INFLUENCE OF RECOMBINANT HIRUDIN ON TISSUE-FACTOR-INDUCED ACTIVATION OF COAGULATION IN RABBITS

Uncontrolled activation of the tissue-factor (TF)-dependent extrinsic pathway of coagulation can lead to severe impairment of the hemostatic balance. As thrombin plays the central role in the initiation of clot ting, we used the highly specific thrombin inhibitor recombinant hirud in to prevent TF-induced coagulation activation in a rabbit model. Inf usion of 0.5 mu g . kg(-1). h(-1) TF in rabbits for 7 h led to a decre ase in fibrinogen and platelets, to an increase in fibrin monomers and to a prolongation of TT, aPTT and PT. Recombinant hirudin was adminis tered in doses of 0.5, 1 and 2 mg . kg(-1) body weight (intravenous bo lus), the protocol included a pre-TF (recombinant hirudin given at t = 0) and a post-TF study group (recombinant hirudin given at t = 2 h af ter the start of the TF infusion). Fibrinogen plasma levels, platelet counts and recombinant hirudin plasma levels were measured at baseline (t = 0) at 0.5, 1, 2, 3, 4, 5, 6 and 7 h; the deceleration rate of fi brinogen and platelets per hour was calculated for the control and the recombinant-hirudin-treated groups. The deceleration rate for fibrino gen in the TF group was -0.227 g . l(-1). h(-1) and was reduced by rec ombinant hirudin to -0.119, -0.116 and -0.095 g . l(-1). h(-1) for 0.5 , 1 or 2 mg . kg(-1), respectively (significant differences to control group, Jonckheere-Terpstra test). The inhibitor similarly prevented t he decrease of platelets dose-dependently. Recombinant hirudin was cle ared from plasma with a terminal half-life of about 100 min; however, even after its clearance from plasma, recombinant hirudin significantl y prevented the fibrinogen and platelet drop. Recombinant hirudin was effective when given in the pre-TF as well as in the post-TF phase.