title: Long-term anti-FVIII antibody response in Bethesda-negative haemophilia A patients receiving continuous replacement therapy.
abstract: It has previously been shown that patients with haemophilia A may develop non-neutralizing anti-factor VIII (FVIII) antibodies (NNA) that escape detection by the Bethesda assay, but are detected using immune-based assays. We and others found NNAs to be directed not only towards non-functional parts of the protein, but towards all regions of the FVIII protein. We also showed a heterogeneous antibody response towards different FVIII products. However, the clinical relevance and the natural history of NNA remain unclear. Therefore, we followed a cohort of unrelated subjects with haemophilia A for 4 years with the goal of exploring the long-term development of NNA using an enzyme-linked immunosorbent assay (ELISA). Ten of 78 subjects (12·8%) exhibited an immune response that was transient and heterogeneous, and none of the subjects developed an FVIII inhibitor. The result of the ELISA was examined in relation to clinical variables and no significant associations between a positive ELISA and age, F8 mutation, port-à-cath implantation and HCV infection were shown. Interestingly, patients with NNA had significantly fewer bleeding episodes (P = 0·048) compared with NNA-negative subjects. The results indicate that the immune response to FVIII products within an individual may vary over time. However, the clinical impact of NNA remains unclear.
authors.affiliation: Haematology and Coagulation Disorders, Malmö, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Klintman
authors.forename: Andreas
authors.initials: A
authors.lastname: Hillarp
authors.forename: Erik
authors.initials: E
authors.lastname: Berntorp
authors.forename: Jan
authors.initials: J
authors.lastname: Astermark
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology; D005169:Factor VIII / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D007223:Infant; D007518:Isoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: D000939:Epitopes; D007518:Isoantibodies; C078147:F8 protein, human; D005169:Factor VIII
keywords: clotting factors; factor VIII; haemophilia A; immunogenicity; non-neutralizing anti-FVIII antibodies