| Author | Zuccherato, Luciana Werneck | |
| Author | Souza, Renan Pedra de | |
| Author | Camelo, Ricardo Mesquita | |
| Author | Dias, Maise Moreira | |
| Author | Jardim, Letícia Lemos | |
| Author | Santana, Marcio Antônio Portugal | |
| Author | Oliveira, Andrea Gonçalves | |
| Author | Lorenzato, Claudia Santos | |
| Author | Cerqueira, Monica Hermida | |
| Author | Franco, Vivian Karla Brognoli | |
| Author | Ribeiro, Rosangela de Albuquerque | |
| Author | Etto, Leina Yukari | |
| Author | Roberti, Maria do Rosario Ferraz | |
| Author | Callado, Fábia Michelle de Araújo | |
| Author | Cerqueira, Maria Aline Ferreira de | |
| Author | Pinto, Ieda Solange de Souza | |
| Author | Garcia, Andrea Aparecida | |
| Author | Anegawa, Tania Hissa | |
| Author | Neves, Daniele Campos Fontes | |
| Author | Tan, Doralice Marvulle | |
| Author | Tou, Rafael Pereira | |
| Author | Chaves, Daniel Gonçalves | |
| Author | Bom, Johanna van der | |
| Author | Rezende, Suely Meireles | |
| Author | HEMFIL Study and the Brazilian Immune Tolerance (BrazIT) Study | |
| Access date | 2025-01-09T16:09:42Z | |
| Available date | 2025-01-09T16:09:42Z | |
| Document date | 2024 | |
| Citation | ZUCCHERATO, Luciana Werneck et al. Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors. Thromb Res, v. 242, p. 109115, 2024. | en_US |
| ISSN | 0049-3848 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/67986 | |
| Language | eng | en_US |
| Publisher | Elsevier | en_US |
| Rights | restricted access | |
| Title | Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors. | en_US |
| Type | Article | |
| DOI | 10.1016/j.thromres.2024.109115 | |
| Abstract | Introduction: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome.
Material and methods: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing.
Results: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively.
Conclusion: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. / Fundação Oswaldo Cruz. Instituto René Rachou. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Fundação HEMOMINAS. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Fundação HEMOMINAS. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Hemocentro do Paraná. Curitiba, PR, Brasil. | en_US |
| Affilliation | Instituto de Hematologia do Estado do Rio de Janeiro. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Centro de Hematologia e Hemoterapia de Santa Catarina. Florianópolis, SC, Brasil. | en_US |
| Affilliation | Centro de Hematologia e Hemoterapia do Ceará. Fortaleza, CE, Brasil. / Universidade Federal do Ceará. Fortaleza, CE, Brasil. | en_US |
| Affilliation | Hemocentro da Paraíba. João Pessoa, PB, Brasil. / Universidade Federal da Paraíba. João Pessoa, PB, Brasil. | en_US |
| Affilliation | Hemocentro de Goiás. Goiânia, GO, Brasil; Universidade Federal de Goiás. Goiânia, GO, Brasil. | en_US |
| Affilliation | Fundação de Hematologia e Hemoterapia de Pernambuco. Recife, PE, Brasil. | en_US |
| Affilliation | Centro de Hematologia e Hemoterapia do Piauí. Teresina, PI, Brasil. | en_US |
| Affilliation | Centro de Hematologia e Hemoterapia do Pará. Belém, PA, Brasil. / Universidade Federal do Pará. Belém, PA, Brasil. | en_US |
| Affilliation | Hemocentro de São José do Rio Preto. São José do Rio Preto, SP, Brasil. / Faculdade Regional de Medicina de São José do Rio Preto. São José do Rio Preto, SP, Brasil. | en_US |
| Affilliation | Centro de Hematologia Regional de Londrina. Londrina, PR, Brasil. / Universidade Estadual de Londrina. Faculdade de Medicina. Londrina, PR, Brasil. | en_US |
| Affilliation | Fundação Hemocentro de Rondônia. Porto Velho, RO, Brasil. / Universidade de Rondônia. Porto Velho, RO, Brasil. | en_US |
| Affilliation | Faculdade de Medicina de Marília. Marília, SP, Brasil. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Fundação HEMOMINAS. Belo Horizonte, MG, Brasil. | en_US |
| Affilliation | Department of Clinical Epidemiology. Leiden University Medical Center. Leiden, the Netherlands. | en_US |
| Affilliation | Universidade Federal de Minas Gerais. Belo Horizonte, MG, Brasil. | en_US |
| Subject | Factor VIII gene | en_US |
| Subject | Hemophilia A | en_US |
| Subject | Immune tolerance induction | en_US |
| Subject | Inhibitor | en_US |
| Subject | Mutation | en_US |
| Subject | Variant | en_US |
| Embargo date | 3100-12-31 | |
