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We prospectively studied 15 patients suffering from acute heparin-induced thrombocytopenia (HIT) type II with n =10 and without n =5 thromboembolic events and 4 patients with anamnestically known HIT type II recurrently requiring thromboprophylaxis in order to develop new therapeutic strategies by subcutaneous recombinant hirudin administration. Patients with acute venous or arterial thromboembolism were treated with aPTT-controlled intravenous (mean: 19.3 days) followed by subcutaneous r-hirudin (mean: 22.5 days). Patients without thromboembolism were treated with subcutaneous r-hirudin (mean: 25.9 days). Four patients were readmitted to subcutaneous r-hirudin (mean: 32 days). When r-hirudin was administered subcutaneously following intravenous treatment, mean baseline (prior to the injection) and mean peak (1.5–2.5 hours after the injection) aPTT ratios were 1.1 (±0.2) to 1.7 (±0.48) and 2.48 (±0.43) to 2.52 (±0.4) times normal value, respectively. Mean baseline and mean peak ECT ratios were 1.2 (±0.12) to 1.9 (±0.22) and 2.2 (±0.25) to 2.6 (±0.11) times the upper normal value, respectively. When r-hirudin was initially administered subcutaneously, mean baseline and mean peak aPTT ratios were 1.41 (±0.25) to 1.61 (±00.28) and 1.88 (±0.26) to 2.06 (±0.09) times the normal value, respectively. Mean baseline and mean peak ECT ratios were 1.25 (±0.2) to 1.5 (±0.38) and 2.01 (±0.21) to 2.23 (±0.25) times the upper limit of normal, respectively. Patients who received recurrent subcutaneous r-hirudin had mean baseline and peak aPTT values of 1.5 (±0.35) to 1.75 (±0.156) and 2.0 (±0.33) to 2.1 (±0.18) times the normal value, respectively. Mean baseline and peak ECT ratios were 1.3 (±0.26) to 1.65 (±0.09) and 1.94 (±0.256) to 2.7 (±0.23) times the upper limit of normal, respectively. The overall cumulative incidence of r-hirudin antibodies was 12/19 (63%) with a significant accumulation of r-hirudin in antibody-positive patients compared to antibody-negative patients (p

After daily administration of 1 mg/kg over a period of 4 weeks, hirudin did not influence growth and general behaviour of the animals. There was no indication of treatment-related effects on the liver and the kidneys, on number and function of thrombocytes, on number and differentiation of white cells or on the erythrocytic system. Haemorrhagic complications did not occur. Formation of antibodies was not detectable. Histopathological changes due to application of r-hirudin were not found. LD50 is greater than 50 mg/kg body weight for intravenous application.

Early studies dating back to 1884 revealed that extracts from medicinal leeches contain a substance which is able to prevent blood from clotting. Since our successful isolation of hirudin, the pure anticoagulant substance, in the late 1950s and its characterization as a selective thrombin inhibitor with polypeptide structure, hirudin preparations have been employed for diagnostic and scientific uses in haemostaseology. As early as 25 years ago we have shown in experimental pharmacotoxicological studies that hirudin is an anticoagulant of high quality. The antithrombotic effect of hirudin was demonstrated in several thrombosis models. But the clinical use of hirudin remained limited since it was not available in adequate amounts for therapeutic purposes. One hundred years after its discovery there is a renewed interest in this naturally occurring thrombin inhibitor. Advanced methods of peptide isolation and genetic engineering are about to provide sufficient quantities of hirudin in purified form. This prompted us to resume our investigations in hirudin and to represent new experimental and clinical pharmacological studies with natural hirudin prepared from medicinal leeches and genetically engineered recombinant hirudin, thus appreciating the comeback of hirudin into the focus of interest.