HMGB-1 as a predictor of massive transfusion protocol activation in major trauma: a prospective observational study

HMGB-1 as a predictor of massive transfusion protocol activation in major trauma: a prospective observational study | 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 HMGB-1 as a predictor of massive transfusion protocol activation in major trauma: a prospective observational study Michal Frelich, Marek Bebej, Jan Pavlíček, Filip Burša, Vojtěch Vodička, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4734362/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 2 You are reading this latest preprint version Abstract Background Massive bleeding causes approximately 50% of deaths in patients with major trauma. Most patients die within 6 hours of injury, which is preventable in at least 10% of cases. For these patients, early activation of the massive transfusion protocol (MTP) is a critical survival factor. With severe trauma, high-mobility group box 1 (HMGB-1, i.e., amphoterin) is released into the blood, and its levels correlate with the development of a systemic inflammatory response, traumatic coagulopathy, and fibrinolysis. Previous work has shown that higher levels of HMGB-1 are associated with a higher use of red blood cell transfusions. We conducted a single-center, prospective, observational study to assess the value of admission HMGB-1 levels in predicting activation of MTP in the emergency department. Methods From July 11, 2019, to April 23, 2022, a total of 104 consecutive adult patients with severe trauma (injury severity score > 16) were enrolled. A blood sample was taken at admission, and HMGB-1 was measured. MTP activation in the emergency department was recorded in the study documentation. The total amount of blood products and fibrinogen administered to patients within 6 hours of admission was monitored. Results Among those patients with massive bleeding requiring MTP activation, we found significantly higher levels of HMGB-1 compared to patients without MTP activation (median [interquartile range]: 84.3 µg/L [34.2–145.9] vs. 21.1 µg/L [15.7–30.4]; p < 0.001). HMGB-1 level showed good performance in predicting MTP activation, with an area under the curve of 0.84 (95% CI 0.75–0.93) and a cut-off value of 30.55 µg/L. HMGB-1 levels correlated significantly with the number of red blood cell units (r s [95% CI] 0.46 [0.28–0.61]; p < 0.001), units of fresh frozen plasma (r s 0.46 [0.27–0.61]; p < 0.001), platelets (r s 0.48 [0.30–0.62]; p < 0.001), and fibrinogen (r s 0.48 [0.32–0.62]; p < 0.001) administered in the first 6 hours after hospital admission. Conclusions Admission HMGB-1 levels reliably predict MTP activation in the emergency department and correlate with the amount of blood products and fibrinogen administered during the first 6 hours of hemorrhagic shock resuscitation. Trial registration NCT03986736 Registration date : June 4, 2019 major trauma bleeding massive transfusion protocol HMGB-1 Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Severe trauma is the leading cause of death in patients aged 1–44 years, despite advances in prevention, resuscitation, and surgical treatment [ 1 , 2 ]. Uncontrolled bleeding is responsible for around 50% of all trauma-related deaths, and at least 10% of these deaths are potentially preventable [ 2 , 3 ]. Surgical control of bleeding and early activation of a massive transfusion protocol (MTP), along with other damage-control resuscitation (DCR) measures, improve outcomes for critically injured patients [ 4 ]. MTP is activated when massive blood loss is suspected based on the mechanism of injury, diagnosed anatomical injuries, patient physiology, and response to initial resuscitation efforts [ 5 , 6 ]. However, in clinical practice, early detection of life-threatening bleeding can be difficult in some patients. In recent years, based on retrospective studies, several predictive models have been developed to determine the risk of MT, such as the TASH (Trauma Associated Severe Hemorrhage) [ 7 ], ABC (i.e., assessment of blood consumption) [ 8 ], and ETS (i.e., emergency room transfusion score) [ 9 ]. These models incorporate vital signs, laboratory test results, and other variables to determine the likelihood of the need for a massive blood transfusion. However, they are based on the traditional definition of massive transfusion (MT), which is the need for ≥ 10 units of red blood cells (RBCs) in 24 hours [ 10 ]. This definition is retrospective and excludes patients who die before 10 units are administered or before 24 hours have elapsed (survivorship bias), thus representing less acute patients [ 11 , 12 ]. Patients with severe trauma develop a systemic inflammatory response almost immediately after injury. This response is triggered by complement and damage-associated molecular patterns (i.e., DAMPs), which are released from damaged tissue [ 13 ]. Among these molecules, high-mobility group box protein 1 (HMGB-1) is one of the most important mediators of the early phase of post-traumatic inflammation. HMBG-1 (also known as amphoterin) is a nuclear protein that acts as a DNA chaperone and is involved in the regulation of transcription, DNA replication, and a variety of other functions [ 14 , 15 ]. A previous study showed that amphoterin is released into the bloodstream within 45 minutes of severe trauma and that its levels correlate with the severity of injury, traumatic coagulopathy, and hyperfibrinolysis. In the same investigation, patients with high HMGB-1 levels had a greater blood loss and required more RBC transfusions compared to patients with low levels of the protein [ 14 ]. In the present study, we tested the hypothesis that HMGB-1 levels at admission can identify patients with severe bleeding requiring MTP activation. Rapid and correct identification of these patients is essential because without prompt treatment, most of them will die within 3–6 hours of admission [ 16 ]. Methods This study was designed as a prospective observational single-center study. Following Institutional Review Board approval (April 25, 2019; reference number:424/2019) and registration (June 4, 2019; NCT03986736), 121 consecutive patients were enrolled during the study period from July 11, 2019, to April 23, 2022. We included adults (age > 18 years) with major trauma (Injury Severity Score [ISS] > 16), admitted to the emergency department (ED) of the Level I trauma center directly from the scene. Each patient enrolled in the study signed an informed consent form. In cases in which the patient’s medical condition did not allow consent, it was obtained from two physicians not involved in the study; however, efforts were made to obtain consent from these patients retrospectively. Patients with injuries incompatible with life, an expected survival of < 24 hours, or circulatory arrest at the scene or during transport were excluded from the study. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (i.e., STROBE) guidelines [ 17 ] and closely followed the principles of the Declaration of Helsinki. Outcome measures The objectives of the study were predefined. The main objective was to determine whether HMGB-1 levels at admission could identify patients with life-threatening bleeding requiring MTP activation in the ED. Another aim of the study was to analyze the relationship between HMGB-1 and the use of blood products and fibrinogen in the first 6 hours after hospital admission. Blood sampling During the first 10 minutes after admission, 2.6 ml of blood was drawn into a tube (Monovette EDTA K3E 2.6 ml; Sarstedt, Germany) with EDTA as an anticoagulant agent. The sample was centrifuged (2500 g for 10 minutes at 4°C) in a central laboratory, snap-frozen in liquid nitrogen at -80°C, and stored. Samples were analyzed by a single investigator blinded to patient data and using the HMGB-1 enzyme-linked immunosorbent assay (ELISA; Biovendor LM; Brno, Czech Republic). All study blood samples were analyzed with two of these kits, and measurements were taken according to the manufacturer’s instructions. The analysis showed satisfactory intra- and inter-assay stability, with coefficients of variation < 15% [ 18 ]. Data collection We prospectively recorded baseline demographic data, vital signs, mechanism of injury, and length of time spent in pre-hospital care. The severity of the injury was assessed according to the ISS [ 19 ]. When the research sample was drawn, arterial blood also was taken for basic laboratory tests as part of standard management of a patient with severe trauma. The presence of tissue hypoperfusion (shock) was determined based on the methodology of a previous study using an admission base deficit > 6 mmol/L [ 14 ]. To identify trauma-induced coagulopathy (TIC), we used a conventional coagulation test with an