The role of recombinant hirudins in the management of thrombotic disorders.
Native hirudin is the most potent natural direct thrombin inhibitor currently known; it is capable of inhibiting not only fluid phase, but also clot-bound thrombin. Recombinant technology now allows production of recombinant hirudins (r-hirudins), which are available in sufficient purity and quantity with essentially unaltered thrombin-inhibitory potency. As thrombin is known to play a key role in a number of thrombotic disorders, numerous studies focused on the impact of r-hirudins on the clinical course in these diseases. R-hirudins provided significantly more stable anticoagulation than standard heparin, but demonstrated a relatively narrow therapeutic range with relevant bleeding risk even at clinically effective doses. In doses that are not associated with an increased bleeding risk, r-hirudins often failed to demonstrate significant superiority to heparin. To date, r-hirudins have a definite role in the treatment of heparin-induced thrombocytopenia, where they markedly reduce the high risk of thrombosis. For prophylaxis of deep vein thrombosis, r-hirudins have been shown to be superior to both unfractionated and low molecular weight heparin, but are not extensively used in this indication. In acute coronary syndromes, a definite role of r-hirudins has not yet been firmly established. When applied in an appropriate dose as adjunct to thrombolysis in patients with acute myocardial infarction, randomized, controlled trials did not show a consistent benefit of r-hirudins, especially in the long-term. In patients undergoing coronary balloon angioplasty for acute coronary syndromes, promising effects in the early postprocedural phase did not translate to an improved outcome after 6 months. In patients with unstable angina pectoris, efficacy and safety of r-hirudins as primary antithrombotic therapy are still under debate. In the future, r-hirudins are to be compared with alternative or additional potent antithrombotic agents or treatment strategies. This comparison will ultimately lead to their final placement in the management of thrombotic disorders.
Fischer
Karl-Georg
KG
Department of Medicine, University Hospital Freiburg, Freiburg, Germany. fischer@med1.ukl.uni-freiburg.de
D002986:Clinical Trials as Topic; D003327:Coronary Disease / Q000628:therapy*; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006493:Heparin / Q000009:adverse effects; D006629:Hirudins / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism; D010314:Partial Thromboplastin Time; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use*; D013917:Thrombin / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced / Q000628:therapy*; D014018:Tissue Distribution; D020246:Venous Thrombosis / Q000628:therapy*
D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D006493:Heparin; D013917:Thrombin; C060225:desirudin; C083544:lepirudin