In two thirds of a group of patients with vascular disease, 200 to 300 mg ASA was insufficient to block platelet reactivity in the presence of erythrocytes despite abolishing thromboxane A2 synthesis. Platelet activation in the presence of erythrocytes can induce the release reaction and generate biologically active products that recruit additional platelets into a developing thrombus. Insufficient blockade of this proaggregatory property of erythrocytes can lead to development of additional ischemic complications.

Inhibition of erythrocyte (RBC) promotion of platelet reactivity could improve the antiplatelet effect of aspirin (ASA). We tested different ASA regimens for optimal inhibition of platelets and the effects of RBC in patients with a history of vascular diseases. Collagen-induced platelet activation ( 14 C-5HT, TXA 2 release) and platelet recruitment (proaggregatory activity of cell-free releasates from activated platelets) were measured in PRP, platelet-RBC (Hct 40%) and whole blood (WB) in 206 patients initially on 200-300 mg ASA/day. Their regimen was modified to bi-weekly 500 mg (loading dose, L) plus daily or twice-daily low-dose ASA (50 or 100 mg). TXA 2 was inhibited with all regimens. Percentage of patients with suboptimal inhibition of platelet recruitment in WB was: 200-300 ASA/ day (41%), L-50/day (87%), L-100/day (58%), L-50/twice-daily (39%) and L-100/twice-daily (20%; p<0.05 vs. other regimens). 14 C-5HT release was inhibited to the greatest extent with L-100/twicedaily in PRP+RBC or WB (p<0.05 vs. other regimens) due to greater inhibition of the RBC prothrombotic effect. Compared to other ASA regimens, L-100 twice-daily (equivalent to 221 mg ASA/day in the 14 day cycle), reduced by >50% the proportion of patients with suboptimal inhibition of platelet recruitment in WB and inhibited 14 C-5HT release to the greatest extent.

Summary. 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 lg mL )1 )-induced platelet activation ( 14 C-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 14 C-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, 14 C-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.

The two groups achieved similar levels of pain control in supine, seated and standing positions. Quality of life also improved in both groups. However, the higher dose (8 Gy dose) in combination with zoledronic acid is associated with a longer period without skeletal events.