title: Factor VIII hydrolysis mediated by anti-factor VIII autoantibodies in acquired hemophilia.
abstract: Acquired hemophilia is a rare hemorrhagic disorder caused by the spontaneous appearance of inhibitory autoantibodies directed against endogenous coagulation factor VIII (FVIII). Inhibitory Abs also arise in patients with congenital hemophilia A as alloantibodies directed to therapeutic FVIII. Both autoimmune and alloimmune inhibitors neutralize FVIII by steric hindrance. We have described FVIII-hydrolyzing IgG in 50% of inhibitor-positive patients with severe hemophilia A that inactivate therapeutic FVIII. In this study, we investigated the presence of autoimmune FVIII-hydrolyzing IgG in patients with acquired hemophilia. Pooled IgG from healthy donors demonstrated moderate FVIII-hydrolyzing activity (56 +/- 26 micromol/min/mol). Purified IgG from 21 of 45 patients with acquired hemophilia demonstrated FVIII hydrolysis rates (mean 219 +/- 94 micromol/min/mol) significantly greater than that of control IgG. Three of four patients followed over the course of the disease had rates of FVIII hydrolysis that co-evolved with inhibitory titers in plasma, suggesting that IgG-mediated FVIII hydrolysis participates, in part, in FVIII inactivation. The present work extends the scope of the diseases associated with FVIII proteolysis and points toward the importance of FVIII as a key target substrate for hydrolytic immunoglobulins. Our data suggest that elevated levels of FVIII-hydrolyzing IgG in acquired hemophilia result from the exacerbation of a physiological catalytic immune response.
authors.affiliation: Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris6, , Unité Mixte de Recherche, Paris, France.
authors.forename: Bharath
authors.initials: B
authors.lastname: Wootla
authors.forename: Suryasarathi
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Dimitrov
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.forename: Hervé
authors.initials: H
authors.lastname: Lévesque
authors.forename: Jeanne-Yvonne
authors.initials: JY
authors.lastname: Borg
authors.forename: Annie
authors.initials: A
authors.lastname: Borel-Derlon
authors.forename: Desirazu N
authors.initials: DN
authors.lastname: Rao
authors.forename: Alain
authors.initials: A
authors.lastname: Friboulet
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017151:Antibodies, Catalytic / Q000097:blood / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D005169:Factor VIII / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D006467:Hemophilia A / Q000097:blood / Q000276:immunology*; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology / Q000302:isolation & purification; D007518:Isoantibodies / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged
chemical_list: D017151:Antibodies, Catalytic; D001323:Autoantibodies; D007074:Immunoglobulin G; D007518:Isoantibodies; D005169:Factor VIII