international normalized ratio (INR) > 1.5, representing values associated with worse outcomes in severely injured patients [ 20 ]. MTP consisted of four units of RBCs, fresh frozen plasma (FFP), and platelets (1:1:1 ratio) and was immediately available in the emergency room. Activation of the MTP was entirely at the discretion of the attending physician, who was not part of the research team, and was based on the patient’s clinical condition and estimated blood loss. The administration of MTP was subsequently recorded in the trial documentation. In addition, a TASH score was calculated (using the mdcalc tool, available at www.mdcalc.com ) to facilitate the decision to activate MTP as soon as all variables were known [ 7 ]. Patients were followed for 6 hours from admission to the ED. During this time, it was possible for early TIC to develop, characterized by an absence of hemostasis, which can lead to uncontrollable bleeding [ 21 ]. Total RBC, FFP, platelet, and fibrinogen requirements were recorded in the study protocol by an independent staff member using a case report form. HMGB-1 levels were measured after study recruitment to ensure complete blinding of the entire trauma team. The management of patients with severe trauma followed the principles of DCR. Patients were transferred from the ED to the operating room for damage control surgery or directly to the intensive care unit. Statistical analysis Data were analyzed using R (version 4.3.1, www.r-project.org ). Categorical data are presented as absolute and relative frequencies (%). Numerical variables are expressed as medians with minimums–maximums or interquartile ranges [IQRs]. Differences between groups were assessed with the Mann–Whitney U test, the chi-squared test of independence for contingency tables, or the Fisher’s exact test, as appropriate. Analysis of diagnostic accuracy was performed using the area under the receiver operating characteristic curve (AUC), with all parameters presented with 95% confidence intervals (95% CIs). Spearman’s correlation coefficient (r s ) was used for correlation analysis. The significance level was set to 0.05. Results The study included 104 consecutive patients with severe trauma admitted during a 33-month period. The study flowchart is shown in Fig. 1 . The duration of the study was unexpectedly extended because of the COVID-19 pandemic, which significantly reduced the number of patients with severe trauma admitted to the study center. The characteristics of the patients and their injuries are shown in Table 1 . The cohort was predominantly middle-aged men, with a median age of 41 years (IQR: 31–57 years). At admission to the ED, 33 patients were in hemorrhagic shock, and 10 had laboratory evidence of TIC. Four patients died within the first 6 hours of admission, three because of uncontrolled hemorrhage and one who developed malignant cerebral edema confirmed by CT scan (with subsequent transition to palliative care). These patients were not excluded from the study because their blood samples were taken, and in each case, death occurred in the last hour of study observation after all monitored parameters were already recorded. Table 1 Characteristics of the patients and their injuries Characteristics Whole study cohort (N = 104) Demographic data Male gender 77 (74.0) Age, years Physiological variables at admission 41 [31–57] Heart rate > 100 beats/min Systolic blood pressure 6 mmol/L Lactate > 4.4 mmol/L Hemoglobin, g/L Platelet count, ×10 9 /L Fibrinogen 1.5 Injury characteristics ISS Severe head injury (AIS > 3) Blunt trauma Motor vehicle accident Motorbike Fall Pedestrian, bicycle Other Penetrating injury Stab wounds Gunshot wounds TASH Length of prehospital care, min 41 (39.4) 35 (33.7) 33 (31.7) 35 (33.7) 124 [107–138] 224 [193–266] 33 (31.7) 10 (9.6) 32 [25–41] 19 (18.3) 100 (96.2) 30 (30.0) 12 (12.0) 34 (34.0) 22 (22.0) 2 (2.0) 4 (3.8) 3 (75.0) 1 (25.0) 5 [ 4 – 10 ] 41 [35–47] Values are medians with interquartile ranges or absolute and relative frequencies (%). AIS – Abbreviated Injury Scale, INR – international normalized ratio, ISS – Injury Severity Score, TASH – Trauma Associated Severe Hemorrhage MTP was activated in 31 patients with major trauma hemorrhage. In these patients, the median HMGB-1 level at admission was significantly higher than levels among patients without MTP activation (median [IQR]: 84.3 µg/L [34.2–145.9] vs. 21.1 µg/L [15.7–30.4]; p < 0.001; Fig. 2 ). Table 2 gives a comparison of patient data between the MTP and non-MTP groups. HMGB-1 level showed good performance in predicting MTP activation (AUC 0.84; Fig. 3 ). In our cohort, HMBG-1 had 80.6% sensitivity and 75.3% specificity for predicting the need for MTP, with a cut-off value of 30.55 µg/L. Further measures of the diagnostic accuracy of HMGB-1 for predicting MTP are shown in Table 3 . Table 2 Comparison of the MTP and non-MTP groups Characteristics MTP group (n = 31) Non-MTP group (n = 73) p Male gender Age, years Heart rate > 100 beats/min Systolic blood pressure 6 mmol/L Lactate > 4.4 mmol/L Hemoglobin, g/L Platelet count, ×10 9 /L Fibrinogen 1.5 ISS Severe head injury (AIS > 3) TASH score Length of prehospital care, min HMGB-1, µg/L SOFA (24 hour) Number of RBC transfusions Number of FFP transfusions Number of platelet transfusions Dose of fibrinogen, g 24 (77.5) 38 [30–48] 24 (77.4) 21 (67.7) 19 (61.3) 19 (61.3) 113 [99–127] 205 [173–249] 18 (58.1) 10 (32.3) 41 [34–50] 5 (16.1) 11 [ 7 – 16 ] 39 [34–47] 84.3 [34.2–145.9] 9 [ 8 – 11 ] 7 [ 4 – 10 ] 4 [ 4 – 7 ] 1 [ 1 – 2 ] 5 [ 4 – 8 ] 53 (72.6) 46 [34–60] 17 (23.3) 14 (19.2) 14 (19.2) 16 (21.9) 127 [114–141] 236 [198–285] 15 (20.5) 0 (0.0) 27 [22–34] 14 (19.2) 5 [ 2 – 5 ] 41 [37–46] 21.1 [15.7–30.4] 7 [ 6 – 9 ] 1 [0–2] 0 [0–1] 0 [0–0] 2 [0–4] 0.789 0.138 < 0.001 < 0.001 < 0.001 < 0.001 0.001 0.109 < 0.001 < 0.001 < 0.001 0.789 < 0.001 0.352 < 0.001 0.001 < 0.001 < 0.001 < 0.001 < 0.001 Values are medians with interquartile ranges or absolute and relative frequencies (%). The p value was obtained with the Mann–Whitney test, the chi-square test of independence for contingency tables, or the Fisher’s exact test. AIS – Abbreviated Injury Scale, FFP – fresh frozen plasma, HMGB-1 – high-mobility group box 1, INR – international normalized ratio, ISS – Injury Severity Score, MTP – massive transfusion protocol, RBC – red blood cell, SOFA – Sequential Organ Failure Assessment, TASH – Trauma Associated Severe Hemorrhage Table 3 Measures of diagnostic accuracy of HMGB-1 for prediction of MTP activation using the optimal cut-off estimated from the area under the receiver operating characteristic curve Measure of diagnostic accuracy [95% CI] Area under the curve Optimal cut-off, µg/L 0.84 [0.75–0.93] 30.55 Sensitivity, % Specificity, % Positive predictive value, % Negative predictive value, % Positive likelihood ratio Negative likelihood ratio 80.6 [62.5–92.5] 75.3 [63.9–84.5] 58.1 [42.1–73.0] 90.2 [79.8–96.3] 3.27 [2.11–5.06] 0.26 [0.12–0.53] HMGB-1 – high-mobility group box 1, MTP – massive transfusion protocol HMGB-1 levels correlated significantly with RBC units (r s [95% CI] 0.46 [0.28–0.61], p < 0.001), FFP units (0.46 [0.27–0.61], p < 0.001), platelets (0.48 [0.30–0.62], p < 0.001), and fibrinogen (0.48 [0.32–0.62], p < 0.001) administered in the first 6 hours after hospital admission. We found no significant correlation between HMGB-1 level at admission and TASH score (r s [95% CI] 0.07 [-0.31 to 0.42], p = 0.708). Among patients requiring MTP activation, 83.9% (26 of 31) had a TASH score < 18, indicating a predicted < 50% risk for needing MTP (Fig. 4 ). Discussion In this prospective observational study, we found that patients with major bleeding requiring MTP activation had higher HMGB-1 levels at hospital admission compared with patients who did not require MTP activation. In addition, patients with high HMGB-1 levels had higher use of blood transfusion products and fibrinogen in the first 6 hours after admission compared to patients with low HMGB-1 levels. We propose two possible explanations for these findings. First, HMGB-1 level correlates with the extent of injuries [ 14 , 22 ] and may be an indirect indicator of risk for major blood loss. Second, the release of HMBG-1 from damaged tissues into the bloodstream is associated with the development of early TIC [ 23 ], leading to uncontrolled bleeding [ 21 ]. Although the role of HMGB-1 in TIC is not fully understood, a negative effect of this protein on primary hemostasis has recently been reported [ 23 ]. Platelets are essential for a rapid hemostatic response, and platelet dysfunction early after injury leads to increased blood loss [ 24 , 25 ]. Although local release of HMGB-1 is important for proper platelet function [ 26 ], its systemic release from trauma-injured tissues leads to excessive platelet