Aprotinin reduces clopidogrel-induced prolongation of the bleeding time in the rat

High doses of aprotinin have been shown to reduce blood loss and blood transfusion requirements in patients undergoing open heart surgery and recent studies in animals have shown that aprotinin was able to reduce bleeding associated with rt-PA administration. Our study was designed to demonstrate an effect of aprotinin (Iniprol) on the prolongation of the bleeding time associated with the treatment with a potent analogue of ticlopidine: clopidogrel. Bleeding time was determined in rats by transection of the tip of the tail. 2 hours after a single oral administration, clopidogrel (5 mg/kg, p.o.), induced a 4-fold increase in the bleeding time. Aprotinin administered as a bolus iv injection followed by continuous infusion strongly reduced bleeding time prolongation associated with clopidogrel treatment. This effect was dose-related and reached a maximum (congruent to 50% inhibition--P < 0.001) at and above the total dose of 40 U Ph Eur/kg (80,000 KIU/kg). After administration of a total dose of 60 U Ph Eur/kg (120,000 KIU/kg), aprotinin modified neither the antiaggregating effect of clopidogrel nor its antithrombotic activity, as determined in various experimental models. For this reason, aprotinin might constitute a useful antagonist of the haemorrhagic risk associated with interventional therapy under treatment with ticlopidine or clopidogrel.