Thienopyridines (ticlopidine, clopidogrel, and prasugrel) require in vivo metabolism to exhibit a critical thiol group in the active form that binds to the P2Y12 platelet receptor to inhibit platelet activation. We hypothesized that formation of thienopyridine-derived nitrosothiols (ticlopidine-SNO, clopidogrel-SNO, and prasugrel-SNO) occurs directly from the respective parent drug. Pharmaceutical-grade thienopyridine (ticlopidine, clopidogrel chloride, clopidogrel sulfate, clopidogrel besylate, or prasugrel) was added to nitrite in aqueous solution to form the respective thienopyridine-SNO (Th-SNO). An isolated aortic ring preparation was used to test vasoactivity of the Th-SNO derivatives. Increasing nitrite availability resulted in increased Th-SNO formation for all drugs (other than ticlopidine). Th-SNO induced significant endothelium-independent relaxation of preconstricted aortic rings. Clopidogrel-chloride-SNO displayed rapid-release kinetics in a chemical environment, which was reflected by immediate and transient vasorelaxation when compared with the SNO derivatives of the other thienopyridines. Accounting for differences in yield, clopidogrel-chloride-SNO exhibited the greatest propensity to immediately relax vascular tissue. Th-SNO derivatives exhibit nitrovasodilator properties by supplying NO that can directly activate vascular soluble guanylate cyclase to induce vasorelaxation. Differences in SNO yield and vasoactivity exist between thienopyridine preparations that might be important to our understanding of the direct pharmacological effectiveness of thienopyridines on vascular and platelet function.
Methods: VERIFY Pre-Op TIMI 45 was a prospective study of 42 patients with indications for coronary angiography subsequently referred for CABG. All patients were therapeutic on clopidogrel. Platelet function was assessed with VerifyNow™ P2Y 12 Reaction Units (PRU). Chest tube output within 24-hours of CABG was stratified by PRU Ն 208, Ն 230, and Ն 275. Results reported as meanϮSD. Results: Median time from last clopidogrel dose to CABG was 4 days (range 1 to 9 days). Patients who held clopidogrel Ͻ 4 days had lower PRU than those who held for Ն 4 days (190Ϯ84 vs. 271Ϯ21 PRU; pϭ0.015). Thresholds of PRU Ն 208 or Ն 275 correlated with less bleeding but did not reach significance (pϭ0.20 and pϭ0.39). Patients with PRU Ն 230 had significantly less chest tube output than those with PRU Ͻ 230 (622Ϯ220 vs. 1028Ϯ676; pϭ0.026) (Figure).
Conclusions:The VerifyNow™ P2Y 12 platelet function assay can be used to predict perioperative bleeding in patients exposed to clopidogrel undergoing CABG. A threshold of Ն 230 PRU is associated with less bleeding, and may assist clinicians in optimizing the timing of surgery.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.