title: Residual platelet thromboxane A2 and prothrombotic effects of erythrocytes are important determinants of aspirin resistance in patients with vascular disease.
abstract: BACKGROUND
  Permanent inactivation of cyclooxygenase-1 and inhibition of platelet thromboxane A(2) (TxA(2)) constitute the main mechanisms underlying the prevention of vascular disease by aspirin.
  
  
  RESULTS
  We studied platelet TxA(2) synthesis and its impact on platelet reactivity and platelet-erythrocyte [platelet-rich plasma (PRP)-RBC] interactions in 533 aspirin-treated patients with vascular disease. Seventy aspirin-free and 16 aspirin-treated normal subjects were evaluated as controls. Collagen (1 mug mL(-1))-induced platelet activation ((14)C-5HT release) and recruitment (proaggregatory activity of cell-free releasates from activated platelets) were assessed in PRP, PRP + RBC, and whole blood (WB). TxA(2) was quantified in releasates from WB. Aspirin inhibited TxA(2) synthesis and platelet function in all patients, but to different degrees. Forty-two patients (8%) displayed partial (<95%) inhibition of TxA(2) relative to that of aspirin-free controls. They produced >3.5 ng mL(-1) TxA(2) and had higher platelet reactivity than 491 patients who had undetectable TxA(2) or produced residual TxA(2) (R-TxA(2); </=3.5 ng mL(-1)). Patients with R-TxA(2) were distributed into TxA(2) quartiles. Patients in the third and fourth quartiles had significantly elevated (14)C-5HT release in PRP, which was markedly amplified in PRP + RBC and WB. TxA(2) in the fourth quartile translated into increased platelet aggregation and recruitment. Significant correlations were found between R-TxA(2) and platelet hyperfunction.
  
  
  CONCLUSIONS
  Biochemical markers (TxA(2) synthesis, (14)C-5HT release) and biological assays (platelet aggregation and recruitment) used to monitor the aspirin effect in a large population of patients presenting with vascular disease have evidenced the importance of R-TxA(2) and the prothrombotic effects of RBC in aspirin resistance.
authors.affiliation: Research Center, University Hospital La Fe, Valencia, Spain. santos_ter@gva.es
authors.forename: M T
authors.initials: MT
authors.lastname: Santos
authors.forename: J
authors.initials: J
authors.lastname: Valles
authors.forename: A
authors.initials: A
authors.lastname: Lago
authors.forename: J
authors.initials: J
authors.lastname: Tembl
authors.forename: E
authors.initials: E
authors.lastname: Sánchez
authors.forename: A
authors.initials: A
authors.lastname: Moscardo
authors.forename: J
authors.initials: J
authors.lastname: Cosin
mesh_terms: D000368:Aged; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000737:chemistry*; D003094:Collagen / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004351:Drug Resistance / Q000502:physiology; D004912:Erythrocytes / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D053657:Platelet-Rich Plasma; D012701:Serotonin / Q000378:metabolism; D013928:Thromboxane A2 / Q000096:biosynthesis / Q000097:blood*; D014652:Vascular Diseases / Q000097:blood* / Q000188:drug therapy
chemical_list: D016861:Cyclooxygenase Inhibitors; D012701:Serotonin; D013928:Thromboxane A2; D003094:Collagen; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D001241:Aspirin