Clopidogrel induces an acute hemostatic deficit and increases intra abdominal bleeding in rabbits

Abstract

Purpose 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). Conclusion 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.