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Prepublished online as a Blood First Edition Paper on September 19, 2002; DOI 10.1182/blood-2002-07-2336.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 937-942
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
A site involving the "hybrid" and PSI homology domains of
GPIIIa ( 3-integrin subunit) is a common target for antibodies
associated with quinine-induced immune thrombocytopenia
Julie A. Peterson,
Contessa E. Nyree,
Peter J. Newman, and
Richard H. Aster
From the Blood Research Institute, the Blood Center of
Southeastern Wisconsin, and the Departments of Cellular Biology,
Pharmacology, Medicine, and Pathology, Medical College of
Wisconsin, Milwaukee.
Drug-dependent antibodies (DDAbs) can cause the precipitous
destruction of platelets if a patient is exposed to the drug for which
the antibodies are specific. The molecular character of the
epitopes recognized is poorly understood, and the mechanism by which
drugs promote tight binding of these antibodies to platelet glycoproteins without linking covalently to protein or antibody is not
yet known. We studied a group of quinine-dependent antibodies that
react with human glycoprotein IIIa (GPIIIa;  3-integrin subunit) but
fail to recognize rat GPIIIa, despite close homology between the 2 proteins. By characterizing reactions of these antibodies with
human/rat GPIIIa chimeras and selected GPIIIa mutants, we found that
each of 3 quinine-dependent antibodies requires a 17-amino acid
sequence in the newly recognized "hybrid" and PSI homology domains
of GPIIIa for drug-dependent binding. Disulfide bonds are required to
stabilize the target epitope. Monoclonal antibody AP3, which blocks the
binding of these DDAbs to GPIIIa, was found to require a more limited
stretch of the same peptide for its reaction with the glycoprotein. The
findings suggest this region of GPIIIa may be a favored target for
quinine-dependent antibodies and may provide a basis for further
studies to elucidate the molecular basis of
glycoprotein-drug-antibody interaction.
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