activation, a decrease in platelet number, and decreased platelet aggregation. In their work with a mouse model, Sloos et al. found that monoclonal antibody inhibition of HMGB-1 activity led to a significant improvement in clot formation and clot strength, as measured by rotational thromboelastometry [ 23 ]. These findings indicate an important role for HMGB-1 in the development of coagulopathy, especially given that the human HMGB-1 amino acid sequence shares 99% similarity with the murine sequence [ 22 ]. In addition, once released into the blood, HMGB-1 triggers an inflammatory response via the receptor for advanced glycation end products (i.e., RAGE) and Toll-like receptors 2 and 4 [ 27 ]. Inflammation and coagulation are highly interrelated processes that influence each other [ 21 ]. Our results are consistent with those of Cohen et al., who reported that patients receiving ≥ 2 units of RBCs had higher levels of HMGB-1 compared with patients receiving < 2 units [ 14 ]. Our results not only confirm this previous finding but also extend it by showing a positive correlation between HMGB-1 levels and the administration of FFP, platelets, and fibrinogen. Bleeding is the leading preventable cause of death in critically injured patients and is responsible for 1 million deaths worldwide each year [ 28 ]. Most of these patients die within the first 6 hours of admission, making early detection and MTP activation critical to their survival [ 16 ]. Every minute of delay in transfusion leads to a 5% increase in mortality. The decision to activate MTP is usually based on clinical assessment, decision tools, and response to treatment [ 29 ]. Our results suggest that HMGB-1 may be a reliable biomarker for identifying patients with major bleeding requiring MTP activation. An HMGB-1 level > 30.55 µg/L predicts the need for MTP with satisfactory diagnostic accuracy. Of note, we identified several patients who required MTP activation despite low HMGB-1 levels. In all of these patients, the source of the life-threatening bleeding was a lower limb semi-amputation with no significant damage to other tissues, explaining the lack of significantly increased HMGB-1 levels. These patients also were treated in prehospital care with a tourniquet, which prevented HMGB-1 release from the injured limb. We highlight that HMGB-1 identified patients needing MTP activation despite low TASH scores. This finding is not surprising because the TASH score is based on the classic definition of MT, i.e., administration of ≥ 10 RBC units over 24 hours [ 7 ]. However, because of advances in DCR, the incidence of MT defined in this way is low. Therefore, other definitions for MT, such as > 5 RBC units over 4 hours, are now increasingly used [ 11 ]. A recent Delphi study provided a new consensus definition of MT in severely injured adult patients, namely the need for > 4 units of any blood component administered within 2 hours of injury [ 30 ]. Our findings indicate that even with this new definition, HMBG-1 can be a predictor of the need for MT. ELISA is the most commonly used method for measuring HMGB-1 levels in clinical practice. The technique is time-consuming, however, requiring ~ 3 hours, and is therefore not suitable for predicting risk of massive bleeding in the ED. Measurement time can be significantly reduced by using an electrochemical immunosensor, which tracks changes in electrical impedance at the electrodes during the formation of the immunocomplex (HMGB-1 and capture antibody). In this way, HGMB-1 levels can be determined in < 20 minutes. In addition, the measurement can be accelerated by using a single impedance value obtained from a single frequency value [ 31 ]. The main strength of this study is that HMGB-1 levels were measured after patient recruitment had been completed, which completely eliminated the risk of bias associated with the trauma team. However, we acknowledge several study limitations. Given the broad variability in MTPs worldwide in terms of trigger and composition, our results may not be applicable across different systems of care for severely injured patients. The HMGB-1 cut-off for MTP activation presented here relates to patients with a prehospital care time of approximately 40 minutes; with the short half-life of HMGB-1 from the time of an injury [ 22 ], the threshold for MTP activation may be different in trauma systems with longer hospital arrival times. Finally, most of the enrolled patients suffered blunt trauma, so that these results cannot be extrapolated to patients with penetrating injuries in whom the dynamics of HMGB-1 levels may differ. Conclusion Admission HMGB-1 levels are a reliable predictor of MTP activation in the ED and correlate with amounts of blood products and fibrinogen administered during the first 6 hours of hemorrhagic shock resuscitation. Abbreviations ABC – assessment of blood consumption AIS – Abbreviated Injury Scale DCR – damage-control resuscitation ED – emergency department ELISA ­– enzyme-linked immunosorbent assay FFP – fresh frozen plasma INR – international normalized ratio ISS ­– injury severity score HMGB-1 – high-mobility group box protein 1 MT – massive transfusion MTP – massive transfusion protocol RBC – red blood cell STROBE – STrengthening the Reporting of Observational studies in Epidemiology TASH – Trauma Associated Severe Hemorrhage TIC – trauma induced coagulopathy Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of the University Hospital Ostrava on April 25, 2019, with reference number 424/2019. All patients signed a consent form for inclusion in the study. Consent was obtained from two independent physicians for patients whose medical condition did not allow their giving consent. In these cases, every effort was made to obtain consent retrospectively. Consent for publication : Patients in the study signed an informed consent form and consented to the publication of the results. Availability of data and materials The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by the Ministry of Health, Czech Republic- Conceptual Development of Research Organization (FNOs/2019). Authors’ contributions MF, MB, JP, FB, and PS contributed to all aspects of this manuscript, including study conception and design, analysis, interpretation of data, and drafting of the article. VV and OJ contributed to data acquisition and data curation. AK contributed to study design and data analysis. ZŠ analyzed the blood samples. All authors read and approved the final manuscript. 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Current Opinion in Hematology. 2017 Nov;24(6):529–35. doi:10.1097/moh.0000000000000386 Petrosoniak A, Li W, Hicks C. Just the facts: Massive hemorrhage protocol. Canadian Journal of Emergency Medicine. 2022 Dec 5;25(2):115–7. doi:10.1007/s43678-022-00423-9 Wong HS, Curry NS, Davenport RA, Yu L, Stanworth SJ. A Delphi Study to establish consensus on a definition of major bleeding in adult trauma. Transfusion. 2020 Sept 27;60(12):3028–38. doi:10.1111/trf.16055 Štros M, Polanská EV, Hlaváčová T, Skládal P. Progress in assays of HMGB1 levels in human plasma—the potential prognostic value in covid-19. Biomolecules. 2022 Apr 5;12(4):544. doi:10.3390/biom12040544 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-4734362","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":328076966,"identity":"8bb7c4b0-2fe9-495e-80fb-e890d3b0c3c9","order_by":0,"name":"Michal Frelich","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Michal","middleName":"","lastName":"Frelich","suffix":""},{"id":328076967,"identity":"272ebf29-8ff5-4a2c-af10-fa30f052c941","order_by":1,"name":"Marek Bebej","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Marek","middleName":"","lastName":"Bebej","suffix":""},{"id":328076969,"identity":"ceb2b69e-0bc8-43ee-882d-e07f55e3b434","order_by":2,"name":"Jan Pavlíček","email":"","orcid":"","institution":"University Hospital Ostrava, Ostrava University","correspondingAuthor":false,"prefix":"","firstName":"Jan","middleName":"","lastName":"Pavlíček","suffix":""},{"id":328076971,"identity":"c7bf9219-957e-4b52-8af3-aaaaead16553","order_by":3,"name":"Filip Burša","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Filip","middleName":"","lastName":"Burša","suffix":""},{"id":328076972,"identity":"966464a6-943f-4542-a7dc-1fe30812af81","order_by":4,"name":"Vojtěch Vodička","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Vojtěch","middleName":"","lastName":"Vodička","suffix":""},{"id":328076973,"identity":"a04d7c8a-ac97-4881-9c09-89f665c8ccc1","order_by":5,"name":"Zdeněk Švagera","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Zdeněk","middleName":"","lastName":"Švagera","suffix":""},{"id":328076974,"identity":"040ca226-d896-44c7-bf56-4ade4a83e6ec","order_by":6,"name":"Adéla Kondé","email":"","orcid":"","institution":"VSB – Technical University of Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Adéla","middleName":"","lastName":"Kondé","suffix":""},{"id":328076975,"identity":"4fbbf859-900b-4f20-9801-1133eadaf55d","order_by":7,"name":"Ondřej Jor","email":"","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":false,"prefix":"","firstName":"Ondřej","middleName":"","lastName":"Jor","suffix":""},{"id":328076976,"identity":"a6c4c5fb-54de-4d3f-9689-a63f38e64565","order_by":8,"name":"Peter Sklienka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie2QMQrCQBBFJwzMNmLa3VtsCCQI4lmEgF7BQsKCYBW01VvoDRIWtBFtBQsVwd5GtBEXgyAiq6XFvmKqecz8D+Bw/DGyigCegrr/wzKWCpVKS6jfFXgo+rsSs2Fx6EAaEsPZftRd8Zgp73SxKLVMY7AAHRFSO5jMNryW5ci5RZHrhMwveZ2wEokdbVK5bhJIm7I9sKuC1Cj+WexuS/5QmtYrSCY1mscqJKb9vFRya5YkFErq0GSJxHiQcLkoetbaYlbsT6qTBkNfH0V2bnA57xXWxuTLfOLZbrwvOxwOh+MTd+qfRF1YHbLdAAAAAElFTkSuQmCC","orcid":"","institution":"University hospital Ostrava","correspondingAuthor":true,"prefix":"","firstName":"Peter","middleName":"","lastName":"Sklienka","suffix":""}],"badges":[],"createdAt":"2024-07-13 08:49:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4734362/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4734362/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62655664,"identity":"6d8e8cb5-1a1e-4d3a-95d8-0f8df99f70e9","added_by":"auto","created_at":"2024-08-17 01:42:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":192648,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of the study. MTP – massive transfusion protocol.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4734362/v1/fd364738737114ec9505facc.png"},{"id":62654649,"identity":"aa2c73d8-a729-421f-9017-20ca018aa32f","added_by":"auto","created_at":"2024-08-17 01:26:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":179210,"visible":true,"origin":"","legend":"\u003cp\u003eHigh-mobility group box 1 (HMGB-1) levels in patients with versus without massive transfusion protocol (MTP) activation. Logarithmic scale used for better readability.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4734362/v1/49551d5cfb9416169b1d9bb8.png"},{"id":62655377,"identity":"514f16e5-72cf-4c6d-a42c-36cf202a64e4","added_by":"auto","created_at":"2024-08-17 01:34:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":254938,"visible":true,"origin":"","legend":"\u003cp\u003eArea under the receiver operating characteristic curve (AUC) of admission high-mobility group box 1 levels for prediction of massive transfusion protocol activation.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4734362/v1/110b28e70ebaa8fafb0b80cd.png"},{"id":62654646,"identity":"6a170d4e-6a63-425c-a8e4-a20de4206d58","added_by":"auto","created_at":"2024-08-17 01:26:23","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":239005,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelogram of high-mobility group box 1 (HMGB-1) levels and Trauma Associated Severe Hemorrhage (TASH) score in patients with massive transfusion protocol activation.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4734362/v1/5060d770ba25996f9c405802.png"},{"id":62655721,"identity":"60a7b3c2-c717-46ff-92a1-3db2bf490099","added_by":"auto","created_at":"2024-08-17 01:50:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1684302,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4734362/v1/0964d3aa-ee40-44b3-8498-49b41675d8c8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"HMGB-1 as a predictor of massive transfusion protocol activation in major trauma: a prospective observational study","fulltext":[{"header":"Background","content":"\u003cp\u003eSevere trauma is the leading cause of death in patients aged 1\u0026ndash;44 years, despite advances in prevention, resuscitation, and surgical treatment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Uncontrolled bleeding is responsible for around 50% of all trauma-related deaths, and at least 10% of these deaths are potentially preventable [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Surgical control of bleeding and early activation of a massive transfusion protocol (MTP), along with other damage-control resuscitation (DCR) measures, improve outcomes for critically injured patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. MTP is activated when massive blood loss is suspected based on the mechanism of injury, diagnosed anatomical injuries, patient physiology, and response to initial resuscitation efforts [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, in clinical practice, early detection of life-threatening bleeding can be difficult in some patients. In recent years, based on retrospective studies, several predictive models have been developed to determine the risk of MT, such as the TASH (Trauma Associated Severe Hemorrhage) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], ABC (i.e., assessment of blood consumption) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], and ETS (i.e., emergency room transfusion score) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. These models incorporate vital signs, laboratory test results, and other variables to determine the likelihood of the need for a massive blood transfusion. However, they are based on the traditional definition of massive transfusion (MT), which is the need for \u0026ge;\u0026thinsp;10 units of red blood cells (RBCs) in 24 hours [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This definition is retrospective and excludes patients who die before 10 units are administered or before 24 hours have elapsed (survivorship bias), thus representing less acute patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePatients with severe trauma develop a systemic inflammatory response almost immediately after injury. This response is triggered by complement and damage-associated molecular patterns (i.e., DAMPs), which are released from damaged tissue [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Among these molecules, high-mobility group box protein 1 (HMGB-1) is one of the most important mediators of the early phase of post-traumatic inflammation. HMBG-1 (also known as amphoterin) is a nuclear protein that acts as a DNA chaperone and is involved in the regulation of transcription, DNA replication, and a variety of other functions [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A previous study showed that amphoterin is released into the bloodstream within 45 minutes of severe trauma and that its levels correlate with the severity of injury, traumatic coagulopathy, and hyperfibrinolysis. In the same investigation, patients with high HMGB-1 levels had a greater blood loss and required more RBC transfusions compared to patients with low levels of the protein [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In the present study, we tested the hypothesis that HMGB-1 levels at admission can identify patients with severe bleeding requiring MTP activation. Rapid and correct identification of these patients is essential because without prompt treatment, most of them will die within 3\u0026ndash;6 hours of admission [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis study was designed as a prospective observational single-center study. Following Institutional Review Board approval (April 25, 2019; reference number:424/2019) and registration (June 4, 2019; NCT03986736), 121 consecutive patients were enrolled during the study period from July 11, 2019, to April 23, 2022. We included adults (age\u0026thinsp;\u0026gt;\u0026thinsp;18 years) with major trauma (Injury Severity Score [ISS]\u0026thinsp;\u0026gt;\u0026thinsp;16), admitted to the emergency department (ED) of the Level I trauma center directly from the scene. Each patient enrolled in the study signed an informed consent form. In cases in which the patient\u0026rsquo;s medical condition did not allow consent, it was obtained from two physicians not involved in the study; however, efforts were made to obtain consent from these patients retrospectively. Patients with injuries incompatible with life, an expected survival of \u0026lt;\u0026thinsp;24 hours, or circulatory arrest at the scene or during transport were excluded from the study. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (i.e., STROBE) guidelines [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e] and closely followed the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eOutcome measures\u003c/p\u003e\n\u003cp\u003eThe objectives of the study were predefined. The main objective was to determine whether HMGB-1 levels at admission could identify patients with life-threatening bleeding requiring MTP activation in the ED. Another aim of the study was to analyze the relationship between HMGB-1 and the use of blood products and fibrinogen in the first 6 hours after hospital admission.