Download PDF
Thromb Haemost 2000; 84(06): 968-972
DOI: 10.1055/s-0037-1614157
Review Article
Schattauer GmbH

Unopposed Estrogen Increases Total Plasma Factor VII, but not Active Factor VII

A Short-term Placebo-controlled Study in Healthy Postmenopausal Women
Gerdien W. de Valk-de Roo
1   From Department of Endocrinology, Research Institute for Endocrinology, Reproduction and Metabolism, The Netherlands
,
Coen D. A. Stehouwer
2   Department of Internal Medicine, Institute for Cardiovascular Research-Vrije Universiteit, University Hospital Vrije Universiteit Amsterdam, The Netherlands
,
Jef J. Emeis
3   Gaubius Laboratory, TNO-PG, Leiden, The Netherlands
,
Ans Nicolaas-Merkus
2   Department of Internal Medicine, Institute for Cardiovascular Research-Vrije Universiteit, University Hospital Vrije Universiteit Amsterdam, The Netherlands
,
Coen Netelenbos
2   Department of Internal Medicine, Institute for Cardiovascular Research-Vrije Universiteit, University Hospital Vrije Universiteit Amsterdam, The Netherlands
› Author AffiliationsWe are grateful to J.H. Morrissey, Oklahoma Medical Research Foundation, Oklahoma City, USA, for providing the truncated human tissue factor used in the assay for active FVII. Mrs. C. M. van den Hoogen, Gaubius Laboratory, TNO-PG, Leiden, we thank for the expert technical assistance; Edo Westerveen, and Bas Joenje, Department of Endocrinology, University Hospital Vrije Universiteit, Amsterdam, we thank for the expert assistance in the execution of the study.
Further Information

Publication History

Received 16 June 2000

Accepted after resubmission 24 July 2000

Publication Date:
13 December 2017 (online)

    Permissions and Reprints

Summary

Estrogen therapy may increase the risk of arterial thromboembolism, at least in the short term. In a randomized, double-blind and placebocontrolled study in 25 healthy postmenopausal women (52.5 ± 2.8 years), we therefore examined the short-term effect of unopposed estrogen on the fasting and fat-load-stimulated plasma levels of total factor VII versus active factor VII. Plasma total factor VII was measured by use of a chromogenic assay; plasma active FVII by a recently developed method using truncated tissue factor. As compared to placebo, 8 weeks of oral 17β-estradiol (2 mg daily) increased the mean fasting and postprandial plasma levels of total factor VII by 17 and 21% points, respectively (both P < 0.01), but did not affect the fasting and/or postprandial plasma levels of active factor VII (mean change both 0.05 ng/mL; P > 0.35). Furthermore, the change in the fasting level of total factor VII after therapy was not associated with the change in the fasting level of active factor VII (r = 0.27; P = 0.21). These findings argue against the idea that elevated levels of total factor VII underlie an increased risk of arterial thromboembolism in postmenopausal women using unopposed estrogen replacement.

