{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T00:16:34Z","timestamp":1699920994336},"reference-count":49,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bleeding disorders with normal, borderline, or nondiagnostic coagulation tests represent a diagnostic challenge. Disorders of primary hemostasis can be further evaluated by additional platelet function testing modalities, platelet electron microscopy, repeat von Willebrand disease testing, and specialized von Willebrand factor testing beyond the usual initial panel. Secondary hemostasis is further evaluated by coagulation factor assays, and factor XIII assays are used to diagnose disorders of fibrin clot stabilization. Fibrinolytic disorders are particularly difficult to diagnose with current testing options. A significant number of patients remain unclassified after thorough testing; most unclassified patients have a clinically mild bleeding phenotype, and many may have undiagnosed platelet function disorders. High-throughput genetic testing using large gene panels for bleeding disorders may allow diagnosis of a larger number of these patients in the future, but more study is needed. A logical laboratory workup in the context of the clinical setting and with a high level of expertise regarding test interpretation and limitations facilitates a diagnosis for as many patients as possible.<\/jats:p>","DOI":"10.1182\/hematology.2021000236","type":"journal-article","created":{"date-parts":[[2021,12,10]],"date-time":"2021-12-10T12:22:52Z","timestamp":1639138972000},"page":"85-91","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Cryptogenic oozers and bruisers"],"prefix":"10.1182","volume":"2021","author":[{"given":"Kristi J.","family":"Smock","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Utah, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen A.","family":"Moser","sequence":"additional","affiliation":[{"name":"ARUP Laboratories, Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","published-online":{"date-parts":[[2021,12,10]]},"reference":[{"issue":"6","key":"2021121012093726400_hem2021000236C1","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":"7","key":"2021121012093726400_hem2021000236C2","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1515\/cclm-2017-1205","article-title":"Laboratory hemostasis: from biology to the bench","volume":"56","author":"Lippi","year":"2018","journal-title":"Clin Chem Lab Med"},{"issue":"7","key":"2021121012093726400_hem2021000236C3","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1055\/s-0032-1326780","article-title":"Laboratory investigations for bleeding disorders","volume":"38","author":"Hayward","year":"2012","journal-title":"Semin Thromb Hemost"},{"issue":"suppl 1","key":"2021121012093726400_hem2021000236C4","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":"8","key":"2021121012093726400_hem2021000236C5","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"},{"issue":"5","key":"2021121012093726400_hem2021000236C6","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1055\/s-0030-1255440","article-title":"Diagnostics of inherited bleeding disorders of secondary hemostasis: an easy guide for routine clinical laboratories","volume":"42","author":"Lippi","year":"2016","journal-title":"Semin Thromb Hemost"},{"issue":"2","key":"2021121012093726400_hem2021000236C7","doi-asserted-by":"crossref","first-page":"539","DOI":"10.3390\/jcm9020539","article-title":"Diagnosis of inherited platelet disorders on a blood smear","volume":"9","author":"Zaninetti","year":"2020","journal-title":"J Clin Med"},{"issue":"suppl 1","key":"2021121012093726400_hem2021000236C8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/ijlh.12653","article-title":"Controversies in the diagnosis of type 1 von Willebrand disease","volume":"39","author":"Bowman","year":"2017","journal-title":"Int J Lab Hematol"},{"issue":"2","key":"2021121012093726400_hem2021000236C9","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/jth.12792","article-title":"Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH","volume":"13","author":"Gresele","year":"2015","journal-title":"J Thromb Haemost"},{"issue":"2","key":"2021121012093726400_hem2021000236C10","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1055\/s-0029-1220785","article-title":"The level of laboratory testing required for diagnosis or exclusion of a platelet function disorder using platelet aggregation and secretion assays","volume":"35","author":"Mezzano","year":"2009","journal-title":"Semin Thromb Hemost"},{"issue":"6","key":"2021121012093726400_hem2021000236C11","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1080\/09537104.2018.1475636","article-title":"An update on quality control for the PFA-100\/PFA-200","volume":"29","author":"Favaloro","year":"2018","journal-title":"Platelets"},{"issue":"4","key":"2021121012093726400_hem2021000236C12","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/ajh.24620","article-title":"Clinical utility of closure times using the platelet function analyzer-100\/200","volume":"92","author":"Favaloro","year":"2017","journal-title":"Am J Hematol"},{"issue":"4","key":"2021121012093726400_hem2021000236C13","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.transci.2018.07.009","article-title":"Laboratory diagnosis of inherited platelet function disorders","volume":"57","author":"Rand","year":"2018","journal-title":"Transfus Apher Sci"},{"issue":"12","key":"2021121012093726400_hem2021000236C14","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1111\/jth.14310","article-title":"Hemostatic