\u003c/p\u003e\n\u003cp\u003eBlood sampling\u003c/p\u003e\n\u003cp\u003eDuring the first 10 minutes after admission, 2.6 ml of blood was drawn into a tube (Monovette EDTA K3E 2.6 ml; Sarstedt, Germany) with EDTA as an anticoagulant agent. The sample was centrifuged (2500 g for 10 minutes at 4\u0026deg;C) in a central laboratory, snap-frozen in liquid nitrogen at -80\u0026deg;C, and stored. Samples were analyzed by a single investigator blinded to patient data and using the HMGB-1 enzyme-linked immunosorbent assay (ELISA; Biovendor LM; Brno, Czech Republic). All study blood samples were analyzed with two of these kits, and measurements were taken according to the manufacturer\u0026rsquo;s instructions. The analysis showed satisfactory intra- and inter-assay stability, with coefficients of variation\u0026thinsp;\u0026lt;\u0026thinsp;15% [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eData collection\u003c/p\u003e\n\u003cp\u003eWe prospectively recorded baseline demographic data, vital signs, mechanism of injury, and length of time spent in pre-hospital care. The severity of the injury was assessed according to the ISS [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. When the research sample was drawn, arterial blood also was taken for basic laboratory tests as part of standard management of a patient with severe trauma. The presence of tissue hypoperfusion (shock) was determined based on the methodology of a previous study using an admission base deficit\u0026thinsp;\u0026gt;\u0026thinsp;6 mmol/L [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. To identify trauma-induced coagulopathy (TIC), we used a conventional coagulation test with an international normalized ratio (INR)\u0026thinsp;\u0026gt;\u0026thinsp;1.5, representing values associated with worse outcomes in severely injured patients [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eMTP consisted of four units of RBCs, fresh frozen plasma (FFP), and platelets (1:1:1 ratio) and was immediately available in the emergency room. Activation of the MTP was entirely at the discretion of the attending physician, who was not part of the research team, and was based on the patient\u0026rsquo;s clinical condition and estimated blood loss. The administration of MTP was subsequently recorded in the trial documentation. In addition, a TASH score was calculated (using the mdcalc tool, available at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.mdcalc.com\u003c/span\u003e\u003c/span\u003e) to facilitate the decision to activate MTP as soon as all variables were known [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003ePatients were followed for 6 hours from admission to the ED. During this time, it was possible for early TIC to develop, characterized by an absence of hemostasis, which can lead to uncontrollable bleeding [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Total RBC, FFP, platelet, and fibrinogen requirements were recorded in the study protocol by an independent staff member using a case report form. HMGB-1 levels were measured after study recruitment to ensure complete blinding of the entire trauma team. The management of patients with severe trauma followed the principles of DCR. Patients were transferred from the ED to the operating room for damage control surgery or directly to the intensive care unit.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eData were analyzed using R (version 4.3.1, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.r-project.org\u003c/span\u003e\u003c/span\u003e). Categorical data are presented as absolute and relative frequencies (%). Numerical variables are expressed as medians with minimums\u0026ndash;maximums or interquartile ranges [IQRs]. Differences between groups were assessed with the Mann\u0026ndash;Whitney U test, the chi-squared test of independence for contingency tables, or the Fisher\u0026rsquo;s exact test, as appropriate. Analysis of diagnostic accuracy was performed using the area under the receiver operating characteristic curve (AUC), with all parameters presented with 95% confidence intervals (95% CIs). Spearman\u0026rsquo;s correlation coefficient (r\u003csub\u003es\u003c/sub\u003e) was used for correlation analysis. The significance level was set to 0.05.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study included 104 consecutive patients with severe trauma admitted during a 33-month period. The study flowchart is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The duration of the study was unexpectedly extended because of the COVID-19 pandemic, which significantly reduced the number of patients with severe trauma admitted to the study center. The characteristics of the patients and their injuries are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The cohort was predominantly middle-aged men, with a median age of 41 years (IQR: 31\u0026ndash;57 years). At admission to the ED, 33 patients were in hemorrhagic shock, and 10 had laboratory evidence of TIC. Four patients died within the first 6 hours of admission, three because of uncontrolled hemorrhage and one who developed malignant cerebral edema confirmed by CT scan (with subsequent transition to palliative care). These patients were not excluded from the study because their blood samples were taken, and in each case, death occurred in the last hour of study observation after all monitored parameters were already recorded.\u003c/p\u003e \u003cp\u003e \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 patients and their injuries\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWhole study cohort\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;104)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic data\u003c/p\u003e \u003cp\u003eMale gender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (74.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003cp\u003ePhysiological variables at admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 [31\u0026ndash;57]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate\u0026thinsp;\u0026gt;\u0026thinsp;100 beats/min\u003c/p\u003e \u003cp\u003eSystolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;100 mmHg\u003c/p\u003e \u003cp\u003eBase deficit\u0026thinsp;\u0026gt;\u0026thinsp;6 mmol/L\u003c/p\u003e \u003cp\u003eLactate\u0026thinsp;\u0026gt;\u0026thinsp;4.4 mmol/L\u003c/p\u003e \u003cp\u003eHemoglobin, g/L\u003c/p\u003e \u003cp\u003ePlatelet count, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003cp\u003eFibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;2 g/L\u003c/p\u003e \u003cp\u003eINR\u0026thinsp;\u0026gt;\u0026thinsp;1.5\u003c/p\u003e \u003cp\u003eInjury characteristics\u003c/p\u003e \u003cp\u003eISS\u003c/p\u003e \u003cp\u003eSevere head injury (AIS\u0026thinsp;\u0026gt;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eBlunt trauma\u003c/p\u003e \u003cp\u003eMotor vehicle accident\u003c/p\u003e \u003cp\u003eMotorbike\u003c/p\u003e \u003cp\u003eFall\u003c/p\u003e \u003cp\u003ePedestrian, bicycle\u003c/p\u003e \u003cp\u003eOther\u003c/p\u003e \u003cp\u003ePenetrating injury\u003c/p\u003e \u003cp\u003eStab wounds\u003c/p\u003e \u003cp\u003eGunshot wounds\u003c/p\u003e \u003cp\u003eTASH\u003c/p\u003e \u003cp\u003eLength of prehospital care, min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (39.4)\u003c/p\u003e \u003cp\u003e35 (33.7)\u003c/p\u003e \u003cp\u003e33 (31.7)\u003c/p\u003e \u003cp\u003e35 (33.7)\u003c/p\u003e \u003cp\u003e124 [107\u0026ndash;138]\u003c/p\u003e \u003cp\u003e224 [193\u0026ndash;266]\u003c/p\u003e \u003cp\u003e33 (31.7)\u003c/p\u003e \u003cp\u003e10 (9.6)\u003c/p\u003e \u003cp\u003e32 [25\u0026ndash;41]\u003c/p\u003e \u003cp\u003e19 (18.3)\u003c/p\u003e \u003cp\u003e100 (96.2)\u003c/p\u003e \u003cp\u003e30 (30.0)\u003c/p\u003e \u003cp\u003e12 (12.0)\u003c/p\u003e \u003cp\u003e34 (34.0)\u003c/p\u003e \u003cp\u003e22 (22.0)\u003c/p\u003e \u003cp\u003e2 (2.0)\u003c/p\u003e \u003cp\u003e4 (3.8)\u003c/p\u003e \u003cp\u003e3 (75.0)\u003c/p\u003e \u003cp\u003e1 (25.0)\u003c/p\u003e \u003cp\u003e5 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e41 [35\u0026ndash;47]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eValues are medians with interquartile ranges or absolute and relative frequencies (%). AIS \u0026ndash; Abbreviated Injury Scale, INR \u0026ndash; international normalized ratio, ISS \u0026ndash; Injury Severity Score, TASH \u0026ndash; Trauma Associated Severe Hemorrhage\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMTP was activated in 31 patients with major trauma hemorrhage. In these patients, the median HMGB-1 level at admission was significantly higher than levels among patients without MTP activation (median [IQR]: 84.3 \u0026micro;g/L [34.2\u0026ndash;145.9] vs. 21.1 \u0026micro;g/L [15.7\u0026ndash;30.4]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e