{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T03:47:08Z","timestamp":1794023228162,"version":"4.8.0"},"reference-count":55,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,11,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Recent studies have demonstrated that only 30% of patients referred for assessment of a possible bleeding tendency will eventually be diagnosed with a mild bleeding disorder (MBD) such as von Willebrand disease (VWD) or platelet function defect (PFD). Rather, most of these patients will be diagnosed with bleeding disorder of unknown cause (BDUC). There remains an important unmet need to define consensus regarding the clinical and laboratory criteria necessary for a formal BDUC diagnosis. Accumulating recent data suggest that BDUC is being diagnosed with increasing frequency. Objective assessment of bleeding phenotype using a standardized bleeding assessment tool (BAT) therefore represents a fundamental first step in the diagnosis of BDUC. Because BDUC is a diagnosis by exclusion, accurate quantification of bleeding phenotype is critical because this will be the primary determinant on which a diagnosis of BDUC is reached. Importantly, BAT scores suggest that patients with BDUC display bleeding phenotypes comparable to those seen in patients with VWD or PFD. Despite the prevalence of BDUC, diagnosis and management of these patients commonly pose significant clinical dilemmas. We consider these challenges in the context of a number of typical case studies, discuss the available evidence, and outline our approach to the management of these patients.<\/jats:p>","DOI":"10.1182\/blood.2020010038","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T15:04:08Z","timestamp":1629126248000},"page":"1795-1804","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":47,"title":["How I treat bleeding disorder of unknown cause"],"prefix":"10.1182","volume":"138","author":[{"given":"Ross I.","family":"Baker","sequence":"first","affiliation":[{"name":"Western Australia Centre for Thrombosis and Haemostasis, Perth Blood Institute, Murdoch University, Perth, Australia;"},{"name":"Hollywood Hospital Haemophilia Treatment Centre, Perth, Australia;"},{"name":"Irish-Australian Blood Collaborative Network Perth, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0309-3313","authenticated-orcid":false,"given":"James S.","family":"O\u2019Donnell","sequence":"additional","affiliation":[{"name":"Irish-Australian Blood Collaborative Network Perth, Australia;"},{"name":"Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland; and"},{"name":"National Coagulation Centre, St James\u2019s Hospital, Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6","key":"2021111115211312200_B1","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1111\/hae.14174","article-title":"Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management","volume":"26","author":"Thomas","year":"2020","journal-title":"Haemophilia."},{"issue":"1","key":"2021111115211312200_B2","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1182\/asheducation.V2012.1.466.3798741","article-title":"Is my patient a bleeder? A diagnostic framework for mild bleeding disorders","volume":"2012","author":"Quiroga","year":"2012","journal-title":"Hematology (Am Soc Hematol Educ Program)."},{"issue":"2","key":"2021111115211312200_B3","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/jth.14363","article-title":"Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research","volume":"17","author":"Mezzano","year":"2019","journal-title":"J Thromb Haemost."},{"issue":"3","key":"2021111115211312200_B4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.3324\/haematol.10816","article-title":"High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls","volume":"92","author":"Quiroga","year":"2007","journal-title":"Haematologica."},{"issue":"3","key":"2021111115211312200_B5","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3324\/haematol.11231","article-title":"Investigating people with mucocutaneous bleeding suggestive of primary hemostatic defects: a low likelihood of a definitive diagnosis?","volume":"92","author":"Favaloro","year":"2007","journal-title":"Haematologica."},{"issue":"2","key":"2021111115211312200_B6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1111\/ijlh.13124","article-title":"Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment","volume":"42","author":"MacDonald","year":"2020","journal-title":"Int J Lab Hematol."},{"issue":"2","key":"2021111115211312200_B7","doi-asserted-by":"crossref","first-page":"e31","DOI":"10.1111\/hae.13775","article-title":"The bleeding score: useful in predicting spontaneous bleeding events in adults with bleeding of unknown cause?","volume":"26","author":"Relke","year":"2020","journal-title":"Haemophilia."},{"key":"2021111115211312200_B8","doi-asserted-by":"crossref","first-page":"34","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","volume":"78","author":"Gebhart","year":"2020","journal-title":"Eur J Intern Med."},{"issue":"3","key":"2021111115211312200_B9","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."},{"issue":"11","key":"2021111115211312200_B10","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1111\/j.1538-7836.2012.04923.x","article-title":"The evolution and value of bleeding assessment tools","volume":"10","author":"Rydz","year":"2012","journal-title":"J Thromb Haemost."},{"issue":"9","key":"2021111115211312200_B11","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."},{"issue":"6","key":"2021111115211312200_B12","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1111\/hae.12503","article-title":"Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project","volume":"20","author":"Elbatarny","year":"2014","journal-title":"Haemophilia."},{"issue":"4","key":"2021111115211312200_B13","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/hae.13486","article-title":"The diagnostic accuracy of bleeding assessment tools for the identification of patients with mild bleeding disorders: a systematic review","volume":"24","author":"Moenen","year":"2018","journal-title":"Haemophilia."