{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T16:49:02Z","timestamp":1782233342258,"version":"3.54.5"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Anesthesiol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Heparin-binding protein (HBP) is an inflammatory protein released by activated polymorphonuclear white cells. It has been suggested as a predictor of sepsis progression and organ dysfunction and plays a role in the pathophysiology of endothelial dysfunction. Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor with pro-inflammatory effects, and high levels are found in patients with sepsis and acute respiratory distress syndrome. We investigated HBP and ET-1 plasma levels in critical COVID-19 disease with the aim of evaluating whether they were associated with 60-day mortality or the need for invasive mechanical ventilation (IMV). These levels were compared with those of a cohort of post-trauma intensive care unit (ICU) patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We included 96 patients with critical COVID-19 disease in 2020 and ten post-trauma ICU patients. Blood samples were collected at ICU admission, and plasma levels of HBP and ET-1 were measured. Clinical and laboratory data were collected until ICU discharge or death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In COVID-19 patients, plasma levels of HBP were markedly increased, with a median level of 150 ng\/ml (IQR 47\u2013299), compared to 13.3 ng\/ml (IQR 8.8\u201362.1),\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.0001 in the trauma ICU patients. There was no association between HBP levels and 60-day mortality or need for IMV. The levels of ET-1 were 1.6 pg\/ml (IQR 1.2\u20131.9) in the COVID-19 cohort and 2.0 pg\/ml (IQR 1.2\u20132.8),\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.25 in the trauma ICU cohort. COVID-19 patients requiring IMV hade higher ET-1 levels than those who did not require such treatment; however, no association was found in a logistic regression model when adjusted for age, sex and body mass index. There was no correlation between plasma HBP and ET-1 levels. Inflammatory parameters such as C-reactive protein, procalcitonin, ferritin, and interleukin-6, were elevated but did not distinguish survivors from non-survivors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>While HBP levels are markedly elevated in critical COVID-19, they do not predict outcomes at ICU admission. ET-1 levels were also not linked to mortality or the need for IMV.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12871-026-04050-0","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T13:15:11Z","timestamp":1782220511000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Heparin-binding protein and Endothelin-1 in critical COVID-19"],"prefix":"10.1186","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7045-7885","authenticated-orcid":false,"given":"Halla","family":"Halldorsdottir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olav","family":"Rooyackers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Grip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"M\u00e5rtensson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie","family":"Weitzberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Oldner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"issue":"10223","key":"4050_CR1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497\u2013506.","journal-title":"Lancet"},{"issue":"10223","key":"4050_CR2","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S0140-6736(20)30211-7","volume":"395","author":"N Chen","year":"2020","unstructured":"Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507\u201313.","journal-title":"Lancet"},{"issue":"11","key":"4050_CR3","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1001\/jama.2020.1585","volume":"323","author":"D Wang","year":"2020","unstructured":"Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA: J Am Med Association. 