{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T22:13:16Z","timestamp":1790374396666,"version":"4.1.0"},"reference-count":55,"publisher":"American Society of Hematology","issue":"14","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We observed a 55-year-old Italian man who presented with mucosal and cutaneous bleeding. Results of his blood analysis showed low levels of von Willebrand factor (VWF) antigen and VWF activity (both VWF ristocetin cofactor and VWF collagen binding), mild thrombocytopenia, increased ristocetin-induced platelet aggregation, and a deficiency of high-molecular-weight multimers, all typical phenotypic hallmarks of type 2B von Willebrand disease (VWD). The analysis of the VWF gene sequence revealed heterozygous in cis mutations: (1) c.2771G&amp;gt;A and (2) c.6532G&amp;gt;T substitutions in the exons 21 and 37, respectively. The first mutation causes the substitution of an Arg residue with a Gln at position 924, in the D\u2032D3 domain. The second mutation causes an Ala to Ser substitution at position 2178 in the D4 domain. The patient\u2019s daughter did not present the same fatherly mutations but showed only the heterozygous polymorphic c.3379C&amp;gt;T mutation in exon 25 of the VWF gene causing the p.P1127S substitution, inherited from her mother. The in vitro expression of the heterozygous in cis VWF mutant rVWFWT\/rVWF924Q-2178S confirmed and recapitulated the ex vivo VWF findings. Molecular modeling showed that these in cis mutations stabilize a partially stretched and open conformation of the VWF monomer. Transmission electron microscopy and atomic force microscopy showed in the heterozygous recombinant form rVWFWT\/rVWF924Q-2178S a stretched conformation, forming strings even under static conditions. Thus, the heterozygous in cis mutations 924Q\/2178S promote conformational transitions in the VWF molecule, causing a type 2B\u2013like VWD phenotype, despite the absence of typical mutations in the A1 domain of VWF.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002334","type":"journal-article","created":{"date-parts":[[2020,7,28]],"date-time":"2020-07-28T19:42:36Z","timestamp":1595965356000},"page":"3405-3415","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":15,"title":["Noncanonical type 2B von Willebrand disease associated with mutations in the VWF D\u2032D3 and D4 domains"],"prefix":"10.1182","volume":"4","author":[{"given":"Monica","family":"Sacco","sequence":"first","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Facolt\u00e0 di Medicina e Chirurgia Agostino Gemelli, Universit\u00e0 Cattolica S. Cuore, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Lancellotti","sequence":"additional","affiliation":[{"name":"Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7827-9249","authenticated-orcid":false,"given":"Mattia","family":"Ferrarese","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita e Biotecnologie, Universit\u00e0 di Ferrara, Ferrara, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0305-2212","authenticated-orcid":false,"given":"Francesco","family":"Bernardi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita e Biotecnologie, Universit\u00e0 di Ferrara, Ferrara, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Pinotti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita e Biotecnologie, Universit\u00e0 di Ferrara, Ferrara, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maira","family":"Tardugno","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Facolt\u00e0 di Medicina e Chirurgia Agostino Gemelli, Universit\u00e0 Cattolica S. Cuore, Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0942-2819","authenticated-orcid":false,"given":"Erica","family":"De Candia","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina e Chirurgia Traslazionale, Facolt\u00e0 di Medicina e Chirurgia Agostino Gemelli, Universit\u00e0 Cattolica S. Cuore, Rome, Italy;"},{"name":"Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Di Gennaro","sequence":"additional","affiliation":[{"name":"Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Basso","sequence":"additional","affiliation":[{"name":"Servizio Malattie Emorragiche e Trombotiche, Fondazione Policlinico Universitario A. Gemelli, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betti","family":"Giusti","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale e Clinica, Universit\u00e0 di Firenze, Florence, Italy;"},{"name":"Laboratorio Genetico Molecolare Avanzato, Struttura Operativa Dipartimentale (SOD) Malattie Aterotrombotiche, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0029-1309","authenticated-orcid":false,"given":"Massimiliano","family":"Papi","sequence":"additional","affiliation":[{"name":"Dipartimento di Neuroscienze, Facolt\u00e0 di Medicina e Chirurgia Agostino Gemelli, Universit\u00e0 Cattolica S. Cuore, Rome, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-8479","authenticated-orcid":false,"given":"Giordano","family":"Perini","sequence":"additional","affiliation":[{"name":"Dipartimento di Neuroscienze, Facolt\u00e0 di Medicina e Chirurgia Agostino Gemelli, Universit\u00e0 Cattolica S. 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