title: Different effects of various anti-GPIIb-IIIa agents on shear-induced platelet activation and expression of procoagulant activity.
abstract: Inhibitors of the platelet glycoprotein (GP)IIb-IIIa receptor (integrin alphaIIbbeta3) reduce acute thrombotic events in patients with coronary artery disease. To characterize the mechanism of action of these drugs, we evaluated the effects of different GPIIb-IIIa antagonists on shear-induced platelet aggregation, activation, and the expression of procoagulant activity. Samples of platelet-rich plasma from 16 volunteers were exposed to the shear rate of 10 800 s-1 for 6 min in an optically modified cone-plate viscometer. Abciximab, tirofiban and eptifibatide inhibited aggregation to a similar extent (mean +/- SD: 74.1 +/- 8.5%, 69.5 +/- 13.6%, 65.6 +/- 17.0%, respectively), but only abciximab inhibited significantly microparticle release associated with shear-induced platelet activation (64.4 +/- 13.6%, P = 2.2 x 10-7; tirofiban = 20.0 +/- 23.4%; eptifibatide = 23.9 +/- 17.4%). P-selectin platelet surface translocation was also strongly inhibited by abciximab, weakly by eptifibatide, but not by tirofiban. The addition of anti-alphavbeta3 to tirofiban enhanced the inhibiting effects on shear-induced P-selectin translocation and microparticle release. Shearing of platelet-rich plasma shortened the re-calcification clotting time after addition of kaolin from 106.9 +/- 14.3 to 94.2 +/- 10.7 s (mean +/- SD; P = 0.0013). This effect, which is mediated by the appearance of procoagulant phospholipids on the surface of sheared platelets and microparticles, was prevented by abciximab and by the combination of tirofiban and anti-alphavbeta3, but not by tirofiban alone or eptifibatide. The ability to inhibit shear-induced platelet activation, as evidenced by microparticle release and P-selectin surface translocation as well as the expression of procoagulant activity, differentiates the effects of anti-GPIIb-IIIa agents, which may explain the distinct antithrombotic efficacy of the agents.
authors.affiliation: Division of Cardiology, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan. shinichi@is.icc.u-tokai.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.forename: N
authors.initials: N
authors.lastname: Tamura
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Handa
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: S
authors.initials: S
authors.lastname: Handa
authors.forename: Z M
authors.initials: ZM
authors.lastname: Ruggeri
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D003029:Coagulants / Q000097:blood*; D000077542:Eptifibatide; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D019007:P-Selectin / Q000187:drug effects; D010316:Particle Size; D010455:Peptides / Q000494:pharmacology; D010477:Perfusion; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010977:Platelet Factor 3 / Q000096:biosynthesis; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D003029:Coagulants; D007140:Immunoglobulin Fab Fragments; D019007:P-Selectin; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010977:Platelet Factor 3; D014443:Tyrosine; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab