Inhibitor Development In Patients with Mild and Moderate Hemophilia A: Results From a Single Centre.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1407-1407 ◽  
Author(s):  
Yohann Repesse ◽  
Philippe Gautier ◽  
Annie Borel-Derlon
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Immunosuppressive Treatment ◽  
Gene Promoter ◽  
Missense Mutations ◽  
Bleeding Events ◽  
Inhibitor Development ◽  
Treatment Centre

Abstract Abstract 1407 The development of factor VIII (FVIII) inhibitors is usually considered uncommon among patients with mild and moderate hemophilia A (HA) and less frequent than in patients with severe HA. We report here the prevalence of FVIII inhibitors and their caracteristics in 167 patients with mild and moderate HA followed in Caen Hemophilia Treatment Centre (Table). FVIII molecular defects were identified by direct sequencing in 167 patients including 30 and 137 with mild and moderate HA, respectively. Following FVIII concentrates infusions, FVIII inhibitors occured in 7.8% of patients (13/167). Fifteen percent (2/13) were low-responding inhibitors. The risk of inhibitor development appeared to be associated with high-risk FVIII genotypes clustered in the A2 and C2 domains, especially p.Arg2150His (50%) and p.Arg593Cys mutations. Interestingly, we described inhibitor development associated with novel missense-mutations (p.Tyr1786Ser, p.Asp115Tyr and -219C>T substitutions in FVIII gene promoter). In addition, high regimen infusion of FVIII concentrates appeared as risk factor for FVIII inhibitors development. Indeed, 60% (8/13) developped FVIII inhibitors following massive infusion of FVIII concentrates associated with FVIII:C levels above 1.2 UI/dL. Inhibitors in mild HA usually cross-react with endogenous factor VIII reducing the circulating basal FVIII:C level and are associated with more bleeding events. Similarly, we observed the evolution of bleeding patterns in our cohort to severe phenotypes. Bleedings were treated with FVIII concentrates and bypassing therapies (activated FVII and activated-prothrombin complex). About 25% (3/13) of these inhibitors disappeared spontaneously. Induction of Immune Tolerance (ITI) protocoles with high doses of FVIII were initiated for 7 high-responding patients with a success rate of 85 % (6/7). However, inhibitors persisted long-term and remained troublesome in 1 of these patients despite of ITI protocole. For two patients, immunosuppressive treatment with corticosteroids was started. Inhibitors disappeared and the levels of FVIII:C became detectable within 6 months. Development of FVIII inhibitors, their disappearance and the efficacy of ITI regimen seem to be different from our experience between patients with mild or moderate HA and severe HA. Disclosures: No relevant conflicts of interest to declare.

Non-Inversion Factor VIII Mutations in 80 Hemophilia A Families Including 24 with Alloimmune Responses

2002 ◽  
Vol 87 (02) ◽  
pp. 273-276 ◽  
Author(s):  
Miao-Liang Liu ◽  
Shelley Nakaya ◽  
Arthur Thompson
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
De Novo ◽  
High Titer ◽  
Direct Sequencing ◽  
Normal Variant ◽  
Missense Mutations ◽  
Gene Deletions ◽  
Intron Splice ◽  
Splice Junctions

SummaryHeteroduplex screening identified 74 small mutations in the factor VIII genes of 72 families with hemophilia A. In addition, patients from 3 families with high titer inhibitors had partial gene deletions and 5 unrelated families that were negative for heteroduplex formation had a mutation on direct sequencing. The latter had mild hemophilia A with an inhibitor, and sequencing their exon 23 fragments found a transition predicting a recurrent Arg2150 to His. Of 69 distinct mutations (including the 3 partial gene deletions), 47 are novel. Of small mutations, 51 were missense (one possibly a normal variant and two that could also alter splicing) at 39 sites, 13 were small deletions or insertions (3 inframe and one a normal variant in an intron), 13 were nonsense at 12 sites and 2 altered intron splice junctions. In 24 families, at least one affected member had evidence for an alloimmune response to factor VIII; of these, 11 were associated with missense mutations. In 14 families, de novo origin was demonstrated.

