTypes of studies\u003c/h3\u003e\n\u003cp\u003eWe included both randomized controlled trials (RCTs) and observational studies published until June 12, 2024 that met our criteria. Studies without clear reporting on population, treatment, or outcomes of interest, as well as animal studies and non-English publications, were excluded.\u003c/p\u003e\n\u003ch3\u003eStudy population\u003c/h3\u003e\n\u003cp\u003ePatients admitted with severe burns, as defined by TBSA or the burn index, were included. Those with only inhalation injuries were excluded.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIntervention and control\u003c/h2\u003e \u003cp\u003eThe intervention assessed was intravenous administration of AT. Control groups received either standard care or a placebo.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was all-cause mortality. The secondary outcomes were the Sequential Organ Failure Assessment (SOFA) score, occurrence of complications such as multiple organ failure or sepsis, wound-healing time, and ventilator-free days. The wound-healing time was defined as the number of days from grafting to the point at which interstices closed and 90% of the wound re-epithelialized without further grafting.\u003c/p\u003e\n\u003ch3\u003eStudy selection\u003c/h3\u003e\n\u003cp\u003eReferences were stored, and duplicates were removed using EndNote (Thomson Reuters). Two reviewers (YI and YT) independently screened titles and abstracts of the retrieved studies using Rayyan software to identify studies meeting the inclusion criteria. Disagreements on study eligibility were resolved by a third reviewer (MH).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eData extraction\u003c/h2\u003e \u003cp\u003eA standardized form was used for data extraction, covering the study setting, population details, participant characteristics, intervention and control specifics, methodology, outcomes, and bias-risk assessments. Data were independently extracted by two reviewers (YI and YT), with discrepancies resolved by a third reviewer (MH).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eRisk-of-bias assessment\u003c/h2\u003e \u003cp\u003eTwo reviewers (YI and YT) independently evaluated the risk of bias and quality of each study, with disagreements resolved by a third reviewer (MH). The revised Cochrane RoB2 tool was used for RCTs, assessing factors such as random sequence generation, allocation concealment, and outcome reporting [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. For observational studies, the ROBINS-I tool was applied [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData summary and synthesis\u003c/h2\u003e \u003cp\u003eA meta-analysis was performed when data from multiple trials were available, following the Cochrane Handbook for Systematic Reviews guidelines. Binary outcomes are reported as risk or odds ratios with 95% confidence intervals, while continuous outcomes, such as intensive care unit stay duration, are reported as mean difference with 95% confidence interval [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. All statistical analyses, including the assessment of risk of bias within and/or across studies, were performed using Review Manager, Version 5.4. (The Cochrane Collaboration 2019, The Nordic Cochrane Centre) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The level of statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eHeterogeneity assessment\u003c/h2\u003e \u003cp\u003eStatistical heterogeneity was evaluated using the Mantel\u0026ndash;Haenszel χ\u003csup\u003e2\u003c/sup\u003e test and I\u003csup\u003e2\u003c/sup\u003e statistic (where I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50% indicated significant heterogeneity) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Clinical heterogeneity was considered when deciding whether to perform quantitative synthesis or sensitivity analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eStrength of evidence\u003c/h2\u003e \u003cp\u003eTwo reviewers (YI and YT) assessed the evidence strength for each outcome using the GRADE approach, categorizing evidence quality as high, moderate, low, or very low [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003eAfter removing duplicates, a total of 631 records were identified through the literature search. Of these, nine full-text articles were reviewed for eligibility, and two RCTs, along with one observational study, were included in the qualitative synthesis (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e for the PRISMA flowchart) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Insert Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e about here Two RCTs by Kowal-Vern et al. (2000 and 2001) were included based on different reported outcomes. Owing to the potential overlap in patient outcomes, these RCTs were treated as a single study in the review. Only the 2001 study reported mortality outcomes and was therefore included in the meta-analysis. The 2000 study was used for qualitative synthesis in the outcome of time to wound-healing (Additional Files). The observational study, in which a Japanese national database and propensity score matching were utilized, provided further insights. