Hirudin

For centuries, the blood-sucking medicinal leech, Hirudo medicinalis, has been used in European medicine to treat a steadily increasing number of diseases. In the 19^th century, leech therapy was the most frequently chosen treatment modality, which almost led to the eradication of this animal. Prolonged bleeding from skin lesions produced by leeches was well-known and regarded as part of the therapeutic success. However, it was not until the late 19^th century when Haycraft discovered the pharmacologic principle in the secretion of leeches: it inhibits blood coagulation. Decades of intensive research beginning in the 1950s led to detailed characterization of the active substance being produced by the parapharyngeal glands of Hirudo medicinalis: native hirudin, the most potent, natural direct thrombin inhibitor known. Despite constituting an anticoagulant with remarkable potency, however, its limited available amount hindered introduction of purified hirudin into clinical medicine. When the progress in recombinant technology allowed large-scale production of recombinant hirudins (r-hirudins) without markedly diminishing its antithrombin efficacy as compared to their native counterpart, preclinical and clinical trials with r-hirudins were performed. Clinical trials addressing treatment of heparin-induced thrombocytopenia, deep-vein thrombosis, and acute coronary syndromes gave important insights into efficacy and safety of r-hirudin anticoagulation. In 1997, two r-hirudins were approved by the European Agency for the Evaluation of Medicinal Products (EMEA): lepirudin for the treatment of heparin-induced thrombocytopenia (HIT) and thromboembolic disease, and desirudin for the treatment of deep-vein thrombosis in elective hip and knee surgery. FDA approval of lepirudin for the treatment of HIT and thromboembolic disease followed in 1998.

Within the last few years, much has been learned about the role of r-hirudins in the treatment of thrombotic disorders. This issue of Seminars in Thrombosis and Hemostasis focuses on different topics relating to r-hirudin therapy. In the first contribution, Fritz Markwardt reviews the history of hirudin research. Here, scientific progress was closely related to advances in biotechnology and recombinant technology, which finally allowed large-scale production of r-hirudins. Clinical availability of r-hirudins, in turn, paved the way for clinical trials with these thrombin inhibitors. Next, Götz Nowak characterizes the pharmacology of r-hirudins. Both native and recombinant hirudins are single-chain polypeptides with a molecular weight of approximately 7 kDa that inhibit thrombin in a direct, bifunctional mode. With dissociation equilibrium constants in the femtomolar range, hirudins are the most potent direct thrombin inhibitors known. Details on pharmacokinetic and pharmacodynamic properties of r-hirudins are given. In the next article by Gerd Hafner and his colleagues, methods for the monitoring of direct thrombin inhibitors are discussed. Anticoagulation with r-hirudins in therapeutic doses requires adequate monitoring. Sensitivity of activated partial thromboplastin time, especially in detecting higher r-hirudin blood concentration, is limited. Showing excellent correlations with r-hirudin blood levels over a broad concentration range, chromogenic assays and ecarin clotting time are recommended monitoring methods of r-hirudin anticoagulation. Subsequently, Norbert Lubenow and Andreas Greinacher deal with r-hirudin treatment in immune-mediated heparin-induced thrombocytopenia (HIT). Despite being induced by heparin, mere heparin cessation is not a suitable approach in acute HIT. Instead, switching to an alternative anticoagulant is mandatory. Here, r-hirudin (lepirudin) has been shown to constitute an efficient alternative anticoagulant for the treatment of HIT and is approved for this indication. The following article by Edelgard Lindhoff-Last and Rupert Bauersachs discusses alternative anticoagulation in pregnancy and lactation. Owing to its low placental permeability, the authors primarily recommend danaparoid as the drug of choice in pregnancy, whereas oral anticoagulation is favored in lactation. In both conditions, r-hirudin is regarded a reserve anticoagulant. The limited data, however, do not yet allow firm conclusions on this item. Thomas Severin and co-workers report on the use of r-hirudin and danaparoid in children, mainly indicated because of HIT. Although HIT seems to rarely occur in childhood, thrombotic complications in children can be as severe as in adults. In the majority of patients treated with these anticoagulants, effective anticoagulation and clinical improvement were observed. Due to the limited experience in the management and treatment of HIT in young patients, more data are required before optimal guidelines can be determined. In the next article, Bettina Kemkes-Matthes discusses data on r-hirudin for prophylaxis and treatment of deep-vein thrombosis not associated with HIT. For prophylaxis of deep-vein thrombosis in high-risk patients, the superiority of r-hirudin to both unfractionated and fractionated heparin has been well demonstrated and has led to the approval of desirudin for this indication in Europe. With regard to the treatment of deep-vein thrombosis, by contrast, the efficacy and safety of r-hirudin treatment has been shown to be equal, but not superior to heparin. In HIT, the author regards r-hirudin the drug of choice for the treatment of thromboembolic complications. The topic of hirudin in acute coronary syndromes (ACS) is covered by Andreas van de Loo and Christoph Bode. Based on convincing experimental and early clinical data, r-hirudins were regarded superior to unfractionated heparin in the treatment of ACS. Here, the therapeutic range of r-hirudin was determined to be relatively narrow: at higher r-hirudin doses, major bleeding complications occurred; at reduced r-hirudin doses, efficacy and safety in the treatment of ACS appeared comparable to unfractionated heparin. Given the results achieved with other direct thrombin inhibitors such as argatroban and bivalirudin, there is an ongoing debate on the placement of direct thrombin inhibitors in ACS. Karl-Georg Fischer focuses on r-hirudin treatment in renal insufficiency. As r-hirudins are almost exclusively eliminated by the kidneys, their pharmacokinetics are altered in renal insufficiency. The reduction of r-hirudin elimination is most prominent in dialysis-dependent renal failure, but is relevant already in moderate renal insufficiency. Hirudin anticoagulation is feasible in acute or chronic renal failure requiring hemodialysis procedures, if adequate dosing and close monitoring is provided. The last contribution by Volker Liebe and colleagues addresses the issue of anti-hirudin antibodies (AHAb). Whereas early data suggested low immunogenicity of r-hirudins, recent studies report the detection of AHAb in a high percentage of patients treated with r-hirudin for more than five days. AHAb have been shown to affect r-hirudin dosing in HIT patients. AHAb may influence pharmacokinetics and pharmacodynamics of r-hirudins.

Recombinant hirudins are among the most potent treatment options in anticoagulation. Detailed knowledge on both advantages and limitations of these thrombin inhibitors will contribute to maximize the benefit and to minimize the hazard for patients on r-hirudin treatment. We hope this issue of Seminars in Thrombosis and Hemostasis constitutes an informative contribution to achieving this goal.