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Thromb Haemost 1992; 68(04): 392-395
DOI: 10.1055/s-0038-1646283
Original Article
Schattauer GmbH Stuttgart

Coagulation Activation Following Estrogen Administration to Postmenopausal Women

Yehezkel G Caine
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Kenneth A Bauer
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Samad Barzegar
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Hugo ten Cate
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Frank M Sacks
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Brian W Walsh
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Isaac Schiff
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
,
Robert D Rosenberg
The Department of Medicine, Beth Israel Hospital and Brockton-West Roxbury Department of Veterans Affairs Medical Center; Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston; and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
› Author Affiliations
Further Information

Publication History

Received 19 November 1991

Accepted after revision 04 May 1992

Publication Date:
04 July 2018 (online)

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Summary

We investigated coagulation system activation following estrogen treatment in 29 healthy postmenopausal women. Study participants received conjugated estrogens at 0.625 and 1.25 mg per day, and placebo for 3-month periods in a randomized crossover protocol. Blood samples were obtained on two consecutive days at the end of each treatment period for immunoassays of F1+2 and fibrinopeptide A (FPA), markers of factor Xa action on prothrombin and thrombin action on fibrinogen in vivo, respectively. Treatment with estrogens at a dose of 0.625 or 1.25 mg resulted in significant increases in mean F1+2 levels of 40 and 98%, respectively, and in mean FPA levels of 37 and 71%, respectively. The measurements of F1+2 were significantly higher in women receiving 1.25 mg of estrogen than 0.625 mg. We also observed significant declines in the levels of antithrombin III and total protein S antigen. Immunologic levels of protein C increased modestly at only the 1.25 mg estrogen dose level. These data indicate that low doses of oral estrogens (≤1.25 mg per day) frequently increase the amount of thrombin generated in vivo. Our observations may help to explain the increased thrombotic risk that has been observed with higher doses of this medication (≥2.5 mg).

 

