{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:02:00Z","timestamp":1789581720296,"version":"build-2803163510"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum Ulm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Severe tissue injury and hemorrhagic shock can result in trauma-induced coagulopathy (TIC), acidosis, and hypothermia, denoted as lethal triad. This condition exacerbates trauma complications and contributes to organ dysfunction and mortality, prompting the need to better define its complex pathomechanisms in the blood. Therefore, we developed a standardized ex vivo human whole blood (hWB) model to differentiate the impact of various pathophysiological conditions, damage-associated molecular patterns (DAMPs), and key inflammatory mediators on TIC development. Modelling incremental grades of the lethal triad, we assessed the resulting thrombo-coagulopathy by monitoring platelet activation, clot formation, and mediator release. Both acidosis and hypothermia independently triggered platelet activation (with enhanced surface CD62P\/CD63 expression) and platelet consumption, leading to ex vivo clot formation. Completing the lethal triad with additional dilutional coagulopathy revealed even more pronounced effects. Further dissecting underlying cross-talk mechanisms, platelet-rich plasma (PRP) or isolated platelets exposed to similar conditions exhibited no relevant impact on platelet function. Notably, histones\u2014unlike HMGB1, pro-inflammatory cytokines or anaphylatoxins\u2014amplified the lethal triad-driven hypercoagulative TIC response in both hWB and PRP. In conclusion, our findings in a modular, clinically relevant whole blood model highlight histones as a central driver of TIC. Furthermore, tracking early TIC progression in this model provides an effective and efficient platform for evaluating novel therapeutic approaches to target drivers of coagulopathy.<\/jats:p>","DOI":"10.1038\/s41598-025-12431-7","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T15:25:35Z","timestamp":1755617135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histone-driven hypercoagulation contributes to the lethal triad of acute trauma-induced coagulopathy"],"prefix":"10.1038","volume":"15","author":[{"given":"Christian Karl","family":"Braun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mannes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doreen Tabea","family":"Spiegelburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amadeo","family":"Klitzing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Schultze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Achatz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,19]]},"reference":[{"issue":"10258","key":"12431_CR1","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1016\/S0140-6736(20)30925-9","volume":"396","author":"Global burden","year":"2020","unstructured":"Global burden. Of 369 diseases and injuries in 204 countries and territories, 1990\u20132019: a systematic analysis for the global burden of disease study 2019. Lancet 396 (10258), 1204\u20131222 (2020).","journal-title":"Lancet"},{"issue":"1","key":"12431_CR2","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41572-021-00264-3","volume":"7","author":"EE Moore","year":"2021","unstructured":"Moore, E. E. et al. Trauma-induced coagulopathy. Nat. Rev. Dis. Primers. 7 (1), 30 (2021).","journal-title":"Nat. Rev. Dis. Primers"},{"issue":"4","key":"12431_CR3","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1213\/ANE.0000000000004479","volume":"130","author":"AY Mitrophanov","year":"2020","unstructured":"Mitrophanov, A. Y., Szlam, F., Sniecinski, R. M., Levy, J. H. & Reifman, J. Controlled multifactorial coagulopathy: effects of dilution, hypothermia, and acidosis on thrombin generation in vitro. Anesth. Analg. 130 (4), 1063\u20131076 (2020).","journal-title":"Anesth. Analg"},{"issue":"9","key":"12431_CR4","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1161\/ATVBAHA.120.314786","volume":"40","author":"AY Mitrophanov","year":"2020","unstructured":"Mitrophanov, A. Y. et al. Injury length and arteriole constriction shape clot growth and Blood-Flow acceleration in a mouse model of thrombosis. Arterioscler. Thromb. Vasc Biol. 40 (9), 2114\u20132126 (2020).","journal-title":"Arterioscler. Thromb. Vasc Biol."