Metabolic Formation of a Prothrombin Derivative^[*]

Summary

The administration of coumadin to dogs on consecutive days was followed by the simultaneous decrease in prothrombin and autoprothrombin III (F-X) concentration. The decline lasted 4 days. Prethrombin concentration increased. Purified prothrombin complex was infused, while the anticoagulant was still blocking synthesis. This restored the original concentration of prothrombin and autoprothrombin III. Each one of these disappeared in one day while prethrombin concentration temporarily increased and then also declined. Infused prethrombin was cleared in less than 1 day. Human prothrombin complex was also infused intravenously with the same results. Similar results were found with the use of rabbits. A derivative of prothrombin, which is not detected with the two-stage analytical reagents, is normally in plasma and is derived from the prothrombin in the plasma which is responsive to the two-stage analytical reagents. After inhibiting the synthesis of prothrombin and autoprothrombin III, these disappeared far more slowly from plasma than the purified prothrombin and autoprothrombin III which was infused.

^*) This work was supported by a research grant HE-05141 from the National Institutes of Health, U.S. Public Health Service.

^**) Present Address: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.

^***) Present Address: Department of Medicine, Justu Liebig-Universitat, Giessen, Germany.

• References

• 1 Alkjaersig N, Seegers W. H. Formation of prothrombin from autoprothrombin by means of liver mitochondria. Amer. J. Physiol 183: 111 1955;
• 2 Barnhart M. I. Partial activation of prothrombin and generation of prothrombin-R with cathepsin. Amer. J. Physiol 198: 899 1960;
• 3 Barnhart M. I, Hollatz R. G. Intracellular distribution of prothrombin regenerating capacity. Thrombos. Diathes. haemorrh. (Stuttg) 03: 355 1959;
• 4 Cho M. H, Seegers W. H. Prothrombin activation cycle. Proc. Soc. exp. Biol. (N.Y) 97: 642 1958;
• 5 Josso F, Lavergne J. M, Gouault M, Prou-Wartelle O, Soulier J. P. Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps anti-facteur II. Le facteur II chez les sujets traités par les antagonistes de la vitamine K. Thrombos. Diathes. haemorrh. (Stuttg) 20: 88 1968;
• 6 Marciniak E, Seegers W. H. Experiments with prothrombin, prethrombin, autoprothrombin III, and plasmas with prothrombin related deficiencies. New Ist. Contr. clin. Sci 08: 117 1965;
• 7 McClaughry R. I, Andrews E. B, Seegers W. H. Changes in the reactivity of purified prothrombin after freeze drying. Proc. Soc. exp. Biol. (N.Y) 75: 252 1950;
• 8 McGinty D. A, Seegers W. H, Pfeiffer G. C, Loew E. R. Plasma prothrombin concentration in dogs given 3,3’-methylenebis (4-hydroxycoumarin) and purified beef prothrombin. Science 96: 540 1942;
• 9 Mertz E. T, Seegers W. H, Smith H. P. Inactivation of prothrombin by purified thrombin solutions. Proc. Soc. exp. Biol. (N.Y) 41: 657 1939;
• 10 Müller-Berghaus G, Seegers W. H. Some effects of purified autoprothrombin C in blood clotting. Thrombos. Diathes. haemorrh. (Stuttg) 12: 707 1966;
• 11 Prou-Wartelle O, Soulier J. P. Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps anti-facteur II. II. Modifications du facteur II par passage au travers de filtres d’amiante (asbestos). Thrombos. Diathes. haemorrh. (Stuttg) 20: 99 1968;
• 12 Reno R. S, Seegers W. H. Two-stage procedure for the quantitative determination of autoprothrombin III concentration and some applications. Thrombos. Diathes. haemorrh. (Stuttg) 18: 198 1967;
• 13 Seegers W. H. Multiple protein interactions as exhibited by the blood clotting mechanism. J. Physical and Colloid Chem 51: 198 1947;
• 14 Seegers W. H. Coagulation of the blood. Harvey Lect. 47. 180 (1951-52).
• 15 Seegers W. H. The purification of prothrombin. Rec. Chem. Progr 13: 143 1952;
• 16 Seegers W. H, Andrews E. B, McGlaughry R. I. Formation of prothrombin derivatives from purified prothrombin. Amer. J. Physiol 164: 722 1951;
• 17 Seegers W. H, Kagami M. The separation of autoprothrombin I_c from bovine prothrombin preparations. Canad. J. Biochem 42: 1249 1964;
• 18 Seegers W. H, Loomis E. G. Prothrombin and fibrinolysin. Science 104: 461 1946;
• 19 Seegers W. H, Marciniak E. Autoprothrombin C in irregular blood clotting. Thrombos. Diathes. haemorrh. (Stuttg) 08: 1 1962;
• 20 Seegers W. H, Marciniak E, Kipfer R. K, Yasunaga K. Isolation and some properties of prethrombin and autoprothrombin III. Arch. Biochem 121: 372 1967;
• 21 Seegers W. H, Murano G, McCoy L. Structural changes in prothrombin during activation: A theory. Thrombos. Diathes. haemorrh. (Stuttg) 23: 26 1970;
• 22 Shapiro S. S, Martinez J. Human prothrombin metabolism in normal man and in hypocoagulable subjects. J. clin. Invest 48: 1292 1969;
• 23 Soulier J. P, Halle L, Prou-Wartelle O. Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylocoagulase et d’anticorps anti-facteur II. III. Modifications du facteur II (prothrombine humaine) en solution concentrée de citrate de soude ou de sulfate d’ammonium. Thrombos. Diathes. haemorrh. (Stuttg) 20: 121 1968;
• 24 Ware A. G, Seegers W. H. Studies on prothrombin: Purification, inactivation with thrombin, and activation with thromboplastin and calcium. J. biol. Chem 174: 565 1948;
• 25 Ware A. G, Seegers W. H. Two-stage procedure for the quantitative determination of prothrombin concentration. Amer. J. clin. Path 19: 471 1949;