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

SummaryThe 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.

Principles of Hematotoxicology: Laboratory Assessment and Interpretation of Data

“…Blood cells are exposed to any agent absorbed or The acceptable risk: benefit ratio is not always clear injected into the bloodstream, even those rapidly or widely agreed upon, whether the effect represents metabolized and excreted. They sustain a particu&dquo;exaggerated pharmacology,&dquo; such as the bleeding larly high level of exposure to drugs administered associated with some antithrombotic and thromparenterally, just after injection and prior to dilution bolytic agents (2,5), or is unrelated to the action of within the intravascular compartment and equilithe drug, as in the agranulocytosis associated with bration with other tissues. This is the rationale for the tricyclic antidepressant agents (14).…”

Enhancement of Fibrinolysis by EF6265 [(S)-7-Amino-2-[[[(R)-2-methyl-1-(3-phenylpropanoylamino)propyl]hydroxyphosphinoyl] methyl]heptanoic Acid], a Specific Inhibitor of Plasma Carboxypeptidase B

“…The dose of tPA must be high enough to overcome the inhibitory effects of plasminogen activator inhibitor-1 in the plasma, and results in the generation of plasmin in circulating blood (Rijken and Sakharov, 2001). Consequently, these large quantities of generated plasmin can induce thrombolysis and result in hemorrhaging as a side effect (Bloom et al, 1988). Many efforts have therefore been made to identify and develop pharmacologically distinct antithrombotic agents while maintaining a low risk of hemorrhaging.…”