Studies are proposed to examine the pathogenesis of drug-induced, immunologically-mediated thrombocytopenia (DITP), a relatively common disorder reported to have been induced by more than 100 different medications. In most cases of DITP, platelet destruction is thought to be caused by the binding of drug-dependent antibodies (DDAB) to platelets in the presence of the provocative drug. The mechanism(s) by which DDAB is induced is unknown and there is no consensus as to the molecular basis for drug-antibody-platelet interaction in DITP. The applicant proposes to study these questions utilizing purified, radiolabeled DDAB induced by quinidine and quinine, radiolabeled drug, and normal and abnormal target platelets. Studies will be conducted to define the order in which drug, antibody, and platelets interact, the stoichiometry of this interaction, binding affinities of the DDAB, the site(s) on the platelet to which DDAB binds, and the domain(s) of the immunoglobulin molecule involved in this binding. Utilizing structural analogs and metabolites of quinidine and quinine, the """"""""fine"""""""" specificities of quinidine- and quinine-induced DDAB will be characterized and the hypothesis that a specific domain on the drug molecule may be important for the insertion of drug-antibody complexes into the platelet membrane will be investigated. Findings made will be applied where possible to the development of improved methods for detection of DDAB and for identifying the drug(s) responsible for their induction and may provide information relevant to the pathogenesis of other drug-induced, immunologically-mediated disorders.
| Christie, D J; Diaz-Arauzo, H; Cook, J M (1988) Antibody-mediated platelet destruction by quinine, quinidine, and their metabolites. J Lab Clin Med 112:92-8 |
| Christie, D J; Mullen, P C; Aster, R H (1987) Quinine- and quinidine platelet antibodies can react with GPIIb/IIIa. Br J Haematol 67:213-9 |
