Inhibition of platelet-dependent prothrombinase activity and thrombin generation by glycoprotein IIb/IIIa receptor-directed antagonists: potential contributing mechanism of benefit in acute coronary syndromes.
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The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.
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