Thrombotic Variables and Risk of Idiopathic Venous Thromboembolism in Women Aged 45-64 Years

Summary

Hormone replacement therapy (HRT) has been shown to increase the relative risk of idiopathic venous thromboembolism (VTE) about threefold in several observational studies and one randomised controlled trial. Whether or not this relative risk is higher in women with underlying thrombophilia phenotypes, such as activated protein C (APC) resistance, is unknown. We therefore restudied the participants in a case-control study of the relationship between the use of HRT and the occurrence of idiopathic VTE in women aged 45-64 years. After protocol exclusions, 66 of the cases in the original study and 163 of the controls were studied. Twenty haematological variables relevant to risk of VTE were analysed, including thrombotic states defined from the literature. The relative risk of VTE showed significant associations with APC resistance (OR 4.06; 95% CI 1.62, 10.21); low antithrombin (3.33; 1.15, 9.65) or protein C (2.93; 1.06, 8.14); and high coagulation factor IX (2.34; 1.26, 4.35), or fibrin D-dimer (3.84; 1.99, 7.42). HRT use increased the risk of VTE in women without any of these thrombotic states (OR 4.09; 95% CI 1.26, 13.30). A similar effect of HRT use on the relative risk of VTE was also found in women with prothrombotic states. Thus for example, the combination of HRT use and APC resistance increased the risk of VTE about 13-fold compared with women of similar age without either APC resistance or HRT use (OR 13.27; 95% CI 4.30, 40.97).

We conclude that the combination of HRT use and thrombophilias (especially if multiple) increases the relative risk of VTE substantially; hence women known to have thrombophilias (especially if multiple) should be counselled about this increased risk prior to prescription of HRT. However, HRT increases the risk of VTE about fourfold even in women without any thrombotic abnormalities: possible causes are discussed.