gives a comparison of patient data between the MTP and non-MTP groups. HMGB-1 level showed good performance in predicting MTP activation (AUC 0.84; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In our cohort, HMBG-1 had 80.6% sensitivity and 75.3% specificity for predicting the need for MTP, with a cut-off value of 30.55 \u0026micro;g/L. Further measures of the diagnostic accuracy of HMGB-1 for predicting MTP are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the MTP and non-MTP groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMTP group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-MTP group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;73)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender\u003c/p\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003cp\u003eHeart rate\u0026thinsp;\u0026gt;\u0026thinsp;100 beats/min\u003c/p\u003e \u003cp\u003eSystolic blood pressure\u0026thinsp;\u0026lt;\u0026thinsp;100 mmHg\u003c/p\u003e \u003cp\u003eBase deficit\u0026thinsp;\u0026gt;\u0026thinsp;6 mmol/L\u003c/p\u003e \u003cp\u003eLactate\u0026thinsp;\u0026gt;\u0026thinsp;4.4 mmol/L\u003c/p\u003e \u003cp\u003eHemoglobin, g/L\u003c/p\u003e \u003cp\u003ePlatelet count, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003cp\u003eFibrinogen\u0026thinsp;\u0026lt;\u0026thinsp;2 g/L\u003c/p\u003e \u003cp\u003eINR\u0026thinsp;\u0026gt;\u0026thinsp;1.5\u003c/p\u003e \u003cp\u003eISS\u003c/p\u003e \u003cp\u003eSevere head injury (AIS\u0026thinsp;\u0026gt;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eTASH score\u003c/p\u003e \u003cp\u003eLength of prehospital care, min\u003c/p\u003e \u003cp\u003eHMGB-1, \u0026micro;g/L\u003c/p\u003e \u003cp\u003eSOFA (24 hour)\u003c/p\u003e \u003cp\u003eNumber of RBC transfusions\u003c/p\u003e \u003cp\u003eNumber of FFP transfusions\u003c/p\u003e \u003cp\u003eNumber of platelet transfusions\u003c/p\u003e \u003cp\u003eDose of fibrinogen, g\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (77.5)\u003c/p\u003e \u003cp\u003e38 [30\u0026ndash;48]\u003c/p\u003e \u003cp\u003e24 (77.4)\u003c/p\u003e \u003cp\u003e21 (67.7)\u003c/p\u003e \u003cp\u003e19 (61.3)\u003c/p\u003e \u003cp\u003e19 (61.3)\u003c/p\u003e \u003cp\u003e113 [99\u0026ndash;127]\u003c/p\u003e \u003cp\u003e205 [173\u0026ndash;249]\u003c/p\u003e \u003cp\u003e18 (58.1)\u003c/p\u003e \u003cp\u003e10 (32.3)\u003c/p\u003e \u003cp\u003e41 [34\u0026ndash;50]\u003c/p\u003e \u003cp\u003e5 (16.1)\u003c/p\u003e \u003cp\u003e11 [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e39 [34\u0026ndash;47]\u003c/p\u003e \u003cp\u003e84.3 [34.2\u0026ndash;145.9]\u003c/p\u003e \u003cp\u003e9 [\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e7 [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e4 [\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e1 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e5 [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (72.6)\u003c/p\u003e \u003cp\u003e46 [34\u0026ndash;60]\u003c/p\u003e \u003cp\u003e17 (23.3)\u003c/p\u003e \u003cp\u003e14 (19.2)\u003c/p\u003e \u003cp\u003e14 (19.2)\u003c/p\u003e \u003cp\u003e16 (21.9)\u003c/p\u003e \u003cp\u003e127 [114\u0026ndash;141]\u003c/p\u003e \u003cp\u003e236 [198\u0026ndash;285]\u003c/p\u003e \u003cp\u003e15 (20.5)\u003c/p\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003cp\u003e27 [22\u0026ndash;34]\u003c/p\u003e \u003cp\u003e14 (19.2)\u003c/p\u003e \u003cp\u003e5 [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e41 [37\u0026ndash;46]\u003c/p\u003e \u003cp\u003e21.1 [15.7\u0026ndash;30.4]\u003c/p\u003e \u003cp\u003e7 [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003e1 [0\u0026ndash;2]\u003c/p\u003e \u003cp\u003e0 [0\u0026ndash;1]\u003c/p\u003e \u003cp\u003e0 [0\u0026ndash;0]\u003c/p\u003e \u003cp\u003e2 [0\u0026ndash;4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.789\u003c/p\u003e \u003cp\u003e0.138\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.001\u003c/p\u003e \u003cp\u003e0.109\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.789\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.352\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eValues are medians with interquartile ranges or absolute and relative frequencies (%). The\u003c/em\u003e p \u003cem\u003evalue was obtained with the Mann\u0026ndash;Whitney test, the chi-square test of independence for contingency tables, or the Fisher\u0026rsquo;s exact test. AIS \u0026ndash; Abbreviated Injury Scale, FFP \u0026ndash; fresh frozen plasma, HMGB-1 \u0026ndash; high-mobility group box 1, INR \u0026ndash; international normalized ratio, ISS \u0026ndash; Injury Severity Score, MTP \u0026ndash; massive transfusion protocol, RBC \u0026ndash; red blood cell, SOFA \u0026ndash; Sequential Organ Failure Assessment, TASH \u0026ndash; Trauma Associated Severe Hemorrhage\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMeasures of diagnostic accuracy of HMGB-1 for prediction of MTP activation using the optimal cut-off estimated from the area under the receiver operating characteristic curve\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMeasure of diagnostic accuracy [95% CI]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArea under the curve\u003c/p\u003e \u003cp\u003eOptimal cut-off, \u0026micro;g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84 [0.75\u0026ndash;0.93]\u003c/p\u003e \u003cp\u003e30.55\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSensitivity, %\u003c/p\u003e \u003cp\u003eSpecificity, %\u003c/p\u003e \u003cp\u003ePositive predictive value, %\u003c/p\u003e \u003cp\u003eNegative predictive value, %\u003c/p\u003e \u003cp\u003ePositive likelihood ratio\u003c/p\u003e \u003cp\u003eNegative likelihood ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.6 [62.5\u0026ndash;92.5]\u003c/p\u003e \u003cp\u003e75.3 [63.9\u0026ndash;84.5]\u003c/p\u003e \u003cp\u003e58.1 [42.1\u0026ndash;73.0]\u003c/p\u003e \u003cp\u003e90.2 [79.8\u0026ndash;96.3]\u003c/p\u003e \u003cp\u003e3.27 [2.11\u0026ndash;5.06]\u003c/p\u003e \u003cp\u003e0.26 [0.12\u0026ndash;0.53]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eHMGB-1 \u0026ndash; high-mobility group box 1, MTP \u0026ndash; massive transfusion protocol\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHMGB-1 levels correlated significantly with RBC units (r\u003csub\u003es\u003c/sub\u003e [95% CI] 0.46 [0.28\u0026ndash;0.61], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), FFP units (0.46 [0.27\u0026ndash;0.61], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), platelets (0.48 [0.30\u0026ndash;0.62], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and fibrinogen (0.48 [0.32\u0026ndash;0.62], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) administered in the first 6 hours after hospital admission. We found no significant correlation between HMGB-1 level at admission and TASH score (r\u003csub\u003es\u003c/sub\u003e [95% CI] 0.07 [-0.31 to 0.42], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.708). Among patients requiring MTP activation, 83.9% (26 of 31) had a TASH score\u0026thinsp;\u0026lt;\u0026thinsp;18, indicating a predicted\u0026thinsp;\u0026lt;\u0026thinsp;50% risk for needing MTP (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this prospective observational study, we found that patients with major bleeding requiring MTP activation had higher HMGB-1 levels at hospital admission compared with patients who did not require MTP activation. In addition, patients with high HMGB-1 levels had higher use of blood transfusion products and fibrinogen in the first 6 hours after admission compared to patients with low HMGB-1 levels. We propose two possible explanations for these findings. First, HMGB-1 level correlates with the extent of injuries [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and may be an indirect indicator of risk for major blood loss. Second, the release of HMBG-1 from damaged tissues into the bloodstream is associated with the development of early TIC [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], leading to uncontrolled bleeding [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although the role of HMGB-1 in TIC is not fully understood, a negative effect of this protein on primary hemostasis has recently been reported [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Platelets are essential for a rapid hemostatic response, and platelet dysfunction early after injury leads to increased blood loss [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Although local release of HMGB-1 is important for proper platelet function [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], its systemic release from trauma-injured tissues leads to excessive platelet activation, a decrease in platelet number, and decreased platelet aggregation. In their work with a mouse model, Sloos et al. found that monoclonal antibody inhibition of HMGB-1 activity led to a significant improvement in clot formation and clot strength, as measured by rotational thromboelastometry [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. These findings indicate an important role for HMGB-1 in the development of coagulopathy, especially given that the human HMGB-1 amino acid sequence shares 99% similarity with the murine sequence [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In addition, once released into the blood, HMGB-1 triggers an inflammatory response via the receptor for advanced glycation end products (i.e., RAGE) and Toll-like receptors 2 and 4 [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Inflammation and coagulation are highly interrelated processes that influence each other [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur results are consistent with those of Cohen et al., who reported that patients receiving\u0026thinsp;\u0026ge;\u0026thinsp;2 units of RBCs had higher levels of HMGB-1 compared with patients receiving\u0026thinsp;\u0026lt;\u0026thinsp;2 units [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Our results not only confirm this previous finding but also extend it by showing a positive correlation between HMGB-1 levels and the administration of FFP, platelets, and fibrinogen. Bleeding is the leading preventable cause of death in critically injured patients and is responsible for 1\u0026nbsp;million deaths worldwide each year [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Most of these patients die within the first 6 hours of admission, making early detection and MTP activation critical to their survival [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Every minute of delay in transfusion leads to a 5% increase in mortality. The decision to activate MTP is usually based on clinical assessment, decision tools, and response to treatment [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Our results suggest that HMGB-1 may be a reliable biomarker for identifying patients with major bleeding requiring MTP activation. An HMGB-1 level\u0026thinsp;\u0026gt;\u0026thinsp;30.55 \u0026micro;g/L predicts the need for MTP with satisfactory diagnostic accuracy.\u003c/p\u003e \u003cp\u003eOf note, we identified several patients who required MTP activation despite low HMGB-1 levels. In all of these patients, the source of the life-threatening bleeding was a lower limb semi-amputation with no significant damage to other tissues, explaining the lack of significantly increased HMGB-1 levels. These patients also were treated in prehospital care with a tourniquet, which prevented HMGB-1 release from the injured limb.\u003c/p\u003e \u003cp\u003eWe highlight that HMGB-1 identified patients needing MTP activation despite low TASH scores. This finding is not surprising because the TASH score is based on the classic definition of MT, i.e., administration of \u0026ge;\u0026thinsp;10 RBC units over 24 hours [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, because of advances in DCR, the incidence of MT defined in this way is low. Therefore, other definitions for MT, such as \u0026gt;\u0026thinsp;5 RBC units over 4 hours, are now increasingly used [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A recent Delphi study provided a new consensus definition of MT in severely injured adult patients, namely the need for \u0026gt;\u0026thinsp;4 units of any blood component administered within 2 hours of injury [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Our findings indicate that even with this new definition, HMBG-1 can be a predictor of the need for MT.\u003c/p\u003e \u003cp\u003eELISA is the most commonly used method for measuring HMGB-1 levels in clinical practice. The technique is time-consuming, however, requiring\u0026thinsp;~\u0026thinsp;3 hours, and is therefore not suitable for predicting risk of massive bleeding in the ED. Measurement time can be significantly reduced by using an electrochemical immunosensor, which tracks changes in electrical impedance at the electrodes during the formation of the immunocomplex (HMGB-1 and capture antibody). In this way, HGMB-1 levels can be determined in \u0026lt;\u0026thinsp;20 minutes. In addition, the measurement can be accelerated by using a single impedance value obtained from a single frequency value [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe main strength of this study is that HMGB-1 levels were measured after patient recruitment had been completed, which completely eliminated the risk of bias associated with the trauma team. However, we acknowledge several study limitations. Given the broad variability in MTPs worldwide in terms of trigger and composition, our results may not be applicable across different systems of care for severely injured patients. The HMGB-1 cut-off for MTP activation presented here relates to patients with a prehospital care time of approximately 40 minutes; with the short half-life of HMGB-1 from the time of an injury [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], the threshold for MTP activation may be different in trauma systems with longer hospital arrival times. Finally, most of the enrolled patients suffered blunt trauma, so that these results cannot be extrapolated to patients with penetrating injuries in whom the dynamics of HMGB-1 levels may differ.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAdmission HMGB-1 levels are a reliable predictor of MTP activation in the ED and correlate with amounts of blood products and fibrinogen administered during the first 6 hours of hemorrhagic shock resuscitation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eABC \u0026ndash; assessment of blood consumption\u003c/p\u003e\n\u003cp\u003eAIS \u0026ndash; Abbreviated Injury Scale\u003c/p\u003e\n\u003cp\u003eDCR \u0026ndash; damage-control resuscitation\u003c/p\u003e\n\u003cp\u003eED \u0026ndash; emergency department\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eELISA \u0026shy;\u0026ndash; enzyme-linked immunosorbent assay\u003c/p\u003e\n\u003cp\u003eFFP \u0026ndash; fresh frozen plasma\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINR \u0026ndash; international normalized ratio\u003c/p\u003e\n\u003cp\u003eISS \u0026shy;\u0026ndash; injury severity score\u003c/p\u003e\n\u003cp\u003eHMGB-1 \u0026ndash; high-mobility group box protein 1\u003c/p\u003e\n\u003cp\u003eMT \u0026ndash; massive transfusion\u003c/p\u003e\n\u003cp\u003eMTP \u0026ndash; massive transfusion protocol\u003c/p\u003e\n\u003cp\u003eRBC \u0026ndash; red blood cell\u003c/p\u003e\n\u003cp\u003eSTROBE \u0026ndash; STrengthening the Reporting of Observational studies in Epidemiology\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTASH \u0026ndash; Trauma Associated Severe Hemorrhage\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTIC \u0026ndash; trauma induced coagulopathy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of the University Hospital Ostrava on April 25, 2019, with reference number 424/2019. All patients signed a consent form for inclusion in the study. Consent was obtained from two independent physicians for patients whose medical condition did not allow their giving consent. In these cases, every effort was made to obtain consent retrospectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Patients in the study signed an informed consent form and consented to the publication of the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\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.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Ministry of Health, Czech Republic- Conceptual Development of Research Organization (FNOs/2019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMF, MB, JP, FB, and PS contributed to all aspects of this manuscript, including study conception and design, analysis, interpretation of data, and drafting of the article. VV and OJ contributed to data acquisition and data curation. AK contributed to study design and data analysis. Z\u0026Scaron; analyzed the blood samples. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to Zuzana Mučkov\u0026aacute; for help with patient enrollment in the study and study administrative tasks.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCallcut RA, Kornblith LZ, Conroy AS, Robles AJ, Meizoso JP, Namias N, et al. The why and how our trauma patients die: A prospective multicenter western trauma association study. Journal of Trauma and Acute Care Surgery. 2019 May;86(5):864\u0026ndash;70. doi:10.1097/ta.0000000000002205\u003c/li\u003e\n\u003cli\u003eKushimoto S, Kudo D, Kawazoe Y. Acute traumatic coagulopathy and trauma-induced coagulopathy: An overview. 