Impact of inhibitor epitope profile on the neutralizing effect against plasma‐derived and recombinant factor VIII concentrates in vitro

Abstract

The inhibitory capacity of plasma samples from 24 patients with severe haemophilia A and high-responding inhibitors were evaluated in a concentrate-based assay using two plasma-derived (Haemate and Monoclate-P) and three recombinant (Helixate, Recombinate and ReFacto) factor VIII concentrates and correlated with the corresponding epitope profile. In most, but not all, inhibitor plasmas with a relatively low reactivity against the von Willebrand-containing product Haemate, the main epitopes were located in the FVIII light chain. The reactivities within the group of recombinant products varied in that the reactivity against the B-domain deleted ReFacto was in general higher than that against Recombinate and Helixate. This difference did not correlate with any particular epitope profile and indicates that the B-domain, type of formulation and/or purification procedures may have an impact on the inhibitor reactivity in vitro. The ratio between the inhibitor titres in the concentrate-based assay and the Bethesda assay was dependent on the inhibitor plasma and concentrate used. Taken together, our results show that the reactivity of inhibitor plasmas varies considerably between different FVIII concentrates and that it does not fully correlate with the epitope profile. Potential clinical implications of the observed differences in inhibitor reactivity are discussed.

International recommendations on the diagnosis and treatment of patients with acquired hemophilia A

“…16 Autoantibodies to FVIII and a lupus anticoagulant may be present in the same sample, and in complex cases, a FVIII antibody ELISA may be useful to distinguish between a lupus anticoagulant and an acquired FVIII inhibitor. 17,18 An aPTT reagent insensitive to lupus anticoagulant activity may be useful in patients with detectable lupus anticoagulant activity or low FIX, FXI and/or FXII levels.…”

Immune tolerance induction for patients with severe hemophilia A: a critical literature review

“…The role of VWF in inducing and maintaining immune tolerance to FVIII is controversial and not entirely understood [60]. VWF has been shown to stabilize FVIII and to protect FVIII from neutralizing antibodies in vitro [61][62][63][64]. There is some evidence to suggest that VWF may useful in a select group of patients, those with C2 domain inhibitors as the administration of FVIII containing VWF resulted in higher in vivo recovery of FVIII in patients with C2 domain inhibitors [65].…”

Von Willebrand factor in high‐purity factor VIII complex concentrates: chaperone protein or key to therapies? A meeting report

“…The lower inhibitor reactivity observed with VWF-containing pdFVIII concentrates also translates into greater thrombin generation, according to recent in vitro studies [33], further substantiating a role for VWF in the management of inhibitor patients. VWF content is not the only factor that determines inhibitor reactivity, however, and variations have also been observed with different rFVIII concentrates [34].…”