title: 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.
abstract: 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.
authors.affiliation: Department of Experimental Pathology, Smith Kline & French Laboratories, Philadelphia, PA.
authors.forename: J C
authors.initials: JC
authors.lastname: Bloom
authors.forename: T S
authors.initials: TS
authors.lastname: Sellers
authors.forename: G C
authors.initials: GC
authors.lastname: Gries
authors.forename: E B
authors.initials: EB
authors.lastname: Wheeldon
authors.forename: S R
authors.initials: SR
authors.lastname: O'Brien
authors.forename: H B
authors.initials: HB
authors.lastname: Lewis
mesh_terms: D000818:Animals; D001780:Blood Coagulation Tests; D004285:Dogs; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010958:Plasminogen / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013045:Species Specificity; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D011480:Protease Inhibitors; D011994:Recombinant Proteins; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator