Aspirin responsiveness in essential thrombocythemia

Background. Essential thrombocythemia (ET) is associated with risk for bleeding and thrombotic events. Thromboprophylaxis with 100 mg acetylsalicylic acid (ASA) is given to patients at risk. Some ET patients are poor responders (ET-PR) to ASA, as evidenced by inadequate suppression of thromboxane (Tx) A2 synthesis. It was suggested that ASA poor responsiveness in ET is due to increased platelet turnover. Aim of this study was to investigate further the potential mechanism(s) of ASA poor responsiveness in ET. Methods. We enrolled 19 ET patients on treatment with 100 mg enteric-coated (EC)-ASA (commonly used for thromboprophylaxis): 10 were identified as ET-PR and 9 as responders (R) in a previous study. Eleven healthy subjects (HS), treated with 100 mg EC-ASA for 5 days, were also studied. Blood samples were taken in the morning 24h after the last EC-ASA dose and up to 8 h after the morning dose. We measured: serum TxB2 (ELISA); serum ASA (UID-LC-MS-MS); whole blood and plasma enzymatic activities of esterases that hydrolize ASA. The effect of the in vitro addition of ASA (10-100 µM) to whole blood of HS (not on ASA treatment) and ET-PR on collagen (5 µg/ml)-induced TxB2 production was also tested. Reticulated platelets were measured by flow-cytometry in 15 patients (8 R, 7 PR) and 8 HS. Results. In vitro, ASA (10-100 µM) inhibited whole blood TxB2 generation similarly in HS and ET-PR. Esterases activities were similar in all groups. Serum levels of ASA were lower in ET-PR: in 5 ET-PR they were undetectable. When plain-ASA was given instead of EC-ASA, serum ASA was detectable and similar in all groups. After EC-ASA, trough levels of serum TxB2 (6h) were similar in HS and ET-R and higher in ET-PR, but they were similar in all groups after plain-ASA; they tended to be higher in all ET patients at 24h, irrespective of the ASA formulation used. The difference between peak (24h) and trough (6h) TxB2 levels correlated with reticulated platelet count in ET and HS (r=0.6; p=0.002). Conclusions. ASA poor response in ET was observed only with EC-ASA and was associated with poor drug absorption. Increased platelet production is responsible for high TxB2 in ET 24h post-dosing.