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Journal of Trauma: Injury, Infection \u0026amp;amp; Critical Care. 2009 Feb;66(2):346\u0026ndash;52. doi:10.1097/ta.0b013e3181961c35\u003c/li\u003e\n\u003cli\u003eRuchholtz S, Pehle B, Lewan U, Lefering R, M\u0026uuml;ller N, Oberbeck R, et al. The emergency room transfusion score (ETS): Prediction of blood transfusion requirement in initial resuscitation after severe trauma. Transfusion Medicine. 2006 Feb;16(1):49\u0026ndash;56. doi:10.1111/j.1365-3148.2006.00647.x\u003c/li\u003e\n\u003cli\u003eMaegele M, Brockamp T, Nienaber U, Probst C, Schoechl H, Goerlinger K, et al. Predictive models and algorithms for the need of transfusion including massive transfusion in severely injured patients. Transfusion Medicine and Hemotherapy. 2012;39(2):85\u0026ndash;97. doi:10.1159/000337243\u003c/li\u003e\n\u003cli\u003eLin VS, Sun E, Yau S, Abeyakoon C, Seamer G, Bhopal S, et al. Definitions of massive transfusion in adults with critical bleeding: A systematic review. 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The Journal of Trauma: Injury, Infection, and Critical Care. 1974 Mar;14(3):187\u0026ndash;96. doi:10.1097/00005373-197403000-00001 \u003c/li\u003e\n\u003cli\u003ePeltan ID, Vande Vusse LK, Maier RV, Watkins TR. An international normalized ratio\u0026ndash;based definition of acute traumatic coagulopathy is associated with mortality, venous thromboembolism, and multiple organ failure after injury. Critical Care Medicine. 2015 Jul;43(7):1429\u0026ndash;38. doi:10.1097/ccm.0000000000000981 \u003c/li\u003e\n\u003cli\u003eMoore EE, Moore HB, Kornblith LZ, Neal MD, Hoffman M, Mutch NJ, et al. Trauma-induced coagulopathy. Nature Reviews Disease Primers. 2021 Apr 29;7(1). doi:10.1038/s41572-021-00264-3 \u003c/li\u003e\n\u003cli\u003eOttestad W, Rognes IN, Pischke SE, Mollnes TE, Andersson U, Eken T. Biphasic release of the Alarmin High Mobility Group Box 1 protein early after trauma predicts poor clinical outcome. Critical Care Medicine. 2019 Aug;47(8). doi:10.1097/ccm.0000000000003800 \u003c/li\u003e\n\u003cli\u003eSloos PH, Maas MA, Meijers JCM, Nieuwland R, Roelofs JJTH, Juffermans NP, et al. Anti-high-mobility group box-1 treatment strategies improve trauma-induced coagulopathy in a mouse model of trauma and shock. British Journal of Anaesthesia. 2023 Jun;130(6):687\u0026ndash;97. doi:10.1016/j.bja.2023.01.026 \u003c/li\u003e\n\u003cli\u003eSloos PH, Vulliamy P, van \u0026rsquo;t Veer C, Gupta AS, Neal MD, Brohi K, et al. Platelet dysfunction after trauma: From mechanisms to targeted treatment. Transfusion. 2022 Jun 24;62(S1). doi:10.1111/trf.16971 \u003c/li\u003e\n\u003cli\u003eVulliamy P, Kornblith LZ, Kutcher ME, Cohen MJ, Brohi K, Neal MD. Alterations in platelet behavior after major trauma: Adaptive or maladaptive? Platelets. 2020 Jan 27;32(3):295\u0026ndash;304. doi:10.1080/09537104.2020.1718633 \u003c/li\u003e\n\u003cli\u003eVogel S, Bodenstein R, Chen Q, Feil S, Feil R, Rheinlaender J, et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. Journal of Clinical Investigation. 2015 Nov 9;125(12):4638\u0026ndash;54. doi:10.1172/jci81660\u003c/li\u003e\n\u003cli\u003eFink MP. Bench-to-bedside review: High-mobility group box 1 and critical illness. Critical Care. 2007;11(5):229. doi:10.1186/cc6088\u003c/li\u003e\n\u003cli\u003eSpinella PC, Cap AP. Prehospital hemostatic resuscitation to achieve zero preventable deaths after traumatic injury. Current Opinion in Hematology. 2017 Nov;24(6):529\u0026ndash;35. doi:10.1097/moh.0000000000000386\u003c/li\u003e\n\u003cli\u003ePetrosoniak A, Li W, Hicks C. Just the facts: Massive hemorrhage protocol. Canadian Journal of Emergency Medicine. 2022 Dec 5;25(2):115\u0026ndash;7. doi:10.1007/s43678-022-00423-9\u003c/li\u003e\n\u003cli\u003eWong HS, Curry NS, Davenport RA, Yu L, Stanworth SJ. A Delphi Study to establish consensus on a definition of major bleeding in adult trauma. Transfusion. 2020 Sept 27;60(12):3028\u0026ndash;38. doi:10.1111/trf.16055\u003c/li\u003e\n\u003cli\u003e\u0026Scaron;tros M, Polansk\u0026aacute; EV, Hlav\u0026aacute;čov\u0026aacute; T, Skl\u0026aacute;dal P. Progress in assays of HMGB1 levels in human plasma\u0026mdash;the potential prognostic value in covid-19. Biomolecules. 2022 Apr 5;12(4):544. doi:10.3390/biom12040544\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"bmc-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"emmd","sideBox":"Learn more about [BMC Emergency Medicine](http://bmcemergmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/emmd","title":"BMC Emergency Medicine","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"major trauma, bleeding, massive transfusion protocol, HMGB-1","lastPublishedDoi":"10.21203/rs.3.rs-4734362/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4734362/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMassive bleeding causes approximately 50% of deaths in patients with major trauma. Most patients die within 6 hours of injury, which is preventable in at least 10% of cases. For these patients, early activation of the massive transfusion protocol (MTP) is a critical survival factor. With severe trauma, high-mobility group box 1 (HMGB-1, i.e., amphoterin) is released into the blood, and its levels correlate with the development of a systemic inflammatory response, traumatic coagulopathy, and fibrinolysis. Previous work has shown that higher levels of HMGB-1 are associated with a higher use of red blood cell transfusions. We conducted a single-center, prospective, observational study to assess the value of admission HMGB-1 levels in predicting activation of MTP in the emergency department.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom July 11, 2019, to April 23, 2022, a total of 104 consecutive adult patients with severe trauma (injury severity score\u0026thinsp;\u0026gt;\u0026thinsp;16) were enrolled. A blood sample was taken at admission, and HMGB-1 was measured. MTP activation in the emergency department was recorded in the study documentation. The total amount of blood products and fibrinogen administered to patients within 6 hours of admission was monitored.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong those patients with massive bleeding requiring MTP activation, we found significantly higher levels of HMGB-1 compared to patients without MTP activation (median [interquartile range]: 84.3 \u0026micro;g/L [34.2\u0026ndash;145.9] vs. 21.1 \u0026micro;g/L [15.7\u0026ndash;30.4]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). HMGB-1 level showed good performance in predicting MTP activation, with an area under the curve of 0.84 (95% CI 0.75\u0026ndash;0.93) and a cut-off value of 30.55 \u0026micro;g/L. HMGB-1 levels correlated significantly with the number of red blood cell units (r\u003csub\u003es\u003c/sub\u003e [95% CI] 0.46 [0.28\u0026ndash;0.61]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), units of fresh frozen plasma (r\u003csub\u003es\u003c/sub\u003e 0.46 [0.27\u0026ndash;0.61]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), platelets (r\u003csub\u003es\u003c/sub\u003e 0.48 [0.30\u0026ndash;0.62]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and fibrinogen (r\u003csub\u003es\u003c/sub\u003e 0.48 [0.32\u0026ndash;0.62]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) administered in the first 6 hours after hospital admission.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eAdmission HMGB-1 levels reliably predict MTP activation in the emergency department and correlate with the amount of blood products and fibrinogen administered during the first 6 hours of hemorrhagic shock resuscitation.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eNCT03986736 \u003cb\u003eRegistration date\u003c/b\u003e: June 4, 2019\u003c/p\u003e","manuscriptTitle":"HMGB-1 as a predictor of massive transfusion protocol activation in major trauma: a prospective observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-17 01:26:18","doi":"10.21203/rs.3.rs-4734362/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"checksComplete","content":"","date":"2024-07-17T08:02:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Emergency Medicine","date":"2024-07-13T08:46:50+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"emmd","sideBox":"Learn more about [BMC Emergency Medicine](http://bmcemergmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/emmd","title":"BMC Emergency Medicine","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"98638dc9-7146-4d86-9710-d7f402cf128f","owner":[],"postedDate":"August 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-08-17T01:26:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-17 01:26:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4734362","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4734362","identity":"rs-4734362","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}