Comparative analysis of various platelet glycoprotein IIb/IIIa antagonists on shear-induced platelet activation and adhesion.
Platelet accretion into arterial thrombus in stenotic arterial vessels involves shear-induced platelet activation and adhesion. The Cone and Plate(let) Analyzer (CPA) is designed to simulate such conditions in vitro under a rotating high shear rate in whole blood. In the present study, we evaluated various experimental conditions (including aspirin, temperature, and calcium concentration) and investigated the effects of small molecules along with peptide glycoprotein IIb/IIIa antagonists on platelet adhesion using the CPA system. Concentration-dependent effect of glycoprotein IIb/IIIa antagonists on shear-induced platelet adhesion showed marked differences in potencies: IC50 = 34, 35, 91, 438, and 606 nM for DPC802 (a specific glycoprotein IIb/IIIa antagonist), roxifiban, sibrafiban, lotrafiban, and orbofiban (free acid forms), respectively, and IC50 values of 43, 430, and 5781 nM for abciximab, tirofiban, and eptifibatide, respectively. Parallel study was also conducted to evaluate the effect of glycoprotein IIb/IIIa inhibitors using optical aggregometry. The potency of fibans in blocking shear-induced platelet adhesion correlated well with their binding affinity to the resting and activated glycoprotein IIb/IIIa receptors, as well as their "off-rates". Nevertheless, none of these fibans was able to effectively block shear-induced platelet adhesion at targeted clinical dosing regimens except for abciximab. These data suggest that glycoprotein IIb/IIIa antagonists that show similar efficacy in the inhibition of platelet aggregation in a static in vitro assay may differ substantially in a shear-based system of platelet adhesion. The clinical significance of this phenomenon awaits further investigation.
Wang
Xinkang
X
Department of Cardiovascular Sciences, Bristol-Myers Squibb Company, Experimental Station, Wilmington, Delaware 19880-0400, USA. xinkang.wang@bms.com
Dorsam
Robert T
RT
Lauver
Adam
A
Wang
Hugh
H
Barbera
Frank A
FA
Gibbs
Sandra
S
Varon
David
D
Savion
Naphtali
N
Friedman
Steven M
SM
Feuerstein
Giora Z
GZ
D000077284:Abciximab; D000409:Alanine / Q000378:metabolism / Q000494:pharmacology; D000578:Amidines / Q000378:metabolism / Q000494:pharmacology; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000077542:Eptifibatide; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007555:Isoxazoles / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology; D012212:Rheology; D033081:Shear Strength; D013696:Temperature; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000578:Amidines; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D007140:Immunoglobulin Fab Fragments; D007555:Isoxazoles; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011759:Pyrrolidines; D014443:Tyrosine; C120234:orbofiban; D000077466:Tirofiban; D000077542:Eptifibatide; D000409:Alanine; C118235:roxifiban; D001241:Aspirin; D000077284:Abciximab