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Thromb Haemost 2002; 87(05): 910-917
DOI: 10.1055/s-0037-1613104
Review Article
Schattauer GmbH

Tirofiban Blocks Platelet Adhesion to Fibrin with Minimal Perturbation of GpIIb/IIIa Structure

Roy R. Hantgan
1   Department of Biochemistry, Winston-Salem, NC
,
Mary C. Stahle
1   Department of Biochemistry, Winston-Salem, NC
,
Gray W. Jerome
2   Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC
,
Chandrasekaran Nagaswami
3   Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
,
John W. Weisel
3   Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
› Author Affiliations
Further Information

Publication History

Received 02 December 2001

Accepted 24 January 2002

Publication Date:
11 December 2017 (online)

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Summary

A biophysical approach tested the hypothesis that tirofiban, like eptifibatide, perturbs GpIIb/IIIa structure. Tirofiban bound tightly to platelet GpIIb/IIIa (EC50 ∼ 24 nmol/L) and effectively inhibited platelet aggregation (IC50 ∼ 37 nmol/L) but blocked platelet adhesion to clotted fibrin only at much higher doses (IC50 ∼ 580 nmol/L). Electrophoretic analyses demonstrated that tirofiban protected GpIIb/IIIa from SDSinduced 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.

Keywords

GpIIb/IIIa - integrin αIIbβ3 - integrin antagonist - fibrin - structure
 

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