Changes of Hemostatic Variables during Hormone Replacement Therapy

 

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ABSTRACT

Hormone replacement therapy (HRT) is accompanied by many changes in the hemostatic system. Because several individual hemostatic variables have been suspected to be reasonable indicators of the hemostatic balance and because this balance is thought to play an important role in the pathogenesis of several diseases, careful examination of the changes in this system induced by HRT could be helpful, first to improve HRT and second to improve our understanding of mechanisms of cardiovascular disease. The effects of (several forms of) HRT on individual hemostatic variables are discussed in this article. The pattern that emerges is that HRT stimulates coagulation, inhibits anticoagulation, and stimulates fibrinolysis (partly by inhibition of fibrinolysis).

There are, however, few data that give clear insight into the effects of HRT on hemostatic variables. Controlled randomized clinical studies are needed to evaluate further the effects of HRT on the hemostatic system, to understand the interplay between inflammation and coagulation (both pathways being affected by HRT), and to understand how HRT-associated changes are affected by differences in genetic background.

REFERENCES

• 1 Manson J E, Martin K A. Clinical practice.  Postmenopausal hormone-replacement therapy. N Engl J Med . 2001;  345 34-40
  CrossrefPubMedGoogle Scholar
• 2 Hulley S, Grady D, Bush T. 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;  280 605-613
  CrossrefPubMedGoogle Scholar
• 3 Beral V, Banks E, Reeves G. Evidence from randomised trials on the long-term effects of hormone replacement therapy.  Lancet . 2002;  360 942-944
  CrossrefPubMedGoogle Scholar
• 4 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K. et al . Fibrinogen as a risk factor for stroke and myocardial infarction.  N Engl J Med . 1984;  311 501-505
  CrossrefPubMedGoogle Scholar
• 5 Lee A J, Smith W C, Lowe G D, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study.  J Clin Epidemiol . 1990;  43 913-919
  CrossrefPubMedGoogle Scholar
• 6 Hamsten A, de Faire U, Walldius G. et al . Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.  Lancet . 1987;  2 3-9
  PubMedGoogle Scholar
• 7 Meade T W, Mellows S, Brozovic M. et al . Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study.  Lancet . 1986;  ii 533-537
  PubMedGoogle Scholar
• 8 Heinrich J, Balleisen L, Schulte H, Assmann G, van de Loo J. Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM study in healthy men.  Arterioscler Thromb . 1994;  14 54-59
  CrossrefPubMedGoogle Scholar
• 9 Di Napoli M, Papa F. Inflammation, hemostatic markers, and antithrombotic agents in relation to long-term risk of new cardiovascular events in first-ever ischemic stroke patients.  Stroke . 2002;  33 1763-1771
  CrossrefPubMedGoogle Scholar
• 10 Blann A D, McCollum C N, Lip G Y. Relationship between plasma markers of endothelial cell integrity and the Framingham cardiovascular disease risk-factor scores in apparently healthy individuals.  Blood Coagul Fibrinolysis . 2002;  13 513-518
  CrossrefPubMedGoogle Scholar
• 11 van Baal M W, Kooistra T, Stehouwer C D. Cardiovascular disease risk and hormone replacement therapy (HRT): a review based on randomised, controlled studies in postmenopausal women.  Curr Med Chem . 2000;  7 499-517
  PubMedGoogle Scholar
• 12 Walsh B W, Kuller L H, Wild R A. et al . Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women.  JAMA . 1998;  279 1445-1451
  CrossrefPubMedGoogle Scholar
• 13 de Valk-de Roo W G, Stehouwer C D, Meijer P. et al . 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
  PubMedGoogle Scholar
• 14 Bonduki C E, Lourenco D M, Baracat E. et al . Effect of estrogen-progestin hormonal replacement therapy on plasma antithrombin III of postmenopausal women.  Acta Obstet Gynecol Scand . 1998;  77 330-333
  CrossrefPubMedGoogle Scholar
• 15 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.  JAMA . 1995;  273 199-208
  CrossrefPubMedGoogle Scholar
• 16 Kroon U B, Silfverstolpe G, Tengborn L. The effects of transdermal estradiol and oral conjugated estrogens on haemostasis variables.  Thromb Haemost . 1994;  71 420-423
  PubMedGoogle Scholar
