Tirofiban blocks platelet adhesion to fibrin with minimal perturbation of GpIIb/IIIa structure.

Hantgan RR, Stahle MC, Jerome WG, Nagaswami C, Weisel JW
Thromb Haemost. 2002 87 (5): 910-7

PMID: 12038797

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.

MeSH Terms (18)

Adult Circular Dichroism Dose-Response Relationship, Drug Fibrin Humans Microscopy, Electron Nephelometry and Turbidimetry Platelet Adhesiveness Platelet Aggregation Inhibitors Platelet Glycoprotein GPIIb-IIIa Complex Protein Conformation Protein Interaction Mapping Protein Structure, Secondary Protein Structure, Tertiary Protein Subunits Receptor Aggregation Tirofiban Tyrosine

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