},{"issue":"4","key":"2021111115211312200_B14","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/MBC.0b013e32835274d9","article-title":"The condensed MCMDM-1 VWD bleeding questionnaire as a predictor of bleeding disorders in women with unexplained menorrhagia","volume":"23","author":"Azzam","year":"2012","journal-title":"Blood Coagul Fibrinolysis."},{"issue":"6","key":"2021111115211312200_B15","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1111\/j.1538-7836.2011.04265.x","article-title":"Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation","volume":"9","author":"Tosetto","year":"2011","journal-title":"J Thromb Haemost."},{"issue":"7","key":"2021111115211312200_B16","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/jth.14454","article-title":"Diagnostic utility of the ISTH bleeding assessment tool in patients with suspected platelet function disorders","volume":"17","author":"Adler","year":"2019","journal-title":"J Thromb Haemost."},{"issue":"2","key":"2021111115211312200_B17","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1111\/hae.13922","article-title":"Diagnostic work up of patients with increased bleeding tendency","volume":"26","author":"Zegers","year":"2020","journal-title":"Haemophilia."},{"issue":"3","key":"2021111115211312200_B18","doi-asserted-by":"crossref","first-page":"e106","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","volume":"26","author":"Veen","year":"2020","journal-title":"Haemophilia."},{"issue":"6","key":"2021111115211312200_B19","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/EJA.0000000000000985","article-title":"Thromboelastometry as a diagnostic tool in mild bleeding disorders: a prospective cohort study","volume":"36","author":"Wieland Greguare-Sander","year":"2019","journal-title":"Eur J Anaesthesiol."},{"issue":"5","key":"2021111115211312200_B20","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1055\/s-0036-1597289","article-title":"Bleeding scores for the diagnosis of von Willebrand disease","volume":"43","author":"Bowman","year":"2017","journal-title":"Semin Thromb Hemost."},{"issue":"4","key":"2021111115211312200_B21","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."},{"issue":"2","key":"2021111115211312200_B22","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/hae.12020","article-title":"Suspected collagen disorders in the bleeding disorder clinic: a case-control study","volume":"19","author":"Jackson","year":"2013","journal-title":"Haemophilia."},{"key":"2021111115211312200_B23","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/ijlh.12822","article-title":"How I investigate for bleeding disorders","volume":"40","author":"Hayward","year":"2018","journal-title":"Int J Lab Hematol."},{"issue":"25","key":"2021111115211312200_B24","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.1182\/blood.2020005843","article-title":"The relationship between ABO blood group, von Willebrand factor, and primary hemostasis","volume":"136","author":"Ward","year":"2020","journal-title":"Blood."},{"issue":"20","key":"2021111115211312200_B25","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."},{"issue":"1","key":"2021111115211312200_B26","doi-asserted-by":"crossref","first-page":"280","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."},{"issue":"12","key":"2021111115211312200_B27","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1111\/j.1538-7836.2007.02752.x","article-title":"Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time","volume":"5","author":"Podda","year":"2007","journal-title":"J Thromb Haemost."},{"issue":"2","key":"2021111115211312200_B28","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."},{"issue":"9","key":"2021111115211312200_B29","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."},{"issue":"3","key":"2021111115211312200_B30","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/ijlh.13155","article-title":"Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity","volume":"42","author":"MacDonald","year":"2020","journal-title":"Int J Lab Hematol."},{"issue":"3","key":"2021111115211312200_B31","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00277-016-2893-6","article-title":"Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause","volume":"96","author":"Gebhart","year":"2017","journal-title":"Ann Hematol."},{"issue":"1","key":"2021111115211312200_B32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1538-7836.2005.01709.x","article-title":"Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis","volume":"4","author":"Agren","year":"2006","journal-title":"J Thromb Haemost."},{"issue":"4","key":"2021111115211312200_B33","doi-asserted-by":"crossref","first-page":"e0125069","DOI":"10.1371\/journal.pone.0125069","article-title":"Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study","volume":"10","author":"Szczepaniak","year":"2015","journal-title":"PLoS One."},{"issue":"9","key":"2021111115211312200_B34","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1007\/s00277-011-1201-8","article-title":"Thrombin generation in patients with a bleeding tendency of unknown origin","volume":"90","author":"Ay","year":"2011","journal-title":"Ann Hematol."},{"issue":"1","key":"2021111115211312200_B35","doi-asserted-by":"crossref","first-page":"e2016014","DOI":"10.4084\/mjhid.2016.014","article-title":"Patients referred for bleeding symptoms of unknown cause: does evaluation of thrombin generation contribute to diagnosis?","volume":"8","author":"Holm","year":"2016","journal-title":"Mediterr J Hematol Infect Dis."},{"issue":"23","key":"2021111115211312200_B36","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1182\/blood.2018891192","article-title":"Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders","volume":"134","author":"Downes","year":"2019","journal-title":"Blood."