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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 156-163
A human antibody directed to the factor VIII C1 domain inhibits
factor VIII cofactor activity and binding to von Willebrand factor
Marc Jacquemin,
Abdellah Benhida,
Kathelijne Peerlinck,
Benoît Desqueper,
Luc Vander
Elst,
Renaud Lavend'homme,
Roseline d'Oiron,
Rainer Schwaab,
Marleen Bakkus,
Kris Thielemans,
Jean-Guy Gilles,
Jos Vermylen, and
Jean-Marie Saint-Remy
From the Center for Molecular and Vascular Biology, Katholieke
Universiteit Leuven, Leuven, Belgium; Hôpital Bicêtre, le
Kremlin-Bicêtre, AP-HP, France; Institut für
Experimentelle Hämatologie und Transfusionsmedizin, Bonn,
Germany; Department of Hematology-Immunology, Vrije Universiteit
Brussels, Brussels, Belgium.
The occurrence of factor VIII (fVIII) inhibitory antibodies is a
rare complication of fVIII substitution therapy in mild/moderate hemophilia A patients. fVIII mutations in certain regions such as the
C1 domain are, however, more frequently associated with inhibitor, for
reasons which remain unclear. To determine whether inhibitors could map
to the mutation site, we analyzed at the clonal level the immune
response of such a patient with an inhibitor to wild-type but not
self-fVIII and an Arg2150His substitution in the C1 domain.
Immortalization of the patient B lymphocytes provided a cell line
producing an anti-fVIII IgG4 antibody, LE2E9, that inhibited fVIII
cofactor activity, following type 2 kinetics and prevented fVIII
binding to von Willebrand factor. Epitope mapping with recombinant
fVIII fragments indicated that LE2E9 recognized the fVIII C1
domain, but not the Arg2150His-substituted C1 domain. Accordingly,
LE2E9 did not inhibit Arg2150His fVIII activity. These observations
identify C1 as a novel target for fVIII inhibitors and
demonstrate that Arg2150His substitution alters a
B-cell epitope in the C1 domain, which may contribute to the
higher inhibitor incidence in patients carrying such substitution. (Blood. 2000; 95:156-163)
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