title: Preserved thrombin-inducible platelet activation in thienopyridine-treated patients.
abstract: BACKGROUND
  Abundant thrombin generation may be a major reason for subsequent thromboembolic events in patients with cardiovascular disease receiving dual antiplatelet therapy. We therefore investigated the susceptibility of thienopyridine responders and nonresponders to thrombin receptor-activating peptide (TRAP)-6- and adenosine diphosphate (ADP)-inducible platelet activation.
  
  
  METHODS
  Response to clopidogrel or prasugrel was determined by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) in 317 patients undergoing angioplasty and stenting for cardiovascular disease. Baseline, TRAP-6-, and ADP-inducible P-selectin expression, activated glycoprotein IIb/IIIa (GPIIb/IIIa) and monocyte-platelet aggregate (MPA) formation were measured as sensitive parameters of platelet activation.
  
  
  RESULTS
  In patients with high on-treatment residual ADP-inducible platelet reactivity (HRPR), baseline P-selectin expression, GPIIb/IIIa and MPA formation were similar to those in patients without HRPR (all P > 0.05). After platelet activation with TRAP-6 or ADP, patients with HRPR by both assays exhibited significantly higher levels of P-selectin expression, GPIIb/IIIa and MPA formation than patients with an adequate thienopyridine-mediated platelet inhibition (all P ≤ 0.02). However, high levels of TRAP-6-inducible P-selectin, GPIIb/IIIa and MPA formation also occurred in 20.4%, 19.1% and 20.1% of the good responders by the VASP assay, and in 19.6%, 16.6% and 20.6% of the good responders by MEA, respectively.
  
  
  CONCLUSIONS
  Thienopyridine nonresponders are more susceptible to thrombin- and ADP-inducible platelet activation than patients with good platelet inhibition. However, even patients with adequate thienopyridine-mediated platelet inhibition often show a preserved responsiveness to thrombin. These patients may benefit from additional thrombin receptor blockage or inhibition of thrombin generation.
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. thomas.gremmel@meduniwien.ac.at
authors.forename: Thomas
authors.initials: T
authors.lastname: Gremmel
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Kopp
authors.forename: Daniela
authors.initials: D
authors.lastname: Seidinger
authors.forename: Renate
authors.initials: R
authors.lastname: Koppensteiner
authors.forename: Sabine
authors.initials: S
authors.lastname: Steiner
authors.forename: Simon
authors.initials: S
authors.lastname: Panzer
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000368:Aged; D017130:Angioplasty; D001241:Aspirin / Q000627:therapeutic use; D001792:Blood Platelets / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000097:blood / Q000188:drug therapy* / Q000601:surgery; D000077144:Clopidogrel; D005260:Female; D006801:Humans; D039661:Integrin beta3 / Q000097:blood; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D040201:Platelet Membrane Glycoprotein IIb / Q000097:blood; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D015607:Stents; D013876:Thiophenes / Q000627:therapeutic use; D013917:Thrombin / Q000378:metabolism*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D039661:Integrin beta3; D019007:P-Selectin; D010446:Peptide Fragments; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D040201:Platelet Membrane Glycoprotein IIb; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; C082835:thrombin receptor peptide (42-47); D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013917:Thrombin; D000068799:Prasugrel Hydrochloride; D013988:Ticlopidine; D001241:Aspirin