On the fibrinolytic and thrombolytic properties of active-site p-anisoylated streptokinase-plasminogen complex (BRL 26921).

Abstract

Abstract The fibrinolytic and thrombolytic properties of BRL 26921, a p-anisoylated streptokinase-plasminogen complex, were studied in vivo and in vitro. The in vivo studies were performed in rabbits with an experimental pulmonary embolus consisting of a 0.15 ml 125I-fibrinogen labeled whole human blood clot. The degree of thrombolysis was calculated as the difference in isotope content of the thrombus before injection and after its recovery from the pulmonary artery of the animals sacrificed after 9 hours. In four control animals the extent of thrombolysis was 3.2 ± 1.5 (mean ± S.D.) percent. BRL 26921 given as a single bolus injection of 2,000, 10,000 or 60,000 streptokinase equivalent units in groups of three or four rabbits resulted in 10.3 ± 6.5, 29.4 ± 10.2 and 28.4 ± 9.3 percent lysis. A mixture of 60,000 IU of streptokinase and 1 mg of human plasminogen caused 11.2 ± 7.2 percent lysis and a tenfold higher amount 38.4 ± 16.9 percent. Injection of BRL 26921 or of the low dose of streptokinase and human plasminogen induced negligible systemic activation of plasminogen or consumption of fast-acting antiplasmin and no fibrinogen breakdown. The high dose of streptokinase and human plasminogen (600,000 units and 10 mg) resulted in systemic defibrination. Thus in this experimental model, BRL 26921 is a much more potent thrombolytic agent than an equivalent amount of streptokinase and human plasminogen. In addition BRL 26921 causes specific thrombolysis without systemic fibrinogen breakdown. The in vitro experiments were performed in a system composed of a radioactive human blood clot (125I-fibrinogen labeled), hanging in circulating human or rabbit plasma. Significant thrombolysis (release of radioactivity) in the human plasma system was obtained with 50 units or more of BRL 26921 per ml plasma or with 500 or more units of streptokinase per ml. Specific thrombolysis without systemic plasminogen activation, α2-antiplasmin consumption and fibrinogen breakdown was however not obtained with either agent. Replacement of the normal human plasma with that of a patient with high titers of streptokinase antibodies (3 weeks after streptokinase therapy) abolished the effects of both BRL 26921 and of streptokinase. In the rabbit plasma system significant thrombolysis was already observed with 10 to 50 units of BRL 26921 per ml plasma although this did not result in systemic fibrinolytic activation or fibrinogen breakdown. This was only observed with a concentration of 500 units per ml. The present findings indicate that in the rabbit system, BRL 26921 has a high specific thrombolytic and low fibrinogenolytic effect. In the human plasma system BRL 26921 has a higher specific activity than streptokinase but there is no differentiation between its thrombolytic and fibrinogenolytic effects.