• 17 Scarabin P Y, Alhenc-Gelas M, Plu-Bureau. et al . 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 3071-3078
  CrossrefPubMedGoogle Scholar
• 18 Mannucci P M, Bettega D, Chantarangkul V. et al . Effect of tamoxifen on measurements of hemostasis in healthy women.  Arch Intern Med . 1996;  156 1806-1810
  CrossrefPubMedGoogle Scholar
• 19 Teede H J, McGrath B P, Smolich J J. et al . Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis.  Arterioscler Thromb Vasc Biol . 2000;  20 1404-1409
  PubMedGoogle Scholar
• 20 Caine Y G, Bauer K A, Barzegar S. et al . Coagulation activation following estrogen administration to postmenopausal women.  Thromb Haemost . 1992;  68 392-395
  PubMedGoogle Scholar
• 21 Demirol A, Baykal C, Kirazli S, Ayhan A. Effects of hormone replacement on hemostasis in spontaneous menopause.  Menopause . 2001;  8 135-140
  PubMedGoogle Scholar
• 22 Hoibraaten E, Mowinckel M C, de Ronde H, Bertina R M, Sandset P M. Hormone replacement therapy and acquired resistance to activated protein C: results of a randomized, double-blind, placebo-controlled trial.  Br J Haematol . 2001;  115 415-420
  CrossrefPubMedGoogle Scholar
• 23 Post M S, Rosing J, Van Der Mooren J M. et al . Increased resistance to activated protein C after short-term oral hormone replacement therapy in healthy postmenopausal women.  Br J Haematol . 2002;  119 1017-1023
  CrossrefPubMedGoogle Scholar
• 24 Marcucci R, Abbate R, Fedi S. et al . Acquired activated protein C resistance in postmenopausal women is dependent on factor VIII:c levels.  Am J Clin Pathol . 1999;  111 769-772
  PubMedGoogle Scholar
• 25 Lowe G, Woodward M, Vessey M. et al . Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years. Relationships to hormone replacement therapy.  Thromb Haemost . 2000;  83 530-535
  PubMedGoogle Scholar
• 26 Hunter D J, Anderson A B, Haddon M. Changes in coagulation factors in postmenopausal women on ethinyl oestradiol.  Br J Obstet Gynaecol . 1979;  86 488-490
  PubMedGoogle Scholar
• 27 van Baal M W, Emeis J J, van der Mooren J M. et al . Impaired procoagulant-anticoagulant balance during hormone replacement therapy?.  <~>A randomised, placebo-controlled 12-week study. Thromb Haemost . 2000;  83 29-34
  PubMedGoogle Scholar
• 28 Hoibraaten E, Os I, Seljeflot I. et al . 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
• 29 Gottsater A, Rendell M, Hulthen U L, Berntorp E, Mattiasson I. Hormone replacement therapy in healthy postmenopausal women: a randomized, placebo-controlled study of effects on coagulation and fibrinolytic factors.  J Intern Med . 2001;  249 237-246
  CrossrefPubMedGoogle Scholar
• 30 Hoibraaten E, Qvigstad E, Andersen T O, Mowinckel M C, Sandset P M. The effects of hormone replacement therapy (HRT) on hemostatic variables in women with previous venous thromboembolism-results from a randomized, double-blind, clinical trial.  Thromb Haemost . 2001;  85 775-781
  PubMedGoogle Scholar
• 31 Effects on haemostasis of hormone replacement therapy with transdermal estradiol and oral sequential medroxyprogesterone acetate: a 1-year, double-blind, placebo-controlled study. The Writing Group for the Estradiol Clotting Factors Study.  Thromb Haemost . 1996;  75 476-480
  PubMedGoogle Scholar
• 32 Boschetti C, Cortellaro M, Nencioni T. et al . Short- and long-term effects of hormone replacement therapy (transdermal estradiol vs oral conjugated equine estrogens, combined with medroxyprogesterone acetate) on blood coagulation factors in postmenopausal women.  Thromb Res . 1991;  62 1-8
  CrossrefPubMedGoogle Scholar
• 33 Cushman M, Legault C, Barrett-Connor E. et al . Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study.  Circulation . 1999;  100 717-722
  CrossrefPubMedGoogle Scholar
• 34 van Baal M W, Kenemans P, Emeis J J. et al . Long-term effects of combined hormone replacement therapy on markers of endothelial function and inflammatory activity in healthy postmenopausal women.  Fertil Steril . 1999;  71 663-670
  CrossrefPubMedGoogle Scholar
• 35 Coope J, Thomson J M, Poller L. Effects of "natural oestrogen" replacement therapy on menopausal symptoms and blood clotting.  Br Med J . 1975;  4 139-143
  PubMedGoogle Scholar
