Download PDF
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
1   Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.
,
Herman Mattie
1   Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.
,
Wim Th Hermens
1   Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.
,
Jan J. Veltkamp
1   Haemostasis and Thrombosis Research Unit, Division of Haematology and Division of Clinical Pharmacology, Department of Internal Medicine, University Hospital, Leiden, The Netherlands.
› Author Affiliations
Further Information

Publication History

Received 10 July 1975

Accepted 01 September 1975

Publication Date:
02 July 2018 (online)

Also available at
    Permissions and Reprints

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.

 

  • References

  • 1 Caldwell P. T, Ren P, Bell R. G. 1974; Warfarin and metabolism of vitamin K1 . Biochemical Pharmacology 23: 3353.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 3 Dyggve H, Lund E. 1954; Micromethod for the quantitative determination of plasma prothrombin and proconvertin. Acta Medica Scandinavica 150: 207.
    PubMedGoogle Scholar
  • 4 Egeberg O. 1963; Influence of thyroid function on the blood clotting system. Scandinavian Journal of Clinical and Laboratory Investigation 15: 1.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 6 Frick P. G. 1958; Studies on the turnover rate of stable prothrombin conversion factor in man. Acta Haematologica 19: 20.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 14 Ikkala E, Eisalo A, Heinivaara O. 1962; Plasma coagulation factors in thyrotoxicosis. Acta Endocrinologica 40: 307.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 17 Kekki M. 1964; Serum protein turnover in hypo- and hyperthyroidism. Acta Endocrinologica (Kbn) 46 suppl. 91 137.
    PubMedGoogle Scholar
  • 18 Koller F, Loeliger E. A, Duckert F. 1951; Experiments on a new clotting factor. Acta Haematologica 6: 1.
    CrossrefPubMedGoogle Scholar
  • 19 Larrieu M. J, Meyer D. 1970; Abnormal factor IX during anticoagulant treatment. Lancet II: 1085.
    PubMedGoogle Scholar
  • 20 Larsen P. R. 1972; Direct radioimmunoassay of triio do thyroxine in human serum. Journal of Clinical Investigation 51: 1939.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 22 Lowenthal J, Fisher L. M. 1957; The effect of thyroid function on the prothrombin time response to warfarin in rats. Experienta 13: 253.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 24 Meer J. van der, Loeliger E. A, Hemker H. C. 1968. Pharmacological aspects of vitamin K1 . Thrombosis et Diathesis Haemorrhagica; suppl. 29.
    Google Scholar
  • 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.
    PubMedGoogle Scholar
  • 26 Oosterom A. T. van. 1974 Unpublished observations..
    PubMedGoogle Scholar
  • 27 Oosterom A. T. van, Veltkamp J. J. 1974; Control of anticoagulation in rats. Experientia 30: 953.
    CrossrefPubMedGoogle Scholar
  • 28 Oosterom A. T. van, Zuidervaart W, Veltkamp J. J. 1974; Sampling of rat blood for haemostasis studies. Haemostasis 3: 296.
    PubMedGoogle Scholar
  • 29 Oppenheimer J. H. 1974 a Personal communication..
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 31 O’Reilly R. A, Aggeler P. M. 1970; Determinants of the response to oral anticoagulant drugs in man. Pharmacological Reviews 22: 35.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 34 Pereira M, Couri D. 1971; Studies on the site of action of dicumarol on prothrombin biosynthesis. Biochimica et Biophysica Acta 237: 348.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 36 Prydz H, Giadhaug A. 1971; Factor X, immunological studies. Thrombosis et Diathesis Haemorrhagica 25: 157.
    PubMedGoogle Scholar
  • 37 Pyörälä K. 1965 Determinants of the clotting factor response to warfarin in the rat. Annales Medicinae Experimentalis et Biologiae Fenniae 43. suppl. 3.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 39 Pyörälä K. 1970; Genetic control of the response to coumarin anticoagulants in the rat. Humangenetik 9: 265.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 45 Suttie J. W. 1970; The effect of cycloheximide administration on vitamin K-stimulated prothrombin formation. Archives of Biochemistry and Biophysics 141: 571.
    CrossrefPubMedGoogle Scholar
  • 46 Suttie J. W. 1973; Mechanism of action of vitamin K: Demonstration of a liver precursor of prothrombin. Science 179: 192.
    CrossrefPubMedGoogle Scholar
  • 47 Suttie J. W, Grant G. A, Shah D. V. 1974; Postribosomal function of vitamin K in prothrombin synthesis. Mayo Clinic Proceedings 49: 933.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 50 Wagner J. G. 1971 Biopharmaceutics and relevant pharmacokinetics. Hamilton Ill. Drug Intelligence Publications.
    PubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 52 Zucker S, Cathey M. H, West B. 1970; Preparation of quality control specimens for coagulation. American Journal of Clinical Pathology 53: 924.
    CrossrefPubMedGoogle Scholar