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

Abstract

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.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: J Fareed, J M Walenga, R Pifarre, D Hoppensteadt, M Koza
• Journal: Haemostasis (Haemostasis) Vol. 21 Suppl 1 Pg. 64-72 ( 1991) ISSN: 0301-0147 [Print] Switzerland
• PMID: 1894198 (Publication Type: Journal Article, Review)

Chemical References

• Antifibrinolytic Agents
• Fibrinolytic Agents
• Heparin Antagonists
• Hirudins
• Protamines
• Recombinant Proteins
• Platelet Factor 4
• Heparin
• Factor VIIa
• Polysaccharide-Lyases
• Heparin Lyase

Topics

• 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, toxicity)
• Humans
• Platelet Aggregation (drug effects)
• Platelet Factor 4 (pharmacology)
• Polysaccharide-Lyases (pharmacology)
• Protamines (pharmacology)
• Rabbits
• Recombinant Proteins (antagonists & inhibitors, toxicity)
• Wounds, Stab (complications)