title: Differential antiplatelet effects of various glycoprotein IIb-IIIa antagonists.
abstract: The blockade of platelet glycoprotein IIb-IIIa (GPIIb-IIIa) was recently introduced as a new antiplatelet strategy. At present, various GPIIb-IIIa inhibitors are available to treat patients with acute coronary syndrome or when undergoing percutaneous coronary interventions. The current study systematically evaluates the antiplatelet effects of GPIIb-IIIa inhibitors in clinical use. Using conformation-dependent monoclonal antibodies [ligand-induced binding sites (LIBS-1), PMI-1] and flow cytometry, we showed that the GPIIb-IIIa antagonists abciximab, integrelin, lamifiban, and tirofiban, but not EMD 122347 or YM 337, induced LIBS activity of platelet GPIIb-IIIa. The LIBS activity of GPIIb-IIIa antagonists correlates with a proaggregatory response of fixed platelets pretreated with GPIIb-IIIa antagonists (intrinsic activity). All tested GPIIb-IIIa antagonists completely inhibit concentration-dependent ADP (20 micromol/l)-induced aggregation. In contrast, substantial TRAP (25 micromol/l)-induced platelet aggregation still occurs even at high inhibitor concentrations of the tested GPIIb-IIIa antagonists. In addition, we show that GPIIb-IIIa antagonists are poor inhibitors of platelet release reaction (ATP and P-selectin secretion) especially when strong agonists such as TRAP are used to activate platelets. Inhibition of platelet procoagulant activity (thrombin generation) by GPIIb-IIIa antagonists is dependent on the type and concentration of antagonists and on the strength of stimulus (thrombin, tissue factor) used to induce platelet-dependent thrombin generation. The present data show that significant pharmacological differences exist between GPIIb-IIIa antagonists that may have consequences for antithrombotic strategies and for future drug development.
authors.affiliation: Medizinische Klinik und Poliklinik, Klinikum rechts der Isar and Deutsches Herzzentrum, Technische Universität München, Lazarettstrasse 36, 80636, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Dickfeld
authors.forename: A
authors.initials: A
authors.lastname: Ruf
authors.forename: G
authors.initials: G
authors.lastname: Pogatsa-Murray
authors.forename: I
authors.initials: I
authors.lastname: Müller
authors.forename: B
authors.initials: B
authors.lastname: Engelmann
authors.forename: W
authors.initials: W
authors.lastname: Taubitz
authors.forename: J
authors.initials: J
authors.lastname: Fischer
authors.forename: O
authors.initials: O
authors.lastname: Meier
authors.forename: M
authors.initials: M
authors.lastname: Gawaz
mesh_terms: D000818:Animals; D001665:Binding Sites; D001792:Blood Platelets / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000235:genetics; D022142:Secretory Vesicles / Q000187:drug effects; D013917:Thrombin / Q000096:biosynthesis / Q000187:drug effects; D014162:Transfection
chemical_list: D008024:Ligands; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013917:Thrombin