2020;323(11):1061\u20139.","journal-title":"JAMA: J Am Med Association"},{"key":"4050_CR4","doi-asserted-by":"publisher","first-page":"m1091","DOI":"10.1136\/bmj.m1091","volume":"368","author":"T Chen","year":"2020","unstructured":"Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.","journal-title":"BMJ"},{"issue":"10","key":"4050_CR5","doi-asserted-by":"publisher","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","volume":"26","author":"DM Del Valle","year":"2020","unstructured":"Del Valle DM, Kim-Schulze S, Huang HH, Beckmann ND, Nirenberg S, Wang B, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636\u201343.","journal-title":"Nat Med"},{"key":"4050_CR6","first-page":"332","volume":"95","author":"Z Zhu","year":"2020","unstructured":"Zhu Z, Cai T, Fan L, Lou K, Hua X, Huang Z, et al. Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int J Infect diseases: IJID : official publication Int Soc Infect Dis. 2020;95:332\u20139.","journal-title":"Int J Infect diseases: IJID : official publication Int Soc Infect Dis"},{"issue":"12","key":"4050_CR7","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1016\/S2213-2600(20)30404-5","volume":"8","author":"DE Leisman","year":"2020","unstructured":"Leisman DE, Ronner L, Pinotti R, Taylor MD, Sinha P, Calfee CS, et al. Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir Med. 2020;8(12):1233\u201344.","journal-title":"Lancet Respir Med"},{"issue":"15","key":"4050_CR8","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1093\/cid\/ciaa248","volume":"71","author":"C Qin","year":"2020","unstructured":"Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762\u20138.","journal-title":"Clin Infect Dis"},{"key":"4050_CR9","doi-asserted-by":"publisher","first-page":"827","DOI":"10.3389\/fimmu.2020.00827","volume":"11","author":"B Diao","year":"2020","unstructured":"Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol. 2020;11:827.","journal-title":"Front Immunol"},{"issue":"5","key":"4050_CR10","doi-asserted-by":"publisher","first-page":"2620","DOI":"10.1172\/JCI137244","volume":"130","author":"G Chen","year":"2020","unstructured":"Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130(5):2620\u20139.","journal-title":"J Clin Invest"},{"key":"4050_CR11","doi-asserted-by":"publisher","first-page":"103104","DOI":"10.1016\/j.ebiom.2020.103104","volume":"61","author":"R Bussani","year":"2020","unstructured":"Bussani R, Schneider E, Zentilin L, Collesi C, Ali H, Braga L, et al. Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine. 2020;61:103104.","journal-title":"EBioMedicine"},{"issue":"8","key":"4050_CR12","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1164\/rccm.202107-1774OC","volume":"206","author":"J Joffre","year":"2022","unstructured":"Joffre J, Rodriguez L, Matthay ZA, Lloyd E, Fields AT, Bainton RJ, et al. COVID-19-associated Lung Microvascular Endotheliopathy: A From the Bench Perspective. Am J Respir Crit Care Med. 2022;206(8):961\u201372.","journal-title":"Am J Respir Crit Care Med"},{"issue":"4","key":"4050_CR13","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1111\/bjh.19062","volume":"203","author":"M Scavone","year":"2023","unstructured":"Scavone M, Ghali C, Calogiuri M, Sala M, Bossi E, Mencarini T, et al. Impairment of platelet function in both mild and severe COVID-19 patients. Br J Haematol. 2023;203(4):656\u201367.","journal-title":"Br J Haematol"},{"issue":"10234","key":"4050_CR14","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1016\/S0140-6736(20)30937-5","volume":"395","author":"Z Varga","year":"2020","unstructured":"Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417\u20138.","journal-title":"Lancet"},{"issue":"1","key":"4050_CR15","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1186\/s13054-020-03062-7","volume":"24","author":"S Pons","year":"2020","unstructured":"Pons S, Fodil S, Azoulay E, Zafrani L. The vascular endothelium: the cornerstone of organ dysfunction in severe SARS-CoV-2 infection. Crit Care. 2020;24(1):353.","journal-title":"Crit Care"},{"issue":"1","key":"4050_CR16","doi-asserted-by":"publisher","first-page":"16039","DOI":"10.1038\/s41598-021-95694-0","volume":"11","author":"JM Kruse","year":"2021","unstructured":"Kruse JM, Zickler D, Ludemann WM, Piper SK, Gotthardt I, Ihlow J, et al. Evidence