A novel fast inhibitor to tissue plasminogen activator in plasma, which may be of great pathophysiological significance

A novel, fast inhibitor to tissue plasminogen activator (t-PA) has been demonstrated in plasma samples. The inhibitor can be titrated in plasma. Upon addition of t-PA to plasma, an inactive complex is formed with an estimated rate constant of about 10(7)M-1s-1. The molecular weight of the complex between t-PA and the inhibitor has been determined as about 120,000. Thus, a molecular weight of about 55,000 would be expected for the inhibitor moiety in the complex. However, by gel filtration of plasma, rich in the inhibitor, an apparent molecular weight of about 200,000 was found. About 100,000 fold purification of the complex from plasma has been achieved by employing immuno adsorption chromatography (antibodies against porcine t-PA and monoclonal antibodies against human t-PA), ion-exchange chromatography and gel-filtration. Low concentrations of the new t-PA inhibitor were normally found in healthy individuals (0.7 +/- 0.7 U/ml). However, many patients with thrombosis or coronary heart disease had increased levels (3.8 +/- 3.7 U/ml and 2.8 +/- 2.2 U/ml, respectively). In normal pregnancy the concentration of the fast t-PA inhibitor increases linearly from week 10 to the time about term (5.1 +/- 0.9 U/ml). At present the origin as well as the physiological role of this novel t-PA inhibitor remains unclear. The increased levels observed in many patients with thrombotic diseases or in conditions frequently associated with thrombotic complications anticipates a role in the development of thrombosis. However, more work is needed to prove this hypothesis.