Polymorphisms in the Promoter Region of the IL-10 Gene Is Associated with Inhibitor Development in Hemophilia A.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 212-212 ◽  
Author(s):  
Jan Astermark ◽  
Johannes Oldenburg ◽  
Anna Pavlova ◽  
Erik Berntorp ◽  
Ann-Kari Lefvert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Replacement Therapy ◽  
Promoter Region ◽  
Hemophilia A ◽  
Strong Association ◽  
Causative Factor ◽  
Factor Viii Gene ◽  
Ca Repeat ◽  
Inhibitor Development ◽  
History Of

Abstract The development of inhibitory antibodies is a severe and costly complication to replacement therapy occurring in 10–15% of patients with hemophilia A, and the aim of the Malmo International Brother Study (MIBS) is to evaluate host genetic factors associated with this adverse effect of treatment. In the present study, factor VIII mutations, HLA genotypes and polymorphisms of the interleukin IL-1beta, IL-4 and IL-10 genes known to influence antibody production in autoimmune diseases, were analyzed in 164 patients with hemophilia A (120 severe, 30 moderate and 14 mild) belonging to 78 unrelated families. Seventy-seven (47.0%) of the subjects had a history of inhibitors (57 high-responding, 20 low-responding) in 54 unrelated families (34 discordant, 20 concordant siblings). In 24 families, no inhibitor was reported in any of the siblings. Seventy-five patients (45.7%) in 36 families had an inversion. In this group, 40 patients (53.3%) in 28 families had inhibitors (17 concordant, 11 discordant). Weak associations between inhibitor development and the HLA alleles A26 and B44 were found. No association was found with the IL-1beta Taq 1 RFLP alleles in exon 5, and the −590 C/T SNP in the promoter region of IL-4. There was however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL-10G, located in the promoter region of the IL-10 gene, and development of inhibitor. Allele 134 was found in 32 (41.6%) of the patients with inhibitors compared with 12 (13.8%) of the inhibitor negative patients (p<0.001), corresponding to an odds ratio of 4.4 (95% CI 2.1–9.5, p<0.001). The association was consistent in the subgroup of families with severe hemophilia and an inversion of the factor VIII gene (p=0.002). Only one discordant inhibitor family was identified in which the subject without allele 134 developed an inhibitor, and the allele 134 positive brother did not. IL-10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development in hemophilia and our data indicate this gene to be an important determinant for this side-effect of replacement therapy.

Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (8) ◽  
pp. 3167-3172 ◽  
Author(s):  
Jan Astermark ◽  
Johannes Oldenburg ◽  
Anna Pavlova ◽  
Erik Berntorp ◽  
Ann-Kari Lefvert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Promoter Region ◽  
Hemophilia A ◽  
Strong Association ◽  
Gene Mutations ◽  
Causative Factor ◽  
Factor Viii Gene ◽  
Ca Repeat ◽  
Inhibitor Development ◽  
Mild Disease

Abstract The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and IL10 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taq I RFLP alleles in exon 5 or the –590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.

THE RELATIVE EFFICACY OF GENETIC ANALYSIS AND COAGULATION TESTING IN THE DIAGNOSIS OF CARRIERS OF HEMOPHILIA A

1987 ◽  
Author(s):  
D Lillicrap ◽  
A R Giles ◽  
J J A Holden ◽  
B N White
Keyword(s):  
Factor Viii ◽  
Gene Deletion ◽  
Hemophilia A ◽  
Fragment Length Polymorphism ◽  
Genetic Diagnosis ◽  
Prior History ◽  
Carrier Status ◽  
Factor Viii Gene ◽  
Coagulation Testing ◽  
History Of

This study has assessed the relative benefits of restriction fragment length polymorphism (RFLP) linkage and coagulation testing in the diagnosis of carriers of hemophilia A. 221 samples from 55 families have been studied for intragenic and flanking RFLPs. All samples were tested for the Factor VIII intragenic Bell RFLP and for the flanking marker St 14. 83% of obligate carrier females were heterozygous at oneor both of these two polymorphicsites. However, only38% of these women were heterozygous at the intragenic site and might safely be offered prenatal diagnosis using this marker for the hemophilia mutation. Carrier diagnosis was obtained in 52% of 81 potential carriers tested. Diagnosis wasbased on intragenic RFLP information in only 48% of these cases. Genetic diagnosis was possible in 27 atrisk women from families with no prior history of hemophilia. Four of these women were diagnosed as carriers on the basis of a gross Factor VIII gene deletion and the remaining 23 women were identified as non-carriers by the Bell (11) and Stl4 (12) RFLP data. 39 women remained undiagnosed after gene analysis studies. 23 of these women were female relatives of sporadic hemophiliacs and thus RFLP segregation analysis was inappropriate. A further 9 potential carriers were undiagnosed because of homozygosity in key individuals in their families. In 31 potential carriers we have quantitated Factor VIII:C (one stage assay) and vWf:Ag (Laurell and ELISA) and derived probabilities for carrier status. In 3 women there was conflicting genetic and coagulation data. Meanwhile, in 12 undiagnosed women from sporadic families, carrier diagnostic probabilities of > 0.9 were obtained. These studies indicate that optimal carrier detection for hemophilia A requires more intragenic and closely linked RFLPs and the continuance of coagulation testing to assist women from sporadic families.