for a thromboembolic pathogenesis of lung cavitations in severely ill COVID-19 patients. Sci Rep. 2021;11(1):16039.","journal-title":"Sci Rep"},{"issue":"5","key":"4050_CR17","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1164\/rccm.202106-1514OC","volume":"205","author":"DE Leisman","year":"2022","unstructured":"Leisman DE, Mehta A, Thompson BT, Charland NC, Gonye ALK, Gushterova I, et al. Alveolar, Endothelial, and Organ Injury Marker Dynamics in Severe COVID-19. Am J Respir Crit Care Med. 2022;205(5):507\u201319.","journal-title":"Am J Respir Crit Care Med"},{"issue":"3","key":"4050_CR18","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1097\/SHK.0000000000000862","volume":"48","author":"J Fisher","year":"2017","unstructured":"Fisher J, Russell JA, Bentzer P, Parsons D, Secchia S, Morgelin M, et al. Heparin-Binding Protein (HBP): A Causative Marker and Potential Target for Heparin Treatment of Human Sepsis-Induced Acute Kidney Injury. Shock. 2017;48(3):313\u201320.","journal-title":"Shock"},{"issue":"6","key":"4050_CR19","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1111\/joim.12604","volume":"281","author":"J Fisher","year":"2017","unstructured":"Fisher J, Linder A. Heparin-binding protein: a key player in the pathophysiology of organ dysfunction in sepsis. J Intern Med. 2017;281(6):562\u201374.","journal-title":"J Intern Med"},{"issue":"7","key":"4050_CR20","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1086\/605563","volume":"49","author":"A Linder","year":"2009","unstructured":"Linder A, Christensson B, Herwald H, Bjorck L, Akesson P. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis. 2009;49(7):1044\u201350.","journal-title":"Clin Infect Dis"},{"issue":"11","key":"4050_CR21","doi-asserted-by":"publisher","first-page":"2378","DOI":"10.1097\/CCM.0000000000001265","volume":"43","author":"A Linder","year":"2015","unstructured":"Linder A, Arnold R, Boyd JH, Zindovic M, Zindovic I, Lange A, et al. Heparin-Binding Protein Measurement Improves the Prediction of Severe Infection With Organ Dysfunction in the Emergency Department. Crit Care Med. 2015;43(11):2378\u201386.","journal-title":"Crit Care Med"},{"issue":"3","key":"4050_CR22","doi-asserted-by":"publisher","first-page":"R90","DOI":"10.1186\/cc11353","volume":"16","author":"A Linder","year":"2012","unstructured":"Linder A, Akesson P, Inghammar M, Treutiger CJ, Linner A, Sunden-Cullberg J. Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock. Crit Care. 2012;16(3):R90.","journal-title":"Crit Care"},{"key":"4050_CR23","doi-asserted-by":"publisher","unstructured":"Kaukonen KM, Linko R, Herwald H, Lindbom L, Ruokonen E, Ala-Kokko T, et al. Heparin-binding protein (HBP) in critically ill patients with influenza A(H1N1) infection. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2013. https:\/\/doi.org\/10.1111\/1469-0691.12156.","DOI":"10.1111\/1469-0691.12156"},{"issue":"4","key":"4050_CR24","doi-asserted-by":"publisher","first-page":"e0249570","DOI":"10.1371\/journal.pone.0249570","volume":"16","author":"L Mellhammar","year":"2021","unstructured":"Mellhammar L, Thelaus L, Elen S, Fisher J, Linder A. Heparin binding protein in severe COVID-19-A prospective observational cohort study. PLoS ONE. 2021;16(4):e0249570.","journal-title":"PLoS ONE"},{"issue":"7","key":"4050_CR25","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1007\/s10096-020-04145-7","volume":"40","author":"M Saridaki","year":"2021","unstructured":"Saridaki M, Metallidis S, Grigoropoulou S, Vrentzos E, Lada M, Argyraki K, et al. Integration of heparin-binding protein and interleukin-6 in the early prediction of respiratory failure and mortality in pneumonia by SARS-CoV-2 (COVID-19). Eur J Clin Microbiol Infect Dis. 2021;40(7):1405\u201312.","journal-title":"Eur J Clin Microbiol Infect Dis"},{"key":"4050_CR26","doi-asserted-by":"publisher","unstructured":"Xue M, Zeng Y, Qu HQ, Zhang T, Li N, Huang H, et al. Heparin-binding protein levels correlate with aggravation and multiorgan damage in severe COVID-19. ERJ Open Res. 