abnormalities in patients with Ehlers-Danlos syndrome","volume":"16","author":"Artoni","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2021121012093726400_hem2021000236C15","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":"2","key":"2021121012093726400_hem2021000236C16","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"},{"key":"2021121012093726400_hem2021000236C17","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.thromres.2019.07.010","article-title":"How we make an accurate diagnosis of von Willebrand disease","volume":"196","author":"Baronciani","year":"2020","journal-title":"Thromb Res"},{"issue":"4","key":"2021121012093726400_hem2021000236C18","doi-asserted-by":"crossref","first-page":"e12513","DOI":"10.1002\/rth2.12513","article-title":"Elevated von Willebrand factor levels during heavy menstrual bleeding episodes limit the diagnostic utility for von Willebrand disease","volume":"5","author":"Brown","year":"2021","journal-title":"Res Pract Thromb Haemost"},{"issue":"11","key":"2021121012093726400_hem2021000236C19","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1111\/jth.14591","article-title":"Utility of repeat testing in the evaluation for von Willebrand disease in pediatric patients","volume":"17","author":"Doshi","year":"2019","journal-title":"J Thromb Haemost"},{"issue":"22","key":"2021121012093726400_hem2021000236C20","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1182\/blood-2017-05-782029","article-title":"Advances in the diagnosis and treatment of von Willebrand disease","volume":"130","author":"Sharma","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2021121012093726400_hem2021000236C21","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/rth2.12064","article-title":"Current issues in diagnosis and treatment of von Willebrand disease","volume":"2","author":"Keesler","year":"2018","journal-title":"Res Pract Thromb Haemost"},{"issue":"6","key":"2021121012093726400_hem2021000236C22","doi-asserted-by":"crossref","first-page":"e0179566","DOI":"10.1371\/journal.pone.0179566","article-title":"Type 2B von Willebrand disease with or without large multimers: a distinction of the two sides of the disorder is long overdue","volume":"12","author":"Casonato","year":"2017","journal-title":"PLoS One"},{"issue":"2","key":"2021121012093726400_hem2021000236C23","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1051\/ject\/201850077","article-title":"High molecular weight von Willebrand factor multimer loss and bleeding in patients with short-term mechanical circulatory support devices: a case series","volume":"50","author":"Goldfarb","year":"2018","journal-title":"J Extra Corpor Technol"},{"issue":"4","key":"2021121012093726400_hem2021000236C24","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.ejcts.2007.12.047","article-title":"Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease","volume":"33","author":"Geisen","year":"2008","journal-title":"Eur J Cardiothorac Surg"},{"issue":"25","key":"2021121012093726400_hem2021000236C25","doi-asserted-by":"crossref","first-page":"6777","DOI":"10.1182\/blood-2010-11-297580","article-title":"How I treat the acquired von Willebrand syndrome","volume":"117","author":"Tiede","year":"2011","journal-title":"Blood"},{"issue":"2","key":"2021121012093726400_hem2021000236C26","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1001\/jamacardio.2016.0075","article-title":"von Willebrand factor abnormalities and Heyde syndrome in dysfunctional heart valve prostheses","volume":"1","author":"Blackshear","year":"2016","journal-title":"JAMA Cardiol"},{"issue":"4","key":"2021121012093726400_hem2021000236C27","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1080\/09537104.2020.1771549","article-title":"Harmonizing light transmission aggregometry in the Netherlands by implementation of the SSC-ISTH guideline","volume":"32","author":"Munnix","year":"2021","journal-title":"Platelets"},{"key":"2021121012093726400_hem2021000236C28","article-title":"Recommendations for the standardization of light transmission aggregometry: a consensus of the Working Party from the Platelet Physiology Subcommittee of SSC\/ISTH [published online 10 April 2013]","author":"Cattaneo","journal-title":"J Thromb Haemost"},{"issue":"4","key":"2021121012093726400_hem2021000236C29","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/ijlh.12801","article-title":"Electron microscopy examination of platelet whole mount preparations to quantitate platelet dense granule numbers: implications for diagnosing suspected platelet function disorders due to dense granule deficiency","volume":"40","author":"Brunet","year":"2018","journal-title":"Int J Lab Hematol"},{"issue":"6","key":"2021121012093726400_hem2021000236C30","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1111\/ijlh.12553","article-title":"Variability in platelet dense granule adenosine triphosphate release findings amongst patients tested multiple times as part of an assessment for a bleeding disorder","volume":"38","author":"Badin","year":"2016","journal-title":"Int J Lab Hematol"},{"issue":"8","key":"2021121012093726400_hem2021000236C31","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.3390\/jcm9082508","article-title":"Platelet \u03b4-storage pool disease: an update","volume":"9","author":"Dupuis","year":"2020","journal-title":"J Clin Med"},{"issue":"4","key":"2021121012093726400_hem2021000236C32","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1111\/jth.12836","article-title":"Use of next-generation sequencing and candidate gene analysis to identify underlying defects