The Clot-Promoting Effect of Adenosine-5’- Diphosphate (ADP). I. Mechanisms of Action

Summary

1. ADP accelerates blood coagulation by at least two mechanisms. One is by causing release of coagulant phospholipids from platelets. The other is by activation of a plasma coagulation factor whose action is early in thromboplastin generation.

2. Possible mechanisms of ADP’s effect on blood coagulation are discussed.

3. These findings suggest that ADP may play a more significant role in the mechanisms of hemostasis and in the pathophysiology of thrombosis than has heretofore been supposed.

^* Present address: Hospital de Enfermedades de la Nutricion, Mexico City, Mexico.

^** Present address: Mayo Clinic, Rochester, Minn., U.S.A.

• References

• 1 Arakawa T, Spaet TH. Hypercoagulability and thrombosis: Effect of injected thrombo- kinase and adenosine diphosphate on established microthrombi in rabbits. Proc. Soc. exp. Biol. (N. Y) 16: 1034 1964;
• 2 Born GVR, Gross MJ. The effect of inorganic ions on the aggregation of platelets by ADP. J. Physiol. (Lond) 168: 41P 1963;
• 3 Born GVR, Cross MJ. The aggregation of blood platelets. J. Physiol. (Lond) 168: 178 1963;
• 4 Born GVR, Honour AJ, Mitchell JRA. Inhibition by adenosine and by 2-chloro- adenosine of the formation and embolization of platelet thrombi. Nature 202: 761 1964;
• 5 Caen J, Michel H. L’activité agrégante du serum. (Plasma défibriné par la thrombine). Rev. franç. Étud. clin. biol 09: 1001 1964;
• 6 Ghen RF, Brown DM, Plant GWE. DPN-linked isocitrate dehydrogenase of bovine heart: Structural changes associated with activation by ADP. Biochemistry 03: 552 1964;
• 7 Ghiga M, Plaut GWE. An enzyme system from mitochondria catalyzing ADP, ATP, and orthophosphate ATP exchange reactions. J. biol. Chem 234: 3059 1959;
• 8 Gohn WE. The anion exchange separation of ribonucleotides. J. Amer. chem. Soc 72: 1471 1950;
• 9 Davie EWO, Ratnoff D. Waterfall sequence for intrinsic blood clotting. Science 145: 1310 1964;
• 10 DesPrez RM. Effects of bacterial endotoxin on rabbit platelets. III. Comparison of platelet injury induced by thrombin and by endotoxin. J. exp. Med 120: 305 1964;
• 11 Didisheim P, Mibashan RS. Activation of Hageman factor (Factor XII) by long-chain saturated fatty acids. Thrombos. Diathes. haemorrh. (Stuttg) 09: 346 1963;
• 12 Didisheim P, Pizzuto J, Bunting D. An improved assay for Factor IX (PTC, Christmas factor). In: Brinkhous KM. (ed). The Hemophilias. Univ. North. Carolina Press; Chapel Hill: 1964
• 13 Gaarder A, Jonsen J, Laland S, Hellem AJ, Owren PA. Adenosine diphosphate in red cells as a factor in the adhesiveness of human blood platelets. Nature 192: 531 1961;
• 14 Hellem AJ, Owren PA. The mechanism of the hemostatic function of blood platelets. Actahaemat. (Basel) 31: 230 1964;
• 15 Hovig T, Holmsen H. Release of a platelet-aggregating substance (adenosine diphosphate) from rabbit blood platelets induced by saline “extract” of tendons. Thrombos. Diathes. haemorrh. (Stuttg) 09: 264 1963;
• 16 Kuby AS, Mahowald TA, Noltman EA. Studies on adenosine triphosphate transphos- phorylases. IV. Enzyme substrate interactions. Biochemistry 01: 748 1962;
• 17 Lewis JH, Didisheim P. Differential diagnosis and treatment in hemorrhagic disease. A.M.A. Arch, intern. Med 100: 157 1957;
• 18 Macfarlane RG. An enzyme cascade in the blood clotting mechanism and its function as a biochemical amplifier. Nature 202: 498 1964;