2021;7(1). https:\/\/doi.org\/10.1183\/23120541.00741-2020.","DOI":"10.1183\/23120541.00741-2020"},{"issue":"10","key":"4050_CR27","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1038\/nm1001-1123","volume":"7","author":"N Gautam","year":"2001","unstructured":"Gautam N, Olofsson AM, Herwald H, Iversen LF, Lundgren-Akerlund E, Hedqvist P, et al. Heparin-binding protein (HBP\/CAP37): a missing link in neutrophil-evoked alteration of vascular permeability. Nat Med. 2001;7(10):1123\u20137.","journal-title":"Nat Med"},{"issue":"3","key":"4050_CR28","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/S0092-8674(04)00057-1","volume":"116","author":"H Herwald","year":"2004","unstructured":"Herwald H, Cramer H, Morgelin M, Russell W, Sollenberg U, Norrby-Teglund A, et al. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage. Cell. 2004;116(3):367\u201379.","journal-title":"Cell"},{"issue":"1","key":"4050_CR29","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s40635-016-0104-3","volume":"4","author":"P Bentzer","year":"2016","unstructured":"Bentzer P, Fisher J, Kong HJ, Morgelin M, Boyd JH, Walley KR, et al. Heparin-binding protein is important for vascular leak in sepsis. Intensive Care Med Exp. 2016;4(1):33.","journal-title":"Intensive Care Med Exp"},{"key":"4050_CR30","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.yjmcc.2022.03.007","volume":"167","author":"GR Abraham","year":"2022","unstructured":"Abraham GR, Kuc RE, Althage M, Greasley PJ, Ambery P, Maguire JJ, et al. Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19. J Mol Cell Cardiol. 2022;167:92\u20136.","journal-title":"J Mol Cell Cardiol"},{"key":"4050_CR31","doi-asserted-by":"publisher","first-page":"8671713","DOI":"10.1155\/2021\/8671713","volume":"2021","author":"A Fodor","year":"2021","unstructured":"Fodor A, Tiperciuc B, Login C, Orasan OH, Lazar AL, Buchman C, et al. Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19-Mechanisms and Therapeutic Targets. Oxid Med Cell Longev. 2021;2021:8671713.","journal-title":"Oxid Med Cell Longev"},{"key":"4050_CR32","doi-asserted-by":"publisher","unstructured":"Janaszak-Jasiecka A, Siekierzycka A, Ploska A, Dobrucki IT, Kalinowski L. Endothelial Dysfunction Driven by Hypoxia-The Influence of Oxygen Deficiency on NO Bioavailability. Biomolecules. 2021;11(7). https:\/\/doi.org\/10.3390\/biom11070982.","DOI":"10.3390\/biom11070982"},{"issue":"6163","key":"4050_CR33","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1038\/332411a0","volume":"332","author":"M Yanagisawa","year":"1988","unstructured":"Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411\u20135.","journal-title":"Nature"},{"issue":"Suppl 7","key":"4050_CR34","doi-asserted-by":"publisher","first-page":"S408","DOI":"10.1097\/00005344-199100177-00115","volume":"17","author":"I Miyamori","year":"1991","unstructured":"Miyamori I, Takeda Y, Yoneda T, Takeda R. Endothelin-1 release from mesenteric arteries of spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1991;17(Suppl 7):S408\u201310.","journal-title":"J Cardiovasc Pharmacol"},{"issue":"6607","key":"4050_CR35","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/384353a0","volume":"384","author":"S Sakai","year":"1996","unstructured":"Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996;384(6607):353\u20135.","journal-title":"Nature"},{"issue":"24","key":"4050_CR36","doi-asserted-by":"publisher","first-page":"1732","DOI":"10.1056\/NEJM199306173282402","volume":"328","author":"A Giaid","year":"1993","unstructured":"Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328(24):1732\u20139.","journal-title":"N Engl J Med"},{"issue":"5","key":"4050_CR37","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/0002-9149(93)90452-I","volume":"71","author":"P Cacoub","year":"1993","unstructured":"Cacoub P, Dorent R, Maistre G, Nataf P, Carayon A, Piette C, et al. Endothelin-1 in primary pulmonary hypertension and the Eisenmenger syndrome. Am J Cardiol. 