Hirudin as Anticoagulant in Experimental Hemodialysis

Abstract

After genetically engineered recombinant DNA desulfatohirudin (r-hirudin) had been investigated as to its pharmacokinetic behavior and blood level course in nephrectomized dogs, the compound was studied for its capability to prevent thrombus formation in the extracorporeal circulation. Beagle dogs underwent bilateral functional nephrectomy followed by experimental hemodialysis. r-Hirudin content in blood, fibrinogen level as well as platelet count were determined before and during the dialysis. Furthermore, the blood loss during the experiment was measured as well as the mean arterial pressure and the pressure in the blood line system. Intravenous administration of the thrombin inhibitor resulted in initial distribution in the extracellular space (distribution phase 90 min) followed by retarded decrease of the r-hirudin blood level (t_½β ∼ 6–8 h) which is due to the missing renal excretion of the inhibitor. This caused a long-lasting, dose-dependent anticoagulant effect, which is not only characterized by the prevention of increasing pressure before the capillary dialyzer but also by the reduced drop in fibrinogen and platelets during hemodialysis. The required dose of r-hirudin (0.5 mg/kg) is within a range where bleeding complications will not occur yet.

Pharmacology of Recombinant Hirudin

“…Hemofilters having a high cutoff are able to eliminate the hirudin within a few hours. 21 Renal elimination is considerably impaired by systemic anesthesia. Nearly all generalized anesthesia methods result in a decreased renal blood supply to different degrees.…”

Hirudin and Derivatives as Anticoagulant Agents

“…In cases where the elimination of hirudin is impaired, methods such as haemoperfusion and peritoneal dialysis can be used to remove large amounts of circulating hirudin. This is especially true of high-flux capil lary dialyzers which permit the fast elimination of the miniprotein from the body by haemodialysis (91,92). experimental DIC) is about ten times lower than that required for the inhibition of platelet aggregation-dependent thrombosis (ar terial thrombosis and platelet deposition in experimental DIC).…”

“…Furthermore, r-hirudin was used for anticoagulation in experi mental haemodialysis in nephrectomized dogs (91,92). Depend ent on the permeability of the dialyzer mebranes, hirudin was eliminated during dialysis.…”

Past, Present and Future of Hirudin

“…No occlusion at doses of 40 pg/kg/min, cor responding to a plasma level of 2.5 ± 0.6 pg/ml. After studies in rats had shown that r-hirudin is able to prevent the thrombotic occlusion of an arteriovenous shunt, we studied the effect of r-hirudin in extracor poreal circulation by using it for anticoagula tion in experimental hemodialysis in nephrectomized dogs [77], After a bolus injection, the r-hirudin level decreased slowly. In con trast to untreated animals, no fibrin deposists were found in the apparatus during a 2-hour dialysis following a single r-hirudin administration of 0.5 mg. During this time, platelet counts or fibrinogen level were not significantly changed.…”