{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T15:33:11Z","timestamp":1792251191880,"version":"4.4.0"},"reference-count":65,"publisher":"American Society of Hematology","issue":"17","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,23]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The regulated secretion of von Willebrand factor (VWF) from Weibel-Palade bodies (WPBs) in endothelial cells is fundamental to hemostasis. This process relies on recruiting Rab GTPases and their effectors to the WPB membrane, with the guanine nucleotide exchange factor MAPK-activating death domain (MADD) playing a central role. Biallelic variants in MADD lead to a pleiotropic neurological and developmental disorder that can include bleeding abnormalities. This study investigates the impact of pathogenic MADD variants on VWF secretion using patient-derived endothelial cells. We isolated endothelial colony-forming cells (ECFCs) from 3 pediatric patients with biallelic MADD variants and unaffected heterozygous family members. All patients exhibited low VWF plasma levels (22-30 IU\/dL). Proteomic analysis of patient-derived ECFCs revealed an absence of MADD peptides, reduced VWF, and downregulation of proteins involved in the exocytotic machinery, including Rab3D and the Rab3\/27 effector Slp4-a. Functional assays demonstrated diminished Rab27A and Rab3D activity and their failure to localize to WPBs in patient cells. Biochemical and live-imaging studies showed that histamine-induced VWF and VWF propeptide secretion were significantly reduced in patient cells due to delayed and reduced degranulation of WPBs. Our findings demonstrate the critical role of MADD in maintaining the secretion competence of WPBs and the magnitude of VWF secretion by regulating the recruitment of the endothelial exocytotic machinery. This study highlights the in vivo significance of WPB exocytosis in maintaining plasma VWF levels and establishes MADD as the first causal gene for quantitative von Willebrand disease in patients without pathogenic VWF variants.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027935","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T18:48:47Z","timestamp":1752691727000},"page":"2133-2144","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["A novel cause of type 1 von Willebrand disease: impaired exocytosis of Weibel-Palade bodies due to biallelic\n                    <i>MADD<\/i>\n                    variants"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8454-8967","authenticated-orcid":false,"given":"Sophie","family":"Hordijk","sequence":"first","affiliation":[{"name":"1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9438-9939","authenticated-orcid":false,"given":"Stijn A.","family":"Groten","sequence":"additional","affiliation":[{"name":"2Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7832-8028","authenticated-orcid":false,"given":"Petra E.","family":"B\u00fcrgisser","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9206-8712","authenticated-orcid":false,"given":"Sebastiaan N. J.","family":"Laan","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"},{"name":"3Division of Thrombosis and Hemostasis, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg Christoph","family":"Korenke","sequence":"additional","affiliation":[{"name":"4Department of Neuropediatrics, Pediatric Center, Oldenburg Hospital, Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1\u0161","family":"Honz\u00edk","sequence":"additional","affiliation":[{"name":"5Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Beysen","sequence":"additional","affiliation":[{"name":"6Department of Paediatric Neurology, University Hospital of Antwerp, Edegem, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-1371","authenticated-orcid":false,"given":"Frank W. G.","family":"Leebeek","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"Skehel","sequence":"additional","affiliation":[{"name":"7Department of Biomedical Sciences, Centre for Discovery Brain Sciences, Edinburgh University, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6970-5496","authenticated-orcid":false,"given":"Maartje","family":"van den Biggelaar","sequence":"additional","affiliation":[{"name":"2Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6248-7278","authenticated-orcid":false,"given":"Tom","family":"Carter","sequence":"additional","affiliation":[{"name":"8Division of Neurosciences and Cell Biology, City St. George\u2019s, University of London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1205-9689","authenticated-orcid":false,"given":"Ruben","family":"Bierings","sequence":"additional","affiliation":[{"name":"1Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2025102311222351800_bib1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41572-024-00536-8","article-title":"von Willebrand disease","volume":"10","author":"Seidizadeh","year":"2024","journal-title":"Nat Rev Dis