  • REFERENCES

  • 1 Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2: 199-205
    CrossrefPubMedSearch in Google Scholar
  • 2 The Boston Collaborative Drug Surveillance Program Oral contraceptives and venous thromboembolic disease, surgically confirmed gall-bladder disease, and breast tumours. Lancet 1973; 1: 1399-1404
    PubMedSearch in Google Scholar
  • 3 Wessler S, Gitel SN. Thrombotic complications of oral contraceptives. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice.. Colman RW, Hirsh J, Marder VJ, Salzman EW. (eds) JB Lippincott, Philadelphia, PA: 1987. pp 1158-1164
    Search in Google Scholar
  • 4 Stolley PD, Tonascia JA, Tockman MS, Sartwell PE, Rutledge AH, Jacobs MP. Thrombosis with low-estrogen oral contraceptives. Am J Epidemiol 1975; 102: 197-208
    CrossrefPubMedSearch in Google Scholar
  • 5 Bottiger LE, Boman G, Eklund G, Westerholm B. Oral contraceptives and thromboembolic disease; effects of lowering oestrogen content. Lancet 1980; 1: 1097-1101
    PubMedSearch in Google Scholar
  • 6 The Coronary Drug Project Research Group The coronary drug project. Initial findings leading to modification of its research protocol. JAMA 1970; 214: 1303-1313
    CrossrefPubMedSearch in Google Scholar
  • 7 The Coronary Drug Project Research Group The coronary drug project. Findings leading to discontinuation of the 2.5-mg/day estrogen group. JAMA 1973; 226: 652-657
    CrossrefPubMedSearch in Google Scholar
  • 8 The Boston Collaborative Drug Surveillance Program Surgically confirmed gallbladder disease, venous thromboembolism and breast tumors in relation to postmenopausal estrogen therapy. N Engl J Med 1974; 290: 15-19
    CrossrefPubMedSearch in Google Scholar
  • 9 Devor M, Barrett-Connor E, Renvall M, Feigal Jr D, Ramsdell J. Estrogen replacement therapy and the risk of venous thrombosis. Am J Med 1992; 92: 275-285
    CrossrefPubMedSearch in Google Scholar
  • 10 Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985; 313: 1044-1049
    CrossrefPubMedSearch in Google Scholar
  • 11 Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses’ health study. N Engl J Med 1991; 325: 756-762
    CrossrefPubMedSearch in Google Scholar
  • 12 Bush TL, Cowan LD, Barrett-Connor E, Cirqui MH, Karon JM, Wallace RB. Estrogen use and all-cause mortality: Preliminary results from the Lipid Research Clinics Program follow-up study. JAMA 1983; 249: 903-906
    CrossrefPubMedSearch in Google Scholar
  • 13 Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196-1204
    CrossrefPubMedSearch in Google Scholar
  • 14 Lau HK, Rosenberg JS, Beeler DL, Rosenberg RD. The isolation and characterization of a specific antibody population directed against the prothrombin activation fragments F2 and F1+2 . J Biol Chem. 1979; 254: 8751-8761
    PubMedSearch in Google Scholar
  • 15 Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies of the prothrombin activation pathway utilizing radioimmunoassays for the F2/F1+2 fragment and thrombin-antithrombin complex. Blood. 1982; 59: 1086-1097
    PubMedSearch in Google Scholar
  • 16 Bauer KA, Kass BL, Beeler DL, Rosenberg RD. Detection of protein C activation in humans. J Clin Invest 1984; 74: 2033-2041
    CrossrefPubMedSearch in Google Scholar
  • 17 Bauer KA, Ashenhurst JB, Chediak J, Rosenberg RD. Antithrombin “Chicago”: A functionally abnormal molecule with increased heparin affinity causing familial thrombophilia. Blood 1983; 62: 1242-1250
    PubMedSearch in Google Scholar
  • 18 Nossel HL, Yudelman I, Canfield RE, Butler Jr VP, Spanondis K, Wilner GD, Qureshi GD. Measurement of fibrinopeptide A in human blood. J Clin Invest 1974; 54: 43-53
    CrossrefPubMedSearch in Google Scholar
  • 19 Nossel HL, Ti M, Kaplan KL, Spanondis K, Soland T, Butler Jr VP. The generation of fibrinopeptide A in clinical blood samples: Evidence for thrombin activity. J Clin Invest 1976; 58: 1136-1144
    CrossrefPubMedSearch in Google Scholar
  • 20 Bauer KA, Rosenberg RD. Thrombin generation in acute promyelocytic leukemia. Blood 1984; 64: 791-796
    PubMedSearch in Google Scholar
  • 21 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-1426
    PubMedSearch in Google Scholar
  • 22 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De Stefano V, Palareti G, Manotti C, Mazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. Thromb Haemostas 1992; 67: 200-202
    PubMedSearch in Google Scholar
  • 23 Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging-associated changes in indices of thrombin generation and protein C activation in humans. Normative aging study. J Clin Invest 1987; 80: 1527-1534
    CrossrefPubMedSearch in Google Scholar
  • 24 Alkjaersig N, Fletcher AP, De Ziegler D, Steingold KA, Meldrum DR, Judd HL. Blood coagulation in postmenopausal women given estrogen treatment: Comparison of transdermal and oral administration. J Lab Clin Med 1988; 111: 224-228
    PubMedSearch in Google Scholar
  • 25 Gitel SN, Wessler S. Do natural estrogens pose an increased risk of thrombosis in postmenopausal women? Thromb Res. 1978; 13: 279-283
    PubMedSearch in Google Scholar
  • 26 Notelovitz M, Kitchens CS, Ware MD. Coagulation and fibrinolysis in estrogen-treated surgically menopausal women. Obstet Gynecol 1984; 63: 621-624
    PubMedSearch in Google Scholar
  • 27 Varma TR, Patel Ph, Rosenberg D. Effect of hormone replacement therapy on anti-thrombin III activity in post menopausal women. Int J Gynaecol Obstet 1986; 24: 69-73
    CrossrefPubMedSearch in Google Scholar
  • 28 Huisveld IA, Hospers JEH, Meijers JCM, Starkenburg AE, Erich WBM, Bouma BN. Oral contraceptives reduce total protein S, but not free protein S. Thromb Res 1987; 45: 109-114
    CrossrefPubMedSearch in Google Scholar
  • 29 Malm J, Laurell M, Dahlbäck B. Changes in the plasma levels of vitamin-K dependent proteins C and S and of C4b-binding protein during pregnancy and oral contraception. Br J Haematol 1988; 68: 437-443
    CrossrefPubMedSearch in Google Scholar
  • 30 Wilson PW, Garrison RJ, Castelli WP. Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. N Engl J Med 1985; 313: 1038-1043
    CrossrefPubMedSearch in Google Scholar