Keywords

Venous thromboembolism - thrombophilia - oestrogens

• References

• 1 Greer IA. Haemostasis and thrombosis in pregnancy. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD. Haemostasis and Thrombosis. 3rd edn.. Edinburgh: Churchill Livingstone; 1994: 987-1015.
• 2 Helmerhorst FM, Bloemenkamp KWM, Rosendaal FR, Vandenbroucke JP. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost 1997; 78: 327-34.
• 3 Kluft C, Lansink M. Effect of oral contraceptives on haemostasis variables. Thromb Haemost 1997; 78: 315-26.
• 4 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.
• 5 Jick H, Derby LE, Myers MW, Vasilakis C, Newton KM. Risk of hospital admission for idiopathic venous thromboembolism among users of postmenopausal oestrogens. Lancet 1996; 348: 981-3.
• 6 Grodstein F, Stampfer MJ, Goldhaber SZ. et al. Prospective study of exogenous hormones and risk of pulmonary embolism in women. Lancet 1996; 348: 983-7.
• 7 Gutthann SP, Rodriguez LAG, Castellague J. Hormone replacement therapy and risk of venous thromboembolism: population based case-control study. BMJ 1997; 314: 796-800.
• 8 Varas-Lorenzo C, Garcia-Rodriguez LA, Cattaruzzi C. Hormone replacement therapy and the risk of hospitalization for venous thromboembolism: a population-based study in Southern Europe. Am J Epidemiol 1998; 147: 387-390.
• 9 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc 1998; 280: 605-13.
• 10 Meade TW. Hormone replacement therapy and haemostatic function. Thromb Haemost 1997; 78: 765-9.
• 11 Chae CU, Ridker PM, Manson JE. Postmenopausal hormone replacement therapy and cardiovascular disease. Thromb Haemost 1997; 78: 770-80.
• 12 Lowe GDO, Rumley A, Woodward M, Reid E, Rumley J. Activated protein C resistance and the FV: R506Q mutation in a random population sample: associations with cardiovascular risk factors and coagulation variables. Thromb Haemost 1999; 81: 918-24.
• 13 Whitehead M, Godfree V. Venous thromboembolism and hormone replacement therapy. Baillière’s Clin Obstet Gynaecol 1997; 11: 587-99.
• 14 Lowe GDO, Lee AJ, Rumley A, Price JF, Fowkes FGR. Blood viscosity and risk of cardiovascular events: the Edinburgh Artery Study. Br J Haematol 1997; 96: 168-73.
• 15 Lowe GDO, Rumley A, Woodward M, Morrison CE, Philippou H, Lane DA, Tunstall-Pedoe H. Epidemiology of coagulation factors, inhibitors and activation markers: The Third Glasgow MONICA Survey. I. Illustrative reference ranges by age, sex and hormone use. Br J Haematol 1997; 97: 775-84.
• 16 Lowe GDO, Yarnell JWG, Sweetnam PM, Rumley A, Thomas HF, Elwood PC. Fibrin D-Dimer, tissue plasminogen activator, plasminogen activator inhibitor, and the risk of major ischaemic heart disease in the Caerphilly Study. Thromb Haemost 1998; 79: 129-33.
• 17 Rossi E, Mondonico P, Lombardi A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulometers. Thromb Res 1988; 52: 453-458.
• 18 Lowe GDO. Haemostatic risk factors for arterial and venous thrombosis. In: Poller L, Ludlam CA. Recent Advances in Blood Coagulation, 7. Edinburgh, Churchill Livingstone; 1997: 69-96.
• 19 The Writing Committee for the Second European Conference on Sex Steroids and Metabolism. Consensus Statement of the Consensus development meeting 1995; combined oral contraceptives and cardiovascular disease. Gynecol Endocrinol 1996; 10: 1-5.
• 20 Balendra PR. Deep vein thrombosis of the leg: natural history and haemostatic variables. MD Thesis, Queen’s University of Belfast, 1990
• 21 van der Meer FJM, Koster T, Vandenbroucke JP, Briet E, Rosendaal FR. The Leiden Thrombophilia Study (LETS). Thromb Haemost 1997; 78: 631-5.
• 22 Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. Thromb Haemost 1994; 71: 719-22.
• 23 Vandenbroucke JP, Koster T, Briët E. et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
• 24 Lowe GDO. Prediction of postoperative deep vein thrombosis. Thromb Haemost 1997; 78: 47-52.
• 25 Goldhaber SZ, Grodstein F, Stampfer MJ. et al. A prospective study of risk factors for pulmonary embolism in women. JAMA 1997; 277: 642-5.
• 26 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia. Thromb Haemost 1996; 76 662 824-34.
• 27 Watson HG, Ludlam CA. Replacement therapy and other therapeutic products. In: Rizza CR, Lowe GDO. Haemophilia and other inherited bleeding disorders. London: Saunders; 1997: 151-200.
• 28 Lip GYH, Lowe GDO, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J 1995; 73: 527-33.
• 29 Lip GYH, Zafiris J, Watson RDS, Bareford D, Lowe GDO, Beevers DG. Fibrin D-dimer and β-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low-dose warfarin and aspirin. Circulation 1996; 94: 425-31.
• 30 Gazzard BG, Lewis HL, Ash G, Rizza CR, Bidwell E, Williams R. Coagulation factor concentrate in the treatment of the haemorrhagic diathesis of fulminant hepatic failure. Gut 1974; 15: 993-8.
• 31 de Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of Factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
• 32 Lowe GDO, Haverkate F, Thompson SG, Turner RM, Bertina RM, Turpie AGG, Mannucci PM. on behalf of the ECAT DVT Study Group. Prediction of deep vein thrombosis after elective hip replacement surgery by preoperative clinical and haemostatic variables: the ECAT DVT Study. Thromb Haemost 1999; 81: 879-86.
• 33 Bloemenkamp KWM, Rosendaal FR, Helmerhast FM, Koster T, Bertina RM, Vandenbroucke JP. Hemostatic effects of oral contraceptives in women who developed deep-vein thrombosis while using oral contraceptives. Thromb Haemost 1998; 80: 382-7.
• 34 Comerota AJ. Operative venous dilatation and its relationship to postoperative deep vein thrombosis. In: Bergqvist D, Comerota AJ, Nicolaides AN, Scurr JH. Prevention of venous thromboembolism. London: Med-Orion; 1994: 31-42.
• 35 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. Thromb Haemost 1997; 78: 1-6.