Comparison of in vitro and in vivo properties of rhirudin (HBW 023) and a synthetic analogous peptide

Abstract

Recombinant hirudin and a shortened synthetic analogue, with the amino acid sequence of D-Phe-Pro-Arg-Pro-(Gly)4-Asn-Gly-Asp-Phe-Glu- Glu-Ile-Pro-Glu-Glu-Tyr-Leu, are specific thrombin inhibitors which in a concentration-dependent manner inhibit thrombus formation as well as clot propagation both in vitro and in vivo. In comparison to the analogue, lower molar concentrations of rhirudin affected doubling of aPTT and TT as well as inhibition of thrombin amidolytic activity or thrombin-induced platelet aggregation in vitro. In the rat wire coil-induced thrombosis model, a 50% thromboprotective effect may be brought about with doses of 0.043 mumol/kg of rhirudin and 1.43 mumol/kg of the synthetic peptide. However, doubling of bleeding times is caused, on average, by dosages of between 0.143 and 0.43 mumol/kg rhirudin or approximately 0.143 mumol/kg of the analogue. Treatment groups included animals revealing significant prolongation of bleeding times as well as nonresponders. Despite the 10-fold longer impact on aPTT after application of rhirudin, the extent of mean bleeding time prolongation is identical to that of the analogue.