Prevalence of inversions in introns 1 and 22 of the factor VIII gene and inhibitors in patients from southern Brazil

Corrêa, Maria Cristina S. M.; Ferreira, Elisabete; Veiga, Marcelo T. A.; Bandinelli, Eliane; Rosset, Clévia

doi:10.5935/1676-2444.20190053

Cited by 2 publications

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“…Na hemofilia A grave cerca de 70% apresentam sangramentos de 20-30 vezes por ano, frequentemente espontâneos ou causados por traumas. Cerca de 40% dos casos de hemofilia A grave é causada pela inversão do íntron 22 em que essa mutação inativa por completo o gene do fator VIII (LAVAUT-SÁNCHEZ et al, 2017;CORRÊA et al, 2019).…”

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Tratamento de Hemofílicos A Grave Atendidos no Hospital de Hematologia da Fundação HEMOPE, com Inibidor de Fator VIII Através da Imunotolerância

et al. 2021

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No Brasil, mais de 80% dos casos de hemofilia são do tipo A. A infusão do concentrado do Fator VIII (FVIII) pode desenvolver anticorpos neutralizantes. O tratamento de escolha para indivíduos que desenvolveram inibidor é a imunotolerância (IT). Este estudo objetivou avaliar a conduta e eficácia do tratamento da IT em pacientes com hemofilia A grave na Fundação de Hematologia e Hemoterapia de Pernambuco (HEMOPE), no período de 2012 a 2017. O estudo foi do tipo descritivo com uma abordagem quantitativa com análise dos prontuários de pacientes com hemofilia A grave. No total de 17 pacientes hemofílicos A grave, 47% ainda continuam na IT, 17,7% tiveram insucesso, 17,7% foram excluídos do tratamento, 11,7% conseguiram sucesso parcial e 5,9% obtiveram sucesso total. A média de idade de detecção do inibidor foi de 4 anos a partir do início do tratamento de infusões, variando de 1 a 14 anos; 7 indivíduos apresentaram o primeiro título de baixa resposta (< 5 UB/mL) e os demais título de alta resposta (> 5 UB/ mL); cerca de 70,58% conseguiram começar a IT com um período de detecção < 5 anos. A falta de uma conduta padrão diante do tratamento resulta em uma eficácia não definida, apesar de todas as limitações do presente estudo já relatadas, um pequeno percentual de pacientes obteve sucesso parcial e total do tratamento, sendo um indicativo de que a IT realizada, atualmente, nos pacientes hemofílicos A grave da Fundação HEMOPE (iniciada há apenas 6 anos) apresenta resultados promissores. Palavras-chave: Fator VIII. Anticorpo Neutralizante. Eficácia. Abstract In Brazil, more than 80% of hemophilia cases are type A. Infusion of Factor VIII concentrate (FVIII) can develop neutralizing antibodies. The treatment of choice for individuals who have developed an inhibitor is immunotolerance (IT). This study aimed to evaluate the conduct and effectiveness of treating IT in patients with severe hemophilia A at Fundação de Hematologia e Hemoterapia de Pernambuco (HEMOPE), from 2012 to 2017. The study was the descriptive type with a quantitative approach with analysis of the patients’ medical records with severe hemophilia A. In the total of 17 hemophiliac A severe patients, 47% are still on IT, 17.7% were unsuccessful, 17.7% were excluded from treatment, 11.7% were partially successful and 5.9% were totally successful. The mean detection age of the inhibitor was 4 years from the beginning of the infusions treatment, ranging from 1 to 14 years; 7 individuals had the first low response titer (<5 UB/mL) and the remaining high response titer (> 5 UB/mL); about 70.58% managed to start IT with a detection period <5 years. The lack of a standard approach to treatment results in an undefined efficacy, although all the limitations of the present study already reported, a small percentage of patients achieved partial and total treatment success, being an indication that the IT currently performed on severe hemophiliac A patients from Fundação HEMOPE (started only 6 years ago) shows promising results. Keywords: Factor VIII. Neutralizing Antibody. Effectiveness

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Tratamento de Hemofílicos A Grave Atendidos no Hospital de Hematologia da Fundação HEMOPE, com Inibidor de Fator VIII Através da Imunotolerância

et al. 2021

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Molecular genetic diagnosis in the group of hemophilia A patients in Belarus: 12 new allelic variants in the <i>F8</i> gene

Liubushkin,

Guryanova,

Dmitriev

et al. 2023

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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Hemophilia A is the most common severe bleeding disorder caused by various genetic changes in the F8 gene, leading to coagulation factor VIII deficiency. Hemophilia A is characterized by high heterogeneity of genetic defects. The severity of hemophilia A varies depending on the type of genetic defects in the F8 gene. More than 3000 unique variants of the F8 gene are associated with the hemophilia A. Approximately 30% of genetic defects occur de novo. The aim of this study is to determine the spectrum of genetic defects in the F8 gene in children with hemophilia A in Belarus. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 98 patients with hemophilia A, who had been treated or followed up at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Patients were categorized into 3 groups based on the severity of their disease: severe (n = 82), moderate (n = 3), and mild (n = 13). Twenty (20.4%) patients had a history of inhibitors to factor VIII. For our study, we used venous blood samples. Genomic DNA was isolated from leukocyte suspension (obtained from the whole blood samples) using phenol-chloroform extraction. All severe hemophilia A patients were prescreened for intron 22 and 1 inversions in the F8 gene using inverse and multiplex polymerase chain reaction assays, respectively. Sequencing of F8 coding regions was carried out by next generation sequencing. All clinically relevant variants were confirmed by Sanger sequencing. Genetic testing revealed that 99% of the patients with hemophilia A (n = 97) had pathogenic variants in the F8 gene. Intron 22 and intron 1 inversion mutations within the F8 gene were detected in 45.1% (n = 37) and 1.2% (n = 1) patients with severe hemophilia A, respectively. Two patients had an abnormal pattern of intron 1 inversion, not previously described in the literature. A total of 48 different variants in the F8 gene were detected in 57 patients using next generation sequencing. Eleven of the 48 genetic variants identified have not been previously reported.

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Prevalence of inversions in introns 1 and 22 of the factor VIII gene and inhibitors in patients from southern Brazil

Cited by 2 publications

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Tratamento de Hemofílicos A Grave Atendidos no Hospital de Hematologia da Fundação HEMOPE, com Inibidor de Fator VIII Através da Imunotolerância

Tratamento de Hemofílicos A Grave Atendidos no Hospital de Hematologia da Fundação HEMOPE, com Inibidor de Fator VIII Através da Imunotolerância

Molecular genetic diagnosis in the group of hemophilia A patients in Belarus: 12 new allelic variants in the <i>F8</i> gene

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