Primers"},{"issue":"14","key":"2025102311222351800_bib2","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1182\/blood.2023022457","article-title":"Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies","volume":"143","author":"Atiq","year":"2024","journal-title":"Blood"},{"issue":"1","key":"2025102311222351800_bib3","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":"2025102311222351800_bib4","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1161\/CIRCULATIONAHA.109.869156","article-title":"Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von willebrand factor: the CHARGE (cohorts for heart and aging research in genome epidemiology) Consortium","volume":"121","author":"Smith","year":"2010","journal-title":"Circulation"},{"issue":"26","key":"2025102311222351800_bib5","doi-asserted-by":"crossref","first-page":"5228","DOI":"10.1182\/blood-2012-10-457507","article-title":"The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels","volume":"121","author":"Rydz","year":"2013","journal-title":"Blood"},{"issue":"9","key":"2025102311222351800_bib6","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1172\/JCI96400","article-title":"The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity","volume":"128","author":"Swystun","year":"2018","journal-title":"J Clin Invest"},{"issue":"8","key":"2025102311222351800_bib7","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1111\/jth.14521","article-title":"The scavenger receptor SCARA5 is an endocytic receptor for von Willebrand factor expressed by littoral cells in the human spleen","volume":"17","author":"Swystun","year":"2019","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2025102311222351800_bib8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1083\/jcb.23.1.101","article-title":"New cytoplasmic components in arterial endothelia","volume":"23","author":"Weibel","year":"1964","journal-title":"J Cell Biol"},{"issue":"1","key":"2025102311222351800_bib9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1083\/jcb.95.1.355","article-title":"Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells","volume":"95","author":"Wagner","year":"1982","journal-title":"J Cell Biol"},{"issue":"5","key":"2025102311222351800_bib10","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.jtha.2024.01.015","article-title":"A new look at an old body: molecular determinants of Weibel-Palade body composition and von Willebrand factor exocytosis","volume":"22","author":"Hordijk","year":"2024","journal-title":"J Thromb Haemost"},{"issue":"23","key":"2025102311222351800_bib11","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1182\/bloodadvances.2021004827","article-title":"GDP\/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies","volume":"5","author":"Kat","year":"2021","journal-title":"Blood Adv"},{"issue":"8","key":"2025102311222351800_bib12","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1093\/brain\/awaa204","article-title":"Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder","volume":"143","author":"Schneeberger","year":"2020","journal-title":"Brain"},{"issue":"11-12","key":"2025102311222351800_bib13","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s00439-017-1843-2","article-title":"Expanding the genetic heterogeneity of intellectual disability","volume":"136","author":"Anazi","year":"2017","journal-title":"Hum Genet"},{"issue":"6","key":"2025102311222351800_bib14","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1038\/s41431-021-00844-7","article-title":"Homozygous variant in MADD, encoding a Rab guanine nucleotide exchange factor, results in pleiotropic effects and a multisystemic disorder","volume":"29","author":"Abu-Libdeh","year":"2021","journal-title":"Eur J Hum Genet"},{"issue":"3","key":"2025102311222351800_bib15","doi-asserted-by":"crossref","first-page":"e63463","DOI":"10.1002\/ajmg.a.63463","article-title":"Calloso-adreno-scrotal agenesis associated with biallelic MAPK-activating death domain protein (MADD) variant: further phenotypic delineation of MADD deficiency","volume":"194","author":"Darouich","year":"2024","journal-title":"Am J Med Genet A"},{"issue":"Pt 2","key":"2025102311222351800_bib16","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1042\/bj3620273","article-title":"The death domain of rab3 guanine nucleotide exchange protein in GDP\/GTP exchange activity in living cells","volume":"362","author":"Coppola","year":"2002","journal-title":"Biochem J"},{"issue":"7","key":"2025102311222351800_bib17","doi-asserted-by":"crossref","first-page":"jcs261582","DOI":"10.1242\/jcs.261582","article-title":"MADD regulates natural killer cell degranulation through Rab27a activation","volume":"137","author":"Medlyn","year":"2024","journal-title":"J Cell Sci"},{"issue":"8","key":"2025102311222351800_bib18","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1182\/bloodadvances.2022008195","article-title":"MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity","volume":"7","author":"Sch\u00fctze","year":"2023","journal-title":"Blood Adv"},{"issue":"1","key":"2025102311222351800_bib19","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.abb.2013.05.002","article-title":"MADD\/DENN\/Rab3GEP functions as a guanine nucleotide