Increased Prevalence of Inhibitors in Mexican-Hispanic Patients with Severe Hemophilia A Enrolled in the Universal Data Collection Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3488-3488 ◽  
Author(s):  
Shannon Carpenter ◽  
J. Michael Soucie ◽  
Sophia Sterner ◽  
Rodney J Presley
Keyword(s):  
African Americans ◽  
Data Collection ◽  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Treatment Center ◽  
Hispanic Population ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Insurance Type

Abstract Abstract 3488 Poster Board III-425 Neutralizing inhibitor formation occurs in up to 20-30% of patients with severe factor VIII deficiency, leading to significantly increased morbidity in affected individuals. It has been well-established that patients of African descent have a higher prevalence of inhibitor development. [Oldenburg, J et al. Semin Hematol, 2004] The Hispanic population also has been assumed to have an increase in inhibitor development when compared with Caucasians. The study presented here is the first to definitively demonstrate an increased prevalence of inhibitors in the Hispanic population. We compared inhibitor prevalence among various racial and ethnic groups in a cross-sectional analysis of 6198 males with severe hemophilia A that participated in the Universal Data Collection project sponsored by the Centers for Disease Control and Prevention. We used logistic regression analysis to control for potential confounding variables including age, insurance type (as a proxy for access to care and socio-economic status), age at first bleed, age at diagnosis and use of prophylaxis. The included table shows those variables that were determined to be independently predictive of inhibitors. We assigned Mexican derivation to participants who labeled themselves as Hispanic and who were born either in Mexico, in states bordering Mexico or in states with large Mexican populations as established by Census data. The prevalence of high titer inhibitors in the Mexican-Hispanic population was 26.3% compared to 16.4% for Caucasian patients [OR 1.5, 95% CI 1.1, 1.9], and 26.8% for African-Americans. The underlying cause of increased inhibitor prevalence in these populations is still unknown, though a recent study in African-Americans demonstrated wild-type factors unique from commercially available product. [Viel KR, et al. Inhibitor of Factor VIII in Black Patients with Hemophilia. N Engl J Med, 2009] Further investigation of this phenomenon in the Mexican-Hispanic population, as well as the potential impact of differing immune responses, is warranted. Multivariate analysis of ethnicity and other variables found to be independently predictive of a prevalent inhibitor Characteristic Odds Ratio 95% CI Race/Ethnicity African-American 1.5 1.2 - 1.9 Mexican Hispanic 1.5 1.1 - 1.9 Hispanic 1.2 0.9 - 1.7 Other 1.2 0.9 - 1.6 White Ref Age* (years) <2 4.2 3.0 - 5.9 2-5 6.4 5.1 - 8.0 6-10 2.8 2.2 - 3.5 11-18 1.7 1.4 – 2.1 >18 Ref Insurance type Medicare 1.8 1.4 - 2.3 Medicaid 1.3 1.1 - 1.5 State program 1.1 0.6 - 1.9 TRICARE 1.0 0.4 - 2.1 Other 0.8 0.6 - 1.2 Uninsured 1.6 1.0 - 2.4 Commercial Ref Prophylaxis Yes 0.6 0.5 - 0.7 No Ref * Age with inhibitor or last UDC visit if no inhibitor The authors wish to acknowledge the contributions of the Hemophilia Treatment Center Network Investigators in the completion of this study. Disclosures: No relevant conflicts of interest to declare.

Source and Purity of Factor VIII Products As Risk Factors for Inhibitor Development In Previously Untreated Patients with Severe Hemophilia A

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 25-25
Author(s):  
Maria Elisa Mancuso ◽  
Pier Mannuccio Mannucci ◽  
Angiola Rocino ◽  
Isabella Garagiola ◽  
Annarita Tagliaferri ◽  
...  
Keyword(s):  
Risk Factors ◽  
Factor Viii ◽  
High Purity ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Specific Activity ◽  
Sensitivity Analyses ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Treatment Data

