Use of Aspirin in normalization of recombinant human erythropoietin-mediated hyper-reactivity of platelets in rats

Abstract

Objectives:The cytokine erythropoietin is the primary stimulator of erythropoiesis and recombinant human erythropoietin (rHuEPO), which is widely used in the treatment of anemia associated with advanced chronic kidney disease (CKD). Adverse cardiovascular outcomes have been observed during clinical trials of anemia correction with rHuEPO in CKD patients. We investigated the effects of short-term, high-dose treatment with rHuEPO on platelet reactivity and effects of aspirin on platelet reactivity in healthy rats.Materials and Methods:Animals received three daily dose of rHuEPO (25 μg/kg s.c.). Platelets were isolated after 48 h of last dose of rHuEPO to study the arachidonic acid-induced platelet aggregation. Aspirin (75 mg/kg p.o.) was given to animals just before 1 h of isolation of platelets.Results:In rats, treatment with rHuEPO increased platelet reactivity and platelet count. The increased platelet reactivity was paralleled by decreased time-to-occlusion (TTO) in arterial thrombosis model, and decreased bleeding time after tail transection in rats. Treatment with rHuEPO followed by single dose of aspirin showed significant reduction in TTO and bleeding time as compared with aspirin-treated group.Conclusions:These findings suggest that rHuEPO increases platelet reactivity and aspirin normalizes the hyper-reactive platelet and may reduce the cardiovascular events associated with rHuEPO in CKD patients.

Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers

“…The most frequent and clinically relevant adverse effects of epoetin are thrombosis and hypertension. To reduce the risk of platelet dysfunction in the healthy volunteers, a small dose (100 mg) of aspirin was added to treatment, as previously suggested by animal studies [18] and frequently use in the clinical setting. None of the subjects presented adverse events related to pro‐thrombotic effects of epoetin treatment, suggesting that thrombosis prophylaxis should be considered for other trials involving epoetin treatment, particularly at high doses.…”