{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T07:53:47Z","timestamp":1790409227841,"version":"4.1.0"},"reference-count":34,"publisher":"American Society of Hematology","issue":"22","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products (\u201ctrue PUPs\u201d) and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002731","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T20:47:12Z","timestamp":1607028432000},"page":"5785-5796","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":36,"title":["The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development"],"prefix":"10.1182","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7455-4610","authenticated-orcid":false,"given":"B. M.","family":"Reipert","sequence":"first","affiliation":[{"name":"Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Gangadharan","sequence":"additional","affiliation":[{"name":"Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. J.","family":"Hofbauer","sequence":"additional","affiliation":[{"name":"Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3246-2317","authenticated-orcid":false,"given":"V.","family":"Berg","sequence":"additional","affiliation":[{"name":"Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Schweiger","sequence":"additional","affiliation":[{"name":"Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Bowen","sequence":"additional","affiliation":[{"name":"Indiana Hemophilia and Thrombosis Center, Indianapolis, IN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6261-9157","authenticated-orcid":false,"given":"J.","family":"Blatny","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology, University Hospital Brno, Masaryk University, Brno, Czech Republic;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0904-4360","authenticated-orcid":false,"given":"K.","family":"Fijnvandraat","sequence":"additional","affiliation":[{"name":"Pediatric Hematology, Amsterdam UMC, University of Amsterdam\u2013Emma Children\u2019s Hospital, Department of Molecular Cellular Hemostasis, Sanquin Research, Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1544-9068","authenticated-orcid":false,"given":"E. S.","family":"Mullins","sequence":"additional","affiliation":[{"name":"Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children\u2019s Hospital Medical Center, University of Cincinnati, Cincinnati, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Klintman","sequence":"additional","affiliation":[{"name":"Clinical Coagulation Research Unit, Department of Translational Medicine, Lund University, Malm\u00f6, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4989-6421","authenticated-orcid":false,"given":"C.","family":"Male","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical University of Vienna, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"McGuinn","sequence":"additional","affiliation":[{"name":"Comprehensive Center for Hemophilia and Coagulation Disorders, Weill Cornell Medicine, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3683-8644","authenticated-orcid":false,"given":"S. L.","family":"Meeks","sequence":"additional","affiliation":[{"name":"Aflac Cancer and Blood Disorders Center, Emory University, Children\u2019s Healthcare of Atlanta, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8338-5185","authenticated-orcid":false,"given":"V. C.","family":"Radulescu","sequence":"additional","affiliation":[{"name":"Hemophilia Treatment Center, University of Kentucky, Lexington, KY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. V.","family":"Ragni","sequence":"additional","affiliation":[{"name":"Division Hematology\/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2805-1016","authenticated-orcid":false,"given":"M.","family":"Recht","sequence":"additional","affiliation":[{"name":"Hemophilia Center, Oregon Health & Science University, Portland, OR;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. D.","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Indiana Hemophilia and Thrombosis Center, Indianapolis, IN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2738-4206","authenticated-orcid":false,"given":"J. M.","family":"Staber","sequence":"additional","affiliation":[{"name":"Carver College of Medicine\u2013Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. M.","family":"Yaish","sequence":"additional","affiliation":[{"name":"University of Utah School of Medicine, Salt Lake City, UT;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Santagostino","sequence":"additional","affiliation":[{"name":"IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico, University of Milan, Milan, Italy; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-0477","authenticated-orcid":false,"given":"D. L.","family":"Brown","sequence":"additional","affiliation":[{"name":"University of Texas Health Science Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"issue":"7","key":"2020120315410924200_B1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1056\/NEJM199302183280701","article-title":"Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors","volume":"328","author":"Lusher","year":"1993","journal-title":"N Engl J