Recombinant Hirudin Lepirudin Research Articles

Lepirudin for therapeutic use in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) type II is an antibody mediated severe adverse event to heparin with a paradoxical decrease of platelet count and an increased risk for thromboembolic complications. The antibodies are directed against a neoepitop of platelet factor 4 after its binding to heparin. The incidence of HIT type II is lower with low-molecular-weight heparin compared to unfractionated heparin and lower in not operated patients compared to those after major surgery. In patients with HIT type II alternative anticoagulation has to be performed immediately due to the high thrombogenicity of the antibodies. The recombinant hirudin lepirudin (Refludan) is the anticoagulant drug of choice. A long-term anticoagulation has to be performed depending on the concomitant risk factors, intravenous administration followed by subcutaneous lepirudin overlapping with vitamin K antagonists.

Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin

AbstractBivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody–positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin- and bivalirudin-coated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific. The clinical consequences of this cross-reactivity are unknown but bivalirudin, targeted by antibodies of patients treated with lepirudin previously, could potentially boost antibody titers in such patients or even trigger an immune response by itself. Clinically significant antibody formation in response to bivalirudin monotherapy has not been observed, however. Yet, as lepirudin and antilepirudin antibodies have recently been implicated in severe anaphylactic reactions, caution is warranted when using bivalirudin in patients previously treated with lepirudin.

Lepirudin bei heparininduzierter Thrombozytopenie

ZusammenfassungDie heparininduzierte Thrombozytopenie (HIT) Typ II ist eine antikörpervermittelte unerwünschte Arzneimittelwirkung auf Heparin, die paradoxerweise mit einem Abfall der Thrombozytenkonzentration und einem erhöhten Risiko für thromboembolische Komplikationen einhergeht.Die Antikörper reagieren gegen ein Neoepitop des Plättchenfaktors 4 nach Bindung mit Heparin. Die Inzidenz der HIT II ist geringer unter niedermolekularem Heparin im Vergleich zu unfraktioniertem Heparin und bei nicht operierten Patienten im Vergleich zu Patienten nach großen operativen Eingriffen. Bei der HIT II ist die unverzügliche Einleitung einer alternativen Antikoagulation wegen der hohen, durch Antikörper vermittelten Thrombogenität erforderlich. Das rekombinante Hirudin Lepirudin (Refludan®) ist Antikoagulanz der Wahl. Eine langfristigere Antikoagulation kann in Abhängigkeit von begleitenden Faktoren mit subkutanem Lepirudin und mit oralen Antikoagulanzien erfolgen.

Heparin-induced Thrombocytopenia – Pathogenesis and Treatment

Heparin-induced thrombocytopenia (HIT) is now recognized as the most frequent immune-mediated adverse drug reaction. During the last decade, fundamental aspects of the pathogenesis of HIT have been resolved. The understanding of some the mechanisms underlying the development of new, paradox thromboembolic complications in HIT led to the concept that thrombin generation plays a key-role in clinically manifest HIT. Consequently new therapeutic concepts imply the use of drugs with either indirect or direct anti-thrombin activity such as donaparoid-sodium and the recombinant hirudin lepirudin. During the last years results of first prospective studies assessing various treatment regimens in HIT became available. Although data of randomized trials are still missing some treatment recommendations can already be drawn from these studies. This review summarizes key aspects of the pathogenesis of HIT and provides an overview of current treatment strategies.

Schwere heparininduzierte Thrombozytopenie (HIT II-Syndrom) mit Sinus-Venosus-Thrombose nach Mamma-Operation - erfolgreiche Behandlung mit rekombinantem Hirudin

Heparin-induced thrombocytopenia (HIT) is a very current complication of antithrombotic prophylaxis and therapy. We differentiate between the immunological asymptomatic type I, and type II, characterised by arterial and/or venous thrombosis. We report on a female patient who developed a HIT II-syndrome with a decrease in the number of thrombocytes to 14 000/μl. A biopsy specimen was taken of her breast because of a suspicious mammographic microcalcification and peri- and postoperative subcutaneous standard heparin prophylaxis was performed. Despite an early diagnosis via the platelet aggregation test, immediate discontinuation of the heparin treatment and a change to the low sulfate heparinoid Danaparoid, we observed a newly developed thrombosis of the sinus venosus sagittalis superior with intracerebral bleeding 3 days after the sudden appearance of the neurological symptoms. After having switched over to the recombinant hirudin Lepirudin we could discharge the patient in a satisfactory state of health. We conclude from this course that control of the number of thrombocytes is indispensable. With the appearance of the first symptoms of a HIT II-syndrome today the application of recombinant hirudin proves to be the only method for prevention and therapy of this thromboembolic complication.