1993;71(5):448\u201350.","journal-title":"Am J Cardiol"},{"issue":"8","key":"4050_CR38","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1097\/00003246-199208000-00005","volume":"20","author":"HJ Voerman","year":"1992","unstructured":"Voerman HJ, Stehouwer CD, van Kamp GJ, van Strack RJ, Groeneveld AB, Thijs LG. Plasma endothelin levels are increased during septic shock. Crit Care Med. 1992;20(8):1097\u2013101.","journal-title":"Crit Care Med"},{"key":"4050_CR39","doi-asserted-by":"publisher","unstructured":"Jin Q, Chen D, Zhang X, Zhang F, Zhong D, Lin D, et al. Medical Management of Pulmonary Arterial Hypertension: Current Approaches and Investigational Drugs. Pharmaceutics. 2023;15(6). https:\/\/doi.org\/10.3390\/pharmaceutics15061579.","DOI":"10.3390\/pharmaceutics15061579"},{"issue":"5","key":"4050_CR40","doi-asserted-by":"publisher","first-page":"1169","DOI":"10.1164\/ajrccm\/148.5.1169","volume":"148","author":"W Druml","year":"1993","unstructured":"Druml W, Steltzer H, Waldhausl W, Lenz K, Hammerle A, Vierhapper H, et al. Endothelin-1 in adult respiratory distress syndrome. Am Rev Respir Dis. 1993;148(5):1169\u201373.","journal-title":"Am Rev Respir Dis"},{"issue":"2","key":"4050_CR41","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1378\/chest.104.2.476","volume":"104","author":"C Mitaka","year":"1993","unstructured":"Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Amaha K. Circulating endothelin-1 concentrations in acute respiratory failure. Chest. 1993;104(2):476\u201380.","journal-title":"Chest"},{"issue":"6 Pt 1","key":"4050_CR42","doi-asserted-by":"publisher","first-page":"1646","DOI":"10.1164\/ajrccm\/148.6_Pt_1.1646","volume":"148","author":"D Langleben","year":"1993","unstructured":"Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger RD, Stewart DJ. Endothelin-1 in acute lung injury and the adult respiratory distress syndrome. Am Rev Respir Dis. 1993;148(6 Pt 1):1646\u201350.","journal-title":"Am Rev Respir Dis"},{"key":"4050_CR43","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.thromres.2021.11.027","volume":"209","author":"LH Willems","year":"2022","unstructured":"Willems LH, Nagy M, Ten Cate H, Spronk HMH, Groh LA, Leentjens J, et al. Sustained inflammation, coagulation activation and elevated endothelin-1 levels without macrovascular dysfunction at 3 months after COVID-19. Thromb Res. 2022;209:106\u201314.","journal-title":"Thromb Res"},{"issue":"1","key":"4050_CR44","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12967-022-03346-2","volume":"20","author":"M Haffke","year":"2022","unstructured":"Haffke M, Freitag H, Rudolf G, Seifert M, Doehner W, Scherbakov N, et al. Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME\/CFS). J Transl Med. 2022;20(1):138.","journal-title":"J Transl Med"},{"issue":"6","key":"4050_CR45","doi-asserted-by":"publisher","first-page":"e431","DOI":"10.1016\/S2666-5247(23)00041-1","volume":"4","author":"JF Bermejo-Martin","year":"2023","unstructured":"Bermejo-Martin JF, Garcia-Mateo N, Motos A, Resino S, Tamayo L, Ryan Murua P, et al. Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study. Lancet Microbe. 2023;4(6):e431\u201341.","journal-title":"Lancet Microbe"},{"key":"4050_CR46","doi-asserted-by":"publisher","first-page":"102117","DOI":"10.1016\/j.eclinm.2023.102117","volume":"62","author":"S Shahbazi","year":"2023","unstructured":"Shahbazi S, Vahdat Shariatpanahi Z, Shahbazi E. Bosentan for high-risk outpatients with COVID-19 infection: a randomized, double blind, placebo-controlled trial. EClinicalMedicine. 2023;62:102117.","journal-title":"EClinicalMedicine"},{"key":"4050_CR47","doi-asserted-by":"publisher","first-page":"102082","DOI":"10.1016\/j.pupt.2021.102082","volume":"71","author":"OA Nabeh","year":"2021","unstructured":"Nabeh OA, Matter LM, Khattab MA, Esraa M. The possible implication of endothelin in the pathology of COVID-19-induced pulmonary hypertension. Pulm Pharmacol Ther. 2021;71:102082.","journal-title":"Pulm Pharmacol Ther"},{"issue":"5","key":"4050_CR48","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1111\/aas.12301","volume":"58","author":"BP Persson","year":"2014","unstructured":"Persson BP, Halldorsdottir H, Lindbom L, Rossi P, Herwald H, Weitzberg E, et al. Heparin-binding protein (HBP\/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema? Acta Anaesthesiol Scand. 