A Comparison of the Fibrinolytic and Fibrinogenolytic Effects of Plasminogen Activators and Proteolytic Enzymes in Plasma^[*]

Summary

1. A sensitive test system has been described whereby the respective fibrinolytic and fibrinogenolytic effects of plasminogen activators and proteolytic enzymes in plasma may be quantitated separately by use of isotopically labeled substrates.

2. Plasminogen activators in the plasma-clot system were demonstrated to lyse more fibrin per unit fibrinogen lysed than either plasmin or trypsin. No evidence was obtained to suggest the formation of a plasmin-antiplasmin complex with special “fibrinolytic” porperties.

3. Comparison of the effects of streptokinase and urokinase in plasma revealed discrete differences in the ratio of their fibrinolytic-fibrinogenolytic activities.

^* This work was supported by grants-in-aid from the National Heart Institute (H 3745), Bethesda, Md.; Lederle Laboratories Division, American Cyanamid Co., Pearl River, N. Y.; and Abbott Laboratories, Chicago, Ill.

• References

• 1 Sherry S, Fletcher A. P, Alkjaersig N. Fibrinolysis and fibrinolytic activity in man. Physiol. Rev. 39: 343 1959;
• 2 Sherry S, Fletcher A. P. Proteolytic enzymes: a therapeutic evaluation. Clin. Pharm. and Therap. 01: 202 1960;
• 3 Alkjaersig N, Fletcher A. P, Sherry S. The mechanism of clot dissolution by plasmin. J. clin. Invest. 38: 1086 1959;
• 4 Fletcher A. P, Alkjaersig N, Sherry S. The maintenance of a sustained thrombolytic state in man. I. Induction and effects. J. clin. Invest. 38: 1096 1959;
• 5 Fletcher A. P, Alkjaersig N, Sherry S. Pathogenesis of the hemorrhagic diathesis developing during “fibrinolytic” states: the significance of defective fibrin polymerization. J. clin. Invest. 38: 1005 1959;
• 6 Fletcher A. P. Pathophysiology of thrombolysis. Proc.. Conf. on Thrombolytic Agents; Chicago: 1960
• 7 Sherry S, Lindemeyer R. I, Fletcher A. P, Alkjaersig N. Studies on enhanced fibrinolytic activity in man. J. clin. Invest. 38: 810 1959;
• 8 Sawyer W. D, Alkjaersig N, Fletcher A. P, Sherry S. Qualitative differences between the action of various plasminogen activators on human plasma and on fibrin clots. Fed. Proc. 19: 57 1960;
• 9 Alkjaersig N, Fletcher A. P, Sherry S. The activation of human plasminogen. I. Spontaneous activation in glycerol. J. biol. Chem. 233: 81 1958;
• 10 Kline D. L. Purification and crystallization of plasminogen (profibrinolysin). J. biol. Chem. 204: 949 1953;
• 11 Troll W, Sherry S. Activation of human plasminogen by streptokinase. J. biol. Chem. 213: 881 1955;
• 12 Alkjaersig N, Fletcher A. P, Sherry S. The activation of human plasminogen. II. A kinetic study of activation with trypsin, urokinase, and streptokinase. J. biol. Chem. 233: 86 1958;
• 13 Shulman S, Alkjaersig N, Sherry S. Physicochemical studies on human plasminogen (profibrinolysin) and plasmin (fibrinolysin). J. biol. Chem. 233: 91 1958;
• 14 Ratnoff O. D, Menzie C. A new method for the determination of fibrinogen in small samples of plasma. J. Lab. clin. Med. 37: 316 1951;
• 15 Alkjaersig N, Fletcher A. P, Sherry S. E-Aminocaproic acid: an inhibitor of plasminogen activation. J. biol. Chem. 234: 832 1959;
• 16 Christensen L. R. Streptococcal fibrinolysis: a proteolytic reaction due to a serum enzyme activated by streptococcal fibrinolysin. J. gen. Physiol. 28: 363 1945;
• 17 Permin P. M. Fibrinolytiske Enzymer. Store Nordiske Videnskabsboghandel; Copenhagen: 1949
• 18 Ratnoff O. D. Fibrinogen and fibrin as substrates for the proteolytic enzyme of plasma. J. clin. Invest. 32: 473 1953;
• 19 Shulman N. R. Studies on the inhibition of proteolytic enzymes by serum. I. Mechanism of the inhibition of trypsin, plasmin, and chymotrypsin by serum using fibrin tagged with I¹³¹ as a substrate. J. exp. Med. 95: 571 1952;
• 20 Jacobsson K. Studies on the trypsin and plasmin inhibitors in human blood serum. Scand. J. clin. and Lab. Invest. 07 (Suppl. 14) 55 1955;
• 21 Bundy H. F, Mehl J. W. Trypsin inhibitors of human serum. I. Standardization, mechanism of reaction and normal values. J. clin. Invest. 37: 947 1959;
• 22 Norman P. S. Inhibition of plasmin by serum or plasma. J. exp. Med. 108: 53 1958;
• 23 Norman P. S, Hill B. M. Physical properties of the two plasmin inhibitors in plasma. J. exp. Med. 108: 639 1958;
• 24 Fletcher A. P, Alkjaersig N, Sherry S. The clearance of heterologous protein from the circulation of normal and immunized man. J. clin Invest. 37: 1306 1958;
• 25 Ambrus C. M, Markus G, Benson D. R. Studies on the substrate affinity of plasmin. Fed. Proc. 18: 362 1959;
• 26 Ambrus C. M, Back N, Ambrus J. L. Fibrinolytic effect of plasmin-antiplasmin complex. Fed. Proc. 19: 58 1960;
• 27 Sokal J. E, Ambrus J. L, Ambrus C. M. Treatment of thrombosis with fibrinolysin (plasmin). J. A. M. A. 168: 1314 1958;
• 28 Cliffton E. E. Early experience with fibrinolysin. Angiology 10: 244 1959;
• 29 Fletcher A. P, Alkjaersig N, Sherry S. The assay of thrombolytic (fibrinolytic) mixtures intended for therapeutic use. J. Lab. clin. Med.. In press.
• 30 Sawyer W. D, Fletcher A. P, Alkjaersig N, Sherry S. Studies on the thrombolytic activity of human plasma. J. clin. Invest. 39: 426 1960;
• 31 Smyrniotis F. E, Fletcher A. P, Alkjaersig N, Sherry S. Urokinase excretion in health and its alterations in certain disease states. Thromb. Diath. haem. 03: 257 1959;
• 32 Johnson A. J, McCarty W. R. The lysis of artificially induced intravascular clots in man by intravenous infusions of streptokinase. J. clin. Invest. 38: 1627 1959;
• 33 Mullertz S. Action of plasmin on fibrin and fibrinogen in blood. Acta phvsiol Scand. 28: 29 1953;
• 34 Johnson A. J, Newman J, Schoicket D. P. A mechanism of pathological spontaneous fibrinolysis in man. Fed. Proc. 19: 62 1960;