Mild / Moderate Hemophilia A with Factor VIII Inhibitors (MHAI): Results of a French and Belgian Survey.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3088-3088
Author(s):  
Roseline d’Oiron ◽  
Jean Maurice Lavergne ◽  
Jenny Goudemand ◽  
Annie Borel-Derlon ◽  
Claude Guerois ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Baseline Level ◽  
Hemophilia A ◽  
Immunosuppressive Agents ◽  
Specific Treatment ◽  
Cumulative Exposure ◽  
Anamnestic Response ◽  
Inhibitor Development ◽  
History Of

Abstract The development of anti-factor VIII inhibitors in mild/moderate hemophilia A (MHA) patients was described as an uncommon event. The largest cohort reported so far included 26 MHAI patients (Hay et al, 1998) and with other anecdotic reports underlined a special pattern of the bleeding reminiscent of acquired hemophilia, a generally poor response to immune tolerance protocol compared to severe patients, and potential factors contributing to a high-risk of inhibitor development such as the FVIII genotype, family related factors and intense substitutive therapy. The optimal therapeutic strategy in MAHI remains unknown. A retrospective data collection was therefore conducted. To date 45 MHAI patients from 29 french and belgian centers were included, with a median FVIII:C baseline level of 0.08 IU/ml (1–28). More than a half of the cases were detected within the last 4 years (y) for a total study period of 20 y. The median age for MHA diagnosis, first FVIII treatment and inhibitor disclosure was respectively 5-y (0 to 73-y),10.5-y (0 to 73-y) and 22.5-y (1 month to 81-y). One splice and 22 different missense mutations were identified for 34 patients (8 already described including 5 with inhibitor, and 15 new). Before the inhibitor appearance, patients received plasma derived (13) or recombinant (12) products only, or both (20). The median number of cumulative exposure days before inhibitor diagnosis was 29 (3–150). History of intense substitutive therapy (≥4 consecutive days or prophylactic treatment every other day for ≥8 days) was observed in 35 (77%) patients, and history of intracranial bleeding in 6/45 (13%). The median maximum historical titer was 6.6 UB (0.5 – 288). In 19 out of 45 (42%) patients FVIII:C baseline level was less than 0.01 IU/ml, while decreased but still detectable (0.01 IU/ml or higher) in 16 (35%), stable in 4 (9%), and unknown in the 6 others. No specific treatment to eradicate the inhibitor was used in 24 patients, while 19 received either an immune tolerance protocol (14 patients, including 6 with combined immunosuppressive drugs), either immunosuppressive agents alone (5 patients); specific treatment was unknown in 2. Apart 2 deaths unrelated to MHA and 3 unknown outcomes, the inhibitor disappeared for 30 patients with a median of 8 months, persisted as a plateau in 2, and was still decreasing in 7 after a median follow-up of 5 months. Anamnestic response defined as an increase of at least 30 % of the inhibitor titer after FVIII or aPCC concentrates was observed in 17 out of the 29 (65%) patients that were rechallenged, but none after recombinant factor VIIa (Novoseven®) or DDAVP. When an anamnestic response occured the median delay for inhibitor eradication increased from 3 to 11 months. This survey underlines: i) that MAHI is not rare, but likely better recognized nowadays, ii) the need for systematic inhibitor assessment after substitutive therapy in MHA, iii) the role of FVIII genotype, intense treatment and possibly inracranial bleeds as contributing factors for inhibitor development, iv) how treatment of bleeds in MHA have to be carefully discussed to limit the risk of respectively appearance or anamnestic response in patients without or with inhibitors.

scholarly journals Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (11) ◽  
pp. 1954-1962 ◽  
Author(s):  
Corien L. Eckhardt ◽  
Alice S. van Velzen ◽  
Marjolein Peters ◽  
Jan Astermark ◽  
Paul P. Brons ◽  
...  
Keyword(s):  
Clinical Practice ◽  
High Risk ◽  
Factor Viii ◽  
Hemophilia A ◽  
Factor Viii Gene ◽  
Inhibitor Development ◽  
High Risk Patients ◽  
Key Points ◽  
Risk Patients

