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Tirofiban Blocks Platelet Adhesion To Fibrin With Minimal Perturbation Of GpIIb/IIIa Structure.

R. Hantgan, M. C. Stahle, W. Jerome, C. Nagaswami, J. Weisel
Published 2002 · Chemistry, Medicine

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A biophysical approach tested the hypothesis that tirofiban, like eptifibatide, perturbs GpIIb/IIIa structure. Tirofiban bound tightly to platelet GpIIb/IIIa (EC50 approximately 24 nmol/L) and effectively inhibited platelet aggregation (IC50 approximately 37 nmol/L) but blocked platelet adhesion to clotted fibrin only at much higher doses (IC50 approximately 580 nmol/L). Electrophoretic analyses demonstrated that tirofiban protected GpIIb/IIIa from SDS-induced subunit dissociation. However, saturating tirofiban concentrations had little or no effect on GpIIb/IIIa secondary or tertiary structure, as determined by circular dichroic spectroscopy, dynamic light scattering, and sedimentation velocity measurements performed with purified receptors in octyl glucoside. Moderate dose-dependent effects on GpIIb/IIIa quaternary structure were detected by sedimentation equilibrium. Transmission electron microscopy showed minimal tirofiban-induced receptor activation or oligomerization. Thus, even at the increased concentrations needed to block platelet:fibrin adhesive interactions, tirofiban exhibited only limited effects on GpIIb/IIIa conformation and clustering. Our results provide new insights into the mechanisms and potential prothrombotic complications of integrin antagonists.
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