Novel investigations on the protective role of the FVIII/VWF complex in inhibitor development

Abstract

Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates is the most serious unresolved complication of haemophilia A treatment. Systematic reviews suggest a twofold higher incidence of inhibitors with recombinant (rFVIII) vs. plasma-derived (pdFVIII) FVIII products, but study methodologies vary widely. The lower immunogenicity of pdFVIII concentrates is believed to derive from the presence of von Willebrand factor (VWF) which acts as protector and chaperone for FVIII. Several novel investigations reinforce the protective role of the VWF/FVIII complex in inhibitor development. At the basic science level, numerous in vitro and in vivo experiments have demonstrated that VWF-containing pdFVIII concentrates (pdFVIII/VWF) provide better protection against inhibitor neutralization than rFVIII products. Conformational aspects of the binding between VWF and FVIII are thought to prevent the 'attack' on FVIII by inhibitory antibodies. VWF/FVIII binding is 100% in pdFVIII products but only 80% in recombinant products and this 'free' FVIII may be a target for inhibitory antibodies. At the clinical level, newer strategies to prevent inhibitor development in previously untreated patients with severe haemophilia are under investigation. The concept of early prophylaxis (before the onset of a bleed) is convincing from a theoretical point of view but requires further evaluation. The Study on Inhibitors in Plasma-Product Exposed Toddlers is specifically addressing the issue of relative immunogenicity between classes of FVIII product (recombinant vs. plasma-derived). Currently nearing its target enrolment of 300 patients, this international randomized controlled trial is expected to provide some definitive answers about this ever-present clinical dilemma. © 2014 John Wiley & Sons Ltd.