Abstract Abstract 25 Background: Inhibitor development is influenced by several genetic and environmental factors and the type of factor VIII (FVIII) products may play a role. Methods: We designed a cohort study whose novelty resides in the classification of products not only according to the plasmatic (pdFVIII) or recombinant (rFVIII) source of FVIII but also to the degree of purity expressed as FVIII specific activity per mg of protein. The role of FVIII product as risk factor for inhibitor development was evaluated in a multivariate model adjusting for potential confounders (i.e. age at first FVIII exposure, intensive treatment and prophylaxis). Cumulative incidences of all and high-responding inhibitors were calculated for the whole cohort of 721 patients with severe and moderate hemophilia A followed-up in 3 Italian Hemophilia Centers. Detailed treatment data from the first FVIII infusion up to inhibitor development or 150 exposure days were available for 377 patients and in this group of patients risk factors for inhibitor development including the type of FVIII product and its degree of purity (i.e. low/intermediate-, high-purity pdFVIII and rFVIII) were analysed. Results: The overall cumulative incidence of inhibitors was 22% (n=160; 130 high-responders, 18%) and it was lower in patients first treated with pdFVIII (107/586, 18%) than in those treated with rFVIII (53/135, 39%). Similar results were obtained by evaluating only high-responding inhibitors and patients with severe hemophilia. The adjusted hazard ratio of inhibitor development was 4.9 with rFVIII and 2.0 with high-purity pdFVIII (95%CI: 2.9–8.3 and 1.1–4.0), taking as reference low/intermediate-purity pdFVIII. There was no difference in the frequency of inhibitor testing between treatment groups. Sensitivity analyses - in patients who never switched product type, previously untreated patients, those treated on-demand and those with high-risk F8 mutations - confirmed an increased inhibitor risk in patients first treated with rFVIII or high-purity pdFVIII than in those treated with low/intermediate-purity pdFVIII. In fact, in all the aforementioned subgroups by multivariate analysis the risk of inhibitor development was invariably 3- to 6-fold higher in patients first treated with rFVIII than in those first treated with pdFVIII, and similar results were obtained for both all inhibitors and high-responding inhibitors. Conclusions: This study shows that the degree of purity of FVIII products influences inhibitor development independently from other risk factors, and emphasizes that differences exist also within pdFVIII products. Disclosures: No relevant conflicts of interest to declare.

Assessment Levels of Factor VIII and IX Inhibitors in Patients with Hemophilia in North West of Iran: What Is the Main Reason of Low Inhibitor Titer and Rate in Our Patients?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4662-4662
Author(s):  
Roya Dolatkhah ◽  
Ali Akbar Movasaghpour Akbari ◽  
Iraj Asvadi Kermani ◽  
Zohreh Sanaat ◽  
Azim Rezamand ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Factor Ix ◽  
Haemophilia A ◽  
Inhibitor Development ◽  
Haemophilia B ◽  
On Demand ◽  
Viii And Ix