2014;58(5):549\u201359.","journal-title":"Acta Anaesthesiol Scand"},{"issue":"13","key":"4050_CR49","doi-asserted-by":"publisher","first-page":"981","DOI":"10.2217\/bmm-2022-0265","volume":"16","author":"T Acar","year":"2022","unstructured":"Acar T, Ertekin B, Yortanli M, Kocak S. Prognostic value of heparin-binding protein for mortality in severe COVID-19 pneumonia. Biomark Med. 2022;16(13):981\u201391.","journal-title":"Biomark Med"},{"issue":"3","key":"4050_CR50","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1097\/SHK.0000000000002315","volume":"61","author":"E Kyriazopoulou","year":"2024","unstructured":"Kyriazopoulou E, Dalekos GN, Metallidis S, Poulakou G, Papanikolaou IC, Tzavara V, et al. Heparin-Binding Protein Levels Predict Unfavorable Outcome in Covid-19 Pneumonia: A Post Hoc Analysis of the Save Trial. Shock. 2024;61(3):395\u20139.","journal-title":"Shock"},{"key":"4050_CR51","doi-asserted-by":"publisher","unstructured":"Halldorsdottir HD, Eriksson J, Persson BP, Herwald H, Lindbom L, Weitzberg E, et al. Heparin-binding protein as a biomarker of post-injury sepsis in trauma patients. Acta Anaesthesiol Scand. 2018. https:\/\/doi.org\/10.1111\/aas.13107.","DOI":"10.1111\/aas.13107"},{"key":"4050_CR52","doi-asserted-by":"publisher","unstructured":"Sterner N, Fisher J, Thelaus L, Ketteler C, Lemez S, Dardashti A, et al. The Dynamics of Heparin-Binding Protein in Cardiothoracic Surgery-A Pilot Study. J Cardiothorac Vasc Anesth. 2021. https:\/\/doi.org\/10.1053\/j.jvca.2020.12.033.","DOI":"10.1053\/j.jvca.2020.12.033"},{"key":"4050_CR53","doi-asserted-by":"publisher","first-page":"100256","DOI":"10.1016\/j.bjao.2023.100256","volume":"9","author":"H Halldorsdottir","year":"2024","unstructured":"Halldorsdottir H, Lindbom L, Ebberyd A, Oldner A, Weitzberg E. The effect of heparins on plasma concentration of heparin-binding protein: a pilot study. BJA Open. 2024;9:100256.","journal-title":"BJA Open"},{"issue":"6","key":"4050_CR54","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1097\/SHK.0000000000002021","volume":"58","author":"H Neb","year":"2022","unstructured":"Neb H, Talbot SR, Ruskowski K, Brkic D, Sonntagbauer M, Adam EH, et al. High Heparanase Level in Survivors of Covid-19 - Indicator of Vascular and Pulmonary Recovery? Shock. 2022;58(6):514\u201323.","journal-title":"Shock"},{"issue":"6","key":"4050_CR55","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1056\/NEJMra1608077","volume":"377","author":"BT Thompson","year":"2017","unstructured":"Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017;377(6):562\u201372.","journal-title":"N Engl J Med"},{"issue":"4","key":"4050_CR56","doi-asserted-by":"publisher","first-page":"R155","DOI":"10.1186\/cc12834","volume":"17","author":"Q Lin","year":"2013","unstructured":"Lin Q, Shen J, Shen L, Zhang Z, Fu F. Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome. Crit Care. 2013;17(4):R155.","journal-title":"Crit Care"},{"key":"4050_CR57","doi-asserted-by":"publisher","unstructured":"Banecki K, Dora KA. Endothelin-1 in Health and Disease. Int J Mol Sci. 2023;24(14). https:\/\/doi.org\/10.3390\/ijms241411295.","DOI":"10.3390\/ijms241411295"},{"issue":"12","key":"4050_CR58","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1136\/thx.50.12.1308","volume":"50","author":"RI Cargill","year":"1995","unstructured":"Cargill RI, Kiely DG, Clark RA, Lipworth BJ. Hypoxaemia and release of endothelin-1. Thorax. 1995;50(12):1308\u201310.","journal-title":"Thorax"},{"issue":"6","key":"4050_CR59","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1136\/jcp.48.6.519","volume":"48","author":"C Ferri","year":"1995","unstructured":"Ferri C, Bellini C, De Angelis C, De Siati L, Perrone A, Properzi G, et al. Circulating endothelin-1 concentrations in patients with chronic hypoxia. J Clin Pathol. 1995;48(6):519\u201324.","journal-title":"J Clin Pathol"},{"issue":"3","key":"4050_CR60","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1006\/bbrc.1994.1395","volume":"199","author":"T Fukuroda","year":"1994","unstructured":"Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199(3):1461\u20135.","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"4050_CR61","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1152\/jappl.1996.81.4.1510","volume":"81","author":"J Dupuis","year":"1996","unstructured":"Dupuis J, Goresky CA, Fournier A. Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol. 1996;81(4):1510\u20135.","journal-title":"J Appl Physiol"},{"issue":"4","key":"4050_CR62","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1111\/j.1365-2362.1992.tb01463.x","volume":"22","author":"OF Wagner","year":"1992","unstructured":"Wagner OF, Vierhapper H, Gasic S, Nowotny P, Waldhausl W. Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation. Eur J Clin Invest. 1992;22(4):277\u201382.","journal-title":"Eur J Clin Invest"},{"issue":"6","key":"4050_CR63","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1111\/j.1475-097X.1993.tb00480.x","volume":"13","author":"E Weitzberg","year":"1993","unstructured":"Weitzberg E, Ahlborg G, Lundberg JM. Differences in vascular effects and removal of endothelin-1 in human lung, brain, and skeletal muscle. Clin Physiol. 1993;13(6):653\u201362.","journal-title":"Clin Physiol"},{"issue":"4","key":"4050_CR64","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/S0002-8703(98)70276-5","volume":"135","author":"J Dupuis","year":"1998","unstructured":"Dupuis J, Cernacek P, Tardif JC, Stewart DJ, Gosselin G, Dyrda I, et al. Reduced pulmonary clearance of endothelin-1 in pulmonary hypertension. Am Heart J. 1998;135(4):614\u201320.","journal-title":"Am Heart J"},{"issue":"4","key":"4050_CR65","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1042\/cs0930309","volume":"93","author":"M White","year":"1997","unstructured":"White M, Courtemanche M, Stewart DJ, Talajic M, Mikes E, Cernacek P, et al. Age- and gender-related changes in endothelin and catecholamine release, and in autonomic balance in response to head-up tilt. Clin Sci. 1997;93(4):309\u201316.","journal-title":"Clin Sci"},{"issue":"6","key":"4050_CR66","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1159\/000022111","volume":"45","author":"H Sayama","year":"1999","unstructured":"Sayama H, Nakamura Y, Saito N, Konoshita M. Does the plasma endothelin-1 concentration reflect atherosclerosis in the elderly? Gerontology. 1999;45(6):312\u20136.","journal-title":"Gerontology"},{"key":"4050_CR67","doi-asserted-by":"publisher","unstructured":"Vassiliou AG, Roumpaki A, Keskinidou C, Athanasiou N, Tsipilis S, Jahaj E, et al. Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome. Int J Mol Sci. 2024;25(19). https:\/\/doi.org\/10.3390\/ijms251910640.","DOI":"10.3390\/ijms251910640"},{"issue":"1","key":"4050_CR68","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s13054-016-1412-4","volume":"20","author":"G Ristagno","year":"2016","unstructured":"Ristagno G, Masson S, Tiainen M, Bendel S, Bernasconi R, Varpula T, et al. Elevated plasma heparin-binding protein is associated with early death after resuscitation from cardiac arrest. Crit Care. 2016;20(1):251.","journal-title":"Crit Care"}],"container-title":["BMC Anesthesiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12871-026-04050-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12871-026-04050-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12871-026-04050-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T15:54:31Z","timestamp":1782230071000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12871-026-04050-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4050"],"URL":"https:\/\/doi.org\/10.1186\/s12871-026-04050-0","relation":{},"ISSN":["1471-2253"],"issn-type":[{"value":"1471-2253","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]},"assertion":[{"value":"19 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was designed in accordance with the Declaration of Helsinki and approved by the Swedish Ethical Review Authority (approval numbers 2020\u2009\u2212\u200901302, 2017\/1324-31). Written consent was provided from the patient or a close relative when the patient was unable to provide consent. Presumed consent was used in COVID-19 patients who died before consent could be provided.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"379"}}