Med"},{"issue":"4","key":"2020120315410924200_B2","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1046\/j.1365-2516.2003.00780.x","article-title":"The epidemiology of inhibitors in haemophilia A: a systematic review","volume":"9","author":"Wight","year":"2003","journal-title":"Haemophilia"},{"issue":"6","key":"2020120315410924200_B3","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1160\/TH11-09-0642","article-title":"Experience of Advate rAHF-PFM in previously untreated patients and minimally treated patients with haemophilia A","volume":"107","author":"Auerswald","year":"2012","journal-title":"Thromb Haemost"},{"issue":"21","key":"2020120315410924200_B4","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1056\/NEJMoa1516437","article-title":"A randomized trial of factor VIII and neutralizing antibodies in hemophilia A","volume":"374","author":"Peyvandi","year":"2016","journal-title":"N Engl J Med"},{"issue":"5","key":"2020120315410924200_B5","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1111\/j.1365-2516.2007.01518.x","article-title":"European study on orthopaedic status of haemophilia patients with inhibitors","volume":"13","author":"Morfini","year":"2007","journal-title":"Haemophilia"},{"issue":"6","key":"2020120315410924200_B6","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/hae.13612","article-title":"Bleeding events and safety outcomes in persons with haemophilia A with inhibitors: A prospective, multi-centre, non-interventional study","volume":"24","author":"Mahlangu","year":"2018","journal-title":"Haemophilia"},{"issue":"3","key":"2020120315410924200_B7","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s11096-007-9181-4","article-title":"Cost-of-illness study of severe haemophilia A and B in five French haemophilia treatment centres","volume":"30","author":"Nerich","year":"2008","journal-title":"Pharm World Sci"},{"issue":"3","key":"2020120315410924200_B8","first-page":"869","article-title":"Letter: A more uniform measurement of factor VIII inhibitors","volume":"34","author":"Kasper","year":"1975","journal-title":"Thromb Diath Haemorrh"},{"issue":"2","key":"2020120315410924200_B9","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1055\/s-0038-1653759","article-title":"The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability","volume":"73","author":"Verbruggen","year":"1995","journal-title":"Thromb Haemost"},{"issue":"6","key":"2020120315410924200_B10","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1182\/blood-2012-07-444877","article-title":"Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients","volume":"121","author":"Whelan","year":"2013","journal-title":"Blood"},{"issue":"7","key":"2020120315410924200_B11","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1182\/blood-2014-09-598268","article-title":"Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans","volume":"125","author":"Hofbauer","year":"2015","journal-title":"Blood"},{"issue":"10","key":"2020120315410924200_B12","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1182\/blood-2016-06-720086","article-title":"Nonneutralizing antibodies against factor VIII and risk of inhibitor development in severe hemophilia A [published correction appears in Blood. 2017;130(2):232]","volume":"129","author":"Cannav\u00f2","year":"2017","journal-title":"Blood"},{"issue":"1","key":"2020120315410924200_B13","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1053\/j.seminhematol.2003.11.016","article-title":"Environmental and genetic factors influencing inhibitor development","volume":"41","author":"Oldenburg","year":"2004","journal-title":"Semin Hematol"},{"issue":"12","key":"2020120315410924200_B14","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1111\/j.1538-7836.2009.03636.x","article-title":"Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-alpha and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia A","volume":"7","author":"Pavlova","year":"2009","journal-title":"J Thromb Haemost"},{"issue":"12","key":"2020120315410924200_B15","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1182\/blood-2011-09-379453","article-title":"F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis","volume":"119","author":"Gouw","year":"2012","journal-title":"Blood"},{"issue":"1","key":"2020120315410924200_B16","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1046\/j.1365-2516.1998.0146c.x","article-title":"Inhibitors occur more frequently in African-American and Latino haemophiliacs","volume":"4","author":"Aledort","year":"1998","journal-title":"Haemophilia"},{"issue":"3","key":"2020120315410924200_B17","doi-asserted-by":"crossref","first-page":"e260","DOI":"10.1111\/j.1365-2516.2011.02739.x","article-title":"Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled in the Universal Data Collection database","volume":"18","author":"Carpenter","year":"2012","journal-title":"Haemophilia"},{"key":"2020120315410924200_B18","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.3389\/fimmu.2019.02991","article-title":"Tolerating Factor VIII: Recent Progress","volume":"10","author":"Lacroix-Desmazes","year":"2020","journal-title":"Front Immunol"},{"issue":"1","key":"2020120315410924200_B19","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1146\/annurev-immunol-020711-075032","article-title":"Germinal