Key words

Postmenopausal - estrogen - factor VII - postprandial
 

  • References

  • 1 Barret-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health 1998; 19: 55-72.
    CrossrefPubMedGoogle Scholar
  • 2 Hulley S, Grady D, Bush T. et al. for the Heart and Estrogen/progestin Replacement Study (HERS) Research group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605-13.
    CrossrefPubMedGoogle Scholar
  • 3 Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
    CrossrefPubMedGoogle Scholar
  • 4 Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone Jr MA. Interleukin-1 activation of vascular endothelium. Effects on procoagulant activity and leukocyte adhesion. Am J Pathol 1985; 121: 394-403.
    PubMedGoogle Scholar
  • 5 Rivers RP, Hathaway WE, Weston WL. The endotoxin-induced coagulant activity of human monocytes. Br J Haematol 1975; 30: 311-6.
    CrossrefPubMedGoogle Scholar
  • 6 Drake TA, Hannani K, Fei HH, Lavi S, Berliner JA. Minimally oxidized low-density lipoprotein induces tissue factor expression in cultured human endothelial cells. Am J Pathol 1991; 138: 601-7.
    PubMedGoogle Scholar
  • 7 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WRS, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; 02: 533-7.
    PubMedGoogle Scholar
  • 8 Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol 1997; 17: 1539-44.
    CrossrefPubMedGoogle Scholar
  • 9 Folsom AR, Wu KK, Rosamond WD, Sharrett AR, Chambless LE. Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 1997; 96: 1102-8.
    CrossrefPubMedGoogle Scholar
  • 10 Scarabin PY, Vissac AM, Kirzin JM, Bourgeat P, Amiral J, Agher R, Guize L. Population correlates of coagulation factor VII. Importance of age, sex, and menopausal status as determinants of activated factor VII. Arterioscler Thromb Vasc Biol 1996; 16: 1170-6.
    CrossrefPubMedGoogle Scholar
  • 11 Wright D, Poller L, Thomson JM, Burrows GE, Hirst CF, Sidebotham A. The effect of hormone replacement therapy of the age-related rise of factor VIIc, and its activity state. Thromb Res 1997; 85: 455-64.
    CrossrefPubMedGoogle Scholar
  • 12 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK, Szklo M. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Eng J Med 1993; 328: 1069-75.
    CrossrefPubMedGoogle Scholar
  • 13 Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 1993; 81: 734-44.
    PubMedGoogle Scholar
  • 14 Mennen L, de Maat M, Meijer G, Zock P, Grobbee D, Kok F, Kluft C, Schouten E. Factor VIIa response to a fat-rich meal does not depend on fatty acid composition. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1998; 18: 599-603.
    CrossrefPubMedGoogle Scholar
  • 15 Kapur R, Hoffman CJ, Bhushan V, Haltin MB. Postprandial elevation of activated factor VII in young adults. Arterioscler Thromb Vasc Biol 1996; 16: 1327-32.
    CrossrefPubMedGoogle Scholar
  • 16 Silveira A, Karpe F, Johnsson H, Bauer KA, Hamsten A. In vivo demonstration in humans that large postprandial triglyceride-rich lipoproteins activate coagulation factor VII through the intrinsic coagulation pathway. Arterioscler Thromb Vasc Biol 1996; 16: 1333-9.
    CrossrefPubMedGoogle Scholar
  • 17 Miller GJ, Martin JC, Mitropoulos KA, Esnouf MP, Cooper JA, Morrissey JH, Howarth DJ, Tuddenham EG. Activation of factor VII during alimentary lipemia occurs in healthy adults and patients with congenital factor XII or factor XI deficiency, but not in patients with factor IX deficiency. Blood 1996; 87: 4187-96.
    PubMedGoogle Scholar
  • 18 Miller GJ. Postprandial lipaemia and haemostatic factors. Atherosclerosis 1998; 141: S47-S51.
    CrossrefPubMedGoogle Scholar
  • 19 Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE, Willett WC, Hennekens CH. Prospective study of exogeneous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983-7.
    CrossrefPubMedGoogle Scholar
  • 20 Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348: 977-80.
    CrossrefPubMedGoogle Scholar
  • 21 Coronary Drug Project Research Group. Coronary Drug Project Research Group - Initial findings leading to modifications of its research protocol. JAMA 1970; 214: 1303-13.
    CrossrefPubMedGoogle Scholar
  • 22 Scarabin PY, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol 1997; 17: 3071-8.
    CrossrefPubMedGoogle Scholar
  • 23 Lindoff C, Peterson F, Lecander I, Martinsson G, Astedt B. Transdermal estrogen replacement therapy: beneficial effects on hemostatic risk factors for cardiovascular disease. Maturitas 1996; 24: 43-50.
    CrossrefPubMedGoogle Scholar
  • 24 van Wersch JW, Ubachs JM, van den Ende A, van Enk A. The effect of two regimens of hormone replacement therapy on the haemostatic profile in postmenopausal women. Eur J Clin Chem Clin Biochem 1994; 32: 449-53.
    PubMedGoogle Scholar
  • 25 The writing group for the estradiol clotting factors study. Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. Thromb Haemost 1996; 75: 476-80.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Sporrong T, Mattsson LA, Samsioe G, Stigendal L, Hellgren M. Haemostatic changes during continuous oestradiol-progestogen treatment of postmenopausal women. Br J Obstet Gynaecol 1990; 97: 939-44.
    CrossrefPubMedGoogle Scholar
  • 27 Kroon UB, Tengborn L, Rita H, Backstrom AC. The effects of transdermal oestradiol and oral progestogens on haemostasis variables. Br J Obstet Gynaecol 1997; 104: 32-7.
    CrossrefPubMedGoogle Scholar
  • 28 Medical Research Council’s General practice Research Framework. Randomised comparison of oestrogen versus oestrogen plus progestogen hormone replacement therapy in women with hysterectomy. BMJ 1996; 312: 473-8.
    CrossrefPubMedGoogle Scholar
  • 29 de Valk-de Roo GW, Stehouwer CDA, Meijer P, Mijatovic V, Kluft C, Kenemans P, Cohen F, Watts S, Netelenbos C. Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women: a 2-year, placebo-controlled study. Arterioscler Thromb Vasc Biol 1999; 19: 2993-3000.
    CrossrefPubMedGoogle Scholar
  • 30 Kroon UB, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables. Thromb Haemost 1994; 71: 420-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Lindberg UB, Crona N, Stigendal L, Teger-Nilsson AC, Silfverstolpe G. A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters. Thromb Haemost 1989; 61: 65-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Bernardi F, Arcieri P, Bertina RM, Chiarotti F, Corral J, Pinotti M, Prydz H, Samama M, Sandset PM, Strom R, Garcia VV, Mariani G. Contribution of factor VII genotype to activated FVII levels. Differences in genotype frequencies between northern and southern European populations. Arterioscler Thromb Vasc Biol 1997; 17: 2548-53.
    CrossrefPubMedGoogle Scholar
  • 33 Meilahn E, Ferrell R, Kiss J, Temple A, Green F, Humphries S, Kuller L. Genetic determination of coagulation factor VIIc levels among healthy middle-aged women. Thromb Haemost 1995; 73: 623-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Humphries SE, Lane A, Green FR, Cooper J, Miller GJ. Factor VII coagulant activity and antigen levels in healthy men are determined by interaction between factor VII genotype and plasma triglyceride concentration. Arterioscler Thromb 1994; 14: 193-8.
    CrossrefPubMedGoogle Scholar