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.

Abstract

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 mumol/liter ADP, 5 micrograms/ml collagen and 7.5 and 15 mumol/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 mumol/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 mumol/liter TRAP was inhibited by 53% at 2 h and 30% at 24 h. In contrast, aggregation in response to 15 mumol/liter TRAP was inhibited only 37% at 2 h and 10% at 24 h (p < 0.001 and p = 0.006, respectively vs. 20 mumol/liter ADP). Addition of exogenous c7E3 Fab to platelet-rich plasma led to more complete inhibition of 7.5 mumol/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.

• Authors: N S Kleiman, A E Raizner, R Jordan, A L Wang, D Norton, K F Mace, A Joshi, B S Coller, H F Weisman
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 26 Issue 7 Pg. 1665-71 (Dec 1995) ISSN: 0735-1097 [Print] United States
• PMID: 7594101 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• ITGA2B protein, human
• Immunoglobulin Fab Fragments
• Integrin alpha2
• Membrane Glycoproteins
• Oligopeptides
• Platelet Aggregation Inhibitors
• Platelet Glycoprotein GPIb-IX Complex
• Platelet Membrane Glycoproteins
• Receptors, Cell Surface
• glycoprotein GP III
• glycoprotein receptor GPIb-IX
• thrombin receptor-activating peptide SFLLRNPNDKY
• Adenosine Diphosphate
• Abciximab

Topics

• Abciximab
• Adenosine Diphosphate (pharmacology)
• Adult
• Aged
• Angioplasty, Balloon, Coronary
• Antibodies, Monoclonal (pharmacology, therapeutic use)
• Female
• Humans
• Immunoglobulin Fab Fragments (pharmacology, therapeutic use)
• Integrin alpha2
• Male
• Membrane Glycoproteins (blood)
• Middle Aged
• Oligopeptides (pharmacology)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacokinetics, pharmacology, therapeutic use)
• Platelet Glycoprotein GPIb-IX Complex (antagonists & inhibitors)
• Platelet Membrane Glycoproteins
• Receptors, Cell Surface (antagonists & inhibitors)