Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin

• Published in: Haemostasis Vol. 21 Suppl 1; p. 64
• Main Authors: Fareed, J, Walenga, J M, Pifarre, R, Hoppensteadt, D, Koza, M
• Format: Journal Article
• Language: English
• Published: Switzerland 1991
• Subjects: Animals; Antifibrinolytic Agents - pharmacology; Blood Loss, Surgical - prevention & control; Ear Diseases - chemically induced; Ear, External - injuries; Factor VIIa - pharmacology; Fibrinolytic Agents - toxicity; Hemorrhage - chemically induced; Heparin - pharmacology; Heparin Antagonists - pharmacology; Heparin Lyase; Hirudins - antagonists & inhibitors; Hirudins - toxicity; Humans; Platelet Aggregation - drug effects; Platelet Factor 4 - pharmacology; Polysaccharide-Lyases - pharmacology; Protamines - pharmacology; Rabbits; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - toxicity; Wounds, Stab - complications
• ISSN: 0301-0147
• DOI: 10.1159/000216264

Recombinant hirudin (r-hirudin) is currently under development as an anticoagulant for use in surgery, therapeutic anticoagulation, disseminated intravascular coagulation and other pathologic states involving the generation of thrombin. Circulating levels of r-hirudin as an antithrombotic agent range from 2 to 20 micrograms/ml (0.1-1.0 mg/kg) as determined in an animal model of stasis thrombosis. In order to establish a relationship between the r-hirudin circulating level and bleeding, we utilized a rabbit ear blood loss model. r-Hirudin did not produce any loss of blood at dosages up to 20 micrograms/ml i.v. (1.0 mg/kg). When the circulating levels were maintained at 20 micrograms/ml for periods of up to 3 h, no increase in blood loss was observed. At 50 and 100 micrograms/ml initial circulating levels (2.5 and 5.0 mg/kg) a dose-dependent increase in the blood loss was observed which was equivalent to that observed with 1.25 and 2.5 mg/kg i.v. heparin. Such levels of r-hirudin are not expected in clinical usage. In contrast to heparin, the anticoagulant actions of r-hirudin were not neutralized by protamine sulfate, platelet factor 4, other polycationic agents and heparinase. In our studies, the blood loss induced by greater than 2.0 mg/kg i.v. dosages of r-hirudin in an animal model was neutralized by the administration of an activated prothrombin complex concentrate at 25 U/kg. In a similar experimental setting, r-factor VIIa was also partially effective. These studies suggest that r-hirudin anticoagulation may not require neutralization, since bleeding effects are not observed at effective antithrombotic dosages in individuals with normal hemostatic status.