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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1416-1423
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Functional mapping of anti-factor IX inhibitors developed in
patients with severe hemophilia B
Olivier D. Christophe,
Peter J. Lenting,
Ghislaine Cherel,
Mariette Boon-Spijker,
Jean-Maurice Lavergne,
Ria Boertjes,
Marie-Elisabeth Briquel,
Arja de
Goede-Bolder,
Jenny Goudemand,
Solange Gaillard,
Roseline d'Oiron,
Dominique Meyer, and
Koen Mertens
From the INSERM U143, Hôpital Bicêtre, le
Kremlin-Bicêtre, France; Department of Plasma Proteins, CLB,
Amsterdam, The Netherlands; Centre de Traitement des Hémophiles,
Hôpital Universitaire de Nancy, France; Sophia Children's
Hospital, Rotterdam, The Netherlands; Laboratoire d'hématologie
B, Hôpital Cardiologique, Lille, France; Centre de Traitement des
Hémophiles, Hôpital Universitaire Dupuytren, Limoges,
France; Centre de Traitement des Hémophiles, AP-HP, Faculté
de Médecine Paris-Sud, Hôpital Bicêtre, France; and
Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The
Netherlands.
Development of inhibitory antibodies is a serious complication of
treatment with repeated factor IX infusions in a minority of patients
with hemophilia B. Such antibodies detected in 8 patients have been
characterized. Typing studies revealed that patients' immune response
toward factor IX is highly heterogeneous and involves immunoglobulin G
(IgG) antibodies, preferentially IgG1 and IgG4. The preservation of the
sequence and the 3-dimensional orientation of the amino acids
constituting one epitope are highly important for the assembly of an
antibody-antigen complex. To localize the epitopes on the factor IX
molecule, an original approach was designed using a set of factor X
chimeras carrying regions of factor IX. Results showed that some
patients' antibodies were directed against both the domain containing
the  -carboxy glutamic acid residues (Gla domain) and the protease
domain of factor IX. In contrast, no binding was observed to the
epidermal growth factor-like domains or to the activation peptide.
Functional characterization showed that the purified IgG from
patients' serum inhibited the factor VIIIa-dependent activation of
factor X. Moreover, patients' IgG directed against the Gla domain
inhibited the binding of factor IX to phospholipids as well as the
binding of factor VIII light chain to factor IXa. These data
demonstrate that inhibitors appearing in patients with severe
hemophilia B display specificity against restricted functional domains
of factor IX.
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