in patients with inherited platelet function disorders","volume":"13","author":"Leo","year":"2015","journal-title":"J Thromb Haemost"},{"issue":"7","key":"2021121012093726400_hem2021000236C33","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1080\/09537104.2019.1693039","article-title":"Gene of the issue: ANO6 and Scott syndrome","volume":"31","author":"Millington-Burgess","year":"2020","journal-title":"Platelets"},{"issue":"4","key":"2021121012093726400_hem2021000236C34","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/ijlh.12499","article-title":"In vitro sensitivity of different activated partial thromboplastin time reagents to mild clotting factor deficiencies","volume":"38","author":"Toulon","year":"2016","journal-title":"Int J Lab Hematol"},{"issue":"1","key":"2021121012093726400_hem2021000236C35","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1055\/s-0038-1677018","article-title":"How to optimize activated partial thromboplastin time (APTT) testing: solutions to establishing and verifying normal reference intervals and assessing APTT reagents for sensitivity to heparin, lupus anticoagulant, and clotting factors","volume":"45","author":"Favaloro","year":"2019","journal-title":"Semin Thromb Hemost"},{"issue":"1","key":"2021121012093726400_hem2021000236C36","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1093\/ajcp\/aqaa024","article-title":"Discrepant hemophilia A: an underdiagnosed disease entity","volume":"154","author":"Al-Huniti","year":"2020","journal-title":"Am J Clin Pathol"},{"issue":"4","key":"2021121012093726400_hem2021000236C37","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/hae.13219","article-title":"Discrepancies between the one-stage clotting assay and the chromogenic assay in haemophilia B","volume":"23","author":"Kihlberg","year":"2017","journal-title":"Haemophilia"},{"key":"2021121012093726400_hem2021000236C38","volume-title":"Hemophilia A. GeneReviews((R))","author":"Konkle","year":"2017"},{"key":"2021121012093726400_hem2021000236C39","volume-title":"Hemophilia B. GeneReviews((R))","author":"Konkle","year":"2017"},{"issue":"1","key":"2021121012093726400_hem2021000236C40","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1160\/TH08-06-0353","article-title":"Are laboratories following published recommendations for lupus anticoagulant testing? An international evaluation of practices","volume":"101","author":"Moffat","year":"2009","journal-title":"Thromb Haemost"},{"issue":"1","key":"2021121012093726400_hem2021000236C41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/ijlh.12756","article-title":"Factor XIII deficiency diagnosis: challenges and tools","volume":"40","author":"Karimi","year":"2018","journal-title":"Int J Lab Hematol"},{"issue":"6","key":"2021121012093726400_hem2021000236C42","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.transci.2018.07.006","article-title":"State of the art in factor XIII laboratory assessment","volume":"57","author":"Durda","year":"2018","journal-title":"Transfus Apher Sci"},{"issue":"3","key":"2021121012093726400_hem2021000236C43","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/bjh.14796","article-title":"Diagnosis of inherited bleeding disorders in the genomic era","volume":"179","author":"Sivapalaratnam","year":"2017","journal-title":"Br J Haematol"},{"issue":"5","key":"2021121012093726400_hem2021000236C44","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.transci.2019.08.007","article-title":"Inherited disorders of the fibrinolytic pathway","volume":"58","author":"Jain","year":"2019","journal-title":"Transfus Apher Sci"},{"issue":"4","key":"2021121012093726400_hem2021000236C45","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/jth.13957","article-title":"Measuring fibrinolysis: from research to routine diagnostic assays","volume":"16","author":"Longstaff","year":"2018","journal-title":"J Thromb Haemost"},{"issue":"23","key":"2021121012093726400_hem2021000236C46","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":"23","key":"2021121012093726400_hem2021000236C47","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1182\/blood-2015-12-688267","article-title":"A high-throughput sequencing test for diagnosing inherited bleeding, thrombotic, and platelet disorders","volume":"127","author":"Simeoni","year":"2016","journal-title":"Blood"},{"issue":"13","key":"2021121012093726400_hem2021000236C48","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1182\/bloodadvances.2016002923","article-title":"Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative","volume":"1","author":"Johnsen","year":"2017","journal-title":"Blood Adv"},{"issue":"4","key":"2021121012093726400_hem2021000236C49","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/jth.15247","article-title":"Von Willebrand disease type 2N: an update","volume":"19","author":"Seidizadeh","year":"2021","journal-title":"J Thromb Haemost"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/85\/1851788\/85smock.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2021\/1\/85\/1851788\/85smock.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T22:52:12Z","timestamp":1699915932000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2021\/1\/85\/482936\/Cryptogenic-oozers-and-bruisers"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,10]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12,10]]},"published-print":{"date-parts":[[2021,12,10]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2021000236","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,10]]},"published":{"date-parts":[[2021,12,10]]}}}