title: Inhibition of shear-stress-induced platelet aggregation and phosphotyrosine signaling by GPIIb-IIIa antagonists.
abstract: Shear-stress-mediated platelet thrombus formation has been implicated in the pathophysiology of cardiovascular diseases such as acute myocardial infarction and unstable angina. Although previous studies have established that fluid shear forces cause platelet aggregation, a direct comparison of GPIIb-IIIa antagonists used in the treatment of acute coronary syndromes on shear-induced platelet activation has not been reported. Therefore, the objective of the present study was to characterize the effects of the platelet antagonists abciximab, eptifibatide, and tirofiban on shear-mediated platelet activation and aggregation using flow cytometric and Western blotting techniques. Flow cytometric analyses indicated that all three platelet antagonists, when used at concentrations that saturated all GPIIb-IIIa receptors, significantly inhibited platelet aggregate formation and expression of the platelet activation marker p-selectin. None of the antagonists caused increased expression of GPIbalpha or GPIIb-IIIa on the platelet surface compared to untreated controls. Additionally, Western blotting demonstrated that a 72 kDa protein tentatively identified as Syk became phosphorylated in response to shear stress and that its phosphorylation was inhibited by each antagonist. The findings of this study indicate that abciximab, eptifibatide, and tirofiban, though possessing distinct biochemical and pharmacological properties, effectively and equivalently inhibit platelet aggregation, p-selectin expression, and intracellular tyrosine phosphorylation events induced by fluid shear stress.
authors.affiliation: Department of Biomedical Engineering, The University of Memphis, Memphis, TN 38152-3210, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Haga
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jennings
authors.forename: Steven M
authors.initials: SM
authors.lastname: Slack
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001790:Blood Physiological Phenomena / Q000187:drug effects; D000077542:Eptifibatide; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D019000:Phosphotyrosine / Q000187:drug effects / Q000502:physiology*; D010812:Physical Stimulation; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000502:physiology; D033081:Shear Strength; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013314:Stress, Mechanical; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019000:Phosphotyrosine; D014443:Tyrosine; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab