Pathogenesis of Thrombocytopenia Induced by GPIIb/IIIa Inhibitors

Versiti Wisconsin, Inc., Milwaukee WI

Investigators

Linked publications, trials & patents

Abstract

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