{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T10:48:15Z","timestamp":1772016495063,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,11,8]],"date-time":"2016-11-08T00:00:00Z","timestamp":1478563200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54 HL112309"],"award-info":[{"award-number":["U54 HL112309"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL082609"],"award-info":[{"award-number":["R01 HL082609"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL040921"],"award-info":[{"award-number":["R01 HL040921"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009430","name":"Baxter BioScience","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009430","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The development of neutralizing antibodies (inhibitors) against coagulation factor <jats:styled-content style=\"fixed-case\">VIII<\/jats:styled-content> (<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>) is currently the most serious complication for patients with haemophilia A undergoing <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The domain specificity of <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>\u2010specific IgG was analysed by antibody binding to <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> fragments and homologue\u2010scanning mutagenesis (<jats:styled-content style=\"fixed-case\">HSM<\/jats:styled-content>). The <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>\u2010specific IgG subclasses were measured by direct ELISA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 16 patient analysed with both methods, 12 had A2\u2010 and 13 had C2\u2010specific IgG. The presence of A1\u2010, A3\u2010 or C1\u2010specific IgG was identified in nine of 14 patients analysed by <jats:styled-content style=\"fixed-case\">HSM<\/jats:styled-content>. IgG1, IgG2 and IgG4 subclasses contributed to the anti\u2010<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> IgG response, and the amount of <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>\u2010specific IgG1 (<jats:italic>r<\/jats:italic> = 0.66) and IgG4 (<jats:italic>r<\/jats:italic> = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti\u2010<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> IgG (<jats:italic>r<\/jats:italic> = 0.69) or high inhibitor titres (<jats:italic>r<\/jats:italic> = 0.52) had a high proportion of <jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content>\u2010specific IgG4. Statistical analysis revealed trends\/evidence that the subclass distribution (<jats:italic>P<\/jats:italic> = 0.0847) and domain specificity to <jats:styled-content style=\"fixed-case\">HC<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">LC<\/jats:styled-content> (<jats:italic>P<\/jats:italic> = 0.0883) and A2\/C2 (<jats:italic>P<\/jats:italic> = 0.0011) of anti\u2010<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> IgG were more similar in brothers compared to unrelated subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, our data provide a first hint that anti\u2010<jats:styled-content style=\"fixed-case\">FVIII<\/jats:styled-content> IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients\u2019 antibodies needs to be confirmed in a larger study population.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.13105","type":"journal-article","created":{"date-parts":[[2016,11,8]],"date-time":"2016-11-08T07:39:41Z","timestamp":1478590781000},"page":"292-299","source":"Crossref","is-referenced-by-count":5,"title":["Anti\u2010factor <scp>VIII<\/scp> antibodies in brothers with haemophilia A share similar characteristics"],"prefix":"10.1111","volume":"23","author":[{"given":"J.","family":"Kahle","sequence":"first","affiliation":[{"name":"Department of Paediatrics Clinical and Molecular Haemostasis and Immunodeficiency University Hospital Frankfurt Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Orlowski","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Clinical and Molecular Haemostasis and Immunodeficiency University Hospital Frankfurt Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Stichel","sequence":"additional","affiliation":[{"name":"Department of Paediatrics Clinical and Molecular Haemostasis and Immunodeficiency University Hospital Frankfurt Frankfurt am Main Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. 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