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

John C Bloom; Teresa S Sellers; Gary C Gries; Eric B Wheeldon; Susan R O'Brien; Hugh B Lewis

doi:10.1055/s-0038-1647044

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1988; 60(02): 271-279
DOI: 10.1055/s-0038-1647044

Original Article

Schattauer GmbH Stuttgart

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

John C Bloom

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

,

Teresa S Sellers

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

,

Gary C Gries

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

,

Eric B Wheeldon

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

,

Susan R O'Brien

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

,

Hugh B Lewis

The Departments of Experimental Pathology and Investigative Toxicology, Smith Kline & French Laboratories, Philadelphia, PA, USA

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Abstract

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Summary

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 α₂-anti- plasmin (α₂-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 (>50% decrease in fibrinogen, plasminogen or α₂-AP values) was observed in dogs receiving ≥1.0 mg/kg as a bolus, ≥3.75 mg/kg (20.8 μg or 1.19 × 10⁴ IU kg⁻¹min⁻¹) as a 3 hr infusion and >6 mg/kg (4.2 μg or 2.42 × 10³IU 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.

Keywords

Human recombinant tissue-type plasminogen activator - Dog - Rat - Systemic fibrinogenolysis - Impaired hemostasis

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Referenzen

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