title: Clopidogrel induces an acute hemostatic deficit and increases intra abdominal bleeding in rabbits.
abstract: OBJECTIVE
  Clopidogrel, a potent antiplatelet drug, increases hemorrhagic adverse events when its use is continued up to five days before cardiac surgery but data are lacking in non-cardiac surgery. We sought to determine the dose of clopidogrel which has a maximal antiplatelet and hemorrhagic effect in a rabbit model of non-cardiac surgery.
  
  
  METHODS
  Twenty-four rabbits were divided into three groups according to the dose of clopidogrel administered (5, 10 and 20 mg.kg(-1)). Baseline measurement of platelet aggregation induced with ADP, platelet reactivity index (PRI) of the VASP-phosphorylation assay and hematologic variables were obtained the day before the experiment. Two hours after clopidogrel administration, the same variables were measured, along with intra abdominal bleeding following standardized hepato-splenic lesions.
  
  
  RESULTS
  Platelet aggregation was inhibited in a dose-dependent manner: 46%+/-16% with 5 mg.kg(-1) and 93%+/-7% with 20 mg.kg(-1) of clopidogrel. PRI was reduced by 61%+/-25% with 5 mg.kg(-1) of clopidogrel and by 92%+/-11% and 94%+/-10% with 10 mg.kg(-1) and 20 mg.kg(-1) respectively (p=0.01). Percentage reduction of platelet aggregation was positively correlated with the percentage reduction of PRI (r=0.69; CI(95), 0.40 to 0.86). Bleeding from hepato-splenic lesions was more important in the 10 and 20 mg.kg(-1) groups compared to the 5 mg.kg(-1) group (p<0.05).
  
  
  CONCLUSIONS
  Higher doses of clopidogrel are associated with a more profound inhibition of platelet aggregation and PRI and increased blood losses following standardized hepato-splenic lesions. We conclude that our animal model demonstrates clopidogrel's propensity to increase intra abdominal bleeding after standardized hepato-splenic lesions and may help develop blood sparing strategies for patients undergoing surgery while on clopidogrel.
authors.affiliation: Department of Anesthesiology, of the Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Elise
authors.initials: E
authors.lastname: Lortie
authors.forename: François
authors.initials: F
authors.lastname: Girard
authors.forename: Daniel
authors.initials: D
authors.lastname: Boudreault
authors.forename: Monique
authors.initials: M
authors.lastname: Ruel
authors.forename: Saad
authors.initials: S
authors.lastname: Mansour
authors.forename: Normand
authors.initials: N
authors.lastname: Blais
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hardy
mesh_terms: D000005:Abdomen; D000818:Animals; D015815:Cell Adhesion Molecules / Q000097:blood; D000077144:Clopidogrel; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006470:Hemorrhage / Q000097:blood / Q000139:chemically induced*; D006487:Hemostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D008840:Microfilament Proteins / Q000097:blood; D010750:Phosphoproteins / Q000097:blood; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D010979:Platelet Function Tests; D011817:Rabbits; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077144:Clopidogrel; D013988:Ticlopidine