},{"issue":"3","key":"12431_CR5","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1177\/00031348211048833","volume":"88","author":"JC Balmer","year":"2022","unstructured":"Balmer, J. C. et al. Continued relevance of initial temperature measurement in trauma patients. Am. Surg. 88 (3), 424\u2013428 (2022).","journal-title":"Am. Surg."},{"issue":"2","key":"12431_CR6","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1097\/ACO.0000000000000295","volume":"29","author":"RA Davenport","year":"2016","unstructured":"Davenport, R. A. & Brohi, K. Cause of trauma-induced coagulopathy. Curr. Opin. Anaesthesiol. 29 (2), 212\u2013219 (2016).","journal-title":"Curr. Opin. Anaesthesiol."},{"issue":"4","key":"12431_CR7","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/s41590-018-0064-8","volume":"19","author":"M Huber-Lang","year":"2018","unstructured":"Huber-Lang, M., Lambris, J. D. & Ward, P. A. Innate immune responses to trauma. Nat. Immunol. 19 (4), 327\u2013341 (2018).","journal-title":"Nat. Immunol."},{"issue":"1","key":"12431_CR8","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1111\/anae.15866","volume":"78","author":"A Shah","year":"2023","unstructured":"Shah, A., Kerner, V., Stanworth, S. J. & Agarwal, S. Major haemorrhage: past, present and future. Anaesthesia 78 (1), 93\u2013104 (2023).","journal-title":"Anaesthesia"},{"issue":"6","key":"12431_CR9","first-page":"638","volume":"20","author":"A Cap","year":"2014","unstructured":"Cap, A. & Hunt, B. Acute traumatic coagulopathy. Curr. Opin. Crit. Care. 20 (6), 638\u2013645 (2014).","journal-title":"Curr. Opin. Crit. Care"},{"issue":"6","key":"12431_CR10","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1097\/SHK.0b013e3181a5a632","volume":"32","author":"BB Chesebro","year":"2009","unstructured":"Chesebro, B. B. et al. Increase in activated protein C mediates acute traumatic coagulopathy in mice. Shock 32 (6), 659\u2013665 (2009).","journal-title":"Shock"},{"issue":"5","key":"12431_CR11","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.thromres.2011.11.053","volume":"129","author":"D Frith","year":"2012","unstructured":"Frith, D., Cohen, M. J. & Brohi, K. Animal models of trauma-induced coagulopathy. Thromb. Res. 129 (5), 551\u2013556 (2012).","journal-title":"Thromb. Res."},{"issue":"3","key":"12431_CR12","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1213\/ANE.0b013e31829c3b22","volume":"117","author":"AY Mitrophanov","year":"2013","unstructured":"Mitrophanov, A. Y., Rosendaal, F. R. & Reifman, J. Computational analysis of the effects of reduced temperature on thrombin generation: the contributions of hypothermia to coagulopathy. Anesth. Analg. 117 (3), 565\u2013574 (2013).","journal-title":"Anesth. Analg"},{"issue":"1","key":"12431_CR13","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/s00068-019-01111-7","volume":"46","author":"M Caspers","year":"2020","unstructured":"Caspers, M. et al. Microparticles profiling in trauma patients: high level of microparticles induce activation of platelets in vitro. Eur. J. Trauma. Emerg. Surg. 46 (1), 43\u201351 (2020).","journal-title":"Eur. J. Trauma. Emerg. Surg."},{"issue":"1","key":"12431_CR14","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s13049-018-0536-8","volume":"26","author":"M Caspers","year":"2018","unstructured":"Caspers, M. et al. How do external factors contribute to the hypocoagulative state in trauma-induced coagulopathy? - In vitro analysis of the lethal triad in trauma. Scand. J. Trauma. Resusc. Emerg. Med. 26 (1), 66 (2018).","journal-title":"Scand. J. Trauma. Resusc. Emerg. Med."},{"issue":"2","key":"12431_CR15","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1097\/TA.0000000000000729","volume":"79","author":"GP Dobson","year":"2015","unstructured":"Dobson, G. P., Letson, H. L., Sharma, R., Sheppard, F. R. & Cap, A. P. Mechanisms of early trauma-induced coagulopathy: the clot thickens or not? J. Trauma. Acute Care Surg. 79 (2), 301\u2013309 (2015).","journal-title":"J. Trauma. Acute Care Surg."},{"key":"12431_CR16","first-page":"35","volume":"3","author":"WZ Martini","year":"2016","unstructured":"Martini, W. Z. Coagulation complications following trauma. Mil Med. Res. 3, 35 (2016).","journal-title":"Mil Med. Res."},{"issue":"6","key":"12431_CR17","doi-asserted-by":"publisher","first-page":"692","DOI":"10.23736\/S2724-5691.23.09916-1","volume":"78","author":"FG Bonanno","year":"2023","unstructured":"Bonanno, F. G. Debunking the lethal triad and delineating damage control surgery. Minerva Surg. 78 (6), 692\u2013709 (2023).","journal-title":"Minerva Surg."