Key Points The inhibitor incidence in nonsevere hemophilia A patients with certain F8 mutations approaches the inhibitor incidence in severe patients. These findings are highly relevant for clinical practice, as they facilitate identification of high-risk patients based on F8 genotype.

scholarly journals The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 344-348 ◽  
Author(s):  
CW McMillan ◽  
SS Shapiro ◽  
D Whitehurst ◽  
LW Hoyer ◽  
AV Rao ◽  
...  
Keyword(s):  
Natural History ◽  
Factor Viii ◽  
Hemophilia A ◽  
The Other ◽  
Cooperative Study ◽  
Initial Development ◽  
Inhibitor Development ◽  
History Of ◽  
National Cooperative

During a 4-year multicenter cooperative study of acquired factor VIII inhibitors in persons with hemophilia A, new inhibitors were detected in 31 of 1,306 patients who entered the study without an inhibitor or the history of an inhibitor. The incidence of new inhibitors was eight per 1,000 patient-years of observation. The factor VIII:C level before inhibitor development was less than or equal to 0.03 U/mL in 29 individuals and 0.06 U/mL and 0.07 U/mL in the remaining two. Factor VIII:Ag levels were measured in 27 individuals and were less than 0.03 U/mL in 23 and 0.05 to 0.11 U/mL in the remaining four. Maximum inhibitor levels ranged from 1.0 to 9,044 Bethesda U/mL. In seven patients under the age of 20, relatively weak inhibitors (none higher than 4.3 Bethesda U/mL) were detected on only a single occasion despite continued factor VIII challenge. In the other 24 patients with inhibitors detected on multiple occasions, 50% had appeared by age 20 and 71% by age 30. Seventeen of the 31 inhibitors, including 12 of 15 with maximum values greater than 10 Bethesda U/mL, developed within 75 exposure days to factor VIII.

The Impact of Factor VIII/von Willebrand Factor Concentrate in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

2009 ◽  
Vol 02 ◽  
pp. 13
Author(s):  
Caroline Cromwell ◽  
Louis M Aledort ◽  
Margaret Heisel Kurth ◽  
◽  
◽  
...  
Keyword(s):  
Factor Viii ◽  
Replacement Therapy ◽  
Von Willebrand Factor ◽  
Active Sites ◽  
Hemophilia A ◽  
Safety Issue ◽  
Inhibitor Development ◽  
Von Willebrand ◽  
The Impact ◽  
Willebrand Factor

The development of inhibitor antibodies that bind to active sites on the factor VIII (FVIII) molecule and neutralize its function and/or accelerate its clearance is the most serious adverse event and safety issue associated with the treatment of hemophilia A. Inhibitor development complicates hemostasis management and increases morbidity and the cost of treatment because bleeding episodes do not respond to standard replacement therapy. Risk factors for inhibitor development include genetic and non-genetic factors. Immunogenicity of the type of product used for replacement therapy may also play a role. Within the category of human-derived products, the presence of von Willebrand factor (vWF) bound to FVIII (vWF/FVIII products) may reduce its immunogenicity. The challenge for inhibitors is to reduce their incidence and, when present, to facilitate their eradication. Factor-bypassing agents have been used to treat acute bleeds in patients who have inhibitors. Immune tolerance induction (ITI) therapy is an alternative approach whose goal is to create tolerance to inhibitors and return patients to their native state. The use of ITI therapy has raised many questions, including the optimal regimen and cost. The basic science data on reduced immunogenicity of vWF/FVIII-containing products and their success in achieving ITI have given us an incentive to continue to explore this approach to both primary and secondary ITI.

Impact of Polymorphisms of TNF-α, CTLA-4 and IL-10 Genes on Inhibitor Development In Chinese Patients with Hemophilia A.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3665-3665
Author(s):  
Lulu Zhang ◽  
Ziqiang Yu ◽  
Wei Zhang ◽  
Lijuan Cao ◽  
Changgeng Ruan
Keyword(s):  
Factor Viii ◽  
Replacement Therapy ◽  
Hemophilia A ◽  
Statistical Significance ◽  
Allele Frequencies ◽  
Chinese Patients ◽  
Inhibitor Development ◽  
Tnf Α ◽  
Pcr Products ◽  
Normal Controls