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003e(\u003c/b\u003eCharacteristics of the included studies) summarizes the characteristics of all included studies. (Insert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e about here) In the RCTs, the mean TBSA in both groups exceeded 40%, and AT administration was initiated within 3 days of the burn. Although the TBSA was unavailable in the observational study, the burn index was approximately 40. The secondary outcomes were analyzed in the RCTs and observational study, but none of the outcomes overlapped among the studies. Therefore, we did not create a forest plot for these.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"13\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst author\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStudy type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRegion\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIntervention\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eExperimental group\u003c/p\u003e \u003cp\u003e(Patients number)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003cp\u003e(Patients number)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAge Mean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSeverity of burn injury\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eInhalational injury, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eAT administration dose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eInitiation and duration of AT administration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003ePrimary outcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKowal-Vern A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOpen pilot study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAT 4 (21) \u003c/p\u003e \u003cp\u003eControl 30 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTBSA(%) \u003c/p\u003e \u003cp\u003eAT 40\u0026thinsp;\u0026plusmn;\u0026thinsp;18 \u003c/p\u003e \u003cp\u003eControl45\u0026thinsp;\u0026plusmn;\u0026thinsp;21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAT 4 (50%)\u003c/p\u003e \u003cp\u003eControl 2 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e{175-baseline AT level} x body weight (kg)/1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003estarted within 24 hours after the burn injury continued every 8 hours for 72 hours for a total of 9 infusions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCoagulation laboratory tests\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKowal-Vern A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOpen pilot study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUSA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAT 44 (20) \u003c/p\u003e \u003cp\u003eControl 43 (14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTBSA(%)\u003c/p\u003e \u003cp\u003eAT 42\u0026thinsp;\u0026plusmn;\u0026thinsp;17 \u003c/p\u003e \u003cp\u003eControl 44\u0026thinsp;\u0026plusmn;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAT 4 (44%)\u003c/p\u003e \u003cp\u003eControl 12 (52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e{175-baseline AT level} x body weight (kg)/1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003estarted within 24 hours after the burn injury continued every 8 hours for 72 hours for a total of 9 infusions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eMortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLavrentieva A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGreece\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAT 37.1 (13.6) \u003c/p\u003e \u003cp\u003eControl 44.1 (21.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTBSA(%) \u003c/p\u003e \u003cp\u003eAT 43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;21.4 \u003c/p\u003e \u003cp\u003eControl 44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;22.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAT 4 (26.6%)\u003c/p\u003e \u003cp\u003eControl 5 (31.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e{150-baseline AT level} x body weight (kg)/1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003estarted from the first post-burn day continued for the next three consecutive days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e28day mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTagami T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003epropensity score-matched analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAT61.6(21.8) \u003c/p\u003e \u003cp\u003eControl 63.6(21.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBurn Index AT37.1(22.1) \u003c/p\u003e \u003cp\u003eControl 38.5 (23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAT 1 (1%) \u003c/p\u003e \u003cp\u003eControl 1(1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e28day mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"13\" nameend=\"c13\" namest=\"c1\"\u003e \u003cp\u003eAntithrombin; AT, Total burn surface area; TBSA, Randomized clinical trial; RCT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003ePrimary outcome\u003c/h2\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003eOverall mortality\u003c/h2\u003e \u003cp\u003eFor two RCTs, AT had no significant effect on overall mortality (see Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). With moderate bias risks, limited event numbers, and confidence intervals spanning 1, the certainty of this evidence was determined to be very low.