{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T06:32:09Z","timestamp":1776580329540,"version":"3.51.2"},"reference-count":53,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005788","name":"Medical University of Vienna","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005788","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","award":["20023"],"award-info":[{"award-number":["20023"]}],"id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004061","name":"Oesterreichische Nationalbank","doi-asserted-by":"publisher","award":["18500"],"award-info":[{"award-number":["18500"]}],"id":[{"id":"10.13039\/501100004061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","thrombosisresearch.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Thrombosis Research"],"published-print":{"date-parts":[[2024,3]]},"DOI":"10.1016\/j.thromres.2024.01.018","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T06:39:04Z","timestamp":1706251144000},"page":"98-106","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"special_numbering":"C","title":["Activated protein C and free protein S in patients with mild to moderate bleeding disorders"],"prefix":"10.1016","volume":"235","author":[{"given":"Dino","family":"Mehic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"Schramm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Forstner-Bergauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helmuth","family":"Haslacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cihan","family":"Ay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid","family":"Pabinger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"Gebhart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.thromres.2024.01.018_bb0005","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/hae.13422","article-title":"High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: results from the Vienna Bleeding Biobank (VIBB)","volume":"24","author":"Gebhart","year":"2018","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0010","doi-asserted-by":"crossref","first-page":"e286","DOI":"10.1097\/HS9.0000000000000286","article-title":"Fundamentals for a systematic approach to mild and moderate inherited bleeding disorders: an EHA consensus report","volume":"3","author":"Rodeghiero","year":"2019","journal-title":"HemaSphere"},{"key":"10.1016\/j.thromres.2024.01.018_bb0015","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1111\/jth.13368","article-title":"A diagnostic approach to mild bleeding disorders","volume":"14","author":"Boender","year":"2016","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0020","doi-asserted-by":"crossref","DOI":"10.1182\/blood.2020010038","article-title":"Bleeding disorder of unknown cause (BDUC)","author":"Baker","year":"2021","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0025","article-title":"The necessity of repeat testing for von Willebrand disease in adult patients with mild to moderate bleeding disorders","author":"Mehic","year":"2023","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0030","doi-asserted-by":"crossref","DOI":"10.1016\/j.jtha.2023.03.006","article-title":"Risk factors for future bleeding in patients with mild bleeding disorders: longitudinal data from the Vienna Bleeding Biobank","author":"Mehic","year":"2023","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0035","article-title":"Health related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank","volume":"102176","author":"Mehic","year":"2023","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0040","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejim.2020.04.023","article-title":"The discriminatory power of bleeding assessment tools in adult patients with a mild to moderate bleeding tendency","author":"Gebhart","year":"2020","journal-title":"Eur. J. Intern. Med."},{"key":"10.1016\/j.thromres.2024.01.018_bb0045","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1172\/JCI69091","article-title":"Coagulation factor VA2440G causes east Texas bleeding disorder via TFPI\u03b1","volume":"123","author":"Vincent","year":"2013","journal-title":"J. Clin. Investig."},{"key":"10.1016\/j.thromres.2024.01.018_bb0050","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1182\/blood-2014-08-592733","article-title":"A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function","volume":"125","author":"Cunha","year":"2015","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0055","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1111\/jth.15314","article-title":"F5-Atlanta: a novel mutation in F5 associated with enhanced East Texas splicing and FV-short production","volume":"19","author":"Zimowski","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0060","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1182\/blood-2014-10-604553","article-title":"Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation","volume":"125","author":"Dargaud","year":"2015","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0065","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1182\/blood-2014-02-557538","article-title":"A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop)","volume":"124","author":"Langdown","year":"2014","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0070","doi-asserted-by":"crossref","DOI":"10.1111\/jth.14990","article-title":"A new pedigree with thrombomodulin-associated coagulopathy in which delayed fibrinolysis is partially attenuated by co-inherited TAFI deficiency","author":"Westbury","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0075","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1182\/bloodadvances.2020003464","article-title":"Elevated levels of tissue factor pathway inhibitor in patients with mild to moderate bleeding tendency","volume":"5","author":"Mehic","year":"2021","journal-title":"Blood Adv."