• 36 Gordon E M, Williams S R, Frenchek B, Mazur C A, Speroff L. Dose-dependent effects of postmenopausal estrogen and progestin on antithrombin III and factor XII.  J Lab Clin Med . 1988;  111 52-56
  PubMedGoogle Scholar
• 37 Fossum S, Hoem N O, Gjonnaess H, Briseid K. Contact activation factors in plasma from women on estrogen replacement therapy after ovariohysterectomy.  Thromb Res . 1999;  93 161-170
  CrossrefPubMedGoogle Scholar
• 38 Signorelli S S, Sciacchitano S, Di Pino L. et al . Effects of long-term hormone replacement therapy on arterial wall thickness, lipids and lipoproteins, fibrinogen and antithrombin III.  Gynecol Endocrinol . 2001;  15 367-372
  PubMedGoogle Scholar
• 39 Stachowiak G, Owczarek D, Polac I, Pertynski T, Jedrzejczyk S. The influence of hormone replacement therapy containing transdermal 17- beta estradiol and oral medroxyprogesterone acetate on coagulation and fibrinolysis.  Ginekol Pol . 1999;  70 527-533
  PubMedGoogle Scholar
• 40 Nabulsi A A, Folsom A R, White A. 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 1069-1075
  CrossrefPubMedGoogle Scholar
• 41 Gilabert J, Estelles A, Cano A. et al . The effect of estrogen replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status.  Am J Obstet Gynecol . 1995;  173 1849-1854
  CrossrefPubMedGoogle Scholar
• 42 Conard J. Modifications of the hemostatic balance during estrogen treatments: menopause and its treatment.  Therapie . 1999;  54 363-367
  PubMedGoogle Scholar
• 43 Conard J, Basdevant A, Thomas J L. et al . Cardiovascular risk factors and combined estrogen-progestin replacement therapy: a placebo-controlled study with nomegestrol acetate and estradiol.  Fertil Steril . 1995;  64 957-962
  PubMedGoogle Scholar
• 44 Luyer M D, Khosla S, Owen W G, Miller V M. Prospective randomized study of effects of unopposed estrogen replacement therapy on markers of coagulation and inflammation in postmenopausal women.  J Clin Endocrinol Metab . 2001;  86 3629-3634
  CrossrefPubMedGoogle Scholar
• 45 Peverill R E, Teede H J, Smolich J J. et al . Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII.  Clin Sci . 2001;  101 93-99
  PubMedGoogle Scholar
• 46 Gebara O C, Mittleman M A, Sutherland P. et al . Association between increased estrogen status and increased fibrinolytic potential in the Framingham Offspring Study.  Circulation . 1995;  91 1952-1958
  PubMedGoogle Scholar
• 47 Koh K K, Mincemoyer R, Bui M N. et al . Effects of hormone-replacement therapy on fibrinolysis in postmenopausal women.  N Engl J Med . 1997;  336 683-690
  CrossrefPubMedGoogle Scholar
• 48 Vehkavaara S, Silveira A, Hakala-Ala-Pietila T. et al . Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women.  Thromb Haemost . 2001;  85 619-625
  PubMedGoogle Scholar
• 49 Gebara O C, Mittleman M A, Walsh B W. et al . Fibrinolytic potential is significantly increased by oestrogen treatment in postmenopausal women with mild dyslipidaemia.  Heart . 1998;  80 235-239
  PubMedGoogle Scholar
• 50 Koh K K, Horne III K M, Csako G, Waclawiw M A, Cannon III O R. Relation of fibrinolytic potentiation by estrogen to coagulation pathway activation in postmenopausal women.  Am J Cardiol . 1999;  83 466-469
  CrossrefPubMedGoogle Scholar
• 51 Post M S, Hendriks D F, van der Mooren J M. et al . Oral oestradiol/trimegestone replacement reduces procarboxypeptidase U (TAFI): a randomized, placebo-controlled, 12-week study in early postmenopausal women.  J Intern Med . 2002;  251 245-251
  CrossrefPubMedGoogle Scholar
• 52 Braunstein J B, Kershner D W, Bray P. et al . Interaction of hemostatic genetics with hormone therapy: new insights to explain arterial thrombosis in postmenopausal women.  Chest . 2002;  121 906-920
  CrossrefPubMedGoogle Scholar
• 53 Grancha S, Estelles A, Tormo G. et al . Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease.  Thromb Haemost . 1999;  81 516-521
  PubMedGoogle Scholar
• 54 Psaty B M, Smith N L, Lemaitre R N. et al . Hormone replacement therapy, prothrombotic mutations, and the risk of incident nonfatal myocardial infarction in postmenopausal women.  JAMA . 2001;  285 906-913
  CrossrefPubMedGoogle Scholar
• 55 Herrington D M, Howard T D, Hawkins G A. et al . Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease.  N Engl J Med . 2002;  346 967-974
  CrossrefPubMedGoogle Scholar