Author + information
- Received February 15, 1995
- Revision received July 19, 1995
- Accepted July 26, 1995
- Published online December 1, 1995.
- Neal S. Kleiman, MD, FACCa,*,
- Albert E. Raizner, MD, FACCa,
- Robert Jordan, PhD*,
- Ann L. Wang, MS*,
- Daniel Norton, MS*,
- Kenneth F. Mace, PhD*,
- Alaknanda Joshi, MS*,
- Barry S. Coller, MD† and
- Harlan F. Weisman, MD, FACC*
- ↵*Address for correspondence: Dr. Neal S. Kleiman, Section of Cardiology, Baylor College of Medicine, The Methodist Hospital, 6535 Fannin, MS F-905, Houston, Texas 77030.
Objectives. This study sought to describe in detail the pharmacokinetics and pharmacodynamics of chimeric monoclonal 7E3 Fab (c7E3 Fab) and to compare platelet responses to adenosine diphosphate (ADP) and the 11-amino acid thrombin receptor-activating peptide (TRAP [SFLLRNPNDKY-NH2]) 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 ischemic complications after angioplasty and is being considered for treatment of other acute ischemic syndromes.
Methods. Patients undergoing elective coronary angioplasty received aspirin (325 mg orally), heparin (12,000 U intravenously) and a bolus of c7E3 Fab (0.25 mg/kg body weight). Surface GPIIb/IIIa receptor blockade and aggregation in response to 20 μmol/liter ADP, 5 μg/ml collagen and 7.5 and 15 μmol/liter 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 μmol/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 μmol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 μmol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 μmol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 μmol/liter TRAP-induced aggregation.
Conclusions. After c7E3 Fab treatment, inhibition of platelet aggregation depends on the agonist and can be overcome by increased thrombin activity but is restored if additional c7E3 Fab is added to block additional GPIIb/IIIa receptors. This phenomenon may be related to an internal pool of GPIIb/IIIa receptors joining the surface membrane and has implications concerning the duration of therapy with c7E3 Fab for patients with unstable angina or acute myocardial infarction.
This study was supported by Grant 19278 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; and by a grant from Centocor Inc., Malvern, Pennsylvania. It was presented in part at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 1994.
- Received February 15, 1995.
- Revision received July 19, 1995.
- Accepted July 26, 1995.
- American College of Cardiology