{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:17:34Z","timestamp":1790821054815,"version":"4.1.0"},"reference-count":23,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T00:00:00Z","timestamp":1603238400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Bando Ricerca Corrente"],"award-info":[{"award-number":["Bando Ricerca Corrente"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30\u201350% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (\u03b2 \u22123.34, 95%CI \u22126.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.<\/jats:p>","DOI":"10.3390\/jcm9103379","type":"journal-article","created":{"date-parts":[[2020,10,23]],"date-time":"2020-10-23T02:01:42Z","timestamp":1603418502000},"page":"3379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The HLA Variant rs6903608 Is Associated with Disease Onset and Relapse of Immune-Mediated Thrombotic Thrombocytopenic Purpura in Caucasians"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5059-5212","authenticated-orcid":false,"given":"Ilaria","family":"Mancini","sequence":"first","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Giacomini","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Pontiggia","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Artoni","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Pappalardo","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6465-7624","authenticated-orcid":false,"given":"Roberta","family":"Gualtierotti","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy"},{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia Maria","family":"Trisolini","sequence":"additional","affiliation":[{"name":"Hematology, Department of Translational and Precision Medicine, \u201cSapienza\u201d University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saveria","family":"Capria","sequence":"additional","affiliation":[{"name":"Hematology, Department of Translational and Precision Medicine, \u201cSapienza\u201d University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Facchini","sequence":"additional","affiliation":[{"name":"Hematology Unit, Azienda Unit\u00e0 Sanitaria Locale\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Codeluppi","sequence":"additional","affiliation":[{"name":"Hematology Unit, Azienda Unit\u00e0 Sanitaria Locale\u2014IRCCS di Reggio Emilia, 42122 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erminia","family":"Rinaldi","sequence":"additional","affiliation":[{"name":"Hematology Unit, A. Perrino Hospital, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Pastore","sequence":"additional","affiliation":[{"name":"Hematology Unit, A. Perrino Hospital, 72100 Brindisi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Campus","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Ospedale Microcitemico, 09121 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cinzia","family":"Caria","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, S.S. Trinit\u00e0 Hospital, 09121 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Caddori","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, S.S. Trinit\u00e0 Hospital, 09121 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Nicolosi","sequence":"additional","affiliation":[{"name":"Hematology Division, Department of Clinical and Molecular Biomedicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Giuffrida","sequence":"additional","affiliation":[{"name":"Hematology Division, Department of Clinical and Molecular Biomedicine, University of Catania, 95123 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Agostini","sequence":"additional","affiliation":[{"name":"U.O. Medicina Trasfusionale, IRCCS\u2014Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Roncarati","sequence":"additional","affiliation":[{"name":"U.O. 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Medicina III, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Birocchi","sequence":"additional","affiliation":[{"name":"U.O. Medicina III, ASST Santi Paolo e Carlo, Dipartimento di Scienze della Salute, Universit\u00e0 degli Studi di Milano, 20142 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Cerbone","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, AOU Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Tufano","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, AOU Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Menna","sequence":"additional","affiliation":[{"name":"Department of Oncology, AORN Santobono-Pausilipon, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Pizzuti","sequence":"additional","affiliation":[{"name":"Hematology Unit, AO San Carlo, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, Department of Medicine, Lugo Hospital, Lugo, 48022 Ravenna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"De Fanti","sequence":"additional","affiliation":[{"name":"Departmental Simple Unit of Pediatric Rheumatology, AUSL-IRCSS Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Amarri","sequence":"additional","affiliation":[{"name":"Paediatrics Unit, AUSL-IRCSS Reggio Emilia, 42123 Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Defina","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgery and Neuroscience, Hematology Unit, Azienda Ospedaliera Universitaria Senese, Universit\u00e0 degli Studi di Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3538-3913","authenticated-orcid":false,"given":"Monica","family":"Bocchia","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgery and Neuroscience, Hematology Unit, Azienda Ospedaliera Universitaria Senese, Universit\u00e0 degli Studi di Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Cer\u00f9","sequence":"additional","affiliation":[{"name":"Hematology Unit, Santa Chiara Hospital, 38122 Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Gattillo","sequence":"additional","affiliation":[{"name":"Immuno-Hematology and Transfusion Medicine Unit, San Raffaele Hospital, 20132 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits R.","family":"Rosendaal","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Peyvandi","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, and Fondazione Luigi Villa, 20122 Milan, Italy"},{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1111\/jth.13571","article-title":"Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies","volume":"15","author":"Scully","year":"2017","journal-title":"J. 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