Immunobiology of GPIIb/IIIa

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Fibrinogen receptor antagonists (FRAs) are a promising new family of anti-thrombotic drugs. However, in clinical trial of these agents conducted to date, 0.1-1.0% of treated patients has experienced acute, severe thrombocytopenia. Although clinical presentation suggests an immunologic etiology, very little published information on this point is available. In preliminary studies, we have obtained evidence that FRA- induced thrombocytopenia is caused by antibodies (abs), often "naturally occurring", that recognize GPIIb/IIIa on platelets treated with an FRA. In this application, we propose studies to characterize the pathogenesis of this disorder, explore the significance of the responsible "natural" antibodies, and develop improved methods for diagnosis and for identifying patients at risk to develop this complication. Pathogenesis-Abs associated with FRA-induced thrombocytopenia will be characterized with emphasis on the following hypotheses: 1) Abs that cause thrombocytopenia in patients treated with abciximab (ReoPro) are specific for C terminal (human) peptide sequences and/or murine sequences in the chimeric abciximab molecule and 2) Abs in patients treated with ligand-mimetic compounds recognized ligand-binding sites (LIBS) on BPII/IIIA. We will seek to develop a murine model of thrombocytopenia induced by ligand-mimetic FRAs in which mechanisms of FRA-induced thrombocytopenia and the origin of the responsible abs can be systematically studied. Information gained will be used to develop sensitive, specific and practical methods for identifying abs capable of causing thrombocytopenia in FRA-treated patients and for predicting whether an FRA can be safely administered. "Natural Antibodies" (NA)-NA have been implicated in normal body homeostasis and in various immune disorders. We propose to explore the hypothesis that some relative common NA recognize ligand-induced conformation changes in the GPIIb/IIIa heterodimer, to characterize the relationship of these NA to FRA-induced thrombocytopenia, and to define their immunologic origin, their potential role in platelet and their effects on the quality of platelets stored prior to transfusion. B cell repertoire- We will utilize immunoglobin V gene amplification and phage display technology to define the B cell repertoire utilized by patients and normal subjects to generate abs specific for ligand-occupied GPIIb/IIIa and to characterize the relationship between NA and pathologic antibodies at a molecular level.