Abstract Abstract 3665 Introduction: The inhibitor against factor VIII would develop in one-third to one-fourth patients with hemophilia A, which is the severe complication during replacement therapy. Although mutation in factor VIII gene is the main determinant, HLA alleles and gene polymorphism of cytokines, such as TNF-α, CTLA-4 and IL-10, are also associated with inhibitor development. The polymorphisms of TNF-α-308G>A, CTLA-4 -318C>T and one of the CA repeat microsatellites in IL-10 gene were analyzed in 140 Chinese patients with hemophilia A treated with plasma-derived F‡[ concentrates and in 108 normal controls, in order to evaluate their contribution to inhibitor development. Methods: Genomic DNA was extracted from citrate-preserved blood from all patients and normal controls. The promoter region of TNF-α and CTLA-4 were amplified by PCR, then the PCR products of TNF-α and CTLA-4 were digested by NcoI or MseI, respectively, then subjected to 2% agarose gel electrophoresis. PCR products were also directly sequenced to identify the genotype. The short tandem repeat in the promotor region of IL-10 was amplified by PCR, then analyzed by capillary electrophoresis. The inhibitor activities against factor VIII in plasma of patients with hemophilia A were measured by modified-Nijmegen assay simultaneously. Results: The frequencies of -308 G allele and A allele in patients with hemophilia A were 90.7% and 9.3% respectively, compared with 90.3% and 9.7% in normal controls. The frequencies of -318 C allele and T allele in patients with hemophilia A were 87.9% and 12.1% respectively, compared with 86.6% and 13.4% in normal controls. The allele 134bp positive and allele 134bp negative in patients with hemophilia A were 27.9% and 72.1% respectively, compared with 29.6 % and 71.4% in normal controls. There were not significant difference of -308G/A allele frequencies ƒ A-318C/T allele frequencies and 134bp allele frequencies between two groups. The F‡[ inhibitor activity was identified in 34/140 (24.3%) patients. In the patients with inhibitor, 13/34(38.2%) patients carried the -308 A allele, the frequencies of -308 G allele and A allele in these patients were 75% and 25% respectively. The patients with hemophilia A who carried -308 A allele had a high risk of inhibitor development (OR,7.519; 95%CI,3.168 ‘17.844), especially for the severe patients with hemophilia A (OR,8.163; 95%CI,2.521 ‘26.434). Also in the patients with inhibitor, 10/34(29.4%) patients carried the -318 T allele, the frequencies of -318 C allele and T allele in these patients were 83.8% and 16.2% respectively. There is no statistical significance regarding the risk of inhibitor development between the patients who were carrier of C allele and T allele (OR,1.586,95%CI,0.729 ‘3.450). The frequencies of allele 134bp positive and allele 134bp negative in patients with inhibitor were 44% and 56% respectively, there was no statistical significance regarding the risk of inhibitor development between the patients who were the allele 134bp positive and those who were allele 134bp negative (OR,1.769,95%CI,0.676 ‘4.627). Conclusion: TNF-α-308G>A polymorphism is significantly associated with factor VIII inhibitor development in Chinese patients with hemophilia A. TNF-αgene may be a useful marker and potential modulator of the immune response to replacement therapy in patients with hemophilia A. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The natural history of factor VIII:C inhibitors in patients with hemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 344-348 ◽  
Author(s):  
CW McMillan ◽  
SS Shapiro ◽  
D Whitehurst ◽  
LW Hoyer ◽  
AV Rao ◽  
...  
Keyword(s):  
Natural History ◽  
Factor Viii ◽  
Hemophilia A ◽  
The Other ◽  
Cooperative Study ◽  
Initial Development ◽  
Inhibitor Development ◽  
History Of ◽  
National Cooperative

Abstract During a 4-year multicenter cooperative study of acquired factor VIII inhibitors in persons with hemophilia A, new inhibitors were detected in 31 of 1,306 patients who entered the study without an inhibitor or the history of an inhibitor. The incidence of new inhibitors was eight per 1,000 patient-years of observation. The factor VIII:C level before inhibitor development was less than or equal to 0.03 U/mL in 29 individuals and 0.06 U/mL and 0.07 U/mL in the remaining two. Factor VIII:Ag levels were measured in 27 individuals and were less than 0.03 U/mL in 23 and 0.05 to 0.11 U/mL in the remaining four. Maximum inhibitor levels ranged from 1.0 to 9,044 Bethesda U/mL. In seven patients under the age of 20, relatively weak inhibitors (none higher than 4.3 Bethesda U/mL) were detected on only a single occasion despite continued factor VIII challenge. In the other 24 patients with inhibitors detected on multiple occasions, 50% had appeared by age 20 and 71% by age 30. Seventeen of the 31 inhibitors, including 12 of 15 with maximum values greater than 10 Bethesda U/mL, developed within 75 exposure days to factor VIII.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Jenny Goudemand ◽  
Chantal Rothschild ◽  
Virginie Demiguel ◽  
Christine Vinciguerrat ◽  
Thierry Lambert ◽  
...  
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Adjusted Relative Risk ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Development ◽  
End Point ◽  
History Of

Abstract Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

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