Factor VIII hydrolysis mediated by anti-factor VIII autoantibodies in acquired hemophilia.
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.
Wootla
Bharath
B
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris6, , Unité Mixte de Recherche, Paris, France.
Dasgupta
Suryasarathi
S
Dimitrov
Jordan D
JD
Bayry
Jagadeesh
J
Lévesque
Hervé
H
Borg
Jeanne-Yvonne
JY
Borel-Derlon
Annie
A
Rao
Desirazu N
DN
Friboulet
Alain
A
Kaveri
Srinivas V
SV
Lacroix-Desmazes
Sébastien
S
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
D017151:Antibodies, Catalytic; D001323:Autoantibodies; D007074:Immunoglobulin G; D007518:Isoantibodies; D005169:Factor VIII