| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
,,,
,,
* Centre de Recherche des Cordeliers, Université Pierre et Marie Curie - Paris6, and
Université Paris Descartes, Unité Mixte de Recherche S 872, Paris,
Institut National de la Santé et de la Recherche Médicale, U872, Paris,
Rouen University Hospital, Rouen,
¶ Université de Caen, Laboratoire d’Hématologie EA 3212, Caen, and
|| Université de Technologie de Compiègne, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6022 Génie Enzymatique et Cellulaire, Compiègne, France; and
# Department of Biochemistry, Indian Institute of Science, Bangalore, India
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 µmol/min/mol). Purified IgG from 21 of 45 patients with acquired hemophilia demonstrated FVIII hydrolysis rates (mean 219 ± 94 µmol/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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Institut National de la Santé et de la Recherche Médicale, by Centre National de la Recherche Scientifique, by Indo-French Center for Promotion of Advanced Research, by Novonordisk (La Defense, France), and by a Grant from Agence Nationale de la Recherche (ANR-05-MRAR-012). B.W., S.D., and J.D.D. are the recipients of fellowships from Laboratoire Français de Fractionnement et des Biotechnologies (LFB, Les Ulis, France), from Fédération de la Recherche Médicale, and from Institut National de la Santé et de la Recherche Médicale postes-verts, respectively.
2 Address correspondence and reprint requests to Dr. Sébastien Lacroix-Desmazes, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche S 872 Equipe 16, Centre de Recherche des Cordeliers, 15 rue de l’école de médecine, 75006 Paris, France. E-mail address: Sebastien.Lacroix-Desmazes{at}crc.jussieu.fr
3 Abbreviations used in this paper: FVIII, factor VIII; IVIg, intravenous immunoglobulin; HSA, human plasma-derived albumin; VWF, von Willebrand factor; aPTT, activated partial thrombosplatin time; BU, Bethesda units; MALDI-TOF, matrix-assisted laser desorption/ionization-time-of-flight; CHU, Centre Hospitalier Universitaire.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