centers","volume":"30","author":"Victora","year":"2012","journal-title":"Annu Rev Immunol"},{"issue":"3","key":"2020120315410924200_B20","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/nri3795","article-title":"The generation of antibody-secreting plasma cells","volume":"15","author":"Nutt","year":"2015","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"2020120315410924200_B21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.smim.2007.12.002","article-title":"Plasma cell development: from B-cell subsets to long-term survival niches","volume":"20","author":"Fairfax","year":"2008","journal-title":"Semin Immunol"},{"issue":"1","key":"2020120315410924200_B22","first-page":"145","article-title":"Transient inhibitors in the Recombinate PUP study","volume":"84","author":"Rothschild","year":"2000","journal-title":"Thromb Haemost"},{"issue":"1-2","key":"2020120315410924200_B23","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jim.2007.08.007","article-title":"Deconvolution of antibody affinities and concentrations by non-linear regression analysis of competitive ELISA data","volume":"328","author":"Stevens","year":"2007","journal-title":"J Immunol Methods"},{"issue":"10","key":"2020120315410924200_B24","doi-asserted-by":"crossref","first-page":"3663","DOI":"10.1182\/blood.V89.10.3663","article-title":"The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies","volume":"89","author":"Prescott","year":"1997","journal-title":"Blood"},{"issue":"3","key":"2020120315410924200_B25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1055\/s-2002-32665","article-title":"New characteristics of anti-factor VIII inhibitor antibody epitopes and unusual immune responses to Factor VIII","volume":"28","author":"Scandella","year":"2002","journal-title":"Semin Thromb Hemost"},{"issue":"2","key":"2020120315410924200_B26","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1097\/00001721-200403000-00001","article-title":"Inhibitors in hemophilia A: mechanisms of inhibition, management and perspectives","volume":"15","author":"Ananyeva","year":"2004","journal-title":"Blood Coagul Fibrinolysis"},{"issue":"16","key":"2020120315410924200_B27","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1182\/blood-2016-02-701805","article-title":"High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors","volume":"128","author":"Batsuli","year":"2016","journal-title":"Blood"},{"issue":"3","key":"2020120315410924200_B28","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1046\/j.1365-2141.1996.d01-1705.x","article-title":"High incidence of anti-FVIII antibodies against non-coagulant epitopes in haemophilia A patients: a possible role for the half-life of transfused FVIII","volume":"93","author":"Dazzi","year":"1996","journal-title":"Br J Haematol"},{"issue":"10","key":"2020120315410924200_B29","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1038\/s41590-020-0765-7","article-title":"NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting","volume":"21","author":"Tan","year":"2020","journal-title":"Nat Immunol"},{"issue":"6","key":"2020120315410924200_B30","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.coi.2019.04.007","article-title":"New players in the gene regulatory network controlling late B cell differentiation","volume":"58","author":"Willis","year":"2019","journal-title":"Curr Opin Immunol"},{"issue":"3","key":"2020120315410924200_B31","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/nri1572","article-title":"Regulation of plasma-cell development","volume":"5","author":"Shapiro-Shelef","year":"2005","journal-title":"Nat Rev Immunol"},{"issue":"11","key":"2020120315410924200_B32","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1084\/jem.20140425","article-title":"The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation","volume":"211","author":"Carotta","year":"2014","journal-title":"J Exp Med"},{"issue":"1","key":"2020120315410924200_B33","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1084\/jem.20160789","article-title":"The aryl hydrocarbon receptor controls cell-fate decisions in B cells","volume":"214","author":"Vaidyanathan","year":"2017","journal-title":"J Exp Med"},{"issue":"12","key":"2020120315410924200_B34","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.it.2018.10.010","article-title":"The aryl hydrocarbon receptor: connecting immunity to the microenvironment","volume":"39","author":"Shinde","year":"2018","journal-title":"Trends Immunol"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/4\/22\/5785\/1790773\/advancesadv2020002731.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/4\/22\/5785\/1790773\/advancesadv2020002731.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T20:47:52Z","timestamp":1607028472000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/4\/22\/5785\/474240\/The-prospective-Hemophilia-Inhibitor-PUP-Study"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":34,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2020,11,24]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2020002731","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,24]]}}}