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eTwenty-eight-day mortality among patients with overt DIC\u003c/h2\u003e \u003cp\u003eA subgroup analysis based on overt DIC criteria revealed that AT administration significantly reduced 28-day mortality rate in one RCT (see Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Although the event number remained below the optimal information size, the evidence certainty was high.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eTwenty-eight-day mortality (observational study)\u003c/h2\u003e \u003cp\u003eData from the observational study indicated a significant reduction in 28-day mortality rate with AT administration (see Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The certainty of this evidence was deemed moderate, given the limited event number. Insert Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e2\u003c/span\u003e about here\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eSecondary outcomes\u003c/h2\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eVentilator-free days\u003c/h2\u003e \u003cp\u003eThe number of ventilator-free days was assessed only in the observational study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In that study, AT administration significantly increased the number of ventilator-free days (mean difference: 3.8, 95% confidence interval: 0.29\u0026ndash;7.31).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eThrombotic events\u003c/h2\u003e \u003cp\u003eThe rate of thrombotic events were also analyzed only in the observational study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In that study, AT did not significantly affect thrombotic event rates (odds ratio: 0.33, 95% CI: 0.01\u0026ndash;8.20)..\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eWound-healing time\u003c/h2\u003e \u003cp\u003eAccording to the observational study, AT significantly reduced wound-healing time in several regions of the body, including the head and neck, back, and hands [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, AT showed no effect on wound-healing times in other areas, such as the chest, upper extremities, and lower extremities.\u003c/p\u003e \u003cp\u003eOwing to the limited number of RCTs and the use of propensity score matching in the observational study, sensitivity analyses were not performed. Additionally, outcomes such as the SOFA score and complications were not consistently reported across studies.\u003c/p\u003e \u003cp\u003eThe risk-of-bias assessment is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and all the meta-analysis results are summarized in Table\u0026nbsp;2 (Summary of findings: Antithrombin versus placebo for burn injury). Insert Table\u0026nbsp;2, and Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003e about here\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the RCTs included in this systematic review and meta-analysis, AT had no effect on overall mortality. However, AT significantly reduced the 28-day mortality rate in the overt-DIC subgroup in one RCT and the observational study. To our knowledge, this is the first comprehensive systematic review and meta-analysis on the effectiveness of AT administration for severe burns. However, as for the secondary outcomes, we could synthesize the data.\u003c/p\u003e \u003cp\u003eAlthough AT administration did not reduce the overall mortality among patients with severe burns, it did in the subgroup of patients with overt DIC, which is induced by systemic activation of coagulation in patients with severe burns. This finding suggests that AT administration may have survival benefits in this patient population, similar to the effects of anticoagulation therapy among patients with sepsis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In the early post-burn period, activation of coagulation induces an elevation in the proportion of thrombin/AT complexes and a decrease in the level of AT in the blood [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Thus, activation of coagulation in patients with severe burns is the main causative factor for overt DIC, explaining why AT administration may be advantageous in patients with burns and overt DIC.\u003c/p\u003e \u003cp\u003eAlthough effective data synthesis was not achieved, the wound-healing time was shortened in the AT group in one RCT. One possible pathophysiological explanation is that AT may contribute to salvaging the zone of stasis, potentially preventing it from progressing to necrosis by decreasing the number of microthrombi and increasing the vascularity of the grafting bed, thus facilitating better graft placement [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, additional evidence is required to draw definitive conclusions.\u003c/p\u003e \u003cp\u003eBurns and inhalation injuries lead to intrapulmonary activation of coagulation [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Such activation increases the risk of thrombosis and impairs normal fibrinolysis, further complicating the respiratory function of patients with severe burns. Thus, AT administration may reduce the number of ventilator days in such patients by mitigating coagulation disturbances and improving pulmonary outcomes. Further research is warranted to elucidate the mechanisms through which AT exerts its protective effects on the pulmonary system in patients with severe burns.