},{"key":"10.1016\/j.thromres.2024.01.018_bb0080","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1111\/hae.14433","article-title":"Thrombomodulin in patients with mild to moderate bleeding tendency","volume":"27","author":"Mehic","year":"2021","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0085","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/jth.14529","article-title":"Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause","volume":"17","author":"Hofer","year":"2019","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0090","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1111\/jth.15524","article-title":"Thrombin generation measured by two platforms in patients with a bleeding tendency: comment","volume":"19","author":"Thomas","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0095","doi-asserted-by":"crossref","DOI":"10.1111\/hae.13991","article-title":"Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: a prospective cohort study","author":"Veen","year":"2020","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0100","doi-asserted-by":"crossref","DOI":"10.1111\/hae.14356","article-title":"Natural anticoagulants: a missing link in mild to moderate bleeding tendencies","author":"Mehic","year":"2021","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0105","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1538-7836.2007.02491.x","article-title":"Activated protein C","volume":"5","author":"Griffin","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0110","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1055\/s-0037-1604092","article-title":"Vitamin K-dependent protein S: beyond the protein C pathway","volume":"44","author":"Dahlb\u00e4ck","year":"2018","journal-title":"Semin. Thromb. Hemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0115","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1055\/s-0038-1665318","article-title":"Protein C deficiency in two Austrian families","volume":"50","author":"Pabinger-Fasching","year":"1983","journal-title":"Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0120","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1111\/j.1365-2516.2008.01775.x","article-title":"Protein S deficiency: a clinical perspective","volume":"14","author":"ten Kate","year":"2008","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0125","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1016\/S0140-6736(94)92497-X","article-title":"Activated protein C resistance caused by Arg506Gln mutation in factor Va","volume":"343","author":"Greengard","year":"1994","journal-title":"Lancet"},{"key":"10.1016\/j.thromres.2024.01.018_bb0130","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.cca.2019.11.005","article-title":"Activated protein C assays: a review","volume":"502","author":"Oto","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"10.1016\/j.thromres.2024.01.018_bb0135","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1097\/00003246-200107001-00024","article-title":"Activated protein C versus protein C in severe sepsis","volume":"29","author":"Yan","year":"2001","journal-title":"Crit. Care Med."},{"key":"10.1016\/j.thromres.2024.01.018_bb0145","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1538-7836.2007.02824.x","article-title":"Coagulation factors and the protein C system as determinants of thrombin generation in a normal population","volume":"6","author":"Dielis","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0150","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1182\/blood-2017-09-800326","article-title":"Targeting anticoagulant protein S to improve hemostasis in hemophilia","volume":"131","author":"Prince","year":"2018","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0155","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1097\/MOH.0000000000000364","article-title":"Targeting activated protein C to treat hemophilia","volume":"24","author":"Polderdijk","year":"2017","journal-title":"Curr. Opin. Hematol."},{"key":"10.1016\/j.thromres.2024.01.018_bb0160","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.jtha.2023.01.033","article-title":"Natural anticoagulant discovery, the gift that keeps on giving: finding FV-Short","volume":"21","author":"Dahlb\u00e4ck","year":"2023","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0170","doi-asserted-by":"crossref","DOI":"10.1182\/bloodadvances.2020003265","article-title":"ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease","volume":"5","author":"James","year":"2021","journal-title":"Blood Adv."},{"key":"10.1016\/j.thromres.2024.01.018_bb0175","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1111\/j.1538-7836.2012.04844.x","article-title":"Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity","volume":"10","author":"Peyvandi","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0180","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1111\/j.1538-7836.2010.03975.x","article-title":"ISTH\/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders","volume":"8","author":"Rodeghiero","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0185","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1111\/j.1538-7836.2005.01663.x","article-title":"The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study","volume":"3","author":"Rodeghiero","year":"2005","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0190","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1089\/bio.2018.0032","article-title":"Usage data and scientific impact of the prospectively established fluid bioresources at the hospital-based MedUni Wien Biobank","volume":"16","author":"Haslacher","year":"2018","journal-title":"Biopreserv. Biobank."