Turnover and Clearance of t-PA

Since the pioneering work of Astrup and Stage ¹ in the early 1950s, several groups have produced highly purified preparations of tissue plasminogen activator (t-PA) from different sources, such as pig hearts, ^{2 , 3} ovaries, ⁴ human uterus ^{3 – 5} and human melanoma cells. ^{6 , 8} When milligram quantities of highly purified t-PA became available, it was possible to study the pharmacological effects of t-PA in different in vitro and in vivo systems. Using the Chandler loop in vitro assay ⁹ it was demonstrated that t-PA, on a molar basis, was more than 100 times as effective as streptokinase or urokinase ¹⁰ as a thrombolytic agent. This effect was more pronounced when aged thrombi were included in the study. Moreover, t-PA caused no fibrinogenolysis; this was not the case with streptokinase and urokinase. ¹⁰ In ensuing animal experiments it was also established that t-PA resulted in a lower hemostatic breakdown in vivo than did urokinase1 ¹¹ and streptokinase. ¹² However, the thrombolytic experiments in vivo also revealed that the superior thrombolytic effect of t-PA which was found in vitro was not the same in vivo; 0.5 mg of streptokinase was, with respect to the thrombolytic effect, equipotent of 0.5 mg of t-PA. ¹² The main reason for this discrepancy between the in vitro and in vivo behavior of t-PA and streptokinase was mainly the very rapid plasma clearance of thrombolytic-active t-PA. This review outlines the present knowledge concerning the turnover and hepatic clearance of t-PA in vivo.