},{"issue":"2","key":"2021111115211312200_B37","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1111\/hae.12811","article-title":"Unclassified bleeding disorders: outcome of haemostatic challenges following tranexamic acid and\/or desmopressin","volume":"22","author":"Obaji","year":"2016","journal-title":"Haemophilia."},{"issue":"26","key":"2021111115211312200_B38","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1182\/blood-2014-02-557264","article-title":"The bleeding score predicts clinical outcomes and replacement therapy in adults with von Willebrand disease","volume":"123","author":"Federici","year":"2014","journal-title":"Blood."},{"issue":"7","key":"2021111115211312200_B39","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.3324\/haematol.2016.160754","article-title":"Bleeding risk of surgery and its prevention in patients with inherited platelet disorders","volume":"102","author":"Orsini","year":"2017","journal-title":"Haematologica."},{"issue":"10","key":"2021111115211312200_B40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3310\/hta17100","article-title":"The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients","volume":"17","author":"Roberts","year":"2013","journal-title":"Health Technol Assess."},{"issue":"10084","key":"2021111115211312200_B41","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1016\/S0140-6736(17)30638-4","article-title":"Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial","volume":"389","author":"Collaborators","year":"2017","journal-title":"Lancet."},{"issue":"4","key":"2021111115211312200_B42","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1055\/s-0038-1646051","article-title":"Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses","volume":"58","author":"Mannucci","year":"1987","journal-title":"Thromb Haemost."},{"issue":"1","key":"2021111115211312200_B43","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1172\/JCI9516","article-title":"Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP","volume":"106","author":"Kaufmann","year":"2000","journal-title":"J Clin Invest."},{"issue":"1","key":"2021111115211312200_B44","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/hae.12763","article-title":"Practical aspects of DDAVP use in patients with von Willebrand disease undergoing invasive procedures: a European survey","volume":"22","author":"Windyga","year":"2016","journal-title":"Haemophilia."},{"issue":"2","key":"2021111115211312200_B45","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1055\/s-0035-1569068","article-title":"The judicious use of recombinant factor VIIa","volume":"42","author":"Goodnough","year":"2016","journal-title":"Semin Thromb Hemost."},{"issue":"17","key":"2021111115211312200_B46","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1056\/NEJMra1513247","article-title":"Postpartum hemorrhage","volume":"384","author":"Bienstock","year":"2021","journal-title":"N Engl J Med."},{"issue":"13","key":"2021111115211312200_B47","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1182\/bloodadvances.2020002038","article-title":"Low VWF: insights into pathogenesis, diagnosis, and clinical management","volume":"4","author":"O\u2019Donnell","year":"2020","journal-title":"Blood Adv."},{"issue":"14","key":"2021111115211312200_B48","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1182\/bloodadvances.2018017418","article-title":"Significant gynecological bleeding in women with low von Willebrand factor levels","volume":"2","author":"Lavin","year":"2018","journal-title":"Blood Adv."},{"issue":"8","key":"2021111115211312200_B49","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1182\/blood-2018-10-844936","article-title":"How I treat low von Willebrand factor levels","volume":"133","author":"Lavin","year":"2019","journal-title":"Blood."},{"issue":"6","key":"2021111115211312200_B50","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1111\/hae.13067","article-title":"Obstetric bleeding among women with inherited bleeding disorders: a retrospective study","volume":"22","author":"Hawke","year":"2016","journal-title":"Haemophilia."},{"issue":"8","key":"2021111115211312200_B51","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1089\/bfm.2014.0027","article-title":"Outcome following tranexamic acid exposure during breastfeeding","volume":"9","author":"Gilad","year":"2014","journal-title":"Breastfeed Med."},{"issue":"4","key":"2021111115211312200_B52","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1111\/bjh.13064","article-title":"The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology","volume":"167","author":"Laffan","year":"2014","journal-title":"Br J Haematol."},{"issue":"1","key":"2021111115211312200_B53","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1365-2516.2011.02573.x","article-title":"A systematic review: the use of desmopressin for treatment and prophylaxis of bleeding disorders in pregnancy","volume":"18","author":"Trigg","year":"2012","journal-title":"Haemophilia."},{"issue":"12","key":"2021111115211312200_B54","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."},{"issue":"14","key":"2021111115211312200_B55","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1182\/blood-2016-05-716092","article-title":"Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy","volume":"128","author":"Burley","year":"2016","journal-title":"Blood."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/138\/19\/1795\/1834679\/bloodbld2020010038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/138\/19\/1795\/1834679\/bloodbld2020010038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T12:36:48Z","timestamp":1725626208000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/138\/19\/1795\/476587\/How-I-treat-bleeding-disorder-of-unknown-cause"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,11]]},"references-count":55,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2021,11,11]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020010038","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,11]]}}}