SHEAR-INDUCED PLATELET-AGGREGATION IS INHIBITED BY IN-VIVO INFUSION OF AN ANTI-GLYCOPROTEIN IIB IIIA ANTIBODY FRAGMENT, C7E3 FAB, IN PATIENTS UNDERGOING CORONARY ANGIOPLASTY/

Background Elevated levels of shear stress such as those that occur in stenotic arterial vessels can directly activate and aggregate platele ts and thus contribute to the pathogenesis of acute arterial thrombosi s. This shear-induced platelet aggregation (SIPA) is mediated by von W illebrand factor binding to platelet membrane glycoprotein (GP) Ib and GPIIb/IIIa. The chimeric Fab fragment of the monoclonal antibody 7E3 (c7E3 Fab) that binds selectively to GPIIb/IIIa is under clinical eval uation in patients undergoing percutaneous transluminal coronary angio plasty (PTCA). This study was undertaken to investigate the effects on ex vivo SIPA of c7E3 Fab administered to patients undergoing PTCA. Me thods and Results Six patients received aspirin (325 mg) and boluses o f heparin (12 000 U) followed by c7E3 Fab 0.25 mg/kg. Blood collected from each patient before and after heparin treatment and at various ti me points after c7E3 Fab administration was subjected to laminar shear stress in a cone-and-plate viscometer. Flow cytometry was used to qua ntify the extents of platelet aggregation and of antibody binding to G PIIb/IIIa. Results indicate that c7E3 Fab injection resulted in a rapi d, extensive blockade of GPIIb/IIIa receptors (98.6+/-0.2%) and a 50% inhibition of ex vivo platelet aggregation induced by shear stress. c7 E3 Fab also completely abolished the formation of large platelet aggre gates (''large'' refers to particles >10 mu m in equivalent sphere dia meter), which are presumably the aggregates of greatest clinical signi ficance. Partial reversibility of the inhibition was noted within 2 da ys after drug administration, but even after 1 week, platelet function had not been fully restored. Conclusions This study demonstrates that c7E3 Fab is a potent inhibitor of SIPA, which may be an important mec hanism of its beneficial effect in the treatment of arterial occlusive diseases and in the prevention of thrombotic complications of coronar y artery disease after angioplasty.