Background. Essential thrombocythemia (ET) is characterized by an increased number of platelets, associated with risk for both bleeding and thrombotic complications. Prophylaxis with 100 mg acetylsalicylic acid (ASA) is indicated in patients at risk. A significant proportion of ET patients (ETs) display an inadequate pharmacodynamics (PD) response to ASA. It has been suggested that poor responsiveness is due to increased platelet production and a bis in die (bid) administration should be preferred. Aim of this study was to investigate further the potential mechanism(s) of poor responsiveness to ASA in ETs. Methods. We enrolled 17 ETs on 100 mg enteric-coated (EC)-ASA (commonly used) treatment and 10 healthy subjects (HS). 7 ETs were identified as poor responders (ET-PR) and 10 as responders (ET-R), based on their levels of serum TxB2 (cut-off=10 ng/ml). Blood samples were taken in the morning, 24 h after the previous intake, and immediately after taking the drug up to 8 h. We measured: serum TxB2 (ELISA) and ASA and salicylic acid (SA) (ID-LC-MS/MS); the enzymatic activity in whole blood and plasma of esterase enzymes able to hydrolyse ASA to SA. Moreover, collagen (5 µg/ml)-induced platelet aggregation and TxA2 production were tested by in vitro addition of ASA (10-1000 µM) to whole blood of HS and ET-PR. Reticulated platelets were also measured by flow-cytometry in 15 ET (8 R, 7 PR) and 8 HS. Results. The in vitro dose-response curve of ASA for inhibition of TxA2 generation was comparable in HS and ET-PR samples. Esterase activities were similar in all groups. The pharmacokinetics (PK) of EC-ASA was very variable within both ETs and HS, while PKs of plain ASA showed a uniform behaviour. All ET-PR and 3 ET-R showed an impaired TxB2 (>10 ng/mL) at 24 h. In these ETs the difference between TxB2 at 24 h and the min value of TxB2 correlated (r=0.6107; p= 0.0020) with reticulated platelets and bid administration suppressed serum TxB2 levels. Conclusions. Causes of poor response may be related from one side to reduced absorption of EC-ASA, on the other to increased platelet turnover.
EVALUATION OF ASPIRIN RESPONSIVENESS IN ESSENTIAL THROMBOCYTHEMIA PATIENTS / J. Rizzo ; tutor: R. C. Paroni ; coordinatore: S. Sonnino. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE DELLA SALUTE, 2018 Dec 11. ((30. ciclo, Anno Accademico 2018.
|Titolo:||EVALUATION OF ASPIRIN RESPONSIVENESS IN ESSENTIAL THROMBOCYTHEMIA PATIENTS|
|Supervisori e coordinatori interni:||SONNINO, SANDRO|
|Data di pubblicazione:||11-dic-2018|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Citazione:||EVALUATION OF ASPIRIN RESPONSIVENESS IN ESSENTIAL THROMBOCYTHEMIA PATIENTS / J. Rizzo ; tutor: R. C. Paroni ; coordinatore: S. Sonnino. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE DELLA SALUTE, 2018 Dec 11. ((30. ciclo, Anno Accademico 2018.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/rizzo-jessica_phd2018-12-11|
|Appare nelle tipologie:||Tesi di dottorato|