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

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medi cal treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, c ritical initiating steps in arterial thrombosis. Their anticoagulant proper ties, particularly when administered conjunctively with heparin preparation s, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or i n combination with unfractionated heparin (UFH) or fractionated heparin (en oxaparin) were added to washed platelets suspended in Tyrode's buffer. Foll owing platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a co ncentration-dependent reduction in platelet-dependent thrombin generation w ith each of the GPIIb/IIIa receptor antagonists. The combination of tirofib an and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The correspondi ng 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 additi onal 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa rec eptor antagonists, beyond their ability to prevent fibrinogen-mediated aggr egation, inhibit platelet-dependent prothrombinase activity and thrombin ge neration in a concentration-dependent manner. Heparin facilitates the exist ing anticoagulant properties, supporting combination therapy in clinical pr actice. The potential added benefit of fractionated heparin over UFH will r equire further investigation.