Trombossano ed attivazione piastrinica: studio sulla variabilità interindividuale nella risposta all'aspirina

Failure in preventing cardiovascular events in high risk patients under chronic treatment with aspirin may be attributed to incomplete inhibition of platelet cyclooxygenase. To explore the functional role of residual thromboxane (TX) A2 biosynthesis, platelet aggregation was measured together with released TXB2 as index of platelet TXA2 synthetic capacity. Patient of either gender (n=80, 26 females, aged 67+7.3) with diabetes mellitus (n= 65) or clinically overt cardiovascular disease (previous stroke or myocardial infarction, n= 15) receiving a standard daily dose of aspirin (100 mg, given orally 12 hour before blood sampling for at least 7 days) were studied. Mean serum TXB2 concentration after clot formation in a glass tube at 37°C for 1 h, was 3.37 ng/mL (95% CI: 2.31-4.45) and exceeded 10 ng/mL in 8 cases. When aspirin 300 μmol/L was added to blood samples before incubation, mean TXB2 was significantly lower (0.48 ng/mL, 0.29-0.67, P<0.001). In a subset of patients platelet aggregation was evaluated in washed platelets using a turbidimetric method and arachidonic acid (AA, 1-10 μmol/L) alone or in combination with 10 μmol/L epinephrine (EPI) as platelet agonists. A maximal platelet aggregation exceeding 25% was observed only in 4 out of 50 patients using 10 μmol/L AA (mean:14.8, 95% CI: 8.9-20.1) and abolished by the addition of aspirin 300 μmol/L to the test tubes (8.7%, 8.1-9.4, P<0.05). Using AA 10 μmol/L plus EPI, platelet aggregation was observed in 10 out of 50 subject (mean:17.5%, 95%CI:12.2-22.8) and was also prevented by the addition of aspirin in vitro (9.4%, 8.7-10.1, P<0.005). When percentage of platelet aggregation was plotted against TXB2 concentration found in the supernatant of each tube at the end of the aggregation test, a sigmoid dose-response curve was defined, with an EC50 for platelet aggregation induced by AA plus EPI of 26.5 ng/mL (95% CI: 12.2-57.3, R2=0.866, n=20). The EC50 for AA-induced platelet aggregation was 215.3 ng/mL (95% CI 115.4-401.6, R2=0.853, n=42). In conclusion, a residual synthesis of TXA2 in platelet from patients at high cardiovascular risk is rarely observed and is associated with platelet activation. The threshold for platelet aggregation may however vary in response to different agonists, and this may translate in vivo into a residual platelet aggregability in aspirin-treated patients.