{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T10:19:14Z","timestamp":1780654754883,"version":"3.54.1"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T00:00:00Z","timestamp":1748131200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Haemophilia A (HA) is an inherited bleeding disorder due to Factor VIII (FVIII) deficiency. Treatment with FVIII can activate immune mechanisms, which may lead to inhibitor development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study aimed to perform a longitudinal and exploratory analysis of immunological biomarkers during replacement with FVIII concentrate and after immune tolerance induction (ITI) in patients who developed a high\u2010responding inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Biological samples and clinical data from severe and moderately severe persons with HA (PwHA; FVIII\u00a0&lt;\u00a00.02 IU\/mL) were obtained before any or after minimal exposure (\u22645 days) to FVIII (T0), at inhibitor development (INB+), at 75 exposure days (ED) without inhibitor (INB\u2212) (T1) and at end of ITI (T2). Biomarkers were assessed at T0, T1 and T2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      One hundred patients were analysed, of whom 32 (86.5%) developed high\u2010responding inhibitor and underwent ITI. We found no difference in the plasma concentration of the 15 immunological biomarkers at T0 or at T1 versus T2 in INB+ compared with INB\u2212. However, at T1, PwHA INB+ who failed ITI had higher median concentration of interleukin (IL)\u20102 (3.50 vs. 0.85 pg\/mL;\n                      <jats:italic>q<\/jats:italic>\n                      = 0.016), IL\u201010 (3.46 vs. 0.74 pg\/mL;\n                      <jats:italic>q<\/jats:italic>\n                      = 0.035), tumour necrosis factor (TNF) (11.18 vs. 0.93 pg\/mL;\n                      <jats:italic>q<\/jats:italic>\n                      = 0.016), interferon\u2010gamma (INF\u2010\u03b3) (98.57 vs. 3.57\u00a0pg\/mL;\n                      <jats:italic>q<\/jats:italic>\n                      = 0.035) and CCL5 (5245.11 vs. 3107.86 pg\/mL;\n                      <jats:italic>p<\/jats:italic>\n                      = 0.037) compared with those who achieved complete response, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Patients who failed ITI had higher concentration of IL\u20102, IL\u201010, TNF, INF\u2010\u03b3\u00a0and CCL5 in comparison with complete responders, suggesting that these biomarkers could be potential predictors of ITI outcome.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/hae.70048","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T02:34:39Z","timestamp":1748226879000},"page":"668-678","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Longitudinal Evaluation of Immunological Biomarkers in Previously Untreated\/Minimally Treated Patients With Severe and Moderately Severe Haemophilia A During Exposure to Factor VIII: Results From the HEMFIL Study"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0658-951X","authenticated-orcid":false,"given":"M\u00e1rcio","family":"Ant\u00f4nio Portugal Santana","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Hemominas  Belo Horizonte Minas Gerais Brazil"},{"name":"Faculty of Medicine Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7431-3884","authenticated-orcid":false,"given":"Daniel","family":"Gon\u00e7alves Chaves","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Hemominas  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9479-4432","authenticated-orcid":false,"given":"Renan Pedra","family":"Souza","sequence":"additional","affiliation":[{"name":"Instituto of Biological Sciences Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3358-0075","authenticated-orcid":false,"given":"Leticia Lemos","family":"Jardim","sequence":"additional","affiliation":[{"name":"Instituto Ren\u00e8 Rachou (Fiocruz Minas), Belo Horizonte  Minas Gerais Brazil"},{"name":"Faculdade de Ci\u00eancias M\u00e9dicas de Minas Gerais, Belo Horizonte  Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Werneck","family":"Zuccherato","sequence":"additional","affiliation":[{"name":"Instituto of Biological Sciences Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendon Ayala Silva","family":"Santos","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f4nica Hermida","family":"Cerqueira","sequence":"additional","affiliation":[{"name":"Instituto de Hematologia Arthur de Siqueira Calvalcanti (HEMORIO)  Rio de Janeiro Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6662-4623","authenticated-orcid":false,"given":"Claudia Santos","family":"Lorenzato","sequence":"additional","affiliation":[{"name":"Centro de Hematologia e Hemoterapia do Paran\u00e1 (HEMEPAR)  Curitiba Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian Karla Brognoli","family":"Franco","sequence":"additional","affiliation":[{"name":"Centro de Hematologia e Hemoterapia de Santa Catarina (HEMOSC)  Florian\u00f3polis Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3083-7093","authenticated-orcid":false,"given":"Suely Meireles","family":"Rezende","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,25]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24117"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.14046"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1159\/000495454"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.13474"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1660816"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-11-056317"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516437"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1657777"},{"issue":"3","key":"e_1_2_10_10_1","first-page":"290","article-title":"Factor VIII Trafficking to CD4+Tcells Shape Its Immunogenicity and Requires Several Types of Antigen\u2010Presenting Cells","volume":"142","author":"Kaczmarek R.","year":"2023","journal-title":"Blood"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-022-03359-z"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00638"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijlh.14139"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-022-02268-5"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2010.04258.x"},{"issue":"7","key":"e_1_2_10_16_1","first-page":"891","article-title":"Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients With Hemophilia A From the HEMFIL Study","volume":"121","author":"Oliveira L. M. M.","year":"2021","journal-title":"Coagulation and Fibrinolysis"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/MBC.0000000000001057"},{"key":"e_1_2_10_18_1","unstructured":"Protocolo de uso de indu\u00e7\u00e3o de imunotoler\u00e2ncia para pacientes com hemofilia A e inibidor.Secretaria de Aten\u00e7\u00e3o Especializada \u00e0 Sa\u00fade Minist\u00e9rio da Sa\u00fade 2015. Brasil Last accessed January 10 2025 https:\/\/bvsms.saude.gov.br\/bvs\/publicacoes\/protocolo_inducao_imunotolerancia_pacientes_hemofilia%20.pdf."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1653759"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12672"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2006.02127.x"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-791756"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17249"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-444877"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/hae.12646"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.transci.2021.103343"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.01.034"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2024.05.017"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/765614"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201040391"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2008.12.002"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14799"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20191247"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100565"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6483490"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1178334"},{"issue":"12","key":"e_1_2_10_37_1","first-page":"726","article-title":"Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Rheumatoid Arthritis by Bioinformatics Analysis","volume":"13","author":"Zhou S.","year":"2021","journal-title":"Frontiers in Immunology"}],"container-title":["Haemophilia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.70048","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/hae.70048","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/hae.70048","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:35:18Z","timestamp":1773002118000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/hae.70048"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,25]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1111\/hae.70048"],"URL":"https:\/\/doi.org\/10.1111\/hae.70048","archive":["Portico"],"relation":{},"ISSN":["1351-8216","1365-2516"],"issn-type":[{"value":"1351-8216","type":"print"},{"value":"1365-2516","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,25]]},"assertion":[{"value":"2024-09-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}