Prevalence of FVIII inhibitors in severe haemophilia A patients: Effect of treatment and genetic factors in an Indian population.

INTRODUCTION: Factor replacement therapy in treatment of haemophilia A is complicated by the production of neutralising antibodies known as inhibitors. The formation of inhibitors is multifactorial being associated with both genetic and environmental factors. AIM: To document the prevalence of inhibitors in severe haemophilia in the community where most patients receive only infrequent episodic replacement therapy and evaluate the factors which could be contributing to it. METHODS: Community based camps were conducted in different parts of the country. Patients were assessed through a structured questionnaire and blood samples were obtained for laboratory evaluation of inhibitors and defined immunological parameters. RESULTS: Inhibitors were present in 87/447 (19.5%) of the evaluated patients. High-titre inhibitor (>5 Bethesda Units [BU]) was identified in 31 (35.6%) patients. HLA DRB1-13-positive cases (RR = 2.04; 95% CI 1.06-3.911; P = 0.033) had an increased risk of inhibitor formation which was retained in the high-titre subset. A decreased risk of inhibitor formation was noted with heterozygous IL4-590 C/T allele (RR = 0.22; 95% CI 0.108-0.442: P = 0.000). There were no significant correlations between any of the evaluated environmental factors and the development of inhibitors in this study. CONCLUSION: The overall prevalence of inhibitors in patients with severe haemophilia A is similar to that reported among patients receiving regular replacement therapy. The data from this study, limited by its retrospective and cross-sectional study design, would suggest that genetic rather than environmental are more likely to impact the development of inhibitors.

Evaluation of nonneutralizing antibodies against factor VIII in severe haemophilia A patients from India.

: Haemophilia A is treated by replacement therapy with factor VIII (FVIII) concentrate. This strategy of treatment is ineffective in some patients due to the development of neutralizing antibodies (NNAs) against FVIII. The inhibitors have been identified to act against the functional domains of FVIII. The presence of NNAs against FVIII has also been identified. There is limited data on the prevalence and significance of NNA in haemophilia. To identify the presence of NNA in severe haemophilia A in our population, patients who were recruited from community-based camps were evaluated for FVIII activity. The patient's samples were further analysed for inhibitor activity with Nijmegen-Bethesda Assay and for NNAs using an in-house ELISA. 312 severe haemophilia patients were analysed for inhibitors and NNA. In-house ELISA picked up antibodies in 56 patients (17.9%). Of these 42 (13.7%) had inhibitory antibodies and in 14 patients (4.5%) there was no evidence of FVIII inhibitory activity. A substantial number of patients with severe haemophilia A have NNA. Continuous long-term follow-up is required in this cohort to evaluate the significance of this observation.