(Circulation. 1997;96:1488-1494.)
© 1997 American Heart Association, Inc.
Articles |
Effect of Ca2+ on GP IIb-IIIa Interactions With Integrilin
Enhanced GP IIb-IIIa Binding and Inhibition of Platelet Aggregation by Reductions in the Concentration of Ionized Calcium in Plasma Anticoagulated With Citrate
From COR Therapeutics, South San Francisco, Calif (D.R.P., W.T., A.A., L.N.-A., A.R., R.M.S.); University of Tennessee, Memphis (M.M.W., C.L., L.K.J.); Lilly Research Laboratories, Indianapolis, Ind (J.A.J.); and Scripps Research Institute (S.J.S.).
Background Integrilin (eptifibatide), a potent inhibitor of the fibrinogen binding function of GP IIb-IIIa, has been shown to reduce the thrombotic complications of angioplasty and of acute coronary syndromes. The present study was designed to determine whether the reduced Ca2+ concentrations in plasma anticoagulated with citrate affect Integrilin binding to GP IIb-IIIa and the ex vivo pharmacodynamic measurements for this drug.
Methods and Results Lower concentrations of Integrilin were
found to inhibit platelet aggregation in plasma anticoagulated with
citrate (for ADP, mean±SD IC50=140±40 nmol/L, n=6;
Ca2+=40 to 50 µmol/L) than with PPACK
(IC50=570±70 nmol/L, P<.0001, n=6;
Ca2+ 
1 mmol/L). Chelation of Ca2+ with
EDTA or citrate caused a similar degree of enhancement in the
inhibitory activity of Integrilin. Measurements of D3 LIBS
epitope expression showed that the enhanced inhibitory
activity was caused by enhanced GP IIb-IIIa occupancy by Integrilin.
Citrate anticoagulation decreased the amounts of Integrilin required to
inhibit the binding of PAC1, a monoclonal antibody that mimics the GP
IIb-IIIa binding activity of fibrinogen. Reduced Ca2+ also
increased Integrilin inhibition of the binding of biotinylated
fibrinogen to purified, immobilized GP IIb-IIIa.
Conclusions These data suggest that citrate anticoagulation removes Ca2+ from GP IIb-IIIa and enhances the apparent inhibitory activity of Integrilin. This finding indicates that the inhibitory activity of Integrilin is overestimated in blood samples collected with citrate, suggesting that it may be possible to achieve greater antithrombotic efficacy beyond that observed in clinical trials to date with Integrilin.
Key Words: calcium • drugs • fibrinogen • glycoproteins • platelets
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