title: Gradual increase in thrombogenicity of juvenile platelets formed upon offset of prasugrel medication.
abstract: In patients with acute coronary syndrome, dual antiplatelet therapy with aspirin and a P2Y12 inhibitor like prasugrel is prescribed for one year. Here, we investigated how the hemostatic function of platelets recovers after discontinuation of prasugrel treatment. Therefore, 16 patients who suffered from ST-elevation myocardial infarction were investigated. Patients were treated with aspirin (100 mg/day, long-term) and stopped taking prasugrel (10 mg/day) after one year. Blood was collected at the last day of prasugrel intake and at 1, 2, 5, 12 and 30 days later. Platelet function in response to ADP was normalized between five and 30 days after treatment cessation and in vitro addition of the reversible P2Y12 receptor antagonist ticagrelor fully suppressed the regained activation response. Discontinuation of prasugrel resulted in the formation of an emerging subpopulation of ADP-responsive platelets, exhibiting high expression of active integrin αIIbβ3. Two different mRNA probes, thiazole orange and the novel 5'Cy5-oligo-dT probe revealed that this subpopulation consisted of juvenile platelets, which progressively contributed to platelet aggregation and thrombus formation under flow. During offset, juvenile platelets were overall more reactive than older platelets. Interestingly, the responsiveness of both juvenile and older platelets increased in time, pointing towards a residual inhibitory effect of prasugrel on the megakaryocyte level. In conclusion, the gradual increase in thrombogenicity after cessation of prasugrel treatment is due to the increased activity of juvenile platelets.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Constance C F M J
authors.initials: CC
authors.lastname: Baaten
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Leo F
authors.initials: LF
authors.lastname: Veenstra
authors.affiliation: Central Diagnostic Laboratory, Maastricht University Medical Centre, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Wetzels
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Johanna P
authors.initials: JP
authors.lastname: van Geffen
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Frauke
authors.initials: F
authors.lastname: Swieringa
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: de Witt
authors.affiliation: Central Diagnostic Laboratory, Maastricht University Medical Centre, The Netherlands.
authors.forename: Yvonne M C
authors.initials: YM
authors.lastname: Henskens
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Crijns
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: J J J
authors.initials: JJ
authors.lastname: van Giezen
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands.
authors.forename: Johan W M
authors.initials: JW
authors.lastname: Heemskerk
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, The Netherlands p.vandermeijden@maastrichtuniversity.nl.
authors.forename: Paola E J
authors.initials: PE
authors.lastname: van der Meijden
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism*; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage*; D058925:Receptors, Purinergic P2Y12 / Q000378:metabolism
chemical_list: C548576:P2RY12 protein, human; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride