The effect of human recombinant tissue-type plasminogen activator on clinical and laboratory parameters of hemostasis and systemic plasminogen activation in the dog and the rat

• Published in: Thrombosis and haemostasis Vol. 60; no. 2; p. 271
• Main Authors: Bloom, J C, Sellers, T S, Gries, G C, Wheeldon, E B, O'Brien, S R, Lewis, H B
• Format: Journal Article
• Language: English
• Published: Germany 31.10.1988
• Subjects: Animals; Blood Coagulation Tests; Dogs; Female; Fibrinogen - metabolism; Hemorrhage - chemically induced; Hemorrhage - pathology; Hemostasis - drug effects; Humans; Infusions, Intravenous; Male; Plasminogen - metabolism; Protease Inhibitors - pharmacology; Rats; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Species Specificity; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacology
• ISSN: 0340-6245
• DOI: 10.1055/s-0038-1647044

The effect of human recombinant tissue-type plasminogen activator (rt-PA) on parameters of hemostasis and systemic plasminogen activation was studied in the dog and rat. Effects on screening coagulation times, fibrinogen concentration, fibrin/fibrinogen degradation products, and plasminogen and alpha 2-antiplasmin (alpha 2-AP) activities in plasma were examined following single bolus injections of 0.5-5.0 mg/kg, single and repeated 3 hr infusions of 0.75-7.5 mg/kg and 24 hr infusions of 6.0 and 30.0 mg/kg administered intravenously to dogs. Rats receiving single or 14 daily injections of 5.0-30.0 mg/kg i.v. were similarly monitored. Systemic fibrinogenolysis (greater than 50% decrease in fibrinogen, plasminogen or alpha 2-AP values) was observed in dogs receiving greater than or equal to 1.0 mg/kg as a bolus, greater than or equal to 3.75 mg/kg (20.8 micrograms or 1.19 x 10(4) IU kg-1min-1) as a 3 hr infusion and greater than or equal to 6 mg/kg (4.2 micrograms or 2.42 x 10(3) IU kg-1min-1) as a 24 hr infusion; and in rats treated with bolus injections of 30 mg/kg rt-PA. Clinical and laboratory indications of impaired hemostasis and bleeding (anemia, prolonged coagulation times and post-mortem evidence of hemorrhage) were associated with these effects, which together were dose-dependent and influenced by the rate of infusion. The incidence of major hemorrhage was variable and limited to animals receiving prolonged (24 hr) or repeated infusions.