title: Different factor VIII neutralizing effects on anti-factor VIII inhibitor antibodies associated with epitope specificity and von Willebrand factor.
abstract: Inhibitor neutralization therapy based on factor (F)VIII replacement is used for haemostatic treatment in haemophilia A patients with inhibitors on low responder, but effects appear to depend on various properties of inhibitors. We investigated this nature by evaluating the global coagulation function in timed-reactions after mixing FVIII (1 U/ml) with anti-FVIII alloantibodies containing distinct epitopes (2·5 Bethesda units/ml). Thrombin generation assays showed that peak thrombin and mean velocity to peak thrombin were depressed by anti-C2 type 1 inhibitors to significantly greater extents than by anti-A2 type 1 and anti-C2 type 2 (2- to 6-fold and 10- to 20-fold, respectively). In the presence of FVIII-von Willebrand Factor (VWF) complex, the anti-C2 type 1-mediated decreased thrombin generation was reduced by 20-40%, reflecting the protective function of VWF. However, the activities of anti-A2 type 1 were little affected, and that of anti-C2 type 2 was rather enhanced by c. 2·5-fold, relative to FVIII. Clot waveform analysis also showed similar patterns. Anti-FVIII monoclonal antibodies with well-defined characteristics demonstrated similar reactions to those with polyclonal inhibitors. In conclusion, the neutralizing effects of FVIII(-VWF) depending on epitopes could have significant therapeutic implications, and it could be important to determine inhibitor properties in order to predict the effects of infused FVIII in neutralization therapy.
authors.affiliation: Department of Paediatrics, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yada
authors.forename: Keiji
authors.initials: K
authors.lastname: Nogami
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D001777:Blood Coagulation / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005169:Factor VIII / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006467:Hemophilia A / Q000097:blood / Q000276:immunology / Q000628:therapy; D006801:Humans; D007518:Isoantibodies / Q000276:immunology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D013917:Thrombin / Q000378:metabolism; D013918:Thrombin Time; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D000939:Epitopes; D007518:Isoantibodies; D014841:von Willebrand Factor; D005169:Factor VIII; D013917:Thrombin
keywords: epitopes; factorVIII; haemophilia A; inhibitor; neutralization therapy