exchange factor for Rab27 during granule exocytosis of rat parotid acinar cells","volume":"536","author":"Imai","year":"2013","journal-title":"Arch Biochem Biophys"},{"issue":"9","key":"2025102311222351800_bib20","doi-asserted-by":"crossref","first-page":"jcs212035","DOI":"10.1242\/jcs.212035","article-title":"Nucleotide exchange factor Rab3GEP requires DENN and non-DENN elements for activation and targeting of rab27a","volume":"132","author":"Sanz\u00e0","year":"2019","journal-title":"J Cell Sci"},{"issue":"11","key":"2025102311222351800_bib21","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1038\/ncb1785","article-title":"KIF1B\u03b2- and KIF1A-mediated axonal transport of presynaptic regulator Rab3 occurs in a GTP-dependent manner through DENN\/MADD","volume":"10","author":"Niwa","year":"2008","journal-title":"Nat Cell Biol"},{"issue":"10","key":"2025102311222351800_bib22","doi-asserted-by":"crossref","first-page":"e167598","DOI":"10.1172\/jci.insight.167598","article-title":"A splice site variant in MADD affects hormone expression in pancreatic \u03b2 cells and pituitary gonadotropes","volume":"9","author":"Pulli","year":"2024","journal-title":"JCI Insight"},{"issue":"5","key":"2025102311222351800_bib23","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.2337\/db13-0707","article-title":"IG20\/MADD plays a critical role in glucose-induced insulin secretion","volume":"63","author":"Li","year":"2014","journal-title":"Diabetes"},{"issue":"9","key":"2025102311222351800_bib24","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1038\/nprot.2012.093","article-title":"Establishment of outgrowth endothelial cells from peripheral blood","volume":"7","author":"Martin-Ramirez","year":"2012","journal-title":"Nat Protoc"},{"issue":"8","key":"2025102311222351800_bib25","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1038\/s41592-018-0051-x","article-title":"Strelka2: fast and accurate calling of germline and somatic variants","volume":"15","author":"Kim","year":"2018","journal-title":"Nat Methods"},{"issue":"18","key":"2025102311222351800_bib26","doi-asserted-by":"crossref","first-page":"i333","DOI":"10.1093\/bioinformatics\/bts378","article-title":"DELLY: structural variant discovery by integrated paired-end and split-read analysis","volume":"28","author":"Rausch","year":"2012","journal-title":"Bioinformatics"},{"issue":"7","key":"2025102311222351800_bib27","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1016\/j.jtha.2024.03.018","article-title":"Transcriptional and functional profiling identifies inflammation and endothelial-to-mesenchymal transition as potential drivers for phenotypic heterogeneity within a cohort of endothelial colony forming cells","volume":"22","author":"Laan","year":"2024","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2025102311222351800_bib28","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1038\/s42003-024-06649-w","article-title":"The proteomic landscape of in vitro cultured endothelial cells across vascular beds","volume":"7","author":"Groten","year":"2024","journal-title":"Commun Biol"},{"issue":"7","key":"2025102311222351800_bib29","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"2025102311222351800_bib30","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.3324\/haematol.2019.242727","article-title":"Sec22b determines Weibel-Palade body length by controlling anterograde endoplasmic reticulum-Golgi transport","volume":"106","author":"Karampini","year":"2021","journal-title":"Haematologica"},{"issue":"2","key":"2025102311222351800_bib31","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.jtha.2024.10.023","article-title":"The severe von Willebrand disease variant p.M771V leads to impaired anterograde trafficking of von Willebrand factor in patient-derived and base-edited endothelial colony-forming cells","volume":"23","author":"B\u00e4r","year":"2025","journal-title":"J Thromb Haemost"},{"issue":"1","key":"2025102311222351800_bib32","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1186\/s12859-021-04344-9","article-title":"CellProfiler 4: improvements in speed, utility and usability","volume":"22","author":"Stirling","year":"2021","journal-title":"BMC Bioinformatics"},{"issue":"6","key":"2025102311222351800_bib33","doi-asserted-by":"crossref","first-page":"e0278009","DOI":"10.1371\/journal.pone.0278009","article-title":"Automated segmentation and quantitative analysis of organelle morphology, localization and content using CellProfiler","volume":"18","author":"Laan","year":"2023","journal-title":"PLoS One"},{"issue":"7","key":"2025102311222351800_bib34","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/j.jtha.2023.03.041","article-title":"Quantitative super-resolution imaging of platelet degranulation reveals differential release of von Willebrand factor and von Willebrand factor propeptide from alpha-granules","volume":"21","author":"Swinkels","year":"2023","journal-title":"J Thromb Haemost"},{"issue":"5","key":"2025102311222351800_bib35","doi-asserted-by":"crossref","first-page":"jcs221952","DOI":"10.1242\/jcs.221952","article-title":"Synaptotagmin 