Plasma levels of a specific inhibitor of tissue-type plasminogen activator (and urokinase) in normal and pathological conditions

Abstract

Rapid inhibition of tissue-type plasminogen activator (t-PA) in human plasma was measured by addition of 5 IU (50 ng) of purified t-PA per ml plasma and measurement of residual t-PA in the euglobulin precipitate after 5 min incubation at 37°C. The recovery of both t-PA activity and t-PA related antigen in pooled plasma from healthy individuals was approximately 90 percent, indicating that one ml of pooled normal plasma inhibits less than 1 IU or 10 ng of t-PA within 5 min. Of 20 control subjects 13 had less than 1 IU inhibitor activity; 5 subjects inhibited between 1 and 3 IU of t-PA and 2 subjects inhibited around 4.5 IU. The inhibitor titer in the latter two had however decreased to 1.8 and 2.7 IU after two days. Markedly increased rapid inhibition of t-PA (> 4 IU per ml) was found in plasma of patients with severe liver disease (3 of 8), pancreatitis (4 of 8), malignancy (5 of 26), but only very occasionally and transiently in that of patients with myocardial infarction (5 of 28) or deep vein thrombosis (2 of 9). Increased inhibition was observed on the first day following coronary bypass (22 of 42) or open heart (16 of 27) surgery but this had disappeared in 15 of 16 patients on the fifth postoperative day. Titration of inhibitor levels revealed maximal amounts of 30 to 50 IU per ml plasma. Gel filtration revealed that inhibition of t-PA was associated with a shift in the elution position of t-PA related antigen from an apparent molecular weight of 70,000 to 120,000. A positive correlation was found between inhibition of t-PA and of urokinase (r=0.82), but not between the t-PA inhibition level and the t-PA antigen concentration in plasma (r=0.46). These findings are compatible with the interpretation that human plasma contains a rapidly acting inhibitor of t-PA and urokinase with an apparent molecular weight of approximately 50,000. Its concentration in healthy individuals is usually less than 10 ng per ml but may increase up to 50-fold in severely ill patients or after major surgery.