{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T07:42:56Z","timestamp":1782373376822,"version":"3.54.5"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL118049"],"award-info":[{"award-number":["R01HL118049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>Aspirin has known effects beyond inhibiting platelet cyclooxygenase\u20101 (COX\u20101) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on\u2010 and off\u2010target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin's effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized crossover study of 81\u2010 <jats:italic>vs<\/jats:italic>. 325\u2009mg\/day, each for 4\u2009weeks. Using mRNA sequencing of purified platelets collected before and after each 4\u2010week exposure, we identified 208 aspirin\u2010responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes, we validated aspirin's effects on five genes: <jats:italic>EIF2S3<\/jats:italic>, <jats:italic>CHRNB1<\/jats:italic>, <jats:italic>EPAS1<\/jats:italic>, <jats:italic>SLC9A3R2<\/jats:italic> and <jats:italic>HLA\u2010DRA<\/jats:italic>. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression <jats:italic>in vitro<\/jats:italic> identified aspirin but no other molecules that share aspirin's known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure\u2014an effect that counteracts aspirin's known antiplatelet effect. In summary, this work collectively demonstrates a dose\u2010independent effect of aspirin on the platelet transcriptome that counteracts the well\u2010known antiplatelet effects of aspirin.<\/jats:p>","DOI":"10.1111\/bcp.15127","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T14:49:35Z","timestamp":1635346175000},"page":"2074-2083","source":"Crossref","is-referenced-by-count":15,"title":["Aspirin effects on platelet gene expression are associated with a paradoxical, increase in platelet function"],"prefix":"10.1111","volume":"88","author":[{"given":"Rachel A.","family":"Myers","sequence":"first","affiliation":[{"name":"Center for Applied Genomics &amp; Precision Medicine Duke University School of Medicine  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Ortel","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine Duke University Medical Center  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Waldrop","sequence":"additional","affiliation":[{"name":"Center for Genomics and Computational Biology Duke University  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep","family":"Dave","sequence":"additional","affiliation":[{"name":"Center for Genomics and Computational Biology Duke University  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey S.","family":"Ginsburg","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics &amp; Precision Medicine Duke University School of Medicine  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0015-5179","authenticated-orcid":false,"given":"Deepak","family":"Voora","sequence":"additional","affiliation":[{"name":"Center for Applied Genomics &amp; Precision Medicine Duke University School of Medicine  Durham NC United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/M16-0577"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI108132"},{"issue":"12","key":"e_1_2_10_4_1","first-page":"377","article-title":"Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin","volume":"128","author":"Grosser T","year":"2012","journal-title":"Circulation"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.675587"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-012-0683-0"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.900589"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12195"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2102137"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-324517"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH16-11-0873"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-11-320788"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-04-280925"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-09-299719"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.073"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2016.08.021"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH16-04-0316"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.014726"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2009.03700.x"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1385"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15541"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315215"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2755"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8052854"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1215327"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.24.11693"},{"key":"e_1_2_10_28_1","first-page":"51","article-title":"Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers","volume":"6","author":"Nagelschmitz J","year":"2014","journal-title":"Clin Pharm"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609996200"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.02.050"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep07896"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37792"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11239-017-1516-y"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15127","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bcp.15127","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.15127","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T22:29:36Z","timestamp":1693002576000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.15127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,27]]},"references-count":32,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1111\/bcp.15127"],"URL":"https:\/\/doi.org\/10.1111\/bcp.15127","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,27]]}}}