Inhibition of Coagulation and Fibrinolysis by Aromatic Amidino Compounds

Summary

1. Aromatic diamidines which are potent inhibitors of trypsin possess a marked inhibitory effect on the clotting activity of human thrombin and on the prothrombin time and partial thromboplastin time of human plasma. They also block the contact activation phase of the coagulation process. The strongest inhibitor among the compounds tested was M & B 4596 which was followed in second place by pentamidine.

2. Pentamidine was 10 times more active than ε-ACA in impeding streptokinase-induced lysis of human plasma clots. It was 100-200 times stronger than ε-ACA in inhibiting the activation of bovine plasminogen by activators formed from the interaction between streptokinase and either human plasmin(ogen) or human plasma.

3. The prothrombin time and partial thromboplastin time of canine plasma were less susceptible to inhibition by pentamidine than the same tests on human plasma. Clot lysis in the canine system was inhibited by pentamidine to a similar degree as in the human system. After intravenous injection of pentamidine in the dog there occurred the expected prolongation of the partial thromboplastin time and of the clot lysis time.

^* This study was supported by U.S. Public Health Service Grants AM 10746 and HE 6350.

• References

• 1 Davies G. E, Holman G, Lowe J. S. Role of Hageman factor in the activation of guinea-pig pre-kallikrein. Brit. J. Pharmacol. Chemother 29: 55 1967;
• 2 Geratz J. D. Synthetic inhibitors and ester substrates of pancreatic kallikrein. Experientia (Basel) 25: 483 1969;
• 3 Geratz J. D. Inhibitory effect of aromatic diamidines on trypsin and enterokinase. Experientia (Basel) 25: 1254 1969;
• 4 Geratz J. D. Inhibition of thrombin, plasmin and plasminogen activation by amidino compounds. Thrombos. Diathes. haemorrh. (Stuttg) 23: 486 1970;
• 5 Kingdon H. S, Davie E. W. O, Ratnoff D. The reaction between activated plasma thromboplastin antecedent and diisopropylphosphofluoridate. Biochemistry 03: 166 1964;
• 6 Ling G-M, Summaria L, Robbins K. C. Mechanism of formation of bovine plasminogen activator from human plasmin. J. biol. Chem 240: 4213 1965;
• 7 Margolis J. Activation of plasma by contact with glass: Evidence for a common reaction which releases plasma kinin and initiates coagulation. J. Physiol. (Lond) 144: 1 1958;
• 8 Margolis J. The mode of action of Hageman factor in the release of plasma kinin. J. Physiol. (Lond) 151: 238 1960;
• 9 Milstone J. H. TAMe esterase activity of blood thrombokinase after repeated electrophoretic fractionations. Proc. Soc. exp. Biol. (N. Y) 103: 361 1960;
• 10 Nagasawa S, Takahashi H, Koida M, Suzuki T, Schoenmakers J. G. G. Partial purification of bovine plasma kallikreinogen, its activation by the Hageman factor. Biochem. biophys. Res. Commun 32: 644 1968;
• 11 Nossel H. L, Rubin H, Drillings M, Hsieh R. Inhibition of Hageman factor activation. J. clin. Invest 47: 1172 1968;
• 12 Nye S. W, Graham J. B, Brinkhous K. M. The partial thromboplastin time as a screening test for the detection of latent bleeders. Amer. J. med. Sci 243: 279 1962;
• 13 Quick A. J. The clinical application of the hippuric acid and the prothrombin tests. Amer. J. clin. Path 70: 222 1940;
• 14 Rodman Jr N. F, Barrow E. M, Graham J. B. Diagnosis and control of the hemophilioid states with the partial thromboplastin (PTT) test. Amer. J. clin. Path 29: 525 1958;
• 15 Schoenbach E. B, Greenspan E. M. The parmacology, mode of action and therapeutic potentialities of stilbamidine, pentamidine, propamidine and other aromatic diamidines - a review. Medicine 27: 327 1948;
• 16 Schoenmakers J. G. G, Matze R, Haanen G, Zilliken F. Hageman factor, a novel sialoglycoprotein with esterase activity. Biochim. biophys. Acta (Amst) 101: 166 1965;
• 17 Sherry S, Troll W. The action of thrombin on synthetic substrates. J. biol. Chem 208: 95 1954;
• 18 Sherry S, Alkjaersig N, Fletcher A. P. Comparative activity of thrombin on substituted arginine and lysine esters. Amer. J. Physiol 209: 577 1965;
• 19 Speer R. J, Ridgway H, Hill J. M. Activated human Hageman factor (XII). Thrombos. Diathes. haemorrh. (Stuttg) 14: 1 1965;
• 20 Sternberger L. S. The stabilization of thrombin in plasma. Development of a simple two-stage method for the determination of prothrombin. Brit. J. exp. Path 28: 168 1947;
• 21 Summaria L, Ling G-M, Groskopf W. R, Robbins K. G. The active site of bovine plasminogen activator. Interaction of streptokinase with human plasminogen and plasmin. J. biol. Chem 243: 144 1968;
• 22 Summaria L, Hsieh B, Groskopf W. R, Robbins K. C. Direct activation of human plasminogen by streptokinase. Proc. Soc. exp. Biol. (N. Y) 130: 737 1969;
• 23 Takada Y, Takada A, Ambrus J. L. Comparative study of proactivators of the fibrinolysin system in three mammalian species. Thrombos. Diathes. haemorrh (Stuttg) 21: 594 1969;
• 24 Temme H, Jahrreis R, Habermann E, Zilliken F. Aktivierung von Gerinnungs- und Kininsystem durch eine Plasmaesterase (Hageman-Faktor). Reinigung und Wirkungsbedingungen. Hoppe-Seyler’s Z. physiol. Chem 350: 519 1969;
• 25 Ts’ao G. H, Kline D. L. Plasminogen activator formed by reaction of streptokinase with human plasminogen. J. appl. Physiol 26: 634 1969;
• 26 Vogt W. Kinin formation by plasmin, an indirect process mediated by activation of kallikrein. J. Physiol. (Lond) 170: 153 1964;
• 27 Waalkes T. P, De Vita V. T. The determination of pentamidine (4,4’-diamidinophenoxypentane) in plasma, urine, and tissues. J. Lab. clin. Med 75: 871 1970;
• 28 Webster M. E, Ratnoff O. D. Hole of Hageman factor in the activation of vasodilator activity in human plasma. Nature (Lond) 192: 180 1961;
• 29 Werle E, Forell M. M, Maier L. Zur Kenntnis der blutdrucksenkenden Wirkung des Trypsins. Arch. exp. Path. Pharmak 225: 369 1955;