},{"issue":"1","key":"12431_CR18","doi-asserted-by":"publisher","first-page":"e0280069","DOI":"10.1371\/journal.pone.0280069","volume":"18","author":"DT Spiegelburg","year":"2023","unstructured":"Spiegelburg, D. T. et al. Impact of surface coating and systemic anticoagulants on hemostasis and inflammation in a human whole blood model. PLoS One. 18 (1), e0280069 (2023).","journal-title":"PLoS One"},{"issue":"20","key":"12431_CR19","doi-asserted-by":"publisher","first-page":"6367","DOI":"10.1182\/bloodadvances.2023010817","volume":"7","author":"M Mannes","year":"2023","unstructured":"Mannes, M. et al. Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals. Blood Adv. 7 (20), 6367\u20136380 (2023).","journal-title":"Blood Adv."},{"issue":"13","key":"12431_CR20","doi-asserted-by":"publisher","first-page":"3708","DOI":"10.1182\/blood-2011-01-332676","volume":"118","author":"TA Fuchs","year":"2011","unstructured":"Fuchs, T. A., Bhandari, A. A. & Wagner, D. D. Histones induce rapid and profound thrombocytopenia in mice. Blood 118 (13), 3708\u20133714 (2011).","journal-title":"Blood"},{"key":"12431_CR21","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.jcrc.2017.11.025","volume":"44","author":"R Halbgebauer","year":"2018","unstructured":"Halbgebauer, R. et al. Hemorrhagic shock drives glycocalyx, barrier and organ dysfunction early after polytrauma. J. Crit. Care. 44, 229\u2013237 (2018).","journal-title":"J. Crit. Care"},{"issue":"4","key":"12431_CR22","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1097\/TA.0000000000002833","volume":"89","author":"KJ Kalkwarf","year":"2020","unstructured":"Kalkwarf, K. J. et al. Bleeding to death in a big city: an analysis of all trauma deaths from hemorrhage in a metropolitan area during 1 year. J. Trauma. Acute Care Surg. 89 (4), 716\u2013722 (2020).","journal-title":"J. Trauma. Acute Care Surg."},{"key":"12431_CR23","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40164-015-0001-6","volume":"4","author":"A Dewitte","year":"2015","unstructured":"Dewitte, A. et al. New frontiers for platelet CD154. Exp. Hematol. Oncol. 4, 6 (2015).","journal-title":"Exp. Hematol. Oncol."},{"issue":"18","key":"12431_CR24","doi-asserted-by":"publisher","first-page":"12459","DOI":"10.1074\/jbc.M809235200","volume":"284","author":"V Babich","year":"2009","unstructured":"Babich, V. et al. Differential effect of extracellular acidosis on the release and dispersal of soluble and membrane proteins secreted from the Weibel-Palade body. J. Biol. Chem. 284 (18), 12459\u201312468 (2009).","journal-title":"J. Biol. Chem."},{"issue":"6","key":"12431_CR25","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1097\/SLA.0000000000003307","volume":"272","author":"HH Henriksen","year":"2020","unstructured":"Henriksen, H. H. et al. Metabolic systems analysis of Shock-Induced endotheliopathy (SHINE) in trauma: A new research paradigm. Ann. Surg. 272 (6), 1140\u20131148 (2020).","journal-title":"Ann. Surg."},{"issue":"1","key":"12431_CR26","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/s13054-017-1605-5","volume":"21","author":"PI Johansson","year":"2017","unstructured":"Johansson, P. I., Stensballe, J. & Ostrowski, S. R. Shock induced endotheliopathy (SHINE) in acute critical illness - a unifying pathophysiologic mechanism. Crit. Care. 21 (1), 25 (2017).","journal-title":"Crit. Care"},{"issue":"3","key":"12431_CR27","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1097\/01.ta.0000226739.30655.75","volume":"61","author":"M Engstrom","year":"2006","unstructured":"Engstrom, M., Schott, U., Romner, B. & Reinstrup, P. Acidosis impairs the coagulation: A thromboelastographic study. J. Trauma. 61 (3), 624\u2013628 (2006).","journal-title":"J. Trauma."},{"issue":"10","key":"12431_CR28","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1111\/jth.13418","volume":"14","author":"M Gissel","year":"2016","unstructured":"Gissel, M. et al. Effects of an acidic environment on coagulation dynamics. J. Thromb. Haemost. 14 (10), 2001\u20132010 (2016).","journal-title":"J. Thromb. Haemost"},{"issue":"1","key":"12431_CR29","first-page":"202","volume":"67","author":"WZ Martini","year":"2009","unstructured":"Martini, W. Z. Coagulopathy by hypothermia and acidosis: mechanisms of thrombin generation and fibrinogen availability. J. Trauma. 67 (1), 202\u2013208 (2009).","journal-title":"J. Trauma."