{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:52:34Z","timestamp":1774533154424,"version":"3.50.1"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T00:00:00Z","timestamp":1607040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"F\u00f3rum Hematol\u00f3gico do Norte"},{"DOI":"10.13039\/501100014148","name":"Centro Hospitalar Universit\u00e1rio do Porto","doi-asserted-by":"crossref","award":["2016\/167-141-DEFI\/130-CES"],"award-info":[{"award-number":["2016\/167-141-DEFI\/130-CES"]}],"id":[{"id":"10.13039\/501100014148","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Rare pathogenic variants in either the<jats:italic>ITGA2B<\/jats:italic>or<jats:italic>ITGB3<\/jats:italic>genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B\/ITGB3-related thrombocytopenia.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Objectives<\/jats:title><jats:p>To describe a series of patients with familial macrothrombocytopenia and decreased expression of \u03b1IIb\u03b23 integrin due to defects in the<jats:italic>ITGA2B<\/jats:italic>or<jats:italic>ITGB3<\/jats:italic>genes.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Methods<\/jats:title><jats:p>We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Results<\/jats:title><jats:p>Patients had absent to moderate bleeding, macrothrombocytopenia, low \u03b1IIb\u03b23 expression, impaired platelet aggregation\/ATP release to physiological agonists and low expression of activation-induced binding sites on \u03b1IIb\u03b23 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive \u03b1IIb\u03b23 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in<jats:italic>ITGA2B<\/jats:italic>(5 families), and 4 in<jats:italic>ITGB3<\/jats:italic>(5 families). Three variants (\u03b1IIb: p.Arg1026Trp and p.Arg1026Gln and \u03b23: p.Asp749His) were previously reported. The remaining (\u03b1IIb: p.Gly1007Val and \u03b23: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the \u03b1IIb\u03b23 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity.<\/jats:p><\/jats:sec><jats:sec id=\"sec005\"><jats:title>Conclusions<\/jats:title><jats:p>Previously reported<jats:italic>ITGA2B<\/jats:italic>and<jats:italic>ITGB3<\/jats:italic>variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of \u03b1IIb, and at the membrane distal cytoplasmic domains of \u03b23. This is the largest single-center series of inherited macrothrombocytopenia associated with \u03b1IIb\u03b23 variants published to date.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0235136","type":"journal-article","created":{"date-parts":[[2020,12,4]],"date-time":"2020-12-04T23:06:35Z","timestamp":1607123195000},"page":"e0235136","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":19,"title":["\u03b1IIb\u03b23 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4266-4457","authenticated-orcid":true,"given":"Sara","family":"Morais","sequence":"first","affiliation":[]},{"given":"Jorge","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Lau","sequence":"additional","affiliation":[]},{"given":"M\u00f3nica","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"Marta","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-4951","authenticated-orcid":true,"given":"Catarina","family":"Monteiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3917-2323","authenticated-orcid":true,"given":"Ana Rita","family":"Gon\u00e7alves","sequence":"additional","affiliation":[]},{"given":"Rui","family":"Matos","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9171-003X","authenticated-orcid":true,"given":"Marco","family":"Sampaio","sequence":"additional","affiliation":[]},{"given":"Eug\u00e9nia","family":"Cruz","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Freitas","sequence":"additional","affiliation":[]},{"given":"Ros\u00e1rio","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Margarida","family":"Lima","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2020,12,4]]},"reference":[{"key":"pone.0235136.ref001","doi-asserted-by":"crossref","first-page":"a004994","DOI":"10.1101\/cshperspect.a004994","article-title":"Integrin structure, activation, and interactions","volume":"3","author":"ID Campbell","year":"2011","journal-title":"Cold Spring Harb Perspect 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