European Heart Journal Advance Access published online on February 12, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn027
Determinants of thrombin generation, fibrinolytic activity, and endothelial dysfunction in dual-antiplatelet therapy: involvement of factors other than platelet aggregability in Virchow's triad
1 Division of Cardiovascular Medicine, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
2 Research Division of Cell and Molecular Medicine, Center for Molecular Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
Received 4 October 2007; revised 27 December 2007; accepted 10 January 2008.
* Corresponding author. Tel: +81 285 58 7397, Fax: +81 285 44 7817, Email: tohmori{at}jichi.ac.jp
Aims: The aim of the study was to assess mechanisms and clinical backgrounds in order to determine residual platelet aggregability in dual-antiplatelet therapy and to ascertain whether platelet aggregability is involved in systemic thrombogenicity.
Methods and results: A cross-sectional study was conducted in 85 consecutive patients who underwent dual-antiplatelet therapy (aspirin and thienopyridine/cilostazol) after percutaneous coronary intervention (PCI). Although serum thromboxane B2 and dephosphorylation of vasodilator-stimulated phosphoprotein were significantly abolished, the platelet aggregation tests showed inter-individual differences that could be partly explained by plasma glucose levels. Platelet aggregability was not related to other factors involved in thrombogenicity. Thrombin generation assessed by soluble fibrin was independently associated with total cholesterol (β = 0.349, P < 0.001), brain natriuretic peptide (β = 0.222, P = 0.018), and ankle-brachial index (β = –0.330, P = 0.001). Plasminogen activator inhibitor-1 was associated with the apnea–hypopnea index (β = 0.300, P = 0.006). E-selectin was correlated with diabetes mellitus (β = 0.279, P = 0.008) and body mass index (β = 0.323, P = 0.002).
Conclusion: Although dual-antiplatelet therapy effectively inhibited its pharmacological targets, thrombin generation, inhibition of fibrinolytic activity, and endothelial dysfunction were determined by other clinical backgrounds. Our data suggested that some patients remain at risk of thrombotic complications after PCI and that these may benefit from anticoagulant treatment despite adequate dual-antiplatelet therapy.
Key Words: Percutaneous coronary intervention • Aspirin • Thienopyridine • Antiplatelet drug resistance • Thrombin generation