Thrombolytic properties of human tissue-type plasminogen activator,
single-chain urokinase-type plasminogen activator, and synergistic
combinations in venous thrombosis models in dogs and rabbits
DJ Spriggs, JM Stassen, Y Hashimoto and D Collen
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Thrombolysis with single and combined four-hour intravenous (IV) infusions
of recombinant tissue-type plasminogen activator (rt-PA), recombinant
single-chain urokinase-type plasminogen activator of 54,000 molecular
weight (mol wt) (rscu-PA), and rscu-PA-32 kD, an rscu-PA derivative of
32,000 mol wt was studied in a femoral vein thrombosis model in the dog and
in a jugular vein thrombosis model in the rabbit. In both species, the
dose-response curves were linear, and no systemic activation of the
fibrinolytic system or fibrinogen breakdown was observed. The steady-state
levels of rt-PA-, rscu-PA-, and rscu-PA-32 kD-related antigens in plasma
were proportional to the infusion rates. In the dog model, 25% lysis was
obtained with 0.11 mg/kg rt-PA, 0.8 mg/kg rscu-PA, and 0.37 mg/kg
rscu-PA-32 kD. Combinations of rt-PA and rscu-PA were 2.6 times more active
(P less than .005) than anticipated on the basis of their pharmacologic
additive effects, whereas combinations of rt-PA and rscu-PA-32 kD were 2.7
times more active (P less than .05). In the rabbit model, 25% lysis was
obtained with 0.24 mg/kg rt-PA, 0.75 mg/kg rscu-PA, and 1.25 mg/kg
rscu-PA-32 kD. Combinations of rt-PA and rscu-PA have a fivefold
synergistic interaction, but surprisingly no synergism was observed between
rt-PA and rscu-PA-32 kD. This study shows that synergism between rt-PA and
rscu-PA occurs both in rabbits and dogs in a relatively narrow
concentration range that allows a fractional reduction of the total
equipotent dose by a factor of 2.5-fold to fivefold. Combination therapy is
not associated with systemic fibrinolytic activation. This range of
synergistic interaction, although limited, may be useful in devising the
best thrombolytic therapy for patients with thromboembolic disease.
Volume 73,
Issue 5,
pp. 1207-1212,
04/01/1989
Copyright © 1989 by The American Society of Hematology
