Differential antiplatelet effects of various glycoprotein IIb-IIIa antagonists

The blockade of platelet glycoprotein IIb-IIIa (GPIIb-IIIa) was recently in troduced as a new antiplatelet strategy. At present, various GPIIb-IIIa inh ibitors are available to treat patients with acute coronary syndrome or whe n undergoing percutaneous coronary interventions. The current study systema tically evaluates the antiplatelet effects of GPIIb-IIla inhibitors in clin ical use. Using conformation-dependent monoclonal antibodies [ligand-induce d binding sites (LIBS-1), PMI-1] and flow cytometry, we showed that the GPI Ib-IIIa antagonists abciximab, integrelin, lamifiban, and tirofiban, but no t EMD 122347 or YM 337, induced LIES activity of platelet GPIIb-IIIa. The L IES activity of GPIIb-IIIa antagonists correlates with a proaggregatory res ponse of fixed platelets pretreated with GPIIb-IIIa antagonists (intrinsic activity). All tested GPIIb-IIIa antagonists completely inhibit concentrati on-dependent ADP (20 mu mol/l)-induced aggregation. In contrast, substantia l TRAP (25 mu mol/l)-induced platelet aggregation still occurs even at high inhibitor concentrations of the tested GPIIb-IIIa antagonists. Ln addition , we show that GPIIb-IIIa antagonists are poor inhibitors of platelet relea se reaction (ATP and P-selectin secretion) especially when strong agonists such as TRAP are used to activate platelets. Inhibition of platelet procoag ulant activity (thrombin generation) by GPIIb-IIIa antagonists is dependent on the type and concentration of antagonists and on the strength of stimul us (thrombin, tissue factor) used to induce platelet-dependent thrombin gen eration. The present data show that significant pharmacological differences exist between GPIIb-IIIa antagonists that may have consequences for antith rombotic strategies and for future drug development. (C) 2001 Elsevier Scie nce Ltd. All rights reserved.