Haemostatic Variables and Menopausal Status: Influence of Hormone Replacement Therapy

Summary

Large cohort studies have shown that postmenopausal estrogen use was associated with a reduction in the risk of coronary heart disease, This putative beneficial effect of hormone replacement therapy (HRT) may be partly mediated through changes in clotting factors and fibrinolytic system. We have measured haemostatic variables in 293 consecutive healthy women aged 45-54 years who attended a health check-up centre in Paris (IPC). Premenopausal women taking hormonal therapy were excluded (n = 34). Most women using HRT were given 17-β estradiol in combination with progestin. Mean levels (m ± sd) of plasma fibrinogen, factor VII coagulant activity and plasminogen activator inhibitor (PAI) were significantly higher in postmenopausal women not taking HRT (n = 99) than in premenopausal women (n = 139) within the same decade (319 ± 52 mg/dl vs 304 ± 60 mg/dl, 107 ± 17% vs 96 ± 16%, 9.73 ± 5.71 U/ml vs 7.61 ± 4.36 U/ml respectively). Allowance for main cardiovascular risk factors made no substantial differences to the results, although the effect of the menopause on fibrinogen was no longer significant. HRT (n = 21) significantly reversed the menopause-related changes in factor VII (94 ± 15%), even after adjustment for confounding factors. The same trend in both fibrinogen (294 ± 46 mg/dl) and PAI (8.22 ± 5.51 U/ml) was observed. Similar results were found in women using oral or percutaneous estrogen. Our findings suggest that 17-β estradiol in combination with progestins may protect against an increased thrombotic tendency in postmenopausal women. Randomized clinical trials are urgently needed for a better understanding of HRT effect on atherothrombotic process.

• References

• 1 Kannel WB, Hjortland M, McNamara PM, Gordon T. Menopause and risk of cardiovascular disease: the Framingham Study. Ann Intern Med 1976; 85: 447-552
• 2 Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N Engl J Med 1987; 316: 1105-1110
• 3 Manson JE, Tosteson H, Ridker P, Satterfield S, Hebert P, O’Connor GT, Buring JE, Hennekens CH. The primary prevention of myocardial infarction. N Engl J Med 1992; 326: 1406-1416
• 4 Bush TL, Miller VT. Effects of pharmacologic agents used during menopause: impact on lipids and lipoproteins. In: Menopause: Physiology and Pharmacology. Mishell Jr DR. (ed) Chicago: Year Book Medical Publishers; 1987: 187-208
• 5 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North RR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; ii: 533-537
• 6 Stone MC, Thorp JM. Plasma fibrinogen: a major coronary risk factor. J R Coll Gen Pract 1985; 35: 565-569
• 7 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen and risk of cardiovascular disease: the Framingham Study. JAMA 1987; 258: 1183-1186
• 8 Yamell JWG, Baker IA, Sweetnam PM, Bainton D, O’Brien JR, Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell Collaborative Heart Disease Studies. Circulation 1991; 83: 836-844
• 9 Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-505
• 10 Wiman B, Hamsten A. The fibrinolytic enzyme system and its role in the etiology of thromboembolic disease. Semin Thromb Hemostas 1990; 16: 207-216
• 11 Meade TW, Imeson JD, Haines AP, Stirling Y, Thompson SG. Menopausal status and haemostatic variables. Lancet 1986; i: 22-24
• 12 Balleisen L, Bailey J, Epping PH, Schulte H, Van de Loo J. Epidemiological study on factor VII, factor VIII and fibrinogen in an industrial population-I. Baseline data on the relation to age, gender, body weight, smoking, alcohol, pill using and menopause. Thromb Haemostas 1985; 54: 475-479
• 13 Scarabin PY, Bonithon-Kopp C, Bara L, Malmejac A, Guize L, Samama M. Factor VII activation and menopausal status. Thromb Res 1990; 57: 227-234
• 14 Folsom AR, Wu KK, Davis CE, Conlan MG, Sorlie PD, Szklo M. Population correlates of plasma fibrinogen and factor VII, putative cardiovascular risk factors. Atherosclerosis 1991; 91: 191-205
• 15 Lee AJ, Smith WCS, Lowe GDO, Tunstall-Pedoe H. Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study. J Clin Epidemiol 1990; 43: 913-919
• 16 Bonithon-Kopp C, Scarabin PY, Dame B, Malmejac A, Guize L. Menopause-related changes in lipoproteins and some other cardiovascular risk factors. Intern J Epidemiol 1990; 19: 42-48
• 17 Scarabin PY, Bonithon-Kopp C, Bara L, Guize L, Samama M. Relationship between plasminogen activator inhibitor activity and menopausal status. Fibrinolysis 1990; 4: 233-236
• 18 Clauss A. Gennungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 231-237
• 19 Scarabin PY, Van Dreden P, Bonithon-Kopp C, Orssaud G, Bara L, Conard J, Samama M. Age-related changes in factor VII activation in healthy women. Clin Sci 1988; 75: 341-343
• 20 Eriksson E, Ranby M, Gyzander E, Risberg B. Determination of plasminogen activator inhibitor in plasma using t-PA and a chromogenic single-point poly-d-lysine stimulated assay. Thromb Res 1988; 50: 91-101
• 21 Scarabin PY, Bara L, Samama M, Orssaud G. Further evidence that activated factor VII is related to plasma lipids. Br J Haematol 1985; 59: 186-187
• 22 Poller L, Thompson JM. Clotting factors during oral contraception. Further report. Br Med J 1966; 2: 23-25
• 23 Lind T, Cameron EC, Hunter WM, Leon C, Moran PF, Oxley A, Gerrard J, Lind UCG. A prospective, controlled trial of six forms of hormone replacement therapy given to postmenopausal women. Br J Obstet Gyn 1979; 86 (Suppl. 03) 1-29
• 24 Gordon EM, Williams SR, Frenchek B, Masur CA, Speroff L. Dosedependent effects of postmenopausal estrogen and progestin on antithrombin III and factor XII. J Lab Clin Med 1988; 111: 52-56
• 25 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 Haemostas 1989; 61: 65-69
• 26 Boschetti C, Cortellaro M, Nencioni T, Bertolli V, Della Volpe A, Zanussi C. 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
• 27 Walker ID, Davidson JF, Richards A, Yates R, McEwan HP. The effect of the synthetic steroid ORG OD 14 on fibrinolysis and blood lipids in postmenopausal women. Thromb Haemostas 1985; 53: 303-305
• 28 Jespersen J, Kluft C. Inhibition of tissue-type plasminogen activator in plasma of women using oral contraceptives and in normal women during a menstrual cycle. Thromb Haemostas 1986; 55: 388-389
• 29 De Lignières B, Basdevant A, Thomas G, Thalabard JC, Mercier-Bodard C, Conard J, Guyene TT, Mairon N, Corvol P, Guy-Grand B, Mauvais-Jarvis P, Sitruk-Ware R. Biological effects of estradiol 17-β in postmenopausal women: oral versus percutaneous administration. J Clin Endocrinol Metab 1986; 62: 536-541