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.
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Zuccherato Luciana Werneck, Souza Renan Pedra, Camelo Ricardo Mesquita, Dias Maise Moreira, Jardim Letícia Lemos, Santana Marcio Antônio Portugal, Oliveira Andrea Gonçalves, Lorenzato Claudia Santos, Cerqueira Monica Hermida, Franco Vivian Karla Brognoli, Ribeiro Rosangela de Albuquerque, Etto Leina Yukari, Roberti Maria do Rosario Ferraz, Callado Fábia Michelle de Araújo, de Cerqueira Maria Aline Ferreira, Pinto Ieda Solange de Souza, Garcia Andrea Aparecida, Anegawa Tania Hissa, Neves Daniele Campos Fontes, Tan Doralice Marvulle, Tou Rafael Pereira, Chaves Daniel Gonçalves, van der Bom Johanna, Rezende Suely Meireles, HEMFIL Study and the Brazilian Immune Tolerance (BrazIT) Study
Аннотация
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.