{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:17:56Z","timestamp":1776313076299,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T00:00:00Z","timestamp":1727049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To examine the association between hypermobility\u2010related disorders, vitamin C status and BDUC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score\u00a0\u2265\u00a010 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high\u2010performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The majority of patients were female (56\/60). Median ISTH BAT score was 13 (range 10\u201323). Beighton score was positive in 29\/60 patients compared to 1\/20 healthy controls (HC) (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a0.001). Hyperextensive skin was observed in (18\/60) patients, and none (0\/20) of the HC (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers\u2013Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4\u00a0\u03bcmol\/L; <jats:italic>p<\/jats:italic>\u00a0=\u00a0.001). Suboptimal, or low vitamin C were identified in 19\/60 compared to 1\/20 HC (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.018).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.15099","type":"journal-article","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T13:56:25Z","timestamp":1727099785000},"page":"1366-1372","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Low vitamin C status and hypermobility\u2010related disorders in patients with bleeding disorder of unknown cause"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0739-7293","authenticated-orcid":false,"given":"Eva","family":"Lein\u00f8e","sequence":"first","affiliation":[{"name":"Department of Haematology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halla","family":"Fridriksdottir","sequence":"additional","affiliation":[{"name":"Department of Haematology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas \u00d8rslev","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0314-5275","authenticated-orcid":false,"given":"Eva","family":"Funding","sequence":"additional","affiliation":[{"name":"Department of Haematology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne Louise T\u00f8lb\u00f8ll","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Department of Haematology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Kampmann","sequence":"additional","affiliation":[{"name":"Department of Haematology Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jens","family":"Lykkesfeldt","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Rossing","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2023.101164"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2023.12.027"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14363"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2021.100726"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.03.005"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2023.102296"},{"key":"e_1_2_10_8_1","volume-title":"The Ehlers Danlos Society","year":"2022"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31552"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2023.04.004"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13800"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2010.02313.x"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31429"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2019-031365"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs\u20104547888\/v1"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31552"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14310"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31548"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000012513.58079.EA"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ccr3.7418"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14195"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.31540"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2000.4592"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0007114509993229"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.2903\/j.efsa.2013.3418"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu15071657"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2014-15-6-r84"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14479"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023020118"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13683"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12020"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/RHU.0000000000001864"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocpiqo.2024.04.001"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rpth.2023.102176"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13249"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.14026"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.03.017"}],"container-title":["Haemophilia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.15099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T04:59:55Z","timestamp":1734670795000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hae.15099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,23]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,11]]}},"alternative-id":["10.1111\/hae.15099"],"URL":"https:\/\/doi.org\/10.1111\/hae.15099","archive":["Portico"],"relation":{},"ISSN":["1351-8216","1365-2516"],"issn-type":[{"value":"1351-8216","type":"print"},{"value":"1365-2516","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,23]]},"assertion":[{"value":"2024-07-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}