Abstract Abstract 4662 Introduction Today, the development of inhibitors against Factor VIII (FVIII) and Factor IX (FIX) is seen as the most serious complication of haemophilia A and B therapy. Recent studies on the role of the causative haemophilic mutation, race and ethnicity, family history of inhibitors and the possible influence of HLA genotype in inhibitor formation have revealed new and exciting insights. That is challenging conventional thinking about inhibitor development risk and type of factor products, recombinant or plasma-derived. The use of recombinant factor concentrates has revolutionized the treatment of severe factor VIII and IX deficiency. One of the most important complications is the development of antibodies (Inhibitors). Material and Methods Ninety two patients with haemophilia A and 12 patients with Haemophilia B have been studied. Confirmatory tests including one stage FVIII and FIX assay has been performed using STA Deficient FVIII and FIX, an immune-depleted plasma intended in plasma by analyzers of the STA line suitable with these reagents (Diagnostica Stago,France).Presence of Factor VIII and IX inhibitors have been tested by Bethesda Assay. All of the patients use mostly plasma-derived factor products, and on-demand treatment. Results Among 92 haemophilia A patients, FVIII levels were between 0.14–14.40 IU/dl (mean 2.91 ± 2.62), FIX levels were between 0.17 to 4.37 IU/dl (mean 1.53 ± 1.38) in12 haemophilia B patients. PT activity was 68.7–134 (mean 101.05 ± 15.13), APTT was 28.90 – 102 (mean 60.66 ± 13.50). FVIII inhibitor levels were between 0–1.14 BU (mean 0.04 ± 0.20) in 5 severe Hemophilia A patients (5.45%) and FIX Inhibitor levels were between 0–0.65 BU (mean 0.10 ± 0.23) in 2 Hemophilia B patients. Discussion Alloantibodies (inhibitors) against FVIII or FIX represent a major complication in patient care because they render classical substitution therapy ineffective. Inhibitors occur at a frequency of 20–30% in severe and 3–13% with mild or moderate haemophilia A, and 3% in haemophilia B, respectively. An alternative pathomechanism may underlie inhibitor development in patients with mild hemophilia A. Although it has been reported that inhibitors in patients with mild haemophilia are related to periods of intensive treatment or surgery, this has never been properly studied in children with severe haemophilia. The low inhibitor rate with Low Titers in our patients may be demonstrate the role of type of factor products, recombinant or plasma-derived, which in this study was mostly use of plasma-derived factor products, and on-demand treatment. Also detailed evaluation of major risk factors of development of Factor VIII and IX inhibitors in our patients is required. Disclosures: No relevant conflicts of interest to declare.

Development of Inhibitory Antibodies to Therapeutic Factor VIII in Severe Hemophilia A Is Associated with Microsatellite Polymorphism in the HMOX1 promoter

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 38-38
Author(s):  
Yohann Repesse ◽  
Ivan Peyron ◽  
Jordan Dimitrov ◽  
Suryasarathi Dasgupta ◽  
Elika Farrokhi Moshai ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Direct Sequencing ◽  
Therapeutic Option ◽  
Cumulative Exposure ◽  
Heme Oxygenase 1 ◽  
Nucleotide Polymorphisms ◽  
Severe Hemophilia ◽  
Anti Inflammatory

Abstract Abstract 38 The occurrence of inhibitory anti-factor VIII (FVIII) antibodies is the major complication of replacement therapy in patients with hemophilia A. Heme oxygenase-1 (HO-1) is a stress inducible enzyme with anti-inflammatory activity. Induction of HO-1 in hemophilic mice reduces the immunogenicity of therapeutic FVIII. Interestingly, polymorphisms in the promoter of the HO-1-encoding gene (HMOX1) modulate the expression of HO-1. We investigated the relationship between polymorphisms in the promoter of HMOX1 in severe hemophilia A patients and the development of FVIII inhibitors. We analyzed 362 patients with severe hemophilia A involving 99 patients with FVIII inhibitors and 263 patients who did not develop inhibitor within the first 150 cumulative exposure days to therapeutic FVIII. Direct sequencing and DNA fragment analysis were used to study the variable (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies and genotypes, and the development of inhibitors. Our results demonstrate a higher frequency of alleles with large (GT)n repeat (n≥30, L, associated with a lesser expression of HO-1) in inhibitor-positive patients [odds ratio (OR) 2.31; 95% CI 1.46–3.66, p<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% vs 17.1%) [OR 2.21, 95% CI 1.30–3.76, p<0.01]. To our knowledge, this is the first association between HMOX1 promoter polymorphism and development of anti-drug antibodies. Modulating the endogenous anti-inflammatory machinery of hemophilia A patients appears as a plausible therapeutic option for reducing the risk of inhibitor development. Disclosures: No relevant conflicts of interest to declare.

