On the Effect on Human Thrombocytes of Synthetic Organic Fibrinolytic Compounds^[*]

Summary

The effect of various synthetic organic fibrinolysis-inducing compounds was investigated on platelets in plasma and on washed platelets. To a varying degree the com pounds induced a concentration-dependent platelet aggregation. Some at higher molarities cause lysis of platelets. The same molecular modifications which reduce the fibrinolytic activity also seem to reduce the effects of the compounds on platelets. Platelet aggregation by the compounds was reduced by adenosine, adenosine monophosphate, and some other ADP-inhibitors, but there was no proof that the compounds act by releasing ADP from the platelets. With fluorescent compounds their attachment to platelets was demonstrated.

• References

• 1 Adams S. S, Cobb R. A possible basis for the anti-inflammatory activity of salicylates and other non-hormonal anti-rheumatic drugs. Nature (Lond) 181: 773-774 1958;
• 2 Barnhart M. I, Cress D. C, Henry R. L, Riddle J. M. Influence of fibrinogen split products on platelets. Thrombos. Diathes. haemorrh. (Stuttg) 27: 79-98 1967;
• 3 Born G. V. R. Quantitative investigations into the aggregation of blood platelets. J. Physiol. (Lond) 162: 67-69 1962;
• 4 Born G. V. R. Strong inhibition by 2-chloroadenosine of the aggregation of blood platelets by ADP. Nature (Lond) 202: 95-96 1964;
• 5 Brecher G, Cronkite E. P. Morphology and enumeration of human blood platelets. J. appl. Physiol 03: 365-377 1950;
• 6 Cayton S, Born G. V. R, Cross M. J. Inhibition of the aggregation of blood platelets by nucleotides. Nature (Lond) 200: 138-139 1963;
• 7 Fantl P. The influence of pyrazole derivatives on blood platelets. Aust. J. exp. Biol. med. Sci 45: 355-362 1967;
• 8 Haslam R. J. Role of adenosine diphosphate in the aggregation of human blood platelets by thrombin and fatty acids. Nature (Lond) 202: 765-768 1964;
• 9 Jacobson W. Cellular injuries caused by folic acid antagonists and some corticosteroids. Ciba Foundation Symposium on Cellular Injury. 136-160 de Reuck A. V. S, Knight J. eds. Churchill, London: 1964
• 10 Jerushalmy Z, Skosa L, Zucker M. B, Grant R. Inhibition by guanidino compounds of platelet aggregation induced by adenosine diphosphate. Biochem. Pharmacol 15: 1791-1803 1966;
• 11 Judah J. D. Protection against cellular injury by drugs. Ciba Foundation Symposium on Enzymes and Drug Action. 350-384 Mongar J. L, de Reuck A. V. S. eds. Churchill, London: 1962
• 12 McLean J. R, Veloso H. Change of shape without aggregation caused by adenosine diphosphate in rabbit platelets at low pH. Life Sci 06: 1983-1986 1967;
• 13 Michal F, Thorp R. H. Enhanced adenosine inhibition of platelet aggregation in the presence of cardiac glycosides. Nature (Lond) 209: 208-209 1966;
• 14 Mills G. B, Roberts G. G. K. Membrane active drugs and the aggregation of human blood platelets. Nature (Lond) 212: 35-38 1967;
• 15 Moran C. J, Walker H. C. The binding of salicylates to human serum. Biochem. Pharmacol 17: 153-156 1968;
• 16 Natelson S, Stein I, Bonas J. E. Improvements in the method of separation of guanidino organic acids by column chromatography. Microchem. J 08: 371-383 1964;
• 17 O’Brien J. R. Platelet aggregation, Part I. Someeffects on the adenosine phosphates, thrombin, and cocaine upon platelet adhesiveness. J. clin. Path 15: 446-455 1962;
• 18 O’Brien J. R, Heywood J. B. Effect of aggregating agents and their inhibitors on the mean platelets shape. J. clin. Path 19: 148-153 1966;
• 19 O’Brien J. R. Changes in platelet membrane possibly associated with platelet stickiness. Nature (Lond) 212: 1057-1058 1966;
• 20 O’Brien J. R. Effects of salicylates on human platelets. Lancet I: 779-783 1968;
• 21 Packham M. A, Warrior E. S, Glynn M. F, Senyi A. S, Mustard J. F. Alteration of the response of platelets to surface stimuli by pyrazole compounds. J. exp. Med 126: 171-188 1966;
• 22 Robinson C. W, Mason R. G, Wagner R. H. Effect of sulfhydryl inhibitors on platelet agglutinability. Proc. Soc. exp. Biol. (N. Y) 113: 857-861 1963;
• 23 Salzman E. W, Chambers D. A. Inhibition of ADP-induced platelet aggregation by substituted aminoacids. Nature (Lond) 204: 698-700 1964;
• 24 Smith M. J. H, Gould B. J, Huggins A. K. Inhibition of glutamate decarboxilase by salicylates congeners. Biochem. Pharmacol 12: 917-918 1963;
• 25 Stafford W. L. The binding of bovine plasma and plasma fractions of salicylic acid and some of its 3-alkyl analogues. Biochem. Pharmacol 11: 685-692 1962;
• 26 Steggle R. A, Huggins A. K, Smith J. H. Inhibition of rat serum glutamic pyruvic transaminase in vitro by congeners of salicylates. Biochem. Pharmacol 07: 151-153 1961;
• 27 von Kaulla K. N. Synthetic clot-dissolving agents. In: Chemistry of Thrombolysis: Human Fibrinolytic Enzymes. 261-287 C.C. Thomas, Springfield/Ill: 1963
• 28 von Kaulla K. N. Inactivation of antiplasmin and complement C’ in human plasma rendered fibrinolytic by synthetic organic compounds. Thrombos. Diathes. haemorrh. (Stuttg). 10. 151-163 (1963/64).
• 29 von Kaulla K. N. Animal plasma as substrate for synthetic fibrinolysis inducers. Proc. Soc. exp. Biol. (N. Y) 121: 46-49 1966;
• 30 von Kaulla K. N. On an in vitro mechanism of action of synthetic fibrinolytic agents. Paper read before the 155th meeting of the American Chemical Society; San Francisco: April 1968
• 31 von Kaulla K. NA simple test tube arrangement for screening fibrinolytic activity of synthetic organic compounds. J. Medicinal Chem 08: 164-166 1965;
• 32 von Kaulla K. N, Ens G. On structure-related properties of synthetic clot-dissolving (thrombolytic) compounds. Biochem. Pharmacol 16: 1023-1034 1967;
• 33 Whitehouse M. W, Haslam J. M. Ability of some antirheumatic drugs to uncouple oxidative phosphorylation. Nature (Lond) 196: 1323-1324 1962;
• 34 Whitehouse M. W. Uncoupling of oxydative phosphorylation by some arylacetic acids (antiinflammatory or hypocholesterolemic drugs). Nature (Lond) 201: 629-630 1964;
• 35 Whitehouse M. W. Biochemical properties of anti-inflammatory drugs. XI. Structure-action relationship for the uncoupling of oxidative phosphorylation and inhibition of chymotrypsin and N-substituted anthranilates and related compounds. Biochem. Pharmacol 16: 753-760 1967;
• 36 Zucker M. B, Peterson J. Inhibition of adenosine diphosphate induced secondary aggregation and other platelet functions by acetylsalicylic acid ingestion. Proc. Soc. exp. Biol. (N. Y) 127: 547-551 1968;