5 regulates calcium-dependent Weibel-Palade body exocytosis in human endothelial cells","volume":"132","author":"Lenzi","year":"2019","journal-title":"J Cell Sci"},{"issue":"9","key":"2025102311222351800_bib36","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1038\/s41587-023-02018-w","article-title":"A monomeric StayGold fluorescent protein","volume":"42","author":"Ivorra-Molla","year":"2024","journal-title":"Nat Biotechnol"},{"issue":"7","key":"2025102311222351800_bib37","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/s41587-022-01278-2","article-title":"A highly photostable and bright green fluorescent protein","volume":"40","author":"Hirano","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"12","key":"2025102311222351800_bib38","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1182\/blood.2019000786","article-title":"Proximity proteomics of endothelial Weibel-Palade bodies identifies novel regulator of von Willebrand factor secretion","volume":"134","author":"Holthenrich","year":"2019","journal-title":"Blood"},{"issue":"5","key":"2025102311222351800_bib39","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1021\/pr300010r","article-title":"Proteomic screen identifies IGFBP7 as a novel component of endothelial cell-specific weibel-palade bodies","volume":"11","author":"Van Breevoort","year":"2012","journal-title":"J Proteome Res"},{"issue":"20","key":"2025102311222351800_bib40","doi-asserted-by":"crossref","first-page":"3185","DOI":"10.1182\/blood-2013-10-535831","article-title":"STXBP1 promotes Weibel-Palade body exocytosis through its interaction with the Rab27A effector Slp4-a","volume":"123","author":"van Breevoort","year":"2014","journal-title":"Blood"},{"issue":"13","key":"2025102311222351800_bib41","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1182\/blood-2012-05-429936","article-title":"The interplay between the Rab27A effectors Slp4-a and MyRIP controls hormone-evoked Weibel-Palade body exocytosis","volume":"120","author":"Bierings","year":"2012","journal-title":"Blood"},{"issue":"20","key":"2025102311222351800_bib42","doi-asserted-by":"crossref","first-page":"5010","DOI":"10.1182\/blood-2008-09-181206","article-title":"Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells","volume":"113","author":"Nightingale","year":"2009","journal-title":"Blood"},{"issue":"15","key":"2025102311222351800_bib43","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1038\/sj.emboj.7600319","article-title":"Rab3D and annexin A2 play a role in regulated of vWF, but not tPA, from endothelial cells","volume":"23","author":"Knop","year":"2004","journal-title":"EMBO J"},{"issue":"pt 20","key":"2025102311222351800_bib44","first-page":"4780","article-title":"A complete rab screening reveals novel insights in Weibel-Palade body exocytosis","volume":"125","author":"Zografou","year":"2012","journal-title":"J Cell Sci"},{"issue":"7","key":"2025102311222351800_bib45","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1161\/ATVBAHA.117.310701","article-title":"Weibel-Palade body localized syntaxin-3 modulates von willebrand factor secretion from endothelial cells","volume":"38","author":"Schillemans","year":"2018","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"10","key":"2025102311222351800_bib46","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.3324\/haematol.2018.207787","article-title":"Defective AP-3-dependent VAMP8 trafficking impairs Weibel-Palade body exocytosis in Hermansky-Pudlak syndrome type 2 blood outgrowth endothelial cells","volume":"104","author":"Karampini","year":"2019","journal-title":"Haematologica"},{"issue":"24","key":"2025102311222351800_bib47","doi-asserted-by":"crossref","first-page":"2824","DOI":"10.1182\/blood.2020005300","article-title":"VWF maturation and release are controlled by 2 regulators of Weibel-Palade body biogenesis: exocyst and BLOC-2","volume":"136","author":"Sharda","year":"2020","journal-title":"Blood"},{"issue":"6","key":"2025102311222351800_bib48","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/jnr.20405","article-title":"Subcellular localization of neural-specific NPDC-1 protein","volume":"79","author":"Evrard","year":"2005","journal-title":"J Neurosci Res"},{"issue":"17","key":"2025102311222351800_bib49","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1093\/emboj\/19.17.4806","article-title":"The Rab3 GDP\/GTP exchange factor homolog AEX-3 has a dual function in synaptic transmission","volume":"19","author":"Iwasaki","year":"2000","journal-title":"EMBO J"},{"issue":"4","key":"2025102311222351800_bib50","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0896-6273(00)80302-5","article-title":"aex-3 encodes a novel regulator of presynaptic activity in C. elegans","volume":"18","author":"Iwasaki","year":"1997","journal-title":"Neuron"},{"issue":"11","key":"2025102311222351800_bib51","doi-asserted-by":"crossref","first-page":"e1009877","DOI":"10.1371\/journal.pgen.1009877","article-title":"rab-27 acts in an intestinal pathway to inhibit axon regeneration