The Influence of the Thyroid Function on the Metabolic Rate of Prothrombin, Factor VII, and Factor X in the Rat

Allan T. van Oosterom; Herman Mattie; Wim Th Hermens; Jan J. Veltkamp

doi:10.1055/s-0038-1647959

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1976; 35(03): 607-619
DOI: 10.1055/s-0038-1647959

Original Article

Schattauer GmbH

The Influence of the Thyroid Function on the Metabolic Rate of Prothrombin, Factor VII, and Factor X in the Rat

Allan T. van Oosterom

¹Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.

,

Herman Mattie

¹Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.

,

Wim Th Hermens

¹Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.

,

Jan J. Veltkamp

¹Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.

› Institutsangaben

Abstract

Summary

The influence of the thyroid function on the metabolic rate of prothrombin, factor VII, and X was studied in the rat. Disappearance rates of the three coagulation factors were measured after synthesis had been blocked with appropriate doses of warfarin, and reappearance rates were assessed upon induction of synthesis by high doses of vitamin K₁ injected into rats displaying coumarin induced hypocoagulability.

No statistically significant difference in the disappearance and production rates of any of the factors could be found between normal euthyroid rats and thyroxin-treated hypothyroid rats proven to be euthyroid. The differences between the two euthyroid groups and the hypothyroid group were highly significant, however: hypothyroidism results in an approximately 50% decrease of the metabolic rates of the three coagulation factors under study.

The reappearance of the three factors, under euthyroid as well as hypothyroid conditions, showed a biphasic pattern: in the first two hours after vitamin K₁ administration to warfarin treated rats, a rapid reappearance was observed, to the same extent for all three factors, in hypo- as well as euthyroid rats. This finding suggests that in vitamin K₁ deficiency an intracellular accumulation of precursor proteins (PIVKAs) occurs, which after rapid conversion into biologically active coagulation factors by vitamin K₁ are shed into circulation.

The subsequent phase of reappearance is much slower and reflects the synthesis rate of coagulation enzymes. It is characteristic for each factor and clearly slower in hypothyroid rats than in euthyroid rats. From this an influence of thyroid function on the synthesis rate of the protein moiety of coagulation factors can be inferred.

An apparent difference between disappearance and reappearance rate of the coagulation factors in the plasma, particularly pronounced for factors VII and X in euthyroid rats, could theoretically be explained as the consequence of the model used for derivation of these rates.

Volltext

Referenzen

References
1 Caldwell P. T, Ren P, Bell R. G. 1974; Warfarin and metabolism of vitamin K₁ . Biochemical Pharmacology 23: 3353.
2 Gullen M. J, Doherty G. J, Iingbar S. H. 1973; The effect of hypothyroidism and thyrotoxicosis on thyroxin metabolism in the rat. Endocrinology 92: 1028.
3 Dyggve H, Lund E. 1954; Micromethod for the quantitative determination of plasma prothrombin and proconvertin. Acta Medica Scandinavica 150: 207.
4 Egeberg O. 1963; Influence of thyroid function on the blood clotting system. Scandinavian Journal of Clinical and Laboratory Investigation 15: 1.
5 Esch B. v. d. 1960 De werking van coumarine praeparatenop de bloedstollingbij hoge initiēle dosering. Verslag van de der de confer ende van de Thrombosediensten van het Nederlandsche Roode K ruis. p. 26.
6 Frick P. G. 1958; Studies on the turnover rate of stable prothrombin conversion factor in man. Acta Haematologica 19: 20.
7 Geertzen H. G. M, Ouderaa F. J. G. v. d, Kassenaar A. A. H. 1973; Isolation and metabolism of male sex-dependent urinary protein from rats. Acta Endocrinologica 72: 197.
8 Goodnight S. H, Feinstein D. I, Østerud B, Rapaport S. I. 1971; Factor VII antibody-neutralizing material in hereditary and acquired factor VII deficiency. Blood 38: 1.
9 Hellemans J, Vorlat M, Verstraete M. 1963; Survival time of prothrombin and factors VII, IX, and X after completely synthesis blocking doses of coumarin derivatives. British Journal of Haematology 9: 506.
10 Hemker H. C, Swart A. C. W, Alink A. J. M. 1972; Artificial reagents for factor VII and factor X, a computer programme for obtaining reference tables for one-stage determination in the extrinsic system. Thrombosis et Diathesis Haemorrhagica 27: 205.
11 Hemker H. C, Veltkamp J. J, Hensen A, Loeliger E. A. 1963; Nature of prothrombin biosynthesis: preprothrombinaemia in vitamin K deficiency. Nature 200: 589.
12 Hemker H. C, Veltkamp J. J, Loeliger E. A. 1968; Kinetic aspects of the interaction of blood clotting enzymes. III. Demonstration of an inhibitor of prothrombin conversion in vitamin K deficiency. Thrombosis et Diathesis Haemorrhagica 19: 346.
13 Hjort P. F, Egeberg O, Mikkelsen S. 1961; Turnover of prothrombin, factor VII and factor IX in a patient with hemophilia A. Scandinavian Journal of Clinical and Laboratory Investigation 13: 668.
14 Ikkala E, Eisalo A, Heinivaara O. 1962; Plasma coagulation factors in thyrotoxicosis. Acta Endocrinologica 40: 307.
15 Johnson H. V, Boyd C, Martinovic J, Valkovich G, Connor Johnson B. 1972; A new blood protein which increases with vitamin K deficiency. Archives of Biochemistry and Biophysics 148: 431.
16 Josso F, Lavergne J. M, Gounault M, Prou-Wartelle O, Soulier J. P. 1968; Différents états moléculaires du facteur II (prothrombine). Leur étude à l’aide de la staphylo coagulase et d’an-ticorps anti-facteur II. Thrombosis et Diathesis Haemorrhagica 20: 88.
17 Kekki M. 1964; Serum protein turnover in hypo- and hyperthyroidism. Acta Endocrinologica (Kbn) 46 suppl. 91 137.
18 Koller F, Loeliger E. A, Duckert F. 1951; Experiments on a new clotting factor. Acta Haematologica 6: 1.
19 Larrieu M. J, Meyer D. 1970; Abnormal factor IX during anticoagulant treatment. Lancet II: 1085.
20 Larsen P. R. 1972; Direct radioimmunoassay of triio do thyroxine in human serum. Journal of Clinical Investigation 51: 1939.
21 Loeliger E. A, Esch B. van der, Mattern M. J, Hemker H. C. 1964; The biological disappearance rate of prothrombin, factor VII, IX and X from plasma in hypothyroidism, hyperthyroidism, and during fever. Thrombosis et Diathesis Haemorrhagica 10: 267.
22 Lowenthal J, Fisher L. M. 1957; The effect of thyroid function on the prothrombin time response to warfarin in rats. Experienta 13: 253.
23 McIntosh T. J, Wilson W. R, Waters L, Fouts J. R. 1971; Response to warfarin in hypothyroid rats. European Journal of Pharmacology 14: 176.
24 Meer J. van der, Loeliger E. A, Hemker H. C. 1968. Pharmacological aspects of vitamin K₁ . Thrombosis et Diathesis Haemorrhagica; suppl. 29.
25 Murphy B. E. P, Jachan C. 1965; The determination of thyroxine by competitive protein-binding analysis employing an anion-exchange resin and radio-thyroxin. Journal of Laboratory and Clinical Medicine 66: 161.
