Dr. Lisa Jennings opened the program with an overview of the biology of GP IIb-IIIa, the mechanism of action of the different antagonists, and the different pharmacokinetics of the currently available, FDA approved GP IIb-IIIa antagonists. She also reviewed the various oral GP IIb-IIIa antagonists remaining in phase trial. An issue emphasized by Dr. Jennings was the importance of choice of anticoagulant in sample preparation since citrate by chelating calcium alters the apparent receptor occupancy of the antagonist relative to native blood.

Dr. Jennings’ presentation was followed by fine presentations describing approaches and instrumentation for assessment of GP IIb-IIIa occupancy and function. Dr. Alan Michelson outlined the use of whole blood flow cytometric approaches for assessment of occupancy and functional response. An advantage of flow cytometry is that only small volumes of blood need be analyzed. Potential disadvantages included the cost of instrumentation and the requirement for a highly trained and dedicated operator. Care also is required to minimize dilutional effects that would lead to dissociation of agonist from receptor leading to underestimation of receptor occupancy. Dr. David Varon described use of a prototype research cone and plate analyzer for rapid assessment of platelet function. The method involves image analysis to quantitate platelet adhesion to polystyrene from whole blood and is sensitive to plasma levels of von Willebrand factor, fibrinogen, and to GP IIb-IIIa occupancy by antagonists. The next three speakers described the use of commercially available instrumentation for assessment of GP IIb-IIIa occupancy. Dr. Robert Hillman from Accumetrics discussed the Ultergra™ RPFA system for bedside assessment of oral and intravenous GP IIb-IIIa antagonists. Dr. Doug Christie from Dade Behring discussed use of a high shear system, the PFA-100, for evaluation of platelet dysfunction in patients receiving GP IIb-IIIa antagonists. Finally, Dr. Bruce Lages of Xylum Corporation presented data using the Xylum Clot Signature Analyzer. All three instruments would appear to provide appropriate methodology for assessment of GP IIb-IIIa receptor occupancy and function that would be useful depending on the clinical and research context.

Dr. Koneti Rao discussed the impact of GP IIb-IIIa antagonists on thrombin generation. He provided data from in vivo assessment in primates for a potential anticoagulant effect of GP IIb-IIIa antagonists on top of that provided by heparin during coronary procedures. Dr. Dick Aster discussed the issue of thrombocytopenia associated with the use of GP IIb-IIIa inhibitors. The incidence of moderate to severe thrombocytopenia reported in the literature associated with the use of GP IIb-IIIa receptor antagonists varies between one and five percent. Dr. Aster presented preliminary data that the thrombocytopenia occurs by an immune mechanism involving circulating pre-existing antibody but that the epitopes recognized by the antibodies may be different depending upon the receptor antagonist that binds to GPIIb-IIIa. Finally, Dr. Barry Coller gave an elegant presentation describing when, where, and why GP IIb-IIIa receptor antagonists need to be monitored in the context of either acute or chronic therapy. It is hoped that Drs. Jennings and Coller will work with the subcommittee to prepare a discussion document on this topic for publication as a subcommittee report.