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 clotting, we used the highly specific thrombin inhibitor recombinant hirudin to prevent TF-induced coagulation activation in a rabbit model. Infusion of 0.5 micrograms.kg-1.h-1 TF in rabbits for 7 h led to a decrease in fibrinogen and platelets, to an increase in fibrin monomers and to a prolongation of TT, aPTT and PT. Recombinant hirudin was administered in doses of 0.5, 1 and 2 mg.kg-1 body weight (intravenous bolus), 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 after 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 fibrinogen and platelets per hour was calculated for the control and the recombinant-hirudin-treated groups. The deceleration rate for fibrinogen in the TF group was -0.227 g.l-1.h-1 and was reduced by recombinant hirudin to -0.119, -0.116 and -0.095 g.1-1.h-1 for 0.5, 1 or 2 mg.kg-1, respectively (significant differences to control group, Jonckheere-Terpstra test). The inhibitor similarly prevented the decrease of platelets dose-dependently. Recombinant hirudin was cleared from plasma with a terminal half-life of about 100 min; however, even after its clearance from plasma, recombinant hirudin significantly prevented the fibrinogen and platelet drop. Recombinant hirudin was effective when given in the pre-TF as well as in the post-TF phase.
Kouz
J
J
Research Laboratories of Behringwerke AG, Marburg, Germany.
Czech
J
J
Nicolay
U
U
Dickneite
G
G
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D005260:Female; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006629:Hirudins / Q000493:pharmacokinetics / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D010314:Partial Thromboplastin Time; D010976:Platelet Count / Q000187:drug effects; D011517:Prothrombin Time; D011817:Rabbits; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000494:pharmacology; D013918:Thrombin Time; D013925:Thromboplastin / Q000494:pharmacology*; D013997:Time Factors
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; C083544:lepirudin