Effects of Thorium Dioxide upon Blood Clotting and Platelets. I. In Vitro Studies^[*]

Summary

Thorium dioxide was found to damage clotting factors and to interfere with platelet functions in vitro:

1. Fibrinogen and factor V were progressively inactivated. Citrate did not prevent damage to these factors. Thorium dioxide was concentrated in the clot, which suggests that it binds to fibrinogen.

2. Factors II, VII, IX, and X were also inactivated. Inactivation of these factors could be prevented or reversed by citrate.

3. Factors VIII, XI, and XII were not altered.

4. Platelets became less adhesive and less subject to aggregation.

These effects were more marked with unfiltered suspensions of thorium dioxide (TDS) than with filtered suspensions (Thorotrast). They were also increased by increasing the concentration of thorium dioxide, and the time and temperature of incubation. Thorium dioxide probably forms complexes with the clotting proteins, thereby making them less reactive.

^* Supported by research grant H-6128-04 from the National Heart Institute, USPH, by The Norwegian Research Council for Science and the Humanities, and by The Norwegian Council on Cardiovascular Diseases.

• References

• 1 Beller F. K, Mammen E. Der Angriffspunkt der seltenen Erden Neodym im Gerinnungssystem. Arch. Gynäk 187: 319-336 1956;
• 2 Blombäck B, Blombäck M. Purification of human and bovine fibrinogen. Ark. Kemi 10: 415-443 1956;
• 3 Brecher G, Gronkite E. P. Morphology and enumeration of human blood platelets. J. appi. Physiol 5: 365-377 1950;
• 4 Clark S. L, Batchelor W. H. The behavior of the formed elements of blood incubated with bacterial endotoxins. Naval med. Res. Inst 15: 361-374 1957;
• 5 Colman P, Alexander B. The effect of lanthanides and actinides on blood coagulation. I. Evidence for and properties of a new serum thromboplastic factor. J. clin. Invest 43: 705-719 1964;
• 6 Colman P, Alexander B. The effect of lanthanides and actinides on blood coagulation. II. Assay of a new serum thromboplastic factor vulnerable to these elements and its variations in health and disease. J. clin. Invest 43: 720-727 1964;
• 7 Council on Pharmacy and Chemistry. Thorotrast. J. Amer. med. Ass 99: 2183-2185 1932;
• 8 Desprez R. M, Horowitz H. I, Hook E. W. Effects of bacterial endotoxin on rabbit platelets. I. Platelet aggregation and release of platelet factors in vitro. J. exp. Med 114: 857-874 1961;
• 9 Glazko A. J, Greenberg D. M. The mechanism of the inhibiting effect of electrolytes and heparin on blood coagulation. Amer. J. Physiol 128: 399-407 1940;
• 10 Godai H. C. A comparison of two heparin-neutralizing agents: protamine and polybrene. Scand. J. clin. Lab. Invest 12: 446-457 1960;
• 11 Good R. A, Thomas L. Studies on the generalized Shwartzman reaction II. The production of bilateral cortical necrosis of the kidneys by a single injection of bacterial endotoxin in rabbits previously treated with Thorotrast or Trypan blue. J. exp. Med 96: 625-641 1952;
• 12 Hjort P. F. Intermediate reactions in the coagulation of blood with tissue thromboplastin. Scand. J. clin. Lab. Invest 9 (Suppl. 27) 183 1957;
• 13 Hjort P. F, Rapaport S. I, Owren P. A. A simple, specific one-stage prothrombin assay using Russell’s viper venom in cephalin suspension. J. Lab. clin. Med 46: 89-97 1955;
• 14 Horowitz H. I, Des Prez R. M, Hook E. W. Effects of bacterial endotoxin on rabbit platelets. II. Enhancement of platelet factor 3 activity in vitro and in vivo. J. exp. Med 116: 619-633 1962;
• 15 Hougie C. A simple assay method for Factor X (Stuart-Prower Factor). Proc. Soc. exp. Biol. (N. Y.) 109: 754-756 1962;
• 16 Hunter R. B, Walker W. Neodymium 3-sulpho-isonicotinate and blood coagulation. Brit, med. J 2: 1214-1216 1956;
• 17 Husom O. A one stage method for the assay of platelet factor 3. Scand. J. clin. Lab. Invest 13: 609-618 1961;
• 18 Hyman G, Paldino R, Bernick S. Thorotrast which does not block the RES. R. E. S. Bull 1: 81 1955;
• 19 Häusler H, Vogel L. Über Met all Wirkungen. IV. Mitteilung Weiteres über die Beeinflussung der Blutgerinnung durch Metalle. Biochem. Z 287: 405-410 1936;
• 20 Lundblad R. L, Davie E. W. The activation of Antihemophilic Factor (Factor VIII) by activated Christmas Factor (activated Factor IX). Biochemistry 3: 1720-1725 1964;
• 21 Rapaport S. I, Schiffman S, Patch M. J, Ames S. B. The importance of activation of antihemophilic globulin and proaccelerin by traces of thrombin in the generation of intrinsic pro-thrombinase activity. Blood 21: 221-236 1963;
• 22 Rapaport S. I, Schiffman S, Patch M. J, Ware A. G. A simple, specific one-stage assay for the plasma thromboplastin antecedent activity. J. Lab. clin. Med 57: 771-780 1961;
• 23 Ratnoff O. D, Davie E. W. The activation of Christmas Factor (Factor IX) by activated plasma thromboplastin antecedent (activated Factor XI). Biochemistry 1: 677-685 1962;
• 24 Schiffman S, Rapaport S. I, Patch M. J. The identification and synthesis of activated plasma thromboplastin component (PTC). Blood 22: 733-749 1963;
• 25 Schiffman S, Rapaport S. I, Patch M. J. Starch block electrophoresis of plasma and serum clotting factors. Separation of activated PTC (PTC). Blood 25: 724-735 1965;
• 26 Slätis P. The synthesis of prothrombin and proconvertin in the retículo-endothelial system. Scand. J. clin. Lab. Invest 10 (Suppl. 33) 83 1958;
• 27 Soulier J. P, Weilland G. Données nouvelles concernant l’action anticoagulante d’un sel de néodyme. Rev. Hémat 11: 265-278 1965;
• 28 Stormorken H. The preparation of proaccelerin deficient (parahemophilia) plasma for the assay of proaccelerin. Scand. J. clin. Lab. Invest 9: 273-276 1957;
• 29 Stormorken H, Lund-Riise Ä, Rörvik T. O. Platelet adhesiveness to glass beads: methodological investigations using automatic platelet counting. Scand. J. clin. Lab. Invest 17 (Suppl. 84) 183-194 1965;
• 30 Voss D. Untersuchungen zur Gerinnsel-retraktion. Proc. VIIth Int. Congr. Soc. Hemat., Rome 1957