DIFFERENTIAL INHIBITION OF PLATELET-AGGREGATION INDUCED BY ADENOSINE-DIPHOSPHATE OR A THROMBIN RECEPTOR-ACTIVATING PEPTIDE IN PATIENTS TREATED WITH BOLUS CHIMERIC 7E3 FAB - IMPLICATIONS FOR INHIBITION OF THE INTERNAL POOL OF GPIIB IIIA RECEPTORS/

Objectives. This study sought to describe in detail the pharmacokineti cs and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 1 1-amino acid thrombin receptor activating peptide (TRAP [SFLLRNPNDKY-N H2]) in patients undergoing elective coronary angioplasty. Background. Inhibition of platelet aggregation with monoclonal antibody c7E3 Fab directed against glycoprotein (GP) IIb/IIIa has been shown to reduce i schemic complications after angioplasty and is being considered for tr eatment of other acute ischemic syndromes. Methods. Patients undergoin g elective coronary angioplasty received aspirin (325 mg orally), hepa rin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in respo nse to 20 mu mol/liter ADP, 5 mu g/ml collagen and 7.5 and 15 mu mol/l iter TRAP were assessed. Results. Surface GPIIb/IIIa receptor blockade by c7E3 Fab was 80% 2 h after injection and decreased to 50% at 24 h, Platelet aggregation in response to 20 mu mol/liter ADP was inhibited by 73% at 2 h, and this inhibition decreased to 27% at 24 h. Platelet aggregation in response to 7.5 mu mol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mu mol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.0 01 and p = 0.006, respectively vs. 20 mu mol/liter ADP). Addition of e xogenous c7E3 Fab to platelet-rich plasma led to more complete inhibit ion of 7.5 mu mol/liter TRAP-induced aggregation. Conclusions. After c 7E3 Fab treatment, inhibition of platelet aggregation depends on the a gonist and can be overcome by increased thrombin activity but is resto red if additional c7E3 Fab is added to block additional GPIIb/IIIa rec eptors. This phenomenon may be related to an internal pool of GPIIb/II Ia receptors joining the surface membrane and has implications concern ing the duration of therapy with c7E3 Fab for patients with unstable a ngina or acute myocardial infarction.