Reply to Dr. Nowak’s Letter

Jeanine M. Walenga, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153 (USA) In reference to the expected circulating blood levels of recombi-nant hirudin for certain clinical indications [1, table 3], we do not totally agree with Dr. Nowak’s statement [2] that these levels do not reflect the actual concentrations in experimental and clinical investigations. It is, however, true that the listed concentrations are based on projections and do not represent data from experimental or clinical results. As indicated in the tables, we have approximated these levels on the basis of experimental data obtained for hirudin in various valid animal models of thrombosis and hemostatic processes [3-5]. The information obtained was compared to that of heparin and then extrapolated to the various clinical situations. The levels represented in these tables were not meant to be absolute concentrations. In contrast to heparin, recombi-nant hirudin is a short-lived, single-target (thrombin) drug. These characteristics are reflected in the wide range of dosages found to produce antithrombotic actions in different models of thrombosis [6-9]. Several recent studies have reported ranges of 5 to > 100 μg/kg for ED50 antithrombotic actions. These values nearly represent our earlier projections. In a recent review, Gray et al. [7] also showed that varying levels of recombinant hirudin are needed to prevent different experimentally induced thromboses and that the stasis time was one important factor in determining a dose. For the prophylaxis of deep vein thrombosis, different dosages of hirudin are needed for different clinical indications. As shown by Kaiser et al. [ 10], in comparison to heparin, recombinant hirudin is a relatively poor inhibitor of thrombin generation. Because of this relatively inefficient thrombin generation inhibition, higher amounts of hirudin are indicated to achieve similar pharmacologic effects as heparin. Dr. Nowak suggests that the literature pertinent to this discussion shows that relatively lower levels of hirudin are required; however, specific references were not quoted by him. Regarding therapeutic antico-agulation, our projected levels of hirudin (5-10 μg/ml) were perceived as too high by Dr. Nowak. We do not believe that 20-50 times lower levels as stated by Dr. Nowak (0.1-0.5 μg/ml) would be sufficient for this purpose. If a 2-2.5 time prolongation of activated partial thromboplastin time is considered