• 19 Martell AE, Calvin M. Chemistry of the metal chelate compounds. Prentice Hall; New York: 1952
• 20 McLean JR, Maxwell RE, Hertler D. Fibrinogen and adenosine diphosphate-induced aggregation of platelets. Nature 202: 605 1964;
• 21 Mustard JF, Hegardt B, Rowsell HC, MacMillan RL. Effect of adenosine nucleotides on platelet aggregation and clotting time. J. Lab. clin. Med 64: 548 1964;
• 22 Nordoy A, Chandler AB. The influence of dietary fats on the adenosine diphosphate induced platelet thrombosis in the rat. Scand. J. Haemat 01: 202 1964;
• 23 Nossel HL. “The Contact Phase of Blood Coagulation.”. F.A. Davis Company, Philadelphia. Blackwell Scientific Publications; 1964
• 24 Nye SW, Graham JB, Brinkhous KM. The partial thromboplastin time as a screening test for the detection of latent bleeders. Amer. J. med. Sei 243: 279 1962;
• 25 O’Brien JR. The effect of some fatty acids and phospholipids on blood coagulation. Brit. J. exp. Path 38: 529 1957;
• 26 O’Brien JR. Platelet aggregation: Part I. Some effects of the adenosine phosphates, thrombin, and cocaine upon platelet adhesiveness. Part II. Some results from a new method of study. J. Clin. Path 15: 446 1962;
• 27 O’Brien JR. A comparison of platelet aggregation produced by seven compounds and a comparison of their inhibitors. J. clin. Path 17: 275 1964;
• 28 Ödegaard AE, Skâlhegg BA, Hellem AJ. ADP induced platelet adhesiveness as a diagnostic test in von Willebrand’s disease. Thrombos. Diathes. haemorrh. (Stuttg) 09: 23 1964;
• 29 Ödegaard AE, Skâlhegg BA, Hellem AJ. Increased activity of “anti-von Willebrand Factor” in diabetic plasma. Thrombos. Diathes. haemorrh. (Stuttg) 09: 27 1964;
• 30 Ödegaard AE, Skâlhegg BA, Hellem AJ. Investigation of adenosine diphosphate (ADP) induced platelet adhesiveness in vitro. Part III. The inactivation of ADP in plasma. Thrombos. Diathes. haemorrh. (Stuttg) 09: 317 1964;
• 31 Owren PA. Physiopathologie du temps de saignement. Nouv. Rev. franc. Hémat 03: 280 1963;
• 32 Owren PA. Nutrition and thrombosing atherosclerosis. Nutr. et Dieta (Basel) 06: 156 1964;
• 33 Owren PA, Hellem AJ, Odegaard A. Linolenic acid for the prevention of thrombosis and myocardial infarction. Lancet Nov 07: 975 1964;
• 34 Rodman Jr. NF, Mason RO, Brinkhous KM. Some pathogenetic mechanisms of white thrombus formation: agglutination and self-destruction of the platelet. Fed. Proc 22: 1356 1963;
• 35 Rowsell HC, Murphy EA, Glynn MF, Mustard JF. Adenosine nucleotides, platelets and thrombosis in swine. Blood 25: 603 1965; (Abstract).
• 36 Salzman EW, Chambers DA. Inhibition of ADP-induced platelet aggregation by substituted amino acids. Nature 204: 698 1964;
• 37 Salzman EW, Chambers DA, Neri LL. Platelet aggregation and incorporation of labelled nucleotides. Fed. Proc 24 No. 2, Part I, 260 1965; (Abstract).
• 38 Skâlhegg A, Hellem AJ, Odegaard AE. Investigations on adenosine diphosphate (ADP) induced platelet adhesiveness in vitro. Part II. Studies on the mechanism. Thrombos. Diathes. haemorrh. (Stuttg) 09: 305 1964;
• 39 Weaver R. Nucleoside diphosphokinases. In: The Enzymes. Vol. 6 Boyer, Lardy, Myrback. editors. Academic Press; New York: 1962
• 40 Zucker-Franklin D, Spaet TH. Partial purification of intermediate coagulation Product I and a study of its properties. Amer. J. Physiol 205: 341 1963;