Pathogenesis of Thrombocytopenia Induced by GPIIb/IIIa Inhibitors

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Agents that inhibit the reaction of activated GPIIb/IIIa (alphallb/betaS integrin) with fibrinogen and other ligands are a promising family of anti-thrombotics now widely used to prevent adverse events following coronary angioplasty. Acute, severe thrombocytopenia, often occurring within hours of first exposure to one of these agents, is a recognized side effect of all drugs in this class. In the previous period of support, we obtained evidence that drug-specific antibodies, which can be naturally occurring (or at least pre-existing), are the major cause of this complication, characterized clinical and serologic aspects of this group of disorders and obtained evidence that the responsible antibodies recognize ligand (drug)-induced structural conformers of GPIIb/IIIa. We now propose to extend these observations with the following specific aims: 1) Characterize epitopes on GPIIb/IIIa recognized by antibodies causing thrombocytopenia in patients treated with GPIIb/IIIa inhibitors. Epitopes on ligand-occupied GPIIb/IIIa for which this apparently unique class of immunoglobulins is specific will be defined at the molecular level. 2) Develop new methods for identification of clinically significant antibodies not detected in conventional immunoassays. We hypothesize that platelet destruction in a significant subset of patients is caused by low affinity antibodies not detected in most immunoassays and propose to improve diagnostic yield with assays that a) detect antibody binding in real time and/or b) increase the Ka by preserving the structural integrity of the target. 3) Characterize the incidence, clinical significance and genetic origin of pre-existing ("naturally occurring") immunoglobulins (NA) that recognize GPIIb/IIIa-inhibitor complexes. The incidence of potentially "dangerous" NA specific for ligand-occupied GPIIb/IIIa in the general population, their genetic origin and their relationship to antibodies causing thrombocytopenia will be defined and their implications for platelet physiology and transfusion therapy and for the design of "safe" GPIIb/IIIa inhibitors will be explored. Findings made are expected to elucidate a previously unrecognized mechanism of disease resulting from the immune response to conformational changes induced in an integrin by its ligand or a ligand-mimetic drug and to advance understanding of the role of "natural" antibodies in health and disease.