\u003c/p\u003e \u003cp\u003eThe rate of thrombotic events did not decrease significantly in patients who received AT in our analyses. However, the control groups did not experience a sufficient number of events for a conclusive comparison. Although hemorrhagic events were not investigated in each study, Kowal-Vern et al. reported that AT administration was not accompanied by significant hemorrhagic complications [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, Tagami et al. reported similar transfusion volumes between the AT and control groups in a national database study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study had several limitations. First, each outcome was analyzed in only one or two of the included trials and studies. Thus, data synthesis was limited. The included number of studies was too small to yield sufficient evidence regarding the effectiveness and safety of antithrombin-based treatment for burns. Second, we did not account for unmeasured confounding factors such as other therapies administered for burn injuries, including fluid resuscitation and surgical approaches (e.g., allograft and artificial dermis transplantation). Further well-constructed clinical trials are required to better assess these outcomes in patients with burns. Third, the observed reduction in mortality rate among patients with overt DIC was based on a subgroup analysis from a single RCT with a small cohort. Although clinically intriguing, this finding should be interpreted with caution and regarded as hypothesis-generating rather than conclusive. Finally, two studies by Kowal-Vern et al. (2000 and 2001) were included in our review. Although these studies may have involved overlapping patient populations, they reported different outcomes. Only the 2001 study, which evaluated mortality, was included in the meta-analysis. The 2000 study, which focused on coagulation parameters, was included for qualitative synthesis only to avoid double-counting in the pooled analysis.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis systematic review and meta-analysis indicate that AT administration has no observable effect on overall mortality among patients with severe burns. However, AT treatment notably decreased 28-day mortality rates in the subgroup of patients experiencing overt DIC, as demonstrated in one RCT and the observational study. Given the limited number of available studies, further research and accumulation of high-quality evidence are warranted.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eDIC,\u0026nbsp;disseminated intravascular coagulation\u003c/p\u003e\n\u003cp\u003eAT,\u0026nbsp;antithrombin\u003c/p\u003e\n\u003cp\u003eTBSA,\u0026nbsp;total burn surface area\u003c/p\u003e\n\u003cp\u003eRCT, randomized controlled trial\u003c/p\u003e\n\u003cp\u003eSOFA, Sequential Organ Failure Assessment\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics committee approval was not required, we conducted the review and meta-analysis using publicly available data without direct patient involvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Department of Emergency Medicine, Hokkaido University Hospital, Japan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMH is a guarantor and contributed to the conception of the study. The manuscript protocol was drafted by YI and revised by MH. All authors developed the search strategy performed by YI and MH. YI and YT independently extracted data from the included studies, assessed the risk of bias, and completed the data synthesis. MH arbitrated in cases of disagreement and ensured the absence of errors. All authors have approved the publication of this protocol. YI was responsible for funding acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; information\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRybarczyk MM, Schafer JM, Elm CM, Sarvepalli S, Vaswani PA, Balhara KS, Carlson LC, Jacquet GA: A systematic review of burn injuries in low- and middle-income countries: Epidemiology in the WHO-defined African Region. Afr J Emerg Med 2017, 7(1):30-37.\u003c/li\u003e\n\u003cli\u003eKowal-Vern A, Orkin BA: Antithrombin in the treatment of burn trauma. World J Crit Care Med 2016, 5(1):17-26.\u003c/li\u003e\n\u003cli\u003eGlas GJ, Levi M, Schultz MJ: Coagulopathy and its management in patients with severe burns. J Thromb Haemost 2016, 14(5):865-874.\u003c/li\u003e\n\u003cli\u003eLavrentieva A, Kontakiotis T, Bitzani M, Papaioannou-Gaki G, Parlapani A, Thomareis O, Tsotsolis N, Giala MA: Early coagulation disorders after severe burn injury: impact on mortality. Intensive Care Med 2008, 34(4):700-706.\u003c/li\u003e\n\u003cli\u003eNikolaidou E KD, Kaldoudi E et al. : Coagulation disorders and mortality in burn injury: A systematic review. Annals of Burns and Fire Disasters 2022, XXXV(June).\u003c/li\u003e\n\u003cli\u003eLavrentieva A KT, Bitzani M, Parlapani A, et al.: The efficacy of antithrombin administration in the acute phase of burn injury. Thromb Haemost 2008, 100(2): 286-290.\u003c/li\u003e\n\u003cli\u003eLonic D, Heidekrueger PI, Bosselmann T, Niclas Broer P, Gertler R, Wolfgang Martin K, Prantl L, Ninkovic M, Giunta R, Ehrl D: Is major burn injury associated with coagulopathy? The value of thrombelastometry in the detection of coagulopathy in major burn injury: A prospective observational study. Clin Hemorheol Microcirc 2020, 76(2):299-308.\u003c/li\u003e\n\u003cli\u003eJeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S: Burn injury. Nat Rev Dis Primers 2020, 6(1):11.