in C. elegans","volume":"17","author":"Lin-Moore","year":"2021","journal-title":"PLoS Genet"},{"issue":"4","key":"2025102311222351800_bib52","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1182\/blood-2007-12-130740","article-title":"Basal secretion of von willebrand factor from human endothelial cells","volume":"112","author":"Giblin","year":"2008","journal-title":"Blood"},{"issue":"2","key":"2025102311222351800_bib53","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1182\/blood-2015-10-677054","article-title":"Von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells","volume":"128","author":"Lopes da Silva","year":"2016","journal-title":"Blood"},{"issue":"6","key":"2025102311222351800_bib54","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1172\/JCI108432","article-title":"The effects of epinephrine infusion in patients with von Willebrand\u2019s disease","volume":"57","author":"Rickles","year":"1976","journal-title":"J Clin Invest"},{"issue":"3","key":"2025102311222351800_bib55","doi-asserted-by":"crossref","first-page":"e91687","DOI":"10.1371\/journal.pone.0091687","article-title":"Performance related factors are the main determinants of the von Willebrand factor response to exhaustive physical exercise","volume":"9","author":"Van Loon","year":"2014","journal-title":"PLoS One"},{"issue":"7","key":"2025102311222351800_bib56","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1111\/j.1538-7836.2010.03884.x","article-title":"Functional variation in the arginine vasopressin 2 receptor as a modifier of human plasma von Willebrand factor levels","volume":"8","author":"Nossent","year":"2010","journal-title":"J Thromb Haemost"},{"issue":"4","key":"2025102311222351800_bib57","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1182\/blood-2016-11-754416","article-title":"Gut microbiota regulate hepatic von Willebrand factor synthesis and arterial thrombus formation via Toll-like receptor-2","volume":"130","author":"J\u00e4ckel","year":"2017","journal-title":"Blood"},{"issue":"11","key":"2025102311222351800_bib58","doi-asserted-by":"crossref","first-page":"8134","DOI":"10.1074\/jbc.M609962200","article-title":"Pathogen recognition by toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells","volume":"282","author":"Into","year":"2007","journal-title":"J Biol Chem"},{"issue":"6","key":"2025102311222351800_bib59","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1111\/hae.15103","article-title":"Patient-reported data on the severity of Von Willebrand disease","volume":"30","author":"van Kwawegen","year":"2024","journal-title":"Haemophilia"},{"issue":"12","key":"2025102311222351800_bib60","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1002\/ajh.24195","article-title":"Bleeding spectrum in children with moderate or severe von Willebrand disease: relevance of pediatric-specific bleeding","volume":"90","author":"Sanders","year":"2015","journal-title":"Am J Hematol"},{"issue":"4","key":"2025102311222351800_bib61","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1111\/j.1538-7836.2006.01847.x","article-title":"A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD)","volume":"4","author":"Tosetto","year":"2006","journal-title":"J Thromb Haemost"},{"issue":"7","key":"2025102311222351800_bib62","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/s41380-017-0012-2","article-title":"Genetics of intellectual disability in consanguineous families","volume":"24","author":"Hu","year":"2019","journal-title":"Mol Psychiatry"},{"issue":"6","key":"2025102311222351800_bib63","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/s10038-024-01236-7","article-title":"New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder","volume":"69","author":"Abdel-Salam","year":"2024","journal-title":"J Hum Genet"},{"issue":"8017","key":"2025102311222351800_bib64","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/S0140-6736(77)91197-7","article-title":"1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands\u2019 diseases","volume":"1","author":"Mannucci","year":"1977","journal-title":"Lancet"},{"issue":"16","key":"2025102311222351800_bib65","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1182\/blood.2024026804","article-title":"DDAVP response and its determinants in bleeding disorders: a systematic review and meta-analysis","volume":"145","author":"Laan","year":"2025","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/146\/17\/2133\/2417575\/blood_bld-2024-027935-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/146\/17\/2133\/2417575\/blood_bld-2024-027935-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T15:22:36Z","timestamp":1761232956000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/146\/17\/2133\/546210\/A-novel-cause-of-type-1-von-Willebrand-disease"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":65,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2025,10,23]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2024027935","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10,23]]},"published":{"date-parts":[[2025,10,23]]}}}