Evidence for the Occurrence of a Fast-Acting Inhibitor for Tissue-Type Plasminogen Activator in Human Plasma^[*]

Summary

Human plasma contains a fast-acting t-PA inhibitor, which is not identical with α₂-antiplasmin or α₂-macroglobulin. The concentration of this inhibitor in normal plasma is highly variable, much lower than that of known plasma protease inhibitors, and in the range of physiologically occurring plasma concentrations of t- PA (0-2 IU/ml).

The inhibitor binds to concanavalin A-Sepharose, is rather stable when heated, is not precipitated in euglobulin fractions and probably does not originate from platelets. The inhibitor seems to form a 190 Kd complex with t-PA. The relation between this plasma inhibitor and the recently discovered endothelial cell inhibitor is not yet clear.

Keywords

Plasminogen activation - Specific inhibitor - Tissue-type activator - Plasma

^* Part of this work has been presented at the IXth International Congress on Thrombosis and Haemostasis, 1983. An abstract appeared as ref 6.

• References

• 1 Korninger C, Collen D. Neutralization of human extrinsic (tissue- type) plasminogen activator in human plasma: No evidence for a specific inhibitor. Thromb Haemostas 1981; 46: 662-665
• 2 Aoki N, Von Kaulla KN. Human serum antiactivator: Its distinction from antiplasmin. Am J Physiol 1971; 220: 1137-1145
• 3 Beattie AG, Ogston D, Bennett B, Douglas AS. Inhibitors of plasminogen activation in human blood. Br J Haematol 1976; 32: 135-143
• 4 Gurewich V, Hyde E, Lipinsky B. The resistance of fibrinogen and soluble fibrin monomer in blood to degradation by a potent plasminogen activator derived from cadaver limbs. Blood 1975; 46: 555-565
• 5 Emeis JJ, Van Hinsbergh VW M, Verheijen JH, Wijngaards G. Inhibition of tissue type plasminogen activator by conditioned medium from cultured human and porcine vascular endothelial cells. Biochem Biophys Res Commun 1983; 110: 392-398
• 6 Verheijen JH, Chang GT G, Mullaart E. Inhibition of extrinsic (tissue-type) plasminogen activator by human plasma: Evidence for the occurrence of a fast acting inhibitor. Thromb Haemostas 1983; 50: 294 (Abstr.)
• 7 Verheijen JH, Mullaart E, Chang GT G, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurement in plasma. Thromb Haemostas 1982; 48: 266-269
• 8 Kluft C, van Wezel AL, van der Velden CA M, Emeis JJ, Verheijen JH, Wijngards G. Large scale production of extrinsic (tissue-type) plasminogen activator from human melanoma cells. In: Advances in Biotechnological Processes. Mizrahi A, van Wezel AL. (eds.) AR Liss Inc; New York: 1983. 2 97-110
• 9 Fraker PJ, Speck Jr JC. Protein and cell membrane iodinations with a sparingly soluble chloroamide, 1, 3, 4, 6-tetrachloro-3a, 6a-diphenylglycoluril. Biochem Biophys Res Commun 1978; 80: 849-857
• 10 Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970; 227: 680-685
• 11 Kluft C. C1-inactivator-resistant fibrinolytic activity in plasma euglobulin fractions: Its relation to vascular activator in blood and its role in euglobulin fibrinolysis. Thromb Res 1978; 13: 135-151
• 12 Kluft C. Quantitation and behaviour of extrinsic or vascular plasminogen activator in blood. In: Progress in Fibrinolysis. Davidson JF, Nilsson IM, Åstedt B. (Eds) Churchill Livingstone; Edingburgh: 1981. 5 24-30
• 13 Kluft C, Vellenga E, Brommer EJ P, Wijngaards G. A familial hemorrhagic diathesis in a Dutch family: An inherited deficiency of α₂- anti-plasmin. Blood 1982; 59: 1169-1180