\u003c/li\u003e\n\u003cli\u003eNiedermayr M, Schramm W, Kamolz L, Andel D, R\u0026ouml;mer W, Hoerauf K, Zimpfer M, Andel H: Antithrombin deficiency and its relationship to severe burns. Burns 2007, 33(2):173-178.\u003c/li\u003e\n\u003cli\u003eTagami T MH, Moroe Y et al.: Antithrombin use and 28-day in-hospital mortality among severe-burn patients：an observational nationwide study. Ann intensive care 2017, 7:18.\u003c/li\u003e\n\u003cli\u003eKowal-Vern A MV, Walenga JM, Gamelli RL: Antithrombin(H) concentrate infusions are safe and effective in patients with thermal injuries. Journal of Burn Care \u0026amp; Rehabilitation 2000(March/April):115-127.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, Shamseer L, Tetzlaff JM, Akl EA, Brennan SE et al: The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021, 372:n71.\u003c/li\u003e\n\u003cli\u003eSterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM et al: RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019, 366:l4898.\u003c/li\u003e\n\u003cli\u003eSterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I et al: ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016, 355:i4919.\u003c/li\u003e\n\u003cli\u003eHiggins JPT TJ CJ, Cumpston M, et al.: Cochrane Handbook for Systematic Reviews of Interventions version 6.0(updated July 2019). Cochrane. Available from www.training.org/handboo. 2019.\u003c/li\u003e\n\u003cli\u003eCopenhagen: The Nordic Cochrane Centre TCC. Review Manager (RevMan) [Computer program]. Version 5.4. 2019.\u003c/li\u003e\n\u003cli\u003eHuedo-Medina TB S-MJ, Mar\u0026iacute;n-Mart\u0026iacute;nez F, et al.: Assessing heterogeneity in meta-analysis- Q statistic or I2 index? Psychol Methods 2006, 11:193-206.\u003c/li\u003e\n\u003cli\u003eSantesso N, Glenton C, Dahm P, Garner P, Akl EA, Alper B, Brignardello-Petersen R, Carrasco-Labra A, De Beer H, Hultcrantz M et al: GRADE guidelines 26: informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol 2020, 119:126-135.\u003c/li\u003e\n\u003cli\u003eKowal-Vern A WJ, McGill V, Gamelli RL The impact of antithrombin (H) concentrate infusions on pulmonary function in the acute phase of thermal injury. Burns 2001, 27 52-60.\u003c/li\u003e\n\u003cli\u003eYamakawa K, Umemura Y, Hayakawa M, Kudo D, Sanui M, Takahashi H, Yoshikawa Y, Hamasaki T, Fujimi S, Japan Septic Disseminated Intravascular Coagulation study g: Benefit profile of anticoagulant therapy in sepsis: a nationwide multicentre registry in Japan. Crit Care 2016, 20(1):229.\u003c/li\u003e\n\u003cli\u003eHofstra JJ, Vlaar AP, Knape P, Mackie DP, Determann RM, Choi G, van der Poll T, Levi M, Schultz MJ: Pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma. J Trauma 2011, 70(6):1389-1397.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"antithrombin, disseminated intravascular coagulation, mortality, thrombosis, wound healing","lastPublishedDoi":"10.21203/rs.3.rs-6895071/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6895071/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Anticoagulation therapies may reduce the rate of mortality associated with severe burns. However, only a few high-quality randomized controlled trials have been conducted in this regard, and clinical recommendations are lacking. In this study, we aimed to evaluate the effectiveness and safety of antithrombin-based interventions for severe burns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain body of the abstract\u003c/strong\u003e: We systematically reviewed and examined randomized controlled trials and observational studies on antithrombin administration for severe burns. Control groups were administered standard therapy or a placebo. The primary outcome was in-hospital mortality. We assessed the studies using the Cochrane risk-of-bias tool and the Grading of Recommendations Assessment, Development, and Evaluation approach.\u003cstrong\u003e \u003c/strong\u003eTwo randomized controlled trials and one observational study were included. In the randomized controlled trials, antithrombin administration did not affect overall mortality (low certainty of evidence). However, antithrombin administration resulted in a significant reduction in 28-day mortality rate among patients with overt disseminated intravascular coagulation in one of these trials (high certainty of evidence). In the observational study, antithrombin administration resulted in a significant reduction in 28-day mortality rate (moderate certainty of evidence).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Although antithrombin does not affect overall mortality, it may be effective in patients with overt disseminated intravascular coagulation. Given the limited number of available studies, further research and accumulation of high-quality evidence are warranted.\u003c/p\u003e","manuscriptTitle":"Antithrombin for severe burns: a systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 07:06:30","doi":"10.21203/rs.3.rs-6895071/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"04e10f72-4c36-441a-b56f-5e6e59f861ce","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-28T00:38:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-02 07:06:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6895071","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6895071","identity":"rs-6895071","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}