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Blood, Vol. 92 No. 7 (October 1), 1998:
pp. 2366-2373
Quinine-Dependent Antibodies Bind a Restricted Set of Epitopes on the
Glycoprotein Ib-IX Complex: Characterization of the Epitopes
Janette K. Burgess,
Jose A. Lopez,
Michael C. Berndt,
Ian Dawes,
Colin N. Chesterman, and
Beng H. Chong
From the University of New South Wales, Centre for Thrombosis and
Vascular Research, Department of Haematology, Prince of Wales Hospital,
Sydney, Australia; Baylor College of Medicine, Houston, TX; Baker
Medical Research Institute, Melbourne, Australia; and the School of
Biochemistry and Molecular Genetics, University of NSW, Sydney,
Australia.
Severe immune thrombocytopenia is an idiosyncratic complication of
quinine therapy. Although in most cases the responsible antibody is
directed against platelet membrane glycoprotein (GP) Ib-IX, specificity
for GPIIb-IIIa or both epitopes has also been reported. The objective
of this study was to characterize the binding site of GPIb-IX-specific
quinine-dependent antibodies. Antibody binding to Chinese hamster ovary
cells or mouse L cells stably transfected with various combinations of
the three genes (Ib , Ib , or IX) that encode this complex was
detected using flow cytometry, monoclonal antibody-specific
immobilization of platelet antigens assay, and differential adsorption
studies. IgG in sera from 15 patients with quinine-induced
thrombocytopenia binding to the cells, in the presence of quinine,
showed three distinct patterns. Group 1 sera contained at least two
antibody populations, one which binds to GPIb and another which
recognizes GPIX. Group 2 sera contained an antibody which binds drug
dependently to GPIX, and Group 3 sera contained an antibody which
recognizes a quinine-dependent epitope on GPIb. Thus, the
quinine-dependent antibodies fall into two distinct populations that
bind to GPIb and GPIX independently. Using proteases which cleave
GPIb at specific sites, we have shown that the GPIb-specific
antibody binds to an 11-amino acid (283 to 293) region. Peptide
inhibition studies provide confirmatory evidence that this region
contains the epitope for the GPIb-specific quinine-dependent
antibody.
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