Haemophilia management: time to get personal? (original) (raw)
Related papers
Haemophilia, 2000
An HLA-DRA-DRB1*0101-restricted Tcell epitope in the factor VIII (FVIII) C2 domain occurred in a mild haemophilia A patient with missense substitution FVIII-A2201P. His T cells responded to synthetic peptides FVIII 2186-2205 and FVIII 2194-2213 (J Thromb Haemost 2007 5: 2399). T cells from family members with genotype FVIII-A2201P were analysed to determine if FVIII-specific T cells occur in individuals with a haemophilic mutation but no clinically significant inhibitor response. Fluorescent MHC class II tetramers corresponding to subjectsÕ HLA-DRB1 types were loaded with 20-mer peptides and utilized to label antigen-specific CD4+ T cells. T-cell responses to peptides spanning the FVIII-C2 sequence were evaluated. T cells recognizing specific peptides were cloned, and antigen specificity was verified by proliferation assays. Plasma and/or purified IgG samples were tested for FVIII inhibitory activity. CD4+ T cells and T-cell clones from two brothers who shared the DRB1*0101 allele responded to FVIII 2194-2213 . A haemophilic cousinÕs HLA-DRA-DRB1*1104-restricted response to FVIII 2202-2221 was detected only when CD4+CD25+ cells were depleted. A great uncle and two obligate carriers had no detectable FVIII-C2-specific T cells. Concentrated IgG from the brother without a clinical inhibitor response showed a low-titre FVIII inhibitor. FVIII-specific T cells and inhibitory IgG were found in a previously infused, haemophilic subject who had a sub-clinical FVIII inhibitor. CD4+CD25+ depleted T cells from a non-infused haemophilic cousin recognized an overlapping FVIII epitope, indicating a latent HLA-DRA-DRB1*1104-restricted T-cell response to FVIII. Specific T-cell responses to FVIII can occur without clinically significant inhibitors.
Alloantibodies to factor VIII in haemophilia
Haemophilia, 2011
Up to one-third of haemophilia A patients develop factor VIII (FVIII) alloantibodies (inhibitors). The Bethesda assay detects inhibitors but is relatively insensitive. Recently, a new fluorescence-based immunoassay (FLI) was developed for antibody detection. The aim of this study was to assess the prevalence of inhibitors as measured by FLI. Assays of FVIII, FVIII inhibitor by Bethesda assay with Nijmegen modification, and FVIII inhibitor by FLI were performed on adult patients with haemophilia A. Data were complete for 46 patients (median age 39), of whom 72% were severe, 7% moderate and 22% mild. The Bethesda assay was positive in only two patients (4%), while FLI was positive in 23 of 46 patients (50%), with values ranging from 0.4 to 33.7 nm (median 3.5 nm). FLI titres exceeded 7.0 nm in 19.5% of patients, all but one of whom had severe haemophilia. FLI antibodypositive patients were less likely to be HIV positive (30% vs. 70%, P = 0.02). The use of a prophylaxis regimen was associated with a lower incidence of antibody; only two of 23 patients with detectable antibody and none of those with antibody >7 nm were on a prophylaxis regimen, while nine of 23 patients without antibody were on prophylaxis, (P = 0.03). There was no difference in inhibitor presence in patients using recombinant versus plasma-derived factor. Antibodies detected by FLI are frequent in patients with haemophilia A, but are less common in those who are HIV positive or are receiving regular FVIII prophylaxis.
Challenges and open issues in the management of acquired hemophilia A (AHA)
Blood cells, molecules & diseases, 2015
Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by antibodies which neutralize the function of factor VIII (FVIII). The disease presents a complex clinical challenge to the treating Physicians and Hematologists. As the disease is associated with high mortality, prompt management is necessary. Early recognition, quick diagnosis and timely referral to a specialized center are important for better management of these patients. The different clinical manifestations, underlying pathology, inhibitor kinetics and the associated age related comorbidities do not allow extrapolation of the treatment protocols of congenital hemophilia to AHA. The basic strategies of the management of AHA patients involve maintaining hemostasis, suppression or eradication of antibodies, diagnosis and treatment of underlying pathology and avoid treatment related complications like thrombosis. The efficiency of hemostatic agents which are generally used to treat AHA is unpredictable. Due...