},{"key":"10.1016\/j.thromres.2024.01.018_bb0195","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1182\/blood.2019004267","article-title":"A high-fat diet delays plasmin generation in a thrombomodulin-dependent manner in mice","volume":"135","author":"Miszta","year":"2020","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0200","series-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2020"},{"key":"10.1016\/j.thromres.2024.01.018_bb0205","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.1093\/ajhp\/59.suppl_1.S19","article-title":"Recombinant human activated protein C in severe sepsis","volume":"59","author":"Mann","year":"2002","journal-title":"Am. J. Health Syst. Pharm."},{"key":"10.1016\/j.thromres.2024.01.018_bb0210","doi-asserted-by":"crossref","first-page":"1869","DOI":"10.3390\/jcm8111869","article-title":"A systematic summary of systematic reviews on anticoagulant therapy in sepsis","volume":"8","author":"Murao","year":"2019","journal-title":"J. Clin. Med."},{"key":"10.1016\/j.thromres.2024.01.018_bb0215","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1001\/jama.2017.0131","article-title":"Management of Sepsis and Septic Shock","volume":"317","author":"Howell","year":"2017","journal-title":"JAMA"},{"key":"10.1016\/j.thromres.2024.01.018_bb0220","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1177\/107602960501100312","article-title":"Severe hemophilia and physiologic inhibitors of coagulation","volume":"11","author":"Kubisz","year":"2005","journal-title":"Clin. Appl. Thromb. Hemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0225","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1182\/blood-2016-05-718635","article-title":"Design and characterization of an APC-specific serpin for the treatment of hemophilia","volume":"129","author":"Polderdijk","year":"2017","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0230","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1002\/jha2.442","article-title":"Non-factor therapies for bleeding disorders: a primer for the general haematologist","volume":"3","author":"Swan","year":"2022","journal-title":"EJHaem"},{"key":"10.1016\/j.thromres.2024.01.018_bb0235","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1182\/bloodadvances.2021006403","article-title":"Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A\/B with inhibitors","volume":"6","author":"Shapiro","year":"2022","journal-title":"Blood Adv."},{"key":"10.1016\/j.thromres.2024.01.018_bb0240","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1365-2516.2011.02678.x","article-title":"Protein C, protein S and von Willebrand factor levels correlate with bleeding symptoms: a population-based study","volume":"18","author":"Rojnuckarin","year":"2012","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0245","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1111\/hae.13860","article-title":"Measurement of plasma and platelet tissue factor pathway inhibitor, factor V and Protein S in people with haemophilia","volume":"25","author":"Ellery","year":"2019","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0250","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/hae.13679","article-title":"Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients","volume":"25","author":"Chelle","year":"2019","journal-title":"Haemophilia"},{"key":"10.1016\/j.thromres.2024.01.018_bb0255","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1055\/s-0038-1651089","article-title":"The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells","volume":"57","author":"de Fouw","year":"1987","journal-title":"Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0260","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/cc5099","article-title":"Bench-to-bedside review: the role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury","volume":"10","author":"Looney","year":"2006","journal-title":"Crit. Care"},{"key":"10.1016\/j.thromres.2024.01.018_bb0265","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1111\/j.1538-7836.2008.02979.x","article-title":"Protein C supports platelet binding and activation under flow: role of glycoprotein Ib and apolipoprotein E receptor 2","volume":"6","author":"White","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"10.1016\/j.thromres.2024.01.018_bb0270","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1182\/blood.V67.2.504.504","article-title":"An abnormal plasma distribution of protein S occurs in functional protein S deficiency","volume":"67","author":"Comp","year":"1986","journal-title":"Blood"},{"key":"10.1016\/j.thromres.2024.01.018_bb0275","doi-asserted-by":"crossref","first-page":"5157","DOI":"10.1182\/bloodadvances.2020002452","article-title":"Association of ABO blood group with bleeding severity in patients with bleeding of unknown cause","volume":"4","author":"Mehic","year":"2020","journal-title":"Blood Adv."}],"container-title":["Thrombosis Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0049384824000185?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0049384824000185?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T17:52:59Z","timestamp":1758736379000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0049384824000185"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3]]},"references-count":53,"alternative-id":["S0049384824000185"],"URL":"https:\/\/doi.org\/10.1016\/j.thromres.2024.01.018","relation":{},"ISSN":["0049-3848"],"issn-type":[{"value":"0049-3848","type":"print"}],"subject":[],"published":{"date-parts":[[2024,3]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Activated protein C and free protein S in patients with mild to moderate bleeding disorders","name":"articletitle","label":"Article Title"},{"value":"Thrombosis Research","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.thromres.2024.01.018","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 The Authors. Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}]}}