Mutations, Hormone Therapy (HRT) and Venous Thromboembolism

To assess the interaction between hormone replacement therapy and the prothrombotic mutations, Factor V Leiden and the recently described prothrombin mutation (20210A) on the incidence of venous thromboembolism (VTE) in a population-based case-control study conducted at Group Health Cooperative of Puget Sound (GHC).

BACKGROUND: Epidemiologic studies have identified Factor V Leiden as the most common cause of heritable thrombophilia, a prothrombotic mutation associated with a 5 to 7-fold increase in the risk of venous thromboembolism (VTE). In pre-menopausal women, the use of oral contraceptives is associated with a 4-fold increase in VTE risk, and the joint effects of oral contraceptive use and Factor V Leiden carriership increase the VTE risk of by a factor of 35. Recently, the results of several observational studies and randomized clinical trials suggest that in post-menopausal women, the use of hormone replacement therapy is associated with a 3-fold increase in VTE risk. Whether post-menopausal women with prothrombotic mutations experience a similar 20-fold increase in risk when they take post-menopausal hormones remains unknown. DESIGN NARRATIVE: In this case-control study, post-menopausal women with a first episode of objectively confirmed venous thromboembolism, and population-based controls were identified and recruited from the GHC enrollment files. Controls were frequency matched to the cases on age and calendar-year. Data collection included a review of ambulatory medical record and a telephone interview. The GHC computerized pharmacy database was used to assess exposure to hormone replacement therapy. A venous blood specimen was obtained from consenting subjects, processed into aliquots of white cells, plasma, and red cells, and stored at 70 degrees C prior to laboratory analysis. DNA was extracted from white cells, and molecular genotyping assays were conducted to assess carriership of prothrombotic mutations.

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Reiner AP, Heckbert SR, Vos HL, Ariens RA, Lemaitre RN, Smith NL, Lumley T, Rea TD, Hindorff LA, Schellenbaum GD, Rosendaal FR, Siscovick DS, Psaty BM. Genetic variants of coagulation factor XIII, postmenopausal estrogen therapy, and risk of nonfatal myocardial infarction. Blood. 2003 Jul 1;102(1):25-30. doi: 10.1182/blood-2002-07-2308. Epub 2002 Nov 27.

Bis JC, Smith NL, Psaty BM, Heckbert SR, Edwards KL, Lemaitre RN, Lumley T, Rosendaal FR. Angiotensinogen Met235Thr polymorphism, angiotensin-converting enzyme inhibitor therapy, and the risk of nonfatal stroke or myocardial infarction in hypertensive patients. Am J Hypertens. 2003 Dec;16(12):1011-7. doi: 10.1016/j.amjhyper.2003.07.018.

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