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dc.contributor.authorFrelinger, Andrew L. III
dc.contributor.authorJakubowski, Joseph A.
dc.contributor.authorLi, YouFu
dc.contributor.authorBarnard, Marc R.
dc.contributor.authorFox, Marsha L.
dc.contributor.authorLinden, Matthew Dean
dc.contributor.authorSugidachi, Atsuhiro
dc.contributor.authorWinters, Kenneth J.
dc.contributor.authorFurman, Mark I.
dc.contributor.authorMichelson, Alan D.
dc.date2022-08-11T08:10:11.000
dc.date.accessioned2022-08-23T16:58:40Z
dc.date.available2022-08-23T16:58:40Z
dc.date.issued2007-07-01
dc.date.submitted2012-04-25
dc.identifier.citationThromb Haemost. 2007 Jul;98(1):192-200. DOI: 10.1160/TH07-01-0010
dc.identifier.issn0340-6245 (Linking)
dc.identifier.doi10.1160/TH07-01-0010
dc.identifier.pmid17598013
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43417
dc.description.abstractThe novel thienopyridine prodrug prasugrel, a platelet P2Y(12) ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation, there are few data on the direct effects of the prasugrel's active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates, platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent inhibition of these ADP-stimulated thrombo-inflammatory markers. These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC(50) values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y(12)-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y(12). In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y(12)-mediated up-regulation of thrombo-inflammatory markers of platelet activation. This inhibition is enhanced in the presence other blood cells and calcium, but not aspirin.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17598013&dopt=Abstract">Link to article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1160/TH07-01-0010
dc.subjectAdenosine Diphosphate
dc.subjectAdult
dc.subjectAspirin
dc.subjectBiological Markers
dc.subjectBlood Cells
dc.subjectCalcium
dc.subjectCells, Cultured
dc.subjectFemale
dc.subjectHumans
dc.subjectInflammation
dc.subjectKinetics
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectPiperazines
dc.subjectPlatelet Activation
dc.subject*Purinergic P2 Receptor Antagonists
dc.subjectThiophenes
dc.subjectThrombosis
dc.subjectUp-Regulation
dc.subjectHematology
dc.subjectOncology
dc.subjectPediatrics
dc.titleThe active metabolite of prasugrel inhibits ADP-stimulated thrombo-inflammatory markers of platelet activation: Influence of other blood cells, calcium, and aspirin
dc.typeJournal Article
dc.source.journaltitleThrombosis and haemostasis
dc.source.volume98
dc.source.issue1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/peds_hematology/95
dc.identifier.contextkey2796585
html.description.abstract<p>The novel thienopyridine prodrug prasugrel, a platelet P2Y(12) ADP receptor antagonist, requires in vivo metabolism for activity. Although pharmacological data have been collected on the effects of prasugrel on platelet aggregation, there are few data on the direct effects of the prasugrel's active metabolite, R-138727, on other aspects of platelet function. Here we examined the effects of R-138727 on thrombo-inflammatory markers of platelet activation, and the possible modulatory effects of other blood cells, calcium, and aspirin. Blood (PPACK or citrate anticoagulated) from healthy donors pre- and post-aspirin was incubated with R-138727 and the response to ADP assessed in whole blood or platelet-rich plasma (PRP) by aggregometry and flow cytometric analysis of leukocyte-platelet aggregates, platelet surface P-selectin, and GPIIb-IIIa activation. Low-micromolar concentrations of R-138727 resulted in a rapid and consistent inhibition of these ADP-stimulated thrombo-inflammatory markers. These rapid kinetics required physiological calcium levels, but were largely unaffected by aspirin. Lower IC(50) values in whole blood relative to PRP suggested that other blood cells affect ADP-induced platelet activation and hence the net inhibition by R-138727. R-138727 did not inhibit P2Y(12)-mediated ADP-induced shape change, even at concentrations that completely inhibited platelet aggregation, confirming the specificity of R-138727 for P2Y(12). In conclusion, R-138727, the active metabolite of prasugrel, results in rapid, potent, consistent, and selective inhibition of P2Y(12)-mediated up-regulation of thrombo-inflammatory markers of platelet activation. This inhibition is enhanced in the presence other blood cells and calcium, but not aspirin.</p>
dc.identifier.submissionpathpeds_hematology/95
dc.contributor.departmentDepartment of Pediatrics
dc.source.pages192-200


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