26 Oosterom A. T. van. 1974 Unpublished observations..
27 Oosterom A. T. van, Veltkamp J. J. 1974; Control of anticoagulation in rats. Experientia 30: 953.
28 Oosterom A. T. van, Zuidervaart W, Veltkamp J. J. 1974; Sampling of rat blood for haemostasis studies. Haemostasis 3: 296.
29 Oppenheimer J. H. 1974 a Personal communication..
30 Oppenheimer J. H, Schwartz H. L, Koerner D, Surks M. I. 1974; b Limited binding capacity sites for L-triio do thyronine in rat liver nuclei. Journal of Clinical Investigation 53: 768.
31 O’Reilly R. A, Aggeler P. M. 1970; Determinants of the response to oral anticoagulant drugs in man. Pharmacological Reviews 22: 35.
32 O’Reilly R. A, Aggeler P. M, Leong L. S. 1963; Studies on the coumarin anticoagulant drugs: the pharmacodynamics of warfarin in man. Journal of Clinical Investigation 42: 1542.
33 Owren P. A, Aas K. 1951; The control of dicumarol therapy and the quantitative determination of prothrombin and proconvertin. Scandinavian Journal of Clinical and Laboratory Investigation 3: 201.
34 Pereira M, Couri D. 1971; Studies on the site of action of dicumarol on prothrombin biosynthesis. Biochimica et Biophysica Acta 237: 348.
35 Prentice C. R. M, McNicol G. P, Douglas A. S. 1970; Studies on the anticoagulant action of aprotinin (Trasylol). Thrombosis et Diathesis Haemorrhagica 24: 265.
36 Prydz H, Giadhaug A. 1971; Factor X, immunological studies. Thrombosis et Diathesis Haemorrhagica 25: 157.
37 Pyörälä K. 1965 Determinants of the clotting factor response to warfarin in the rat. Annales Medicinae Experimentalis et Biologiae Fenniae 43. suppl. 3.
38 Pyörälä K. 1968; Sex difference in the clotting factor response to warfarin and in the rate of warfarin metabolism in the rat. Annales Medicinae Experimentalis et Biologiae Fenniae 46: 23.
39 Pyörälä K. 1970; Genetic control of the response to coumarin anticoagulants in the rat. Humangenetik 9: 265.
40 Reekers P. P. M, Lindhout M. J, Kop-Klaassen B. H. M, Hemker H. C. 1973; Demonstration of three anomalous plasma proteins induced by a vitamin K antagonist. Biochimica et Biophysica Acta 317: 559.
41 Rez G, Prydz H. 1971; The mode of action of warfarin. An intracellular precursor for factor VII in rat liver. Biochemica et Biophysica Acta 244: 495.
42 Schieck A, Habermann E, Kornalik F. 1972; The prothrombin-activating principle from Echis carinatus venom. II. Coagulation studies in vitro and in vivo. Naunyn-Schmiedeberg’s Archiv für Pharmakologie 274: 7.
43 Shah D. V, Suttie J. W. 1971; Mechanism of action of vitamin K: evidence for the conversion of a precursor protein to prothrombin in the rat. Proceedings of the National Academy of Sciences of the United States of America 68: 1653.
44 Surks M. I, Koerner D, Dillman W, Oppenheimer J. H. 1973; Limited capacity binding sites for L-triiodothyronine (T3) in rat liver nuclei. Journal of Biological Chemistry 248: 7066.
45 Suttie J. W. 1970; The effect of cycloheximide administration on vitamin K-stimulated prothrombin formation. Archives of Biochemistry and Biophysics 141: 571.
46 Suttie J. W. 1973; Mechanism of action of vitamin K: Demonstration of a liver precursor of prothrombin. Science 179: 192.
47 Suttie J. W, Grant G. A, Shah D. V. 1974; Postribosomal function of vitamin K in prothrombin synthesis. Mayo Clinic Proceedings 49: 933.
48 Suttie J. W, Nelsestuen G. L, Esmon C. T, Shah D. V. 1973; Metabolism and control of prothrombin formation. Thrombosis et Diathesis Haemorrhagica 54: 37.
49 Veltkamp J. J, Muis H, Muller A. D, Hemker H. C, Loeliger E. A. 1971; Additional evidence for the existence of a precursor molecule of the prothrombin complex in oral anticoagulation. Thrombosis et Diathesis Haemorrhagica 25: 312.
50 Wagner J. G. 1971 Biopharmaceutics and relevant pharmacokinetics. Hamilton Ill. Drug Intelligence Publications.
51 Weintraub M, Breckenridge R. T, Griner P. F. 1973; The effects of dextrothyroxine on the kinetics of prothrombin activity: proposed mechanism of the potentiation of warfarin by D-thyroxine. Journal of Laboratory and Clinical Medicine 81: 273.
52 Zucker S, Cathey M. H, West B. 1970; Preparation of quality control specimens for coagulation. American Journal of Clinical Pathology 53: 924.