These antibodies are detected by immunoassays, such as enzyme-lin

These antibodies are detected by immunoassays, such as enzyme-linked immunosorbent assay (ELISA) [1-3, 11], fluorescence-based immunoassay [12, 13] and immune-precipitation assay [4], but escape detection by the functional Bethesda assay. The frequency of non-neutralizing antibodies (NNA) in patients with haemophilia varies among studies

from 12.2% to 53.8% [1, 3, 7, 11-15]. Several possible functions of these antibodies have been discussed, for example, their potential influence on pharmacokinetic parameters. Dazzi et al. [1] showed an increase in clearance rate of infused FVIII in patients with antibodies detected by ELISA, but negative in the Bethesda assay. Scandella et al. further investigated whether patients selleck inhibitor with low recovery (<66% of expected raise in FVIII concentration after administration of FVIII) and negative Bethesda assays had positive NNA titres detected by immune-precipitation [6]. No clear relationship between low recovery and the presence of such antibodies could be shown, a result confirmed by others [4, 16]. Recently, it was suggested that NNA have restricted binding specificity towards full-length FVIII products MK-2206 research buy in NNA-positive plasma samples [14]. However, Lebreton et al. [13] showed, in a French cohort, epitope

specificity of NNA mainly towards the heavy chain of the FVIII protein, with 18.4% of the antibodies directed towards the B-domain. In addition, other factors, such as epitope spreading and ageing, might influence the entire antibody response [17, 18]. To improve the understanding for inhibitor development, it is important to evaluate the entire antibody response. Many questions remain regarding NNA formation and their possible clinical impact. Most studies aimed at investigating non-neutralizing FVIII antibodies have been performed with small numbers of patients. There are no data from large cohorts on specific immunogenicity towards different FVIII products used in the treatment of patients with

haemophilia A. In addition, there are no studies on the entire antibody response, including both neutralizing and NNA antibodies, within families learn more containing multiple members with haemophilia A. We have analysed the prevalence of NNA towards FVIII in 201 patients with haemophilia A, with and without a history of inhibitors, from two study cohorts of brothers: the Malmö International Brother Study (MIBS) [19] and the Haemophilia Inhibitor Genetics Study (HIGS) [20]. Three different recombinant FVIII products were used, separately or pooled together, as antigen to evaluate differences in antigenicity between them. We further evaluated the presence of FVIII antibodies in subjects exposed to immune tolerance induction therapy (ITI). Plasma samples were obtained from 259 patients in 123 families with severe haemophilia A (factor VIII level <0.01 IU mL−1) from two cohorts: the MIBS (n = 90) and the HIGS (n = 169).

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