Download PDF
Thromb Haemost 2001; 85(05): 775-781
DOI: 10.1055/s-0037-1615717
Review Article
Schattauer GmbH

The Effects of Hormone Replacement Therapy (HRT) on Hemostatic Variables in Women with Previous Venous Thromboembolism – Results from a Randomized, Double-Blind, Clinical Trial

Else Høibraaten
1   Department of Hematology, Hematological Research Laboratory, and Department of Gynecology, Ullevål University Hospital, Oslo, Norway
,
Erik Qvigstad
1   Department of Hematology, Hematological Research Laboratory, and Department of Gynecology, Ullevål University Hospital, Oslo, Norway
,
Trine Opstad Andersen
1   Department of Hematology, Hematological Research Laboratory, and Department of Gynecology, Ullevål University Hospital, Oslo, Norway
,
Marie-Christine Mowinckel
1   Department of Hematology, Hematological Research Laboratory, and Department of Gynecology, Ullevål University Hospital, Oslo, Norway
,
Per Morten Sandset
1   Department of Hematology, Hematological Research Laboratory, and Department of Gynecology, Ullevål University Hospital, Oslo, Norway
› Author Affiliations
Further Information

Publication History

Received 21 August 2000

Accepted after resubmission 14 December 2000

Publication Date:
11 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

In a recent randomized, double-blind, placebo-controlled trial of women with a history of venous thromboembolism (VTE), we found that hormone replacement therapy (HRT) was associated with an early excess risk of recurrent thrombosis. The aims of the present study were to characterize the effects of HRT on coagulation in these women to elucidate the mechanism(s) by which HRT increases the risk of thrombosis. The study comprised 140 women who were randomized to receive continuous treatment for 24 months with once daily 2 mg 17- -estradiol plus 1 mg norethisterone acetate (n = 71) or placebo (n = 69). HRT caused significant increases in prothrombin fragments 1+2, thrombin-antithrombin complex, and D-Dimer after 3 months, but these changes were less pronounced on prolonged treatment. The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis, but was similar in carriers and non-carriers of the factor V Leiden mutation. HRT had no effects on fibrinogen and factor VIII. Activated factor VII, but not factor VII antigen, decreased significantly on HRT as compared with placebo. The coagulation inhibitors antithrombin, protein C, and TFPI, but not protein S, all showed significant sustained decreases in the HRT group as compared with placebo. Antithrombin and protein C decreased by 8-12% on HRT, whereas TFPI activity decreased by 12-17% and TFPI free antigen by 29-30%. In multivariate analysis, only TFPI activity was a significant predictor for the increased activation of coagulation. We conclude that HRT was associated with early activation of coagulation, which corroborates the finding of an early risk of recurrent VTE. This activation may in part be explained by reduction in circulating anticoagulants.

Keywords

Hormone replacement therapy - venous thromboembolism - coagulation factors - coagulation inhibitors - activated coagulation
 