},{"issue":"5","key":"12431_CR30","first-page":"355","volume":"35","author":"F Vardon","year":"2016","unstructured":"Vardon, F., Mrozek, S., Geeraerts, T. & Fourcade, O. Accidental hypothermia in severe trauma. Anaesth. Crit. Care Pain Med. 35 (5), 355\u2013361 (2016).","journal-title":"Anaesth. Crit. Care Pain Med."},{"issue":"1","key":"12431_CR31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/S0020-1383(03)00309-7","volume":"35","author":"BJ Tsuei","year":"2004","unstructured":"Tsuei, B. J. & Kearney, P. A. Hypothermia in the trauma patient. Injury 35 (1), 7\u201315 (2004).","journal-title":"Injury"},{"issue":"1","key":"12431_CR32","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.injury.2011.11.016","volume":"44","author":"KH Park","year":"2013","unstructured":"Park, K. H., Lee, K. H. & Kim, H. Effect of hypothermia on coagulatory function and survival in Sprague-Dawley rats exposed to uncontrolled haemorrhagic shock. Injury 44 (1), 91\u201396 (2013).","journal-title":"Injury"},{"issue":"4","key":"12431_CR33","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1097\/TA.0b013e3182826edd","volume":"74","author":"J Mohr","year":"2013","unstructured":"Mohr, J. et al. Induced hypothermia does not impair coagulation system in a swine multiple trauma model. J. Trauma. Acute Care Surg. 74 (4), 1014\u20131020 (2013).","journal-title":"J. Trauma. Acute Care Surg."},{"issue":"1","key":"12431_CR34","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s13049-021-00847-9","volume":"29","author":"JK Bohm","year":"2021","unstructured":"Bohm, J. K. et al. Plasmatic and cell-based enhancement by microparticles originated from platelets and endothelial cells under simulated in vitro conditions of a dilutional coagulopathy. Scand. J. Trauma. Resusc. Emerg. Med. 29 (1), 38 (2021).","journal-title":"Scand. J. Trauma. Resusc. Emerg. Med."},{"issue":"2","key":"12431_CR35","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1164\/rccm.201206-1037OC","volume":"187","author":"ST Abrams","year":"2013","unstructured":"Abrams, S. T. et al. Circulating histones are mediators of trauma-associated lung injury. Am. J. Respir Crit. Care Med. 187 (2), 160\u2013169 (2013).","journal-title":"Am. J. Respir Crit. Care Med."},{"issue":"1","key":"12431_CR36","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.thromres.2013.04.018","volume":"132","author":"FW Lam","year":"2013","unstructured":"Lam, F. W. et al. Histone induced platelet aggregation is inhibited by normal albumin. Thromb. Res. 132 (1), 69\u201376 (2013).","journal-title":"Thromb. Res."},{"issue":"28","key":"12431_CR37","doi-asserted-by":"publisher","first-page":"25032","DOI":"10.1074\/jbc.M204003200","volume":"277","author":"U Bavendiek","year":"2002","unstructured":"Bavendiek, U. et al. Induction of tissue factor expression in human endothelial cells by CD40 ligand is mediated via activator protein 1, nuclear factor kappa B, and Egr-1. J. Biol. Chem. 277 (28), 25032\u201325039 (2002).","journal-title":"J. Biol. Chem."},{"key":"12431_CR38","doi-asserted-by":"publisher","first-page":"1438984","DOI":"10.3389\/fimmu.2024.1438984","volume":"15","author":"T Yang","year":"2024","unstructured":"Yang, T. et al. Emerging therapeutic strategies targeting extracellular histones for critical and inflammatory diseases: an updated narrative review. Front. Immunol. 15, 1438984 (2024).","journal-title":"Front. Immunol."},{"issue":"3","key":"12431_CR39","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1097\/TA.0000000000002570","volume":"88","author":"RM Ditzel Jr","year":"2020","unstructured":"Ditzel, R. M. Jr. et al. A review of transfusion- and trauma-induced hypocalcemia: is it time to change the lethal triad to the lethal diamond? J. Trauma. Acute Care Surg. 88 (3), 434\u2013439 (2020).","journal-title":"J. Trauma. Acute Care Surg."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12431-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12431-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12431-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T07:11:15Z","timestamp":1757401875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-12431-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,19]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["12431"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-12431-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,19]]},"assertion":[{"value":"15 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30422"}}