Longitudinal Analysis of Factor VIII Inhibitors in a Previously Untreated Mild Haemophilia A Patient with an Arg593→Cys Substitution

1999 ◽  
Vol 81 (05) ◽  
pp. 723-726 ◽  
Author(s):  
Simone Timmermans ◽  
Ellen Turenhout ◽  
Christine Bank ◽  
Karin Fijnvandraat ◽  
Jan Voorberg ◽  
...  
Keyword(s):  
Factor Viii ◽  
Light Chain ◽  
Longitudinal Analysis ◽  
Factor Viii Inhibitor ◽  
Haemophilia A ◽  
Missense Mutations ◽  
Initial Development ◽  
Inhibitor Development ◽  
Epitope Specificity ◽  
A2 Domain

SummaryRecent studies suggest that certain missense mutations associated with mild to moderate haemophilia A predispose to inhibitor development. In this study, we present a longitudinal analysis of the epitope specificity of an inhibitor that developed in a mild haemophiliac with an Arg593→Cys mutation. Immunoprecipitation studies revealed the presence of antibodies directed towards the light chain and A2 domain of factor VIII. Limited reactivity was observed with metabolically labelled C2 domain. Almost complete inhibitor neutralization was achieved upon addition of A2 domain. Binding of the inhibitor was not affected by the presence of the Arg593→Cys substitution in the recombinant A2 fragment. Evaluation of the epitope specificity of anti-factor VIII antibodies in plasma samples obtained at different time-points of inhibitor development revealed initial development of a low titre inhibitor directed towards the A2 domain and factor VIII light chain. A second period of factor VIII replacement therapy resulted in a dramatic rise in factor VIII inhibitor titre, which maintained their original epitope specificity. Based on the results of this and previous studies (Fijnvandraat et al., 1997; Thompson et al., 1997) it is argued that inhibitor development in patients with the Arg593→Cys mutation may proceed via a similar mechanism.

scholarly journals Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A

Blood ◽  
2014 ◽  
Vol 124 (15) ◽  
pp. 2333-2336 ◽  
Author(s):  
Giancarlo Castaman ◽  
Karin Fijnvandraat
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Biological Response ◽  
Interindividual Variation ◽  
Clinical Use ◽  
Clinical Predictors ◽  
Inhibitor Development ◽  
Prevention And Treatment ◽  
Selection Of

Abstract The risk for inhibitor development in mild hemophilia A (factor VIII levels between 5 and 40 U/dL) is larger than previously anticipated, continues throughout life, and is particularly associated with certain mutations in F8. Desmopressin may reduce inhibitor risk by avoiding exposure to FVIII concentrates, but the heterogenous biological response to desmopressin, showing large interindividual variation, may limit its clinical use. However, predictors of desmopressin response have been recently identified, allowing the selection of the best candidates to this treatment.

THE RISK OF INHIBITOR DEVELOPMENT IN 1104 PATIENTS WITH HEMOPHILIA A ACCORDING TO FACTOR VIII GENOTYPE

2007 ◽  
Vol 5 ◽  
pp. O-S-064-O-S-064
Author(s):  
J. Boekhorst ◽  
G. Rastegar Lari ◽  
R. d'Oiron ◽  
J.M. Costa ◽  
I.R.O. Novakova ◽  
...  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Inhibitor Development

scholarly journals Incidence of inhibitor development in a group of young hemophilia A patients treated exclusively with lyophilized cryoprecipitate

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3332-3335 ◽  
Author(s):  
K Peerlinck ◽  
FR Rosendaal ◽  
J Vermylen
Keyword(s):  
Factor Viii ◽  
Patient Group ◽  
Hemophilia A ◽  
Cumulative Risk ◽  
Reference Population ◽  
Single Factor ◽  
Inhibitor Development ◽  
Age Dependent ◽  
The One ◽  
Suitable Reference

Abstract The incidence of neutralizing isoantibody formation to infused factor VIII in a cohort of 67 hemophilia A patients, born between January 1, 1971 and April 30, 1990, who had been treated exclusively with lyophilized cryoprecipitate, was 6% (5.3 per 1,000 patient years of observation). The age-dependent cumulative risk was 4.6% at 4 years of age and 6.7% at 8 years of age. Recent reports in patients treated with a variety of more pure concentrates show a much higher incidence of inhibitor formation and tend to be used as a reference when new concentrates are introduced. We believe that a patient group, such as the one studied here, is a more suitable reference population because these patients have been exclusively treated with a single factor VIII preparation.

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