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Venous thromboembolism (VTE), a leading cause of death and disability in women, principally manifests as deep vein thrombosis (DVT) and acute pulmonary embolism (PE). Every year, as many as 600,000 patients develop a PE in the United States, resulting in up to 200,000 deaths.
Estrogen therapy induces a prothrombotic state by increasing concentrations of fibrinogen and factors II, V, VII, and X, by decreasing free protein S and antithrombin levels, and by promoting resistance to activated protein C.3-6 Not surprisingly, the prevalence of VTE is increased four- to ninefold in OC users, resulting in around 40 cases per 100,000 exposed women-years.6-8 Risk peaks in the first year of use and accelerates after age 39 among smokers, asthmatics, and obese patients (BMI >35 kg/m2).6-8 Third-generation progestin-containing contraceptives, such as desogestrel, are associated with a further modest increased VTE risk (OR 1.7; 95% CI: 1.4–2.0) compared to second-generation progestins.6,9
Thus, its not surprising that thrombophilias greatly increase the risk of VTE in women who take estrogen-containing OCs. Such risks jump 35- to 99-fold and 16-fold among carriers of the factor V Leiden (FVL) and prothrombin G20210A gene mutations, respectively.8 And OC use and thrombophilias may act synergistically. For example, in women who do not use OCs, the annual risk of VTE is 5.7 per 10,000 for FVL carriers, compared with 0.8 per 10,000 for non-carriers (relative risk (RR) of 6.9).10 In contrast, the VTE risk among OC users without FVL is 3.0 per 10,000 women (RR = 3.7), but climbs to 28.5 per 10,000 (RR = 34.7) among carriers!
How can a clinician minimize risk of VTE in women who want to take estrogen-containing OCs or postmenopausal HT? The first step is assessing a patient's individual risk factors. Prior VTE and known thrombophilia should be absolute contraindications to estrogen therapy. I also would not prescribe such treatment to women who are chronically immobilized because of severe neuromuscular or orthopedic abnormalities, morbidly obese, or have nephrotic syndrome or active malignancies.