  • References

  • 1 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
  • 2 Grodstein F, Stampfer MJ, Goldhaber SZ, Manson JE, Colditz GA, Speizer FE. et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983-7.
    CrossrefPubMedGoogle Scholar
  • 3 Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of post-menopausal oestrogens. Lancet 1996; 348: 981-3.
    CrossrefPubMedGoogle Scholar
  • 4 Perez GS, Garcia Rodriguez LA, Castellsague J, Duque OA. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796-800.
    CrossrefPubMedGoogle Scholar
  • 5 Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C, Troncon MG, Agostinis L, Perez-Gutthann S. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in southern Europe. Am J Epidemiol 1998; 147: 387-90.
    CrossrefPubMedGoogle Scholar
  • 6 Hoibraaten E, Abdelnoor M, Sandset PM. Hormone replacement therapy with estradiol and risk of venous thromboembolism – a population-based case-control study. Thromb Haemost 1999; 82: 1218-21.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998; 280: 605-13.
    CrossrefPubMedGoogle Scholar
  • 8 Hoibraaten E, Qvigstad E, Arnesen H, Larssen S, Wickstrom E, Sandset PM. Increased risk of reccurent venous thromboembolism during hormone replacement therapy – Results of the randomized, double-blind, placebo-controlled Estrogen in Venous Thromboembolism Trial (EVTET). Thromb Haemost 2000; 84: 961-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Meade TW, Vickers MR. HRT and cardiovascular disease. J Epidemiol Biostat 1999; 4: 165-90.
    PubMedGoogle Scholar
  • 10 Ostergaard PB, Beck TC, Orsted H, Svendsen A, Nordfang O, Sandset PM. et al. An enzyme linked immunosorption assay for tissue factor pathway inhibitor. Thromb Res 1997; 87: 447-59.
    CrossrefPubMedGoogle Scholar
  • 11 Bendz B, Andersen TO, Sandset PM. A new sensitive chromogenic substrate assay of tissue factor pathway inhibitor type 1. Thromb Res 2000; 97: 463-72.
    CrossrefPubMedGoogle Scholar
  • 12 Caine YG, Bauer KA, Barzegar S, ten CH, Sacks FM, Walsh BW. et al. Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 1992; 68: 392-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Saleh AA, Dorey LG, Dombrowski MP, Ginsburg KA, Hirokawa S, Kowalczyk C. et al. Thrombosis and hormone replacement therapy in post-menopausal women. Am J Obstet Gynecol 1993; 169: 1554-7.
    CrossrefPubMedGoogle Scholar
  • 14 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
  • 15 Conard J, Gompel A, Pelissier C, Mirabel C, Basdevant A. Fibrinogen and plasminogen modifications during oral estradiol replacement therapy. Fertil Steril 1997; 68: 449-53.
    CrossrefPubMedGoogle Scholar
  • 16 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
  • 17 Hoibraaten E, Os I, Seljeflot I, Andersen TO, Hofstad A, Sandset PM. The effects of hormone replacement therapy on hemostatic variables in women with angiographically verified coronary artery disease. Results from the Estrogen in Women with Atherosclerosis study. Thromb Res 2000; 98: 19-27.
    CrossrefPubMedGoogle Scholar
  • 18 van Baal WM, Emeis JJ, van der Mooren MJ, Kessel H, Kenemans P, Stehouwer CD. Impaired procoagulant-anticoagulant balance during hormone replacement therapy? A randomised, placebo-controlled 12-week study. Thromb Haemost 2000; 83: 29-34.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 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 (Suppl. 16) 32-7.
    CrossrefPubMedGoogle Scholar
  • 20 Shahar E, Folsom AR, Salomaa VV, Stinson VL, McGovern PG, Shimakawa T. et al. Relation of hormone-replacement therapy to measures of plasma fibrinolytic activity. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation 1996; 93: 1970-5.
    CrossrefPubMedGoogle Scholar
  • 21 Cushman M, Meilahn EN, Psaty BM, Kuller LH, Dobs AS, Tracy RP. Hormone replacement therapy, inflammation, and hemostasis in elderly women. Arterioscler Thromb Vasc Biol 1999; 19: 893-9.
    CrossrefPubMedGoogle Scholar
  • 22 Koh KK, Horne III MK, Cannon III RO. Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb Haemost 1999; 82: 626-33.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Mann KG. Biochemistry and physiology of blood coagulation. Thromb Haemost 1999; 82: 165-74.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 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
  • 25 Sporrong T, Mattsson LA, Samsioe G, Stigendal L, Hellgren M. Haemo-static changes during continuous oestradiol-progestogen treatment of post-menopausal women. Br J Obstet Gynaecol 1990; 97 (Suppl. 10) 939-44.
    CrossrefPubMedGoogle Scholar
  • 26 Harris GM, Stendt CL, Vollenhoven BJ, Gan TE, Tipping PG. Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives. Am J Hematol 1999; 60: 175-80.
    CrossrefPubMedGoogle Scholar
  • 27 Sandset PM, Lund H, Norseth J, Abildgaard U, Ose L. Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system. Arterioscler Thromb 1991; 11: 138-45.
    CrossrefPubMedGoogle Scholar
  • 28 Bilsel AS, Onaran N, Moini H, Emerk K. Long-term effect of 17-beta-estradiol and thrombin on tissue factor pathway inhibitor release from HUVEC. Thromb Res 2000; 99: 173-8.
    CrossrefPubMedGoogle Scholar
  • 29 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
  • 30 Aune B, Oian P, Omsjo I, Osterud B. Hormone replacement therapy reduces the reactivity of monocytes and platelets in whole blood-a beneficial effect on atherogenesis and thrombus formation?. Am J Obstet Gynecol 1995; 173: 1816-20.
    CrossrefPubMedGoogle Scholar
  • 31 Andersen LF, Gram J, Skouby SO, Jespersen J. Effects of hormone replacement therapy on hemostatic cardiovascular risk factors. Am J Obstet Gynecol 1999; 180: 283-9.
    CrossrefPubMedGoogle Scholar
  • 32 Nabulsi AA, Folsom AR, White A, Patsch W, Heiss G, Wu KK. et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal women. The Atherosclerosis Risk in Communities Study Investigators. N Engl J Med 1993; 328: 1069-75.
    CrossrefPubMedGoogle Scholar
  • 33 Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women.. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial [see comments] [published erratum appears in JAMA 1995 Dec 6; 274 (21): 1676]. JAMA 1995; 273 (Suppl. 03) 199-208.
    CrossrefPubMedGoogle Scholar