Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin.
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)
Fareed
J
J
Department of Pathology, Loyola University Medical Center, Maywood, Ill.
Walenga
J M
JM
Pifarre
R
R
Hoppensteadt
D
D
Koza
M
M
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D016063:Blood Loss, Surgical / Q000517:prevention & control; D004427:Ear Diseases / Q000139:chemically induced; D004431:Ear, External / Q000293:injuries; D015942:Factor VIIa / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000494:pharmacology; D006494:Heparin Antagonists / Q000494:pharmacology*; D019763:Heparin Lyase; D006629:Hirudins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010978:Platelet Factor 4 / Q000494:pharmacology; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011479:Protamines / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000633:toxicity; D014951:Wounds, Stab / Q000150:complications
D000933:Antifibrinolytic Agents; D005343:Fibrinolytic Agents; D006494:Heparin Antagonists; D006629:Hirudins; D011479:Protamines; D011994:Recombinant Proteins; D010978:Platelet Factor 4; D006493:Heparin; D015942:Factor VIIa; D011133:Polysaccharide-Lyases; D019763:Heparin Lyase