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

Abstract

Summary 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.

Inhibitors in Severe Hemophilia A: 25-Year Experience in Slovakia

“…[22][23][24][25][26]60 In vitro and in vivo experiments showed that pdFVIII/VWF provides better protection against inhibitor neutralization than rFVIII, which results in prolonged persistence of FVIII in the circulation. 61 Most of current guidelines for ITI commonly recommend the switch for FVIII/VWF concentrates in patients who failed to achieve ITI success with rFVIII as well as for the rescue ITI. 30,31,54,62 Our study included all consecutive patients with FVIII inhibitors undergoing ITI in two HCCC and showed a high success rate in inhibitor eradication.…”

An update on the ‘danger theory’ in inhibitor development in hemophilia A

“…Proposed explanations for this finding include the presence of Von Willebrand Factor (VWF) in pd-FVIII, reducing FVIII immunogenicity by epitope masking and prevention of endocytosis by DCs. Secondly, the different posttranslational modifications of rFVIII due to its production in mammalian cells rather than human cells might influence its immunogenicity [38][39][40][41][42]. This issue however remains highly debated, which is beyond the scope of this review.…”

Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients

“…Hemophilia A (HA) is an X-linked recessive bleeding disorder resulting from a quantitative or qualitative de ciency in the factor VIII (FVIII) protein [1][2][3][4][5]. Manifestation of neutralizing antibodies (inhibitors) against infused FVIII protein is the most burdensome complication of HA patients [6].…”