EV-077-3201-2TBS, a TP antagonist and TS inhibitor, reduces platelet aggregation in whole blood of type 2 diabetics with coronary artery disease on chronic aspirin therapy.

SAKARIASSEN KS, FEMIA E, ROTHLIN RP, PODDA GM, RAZZARI C, PUGLIANO MT, DARAY FM, ERRASTI AE, ARMESTO AR, NOWAK W, ALBERTS P, HERMOSILLA R, MEYER JP, CATTANEO M, SANTANA SORENSEN A.

Kyoto

Congreso; XXIII Congress of the International Society on Thrombosis and Haemostasis and 57th SSC Meeting.; 2011

Society on Thrombosis and Haemostasis

Background: Aspirin reduces the risk of recurrences of cardiovascular events, but, according to some reports, it may be less effective in patients with type 2 diabetes mellitus. Aim: The aim of the present study was to investigate the in vitro effect of EV-077-3201-2TBS, a thromboxane A2 receptor (TP) antagonist and a thromboxane synthase (TS) inhibitor, on platelet aggregation of patients with type 2 diabetes mellitus (DM) and coronary artery disease (CAD) under chronic treatment with aspirin (≥4 weeks). Methods: 47 patients with type 2 DM and CAD (M/F 38/9; median age 69 y, range 52-90 y) on chronic daily treatment with 100 mg aspirin were studied. In vitro platelet aggregation was induced by 1mM arachidonic acid and measured by impedance aggregometry (Multiplate) in platelet-rich plasma (PRP) or whole blood collected in hirudin anticoagulant 2h after the last dose of aspirin. Results: Arachidonic acid induced very slight platelet aggregation in PRP (18±10 Arbitrary Units) and a significantly higher degree of platelet aggregation in whole blood (61±29 Arbitrary Units). EV-077-3201-2TBS (100 nM) significantly inhibited platelet aggregation in whole blood (39±18 Arbitrary Units, P<0.001). Additional in vitro studies showed that EV-077-3201-2TBS (0.1nM‑100µM) competitively inhibited the constriction of umbilical arteries induced by isoprostane 8-iso-PGE2, which interacts with TPs. Discussion: Aspirin effectively inhibited platelet aggregation in PRP samples from patients with type 2 DM and CAD, but it did not completely inhibit platelet aggregation in whole blood. This residual aggregation could be caused by thromboxane A2 and/or isoprostanes produced by leukocytes. EV-077-3201-2TBS almost completely abolished arachidonic acid-induced platelet aggregation in whole blood of aspirin-treated patients, suggesting that it might potentiate the in vivo anti-thrombotic efficacy of aspirin in type 2 diabetics with CAD.