Residual platelet thromboxane A2 and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease

Background: Permanent inactivation of cyclooxygenase-1 and inhibition of platelet thromboxane A(2) (TxA(2)) constitute the main mechanisms underlying the prevention of vascular disease by aspirin. Methods and Results: We studied platelet TxA(2) synthesis and its impact on platelet reactivity and platelet-erythrocyte [platelet-rich plasma (PRP)-RBC] interactions in 533 aspirin-treated patients with vascular disease. Seventy aspirin-free and 16 aspirin-treated normal subjects were evaluated as controls. Collagen (1 mu g mL(-1))-induced platelet activation (C-14-5HT release) and recruitment (proaggregatory activity of cell-free releasates from activated platelets) were assessed in PRP, PRP + RBC, and whole blood (WB). TxA(2) was quantified in releasates from WB. Aspirin inhibited TxA(2) synthesis and platelet function in all patients, but to different degrees. Forty-two patients (8%) displayed partial (< 95%) inhibition of TxA(2) relative to that of aspirin-free controls. They produced > 3.5 ng mL(-1) TxA(2) and had higher platelet reactivity than 491 patients who had undetectable TxA(2) or produced residual TxA(2) (R-TxA(2); <= 3.5 ng mL(-1)). Patients with R-TxA(2) were distributed into TxA(2) quartiles. Patients in the third and fourth quartiles had significantly elevated C-14-5HT release in PRP, which was markedly amplified in PRP + RBC and WB. TxA(2) in the fourth quartile translated into increased platelet aggregation and recruitment. Significant correlations were found between R-TxA(2) and platelet hyperfunction. Conclusion: Biochemical markers (TxA(2) synthesis, C-14-5HT release) and biological assays (platelet aggregation and recruitment) used to monitor the aspirin effect in a large population of patients presenting with vascular disease have evidenced the importance of R-TxA(2) and the prothrombotic effects of RBC in aspirin resistance.