Introns 1 and 22 inversions and factor VIII inhibitors in patients with severe haemophilia A in southern Brazil

Leiria, Leonardo Barbosa; Roisenberg, Israel; Salzano, Francisco M.; Bandinelli, Eliane

doi:10.1111/j.1365-2516.2008.01868.x

Cited by 17 publications

(13 citation statements)

References 42 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The incidence of inhibitor development among our patients with intron 22 inversions was 36%. The prevalence of inhibitors among patients from several populations with this inversion varies widely (5-51%) [12,21,[23][24][25][32][33][34] and these differences could be explained by the presence of other risk factors [7,[35][36][37]. As expected [31], 22% of our patients who had stop codon mutations and 100% of sHA patients with gross deletions developed inhibitors against exogenous FVIII.…”

Section: Discussionmentioning

confidence: 64%

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

et al. 2011

View full text Add to dashboard Cite

Haemophilia A is caused by mutations in the gene encoding coagulation factor VIII (FVIII). In severe Haemophilia A (sHA), two inversions are responsible for approximately 50% of the genetic alterations (intron 22 and intron 1 inversions). The other mutations are extremely diverse and each affected family generally has its own mutation. Our aim was to detect the genetic alterations present in the FVIII gene (F8) in 54 unrelated male patients with sHA in Venezuela. We initially detected the presence of the intron 22 inversion by performing inverse PCR, and the negative patients for this inversion were analysed for the intron 1 inversion by PCR. Patients negative for both inversions were analysed using Conformation Sensitive Gel Electrophoresis for mutations in all exons, promoter region and 3¢-UTR. sHA causative mutations were identified in 49 patients. Intron-22 and -1 inversions were detected in 41% and 0% of patients respectively. Besides these two mutations, 25 different mutations were identified, including nine nonsense, four small deletions, two small insertions, four missense, three splicing mutations and three large deletions. Seven novel mutations were identified, including two nonsense mutations, two small deletions, one small insertion, one missense mutation and one splicing mutation. Thirty one percent of the patients with identified mutations developed inhibitors against exogenous FVIII. This is the first report of F8 mutations in patients with sHA in Venezuela; the data from this study suggests that the spectrum of gene defects found in these patients is as heterogeneous as reported previously for other populations.

show abstract

Section: Discussionmentioning

confidence: 64%

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Ghosh et al reported that 4 of 17 patients (23.5%) with intron 22 inversion developed inhibitors. 2 In another study from Brazil, 51% of patients with intron 22 inversion had developed inhibitors, 14 whereas only 8% of Iranian patients with the same mutation developed inhibitors. 15 These findings again point to the presence of additional risk factors, probably genetic, that increase the risk of inhibitors in some populations in the developing countries.…”

Section: Predisposing Factorsmentioning

confidence: 98%

Management of Hemophilia in Patients with Inhibitors: The Perspective from Developing Countries

Nair¹,

David²,

Viswabandya³

et al. 2009

Semin Thromb Hemost

View full text Add to dashboard Cite

Data are limited on inhibitors in people with hemophilia (PWH) in developing countries. There is a perception that the overall prevalence of inhibitors, ranging from 7 to 19% in different reports, may be lower in these countries as compared with that reported from developed countries. This is possible given the fact that most patients are treated after 2 years of age with plasma-derived clotting factor concentrates. Whether genetic or other environmental factors also contribute to this needs further evaluation. There is a need to develop laboratory infrastructure and establish quality control programs for laboratory tests for inhibitors in developing countries. Management options vary widely given the socioeconomic diversity among these countries. Significant individualization of approach to management is therefore required depending on the available resources, particularly with regard to the use of bypassing agents. The limited data on immune tolerance induction with some low-dose regimens deserve further evaluation. Even in resource-constrained environments, education and a policy of systematic screening of patients associated with judicious use of bypassing agents can significantly improve the care of PWH who develop inhibitors.

show abstract

“…The present study describes such an analysis. Individuals with intron 1 and intron 22 inversions (previously detected in [2]) were excluded from the analysis, since these mutations are already known as causing high inhibitor incidence [5]. Inhibitors were identified through the Bethesda method [6], and an inhibitor titre above 1 UB/ml was considered positive.…”

Section: Methodsmentioning

confidence: 99%

“…About 15-25% of haemophilia A patients develop inhibitory antibodies overall [1]. In South Brazil, inhibitor incidence in severe haemophilia A patients was estimated at 40% [2]. The aim of the present study was to analyse the relationship between inhibitor development and F8 gene mutation types, and their location in South Brazilian haemophilia A patients.…”

Section: Introductionmentioning

confidence: 99%

Factor VIII mutations and inhibitor formation in a southern Brazilian population

Rosset

Gorziza²,

Botton³

et al. 2014

Blood Coagulation &Amp; Fibrinolysis

View full text Add to dashboard Cite

A total of 110 patients with severe (n = 43), moderate (n = 15) or mild (n = 52) haemophilia A were studied in relation to their F8 gene mutation and inhibitor status. Nineteen percentage of them had anti-factor VIII antibodies. Significant heterogeneity in inhibitor prevalence considering the location of the patients' mutation was found, with higher frequencies in carriers of mutations in the C1 and B domains. Twelve specific mutations showed associations with inhibitor formation, seven deletions, two nonsense, two insertions and one missense changes. Bioinformatic analysis of the missense mutation confirmed the formation of a B-cell epitope in the protein. This information is important for comparative purposes with series of other ethnic constitutions, as well as for individual prevention of this serious clinical problem in the patient population.

show abstract

Introns 1 and 22 inversions and factor VIII inhibitors in patients with severe haemophilia A in southern Brazil

Cited by 17 publications

References 42 publications

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

Management of Hemophilia in Patients with Inhibitors: The Perspective from Developing Countries

Factor VIII mutations and inhibitor formation in a southern Brazilian population

Contact Info

Product

Resources

About