Haemophilia, 2012
Congenital haemophilia A is a chromosomelinked recessive disorder caused by the deficiency or reduction of factor VIII (FVIII) pro-coagulant activity. During treatment, some patients develop alloantibodies (FVIII inhibitors) that neutralize the action of exogenously administered FVIII. Currently, the presence of these inhibitors is the most serious adverse event found in replacement therapy. Some studies have suggested that genetic factors influence the development of the FVIII coagulation inhibitors. To identify the class I and II alleles that may be influencing the formation of inhibitors in severe haemophilic patients. Genotyping of the class I (HLA-A,-B and-C) and class II (HLA-DRB1,-DQA1 and-DQB1) alleles of 122 patients with severe haemophilia A, including 36 who had developed antibodies to factor VIII, was performed. After the comparison of the group without inhibitors and the group with inhibitors, HLA-C*16 [Odds ratio (OR) = 7.73; P = 0.0092] and HLA-DRB1*14 (OR = 4.52; P = 0.0174) were found to be positively associated with the formation of the inhibitors. These results confirm that HLA alleles are involved in inhibitor production and could be used as a tool for recognition of groups at high risk of possible inhibitor development in Southern Brazilian haemophilic patients.
Immunogenicity of Current and New Therapies for Hemophilia A
Pharmaceuticals
Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement therapy, including bioengineered FVIII molecules with enhanced pharmacokinetic profiles: the extended half-life (EHL) recombinant FVIII products. However, the main complication resulting from replacement treatment in hemophilia A is the development of anti-FVIII neutralizing alloantibodies, known as inhibitors, affecting approximately 25–30% of severe hemophilia A patients. Therefore, the immunogenicity of each FVIII product and the mechanisms that could help increase the tolerance to these products have become important research topics in hemophilia A. Furthermore, patients with inhibitors continue to require effective treatment for break...
The inhibitors – a challenge for the management of patients with hereditary haemophilia A
Romanian Journal of Internal Medicine
Introduction. Our research strategy was aimed at evaluating the possible implication of the type of factor VIII product administered as substitution treatment to haemophilia A patients in the occurrence of inhibitors and their consequences on the management. Methods. Scientific articles from July 2015 to July 2017 were searched using the PubMed and PubMed Central databases. The used search terms included “haemophilia A”, “inhibitors”, “plasma-derived factor VIII” and “recombinant factor VIII”. Results. The risk factors for inhibitors occurrence may be patients-related (genetic and nongenetic) and treatment-related. The possibility of a correlation between the increased purity of factor VIII given as substitution treatment and the occurrence of inhibitors is discussed in the light of literature data. Plasma-derived factor VIII is less immunogenic, but not entirely safe from the point of view of the possibility of transmitting biological agents. It is obvious that there is not enough ...
Factor VIII: Perspectives on Immunogenicity and Tolerogenic Strategies for Hemophilia A Patients
International Journal of Molecular and Cellular Medicine (IJMCM), 2020
A major complication in treating hemophilia A is the development of neutralizing antibodies (inhibitors) against therapeutic administered factor VIII (FVIII), which occurs in approximately 20-30% of patients with severe disease. These inhibitors render FVIII replacement therapy ineffective and increase the morbidity and mortality risk. The currently accepted method to eradicate inhibitors is immune tolerance induction (ITI), and frequent intensive administration of FVIII until inhibitor titers drop. Current ITI protocols are extremely costly and not effective in all patients. During the last decade, many types of research have been accomplished to clarify the mechanisms that mediate immune tolerance induction. Novel experimental therapies including monoclonal antibodies, viral vector-mediated gene therapy, regulatory T cell induction using immunosuppressive drugs, and nanoparticle-based immune modulation show promising results in hemophilia A clinical trials. This review focuses on treatment options towards the anti-FVIII immune responses and current novel therapies in clinical trials.