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Thromb Haemost 1987; 57(03): 273-277
DOI: 10.1055/s-0038-1651115
Original Article
Schattauer GmbH Stuttgart

Vitamin K-Dependent Blood Clotting Changes in Female Rats Treated with Oestrogens

J E Hart
The Division of Pharmacology and Toxicology, Department of Biochemistry, University of Surrey, Guildford, UK
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Publication History

Received 20 June 1986

Accepted after revision 16 February 1987

Publication Date:
06 July 2018 (online)

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Summary

Hexoestrol, diethylstilboestrol and ethinyloestradiol administered orally at a dose of 60 mg/kg/day to groups of five rats caused decreases in vitamin K-dependent blood clotting as measured by the Thrombotest reaction. These changes were self-limiting over a twenty-day study period and were not associated with external signs of bleeding. Pretreatment with testosterone and vitamin K1 did not significantly affect the clotting changes, but the antioestrogen clomiphene citrate exacerbated these, in several cases to lethal effect. Death was associated with haemorrhage. Hexoestrol-treated rats receiving clomiphene citrate in a sub-experiment did not show the increase in liver weight seen in animals given hexoestrol alone. In another sub-experiment, the level of clotting factor VII activity in the plasma of rats receiving hexoestrol at 60 mg/kg/day for four days was shown to be about half that of controls. There was probably no abnormal clotting inhibitor activity. It was deduced that the reduction in factor VII activity was more likely to be due to a decrease in synthesis as a result of liver dysfunction than changes in vitamin K availability. Clomiphene citrate may exacerbate the liver-dependent clotting disorders induced by oestrogens by preventing an adaptive increase in liver mass. It is concluded that the rat is a poor model species for investigating the blood clotting disorders seen in humans treated with oestrogens.

Keywords

Oestrogens - Rat - Vitamin K - Liver - Blood clotting
 

  • References

  • 1 Adlercreutz H, Tenhunen R. Some aspects of the interaction between natural and synthetic female sex hormones and the liver. Am J Med 1979; 49: 630-648
    PubMedSearch in Google Scholar
  • 2 Austen D EG, Rhymes IL. A Laboratory Manual of Blood Coagulation. Blackwell Scientific Publications; Oxford and Edinburgh: 1975
  • 3 Beller FK, Ebert C. Effects of oral contraceptives on blood coagulation. A review. Obstet Gynecol Sur 1985; 40: 425-436
    CrossrefPubMedSearch in Google Scholar
  • 4 Bottiger LE, Boman G, Eklund G, Westerholm B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; 1 8178 1097-1101
    PubMedSearch in Google Scholar
  • 5 Culling C FA. Handbook of Histopathological and Histochemical Techniques. 3rd ed.. Butterworths; London: 1974
  • 6 Dodds WJ, Packham MA, Rowsell HC, Mustard JF. Factor VII survival and turnover in dogs. Am J Physiol 1967; 213: 36-42
    PubMedSearch in Google Scholar
  • 7 Frieden EH. Chemical Endocrinology. Academic Press; New York: 1976
  • 8 Fujii M, Yasunaga K, Uchino H. Correlation analysis of relationships between vitamin-K-dependent clotting factors and effective hepatic blood flow, albumin and other liver function tests. Haemostasis 1980; 9: 9-14
    PubMedSearch in Google Scholar
  • 9 Gallop PM, Lian JB, Hauschka PV. Carboxylated calcium-binding proteins and vitamin K. New Engl J Med 1980; 302: 1460-1466
    CrossrefPubMedSearch in Google Scholar
  • 10 Hall DE. Blood Coagulation and Its Disorders in the Dog. Bailliere Tindall; London: 1972
  • 11 Hart JE, Loscombe SM, Hall DE, Parke DV. The effect of oestrogens on blood clotting in the rat. Thromb Haemostas 1979; 42: 1069-1070
    PubMedSearch in Google Scholar
  • 12 Hart JE. Comparative Aspects of Oestrogen Toxicity, PhD Thesis. University of Surrey; Guildford: 1981
  • 13 Hart JE. Hepatotoxicity of the synthetic oestrogen hexoestrol in the female rat. Arch Toxicol 1986; 59: 216-220
    CrossrefPubMedSearch in Google Scholar
  • 14 Hellemans J, Vorlat M, Verstraete M. Survival time of prothrombin and Factors VII, IX and X after completely synthesis blocking doses of coumarin derivatives. Br J Haematol 1963; 9: 506-512
    CrossrefPubMedSearch in Google Scholar
  • 15 Heywood R, Wadsworth PF. Experimental toxicology of estrogens. Pharmacol Ther 1980; 8: 125-142
    CrossrefPubMedSearch in Google Scholar
  • 16 Johnson BC, Mameesh MS, Metta VC. Vitamin K nutrition and irradiation sterilization. Federation Proceedings 1959; 19: 1038-1044
    PubMedSearch in Google Scholar
  • 17 Jolly DW, Kadis BM, Nelson TE. Estrogen and prothrombin synthesis. The prothrombinogenic action of estrogen. Biochem Biophys Res Commun 1977; 74: 41-49
    CrossrefPubMedSearch in Google Scholar
  • 18 Meade TW. Oral contraceptives, clotting factors, and thrombosis. Am J Obstet Gynecol 1982; 142: 758-761
    CrossrefPubMedSearch in Google Scholar
  • 19 Mellette SJ. Vitamin K and estrogenic hormones. Am J Clin Nutr 1961; 9: 109-116
    CrossrefPubMedSearch in Google Scholar
  • 20 Metta VC, Mameesh MS, Johnson BC. Vitamin K deficiency in rats induced by the feeding of irradiated beef. J Nutr 1959; 69: 18-22
    CrossrefPubMedSearch in Google Scholar
  • 21 Nishino Y. Hormonal control of the prothrombin synthesis in rat liver microsomes, with special reference to the role of estradiol, testosterone and prolactin. Arch Toxicol [Suppl] 1979; 2: 397-402
    PubMedSearch in Google Scholar