{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T07:43:57Z","timestamp":1793519037910,"version":"4.5.0"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Chronic lymphocytic leukemia patients have an increased bleeding risk with the introduction of Bruton tyrosine kinase (BTK) inhibitors. BTK is a signaling effector downstream of the platelet GPVI receptor. Innate platelet dysfunction in CLL patients and the contribution of the leukemia microenvironment to the anti-platelet effect of BTK inhibitors are still not well defined. Herein, we investigated platelet function in stable, untreated CLL patients in comparison to age-matched healthy subjects as control. Secondly, we proposed a novel mechanism of platelet dysfunction via the adenosinergic pathway during BTK inhibitor therapy. Our data indicate that the nucleotidase that produces adenosine, CD73, was expressed on one-third of B-cells in CLL patients. Inhibition of CD73 improved platelet response to ADP in the blood of CLL patients ex vivo. Using healthy platelets, we show that adenosine 2A (A2A) receptor activation amplifies the anti-platelet effect of ibrutinib (10 nM). Ibrutinib plus an A2A agonist\u2014but not ibrutinib as a single agent\u2014significantly inhibited collagen (10 \u00b5g\/mL)-induced platelet aggregation. Mechanistically, A2A activation attenuated collagen-mediated inhibition of p-VASP and synergized with ibrutinib to inhibit the phosphorylation of AKT, ERK and SYK kinases. This manuscript highlights the potential role of adenosine generated by the microenvironment in ibrutinib-associated bleeding in CLL patients.<\/jats:p>","DOI":"10.3390\/cancers14235750","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T03:15:24Z","timestamp":1669173324000},"page":"5750","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Adenosine 2A Receptor Activation Amplifies Ibrutinib Antiplatelet Effect; Implications in Chronic Lymphocytic Leukemia"],"prefix":"10.3390","volume":"14","author":[{"given":"Omar","family":"Elaskalani","sequence":"first","affiliation":[{"name":"Telethon Kids Institute, Cancer Centre, Nedlands, WA 6009, Australia"},{"name":"Centre for Child Health Research, University of Western Australia, Crawley, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2071-8680","authenticated-orcid":false,"given":"Grace","family":"Gilmore","sequence":"additional","affiliation":[{"name":"Perth Blood Institute (PBI), Perth, WA 6005, Australia"},{"name":"Western Australian Centre for Thrombosis and Haemostasis (WACTH), Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9538-8436","authenticated-orcid":false,"given":"Madison","family":"Hagger","sequence":"additional","affiliation":[{"name":"Platelet Research Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health and Innovation Research Institute (CHIRI), Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross I.","family":"Baker","sequence":"additional","affiliation":[{"name":"Perth Blood Institute (PBI), Perth, WA 6005, Australia"},{"name":"Western Australian Centre for Thrombosis and Haemostasis (WACTH), Health Futures Institute, Murdoch University, Murdoch, WA 6150, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-8796","authenticated-orcid":false,"given":"Pat","family":"Metharom","sequence":"additional","affiliation":[{"name":"Platelet Research Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health and Innovation Research Institute (CHIRI), Faculty of Health Sciences, Curtin University, Bentley, WA 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1056\/NEJMe1904362","article-title":"Ibrutinib and Venetoclax\u2014Doubling Down on CLL","volume":"380","author":"Wiestner","year":"2019","journal-title":"N. 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