plasma-derived FVIII (pdFVIII) products. Incidence rates of inhibitor development in patients treated with pdFVIII or rFVIII products have been reported in numerous studies, but wide variation
in study characteristics preclude comparing the studies directly. The systematic review of Wight & Paisley included cohort studies, registry data and prospective studies of FVIII in the treatment of PUPs . The cumulative risk of inhibitor development across all studies ranged from 0% to 39% and tended to be lower with single pdFVIII preparations than with multiple pdFVIII preparations or single rFVIII preparations . As newer FVIII products have become www.selleckchem.com/products/azd4547.html available since the review was published in 2003, an update was undertaken to include new studies (Fig. 1). In PUPs treated with pdFVIII products, the crude incidence of inhibitor development was found to be 13.8% (range: 0–28%) whereas, in PUPs treated with recombinant products, the crude incidence of inhibitors was twofold higher (28.5%) albeit with some exceptions. For example, studies evaluating the use of a full-length sucrose-formulated rFVIII concentrate reported comparatively lower incidences of inhibitor development [8, 9]. Collectively, the data suggest that plasma-derived
products are less immunogenic than recombinant products but, due to study heterogeneity, the results cannot be considered conclusive. The potential for rFVIII products to be more immunogenic than pdFVIII selleck chemical products has some plausible biological explanations. First, use of mammalian rather than human cells in rFVIII concentrates induces posttranslational modifications (e.g. glycosylation) which
may have important implications for relative antigenicity [10, 11]. Second, recombinant products are known to contain a protein fraction of FVIII unable to bind to VWF (approximately 20%)  and this population of ‘free’ FVIII has a higher interaction with inhibitory antibodies. Third, it is thought that, in addition to being devoid of VWF which is the ‘chaperone and protector’ of FVIII, recombinant products may be lacking immunosuppressive molecules (e.g. TGFβ) that are present in plasma-derived products. As mentioned previously, results of the updated Wight & Paisley systematic review cannot be considered selleckchem conclusive because the studies on which it is based have many limitations (Table 1). Another recent systematic review also compared rates of inhibitor development in PUPs treated with pdFVIII or rFVIII concentrates . A total of 2094 patients (1965 treated with pdFVIII concentrates; 887 treated with rFVIII concentrates) from 24 individual studies were included in the review. Of these, 420 patients developed inhibitors. The pooled incidence rate of inhibitors was 14.3% (10.4–19.4) with plasma-derived products and 27.4% (23.6–31.5) with recombinant products, which is remarkably similar to those identified in the updated systematic review of Wight & Paisley.