Venous Thrombosis Women who use estrogen containing hormonal contraceptives are at increased risk for venous thrombosis and thromboembolism. Normally the coagulation system maintains a dynamic balance of procoagulant and anticoagulant systems. Estrogens affect both systems in a dose-related fashion. For most women, fibrinolysis (anticoagulation) is increased as much as coagulation, maintaining the dynamic balance at increased levels of production and destruction of fibrinogen (127,128) (Fig. 10.7). Older studies included women with what are now considered contraindications to use of estrogen-containing hormonal contraceptives: previous thrombosis, preexisting vascular disease, coronary artery disease, cancers, and serious trauma (127,128). Current low-dose OCs have a less measurable effect on the coagulation system, and fibrinolytic factors increase at the same rate as procoagulant factors. Lower estrogen dose (30–35 μg EE) OCs reduce the risk of a thromboembolic event when compared with higher dose (50 μg estrogen) OCs (129) (Table 10.5). A very large Danish study showed for the first time that combination OCs with 20 μgof ethinyl estradiol have an 18% further reduction in thrombosis risk compared with 30 to 40 μg OCs after adjustment for duration of use (130). The progesterone-only OCs and the levonorgestrel-releasing intrauterine device were not associated with venous thrombosis.
Figure 10.7 Dynamic balance of hemostasis. (From Winkler UH, Buhler K, Schlinder AE. The dynamic balance of hemostasis: implications for the risk of oral contraceptive use. In: Runnebaum B, Rabe T, Kissel L, eds. Female contraception and male fertility regulation. In Advances in Gynecological and Obstetric Research Series. Confort, England: Parthenon Publishing Group, 1991:85–92, with permission.)
The absolute risk of deep vein thrombosis was strongly inﬂuenced by age, increasing from 1.84 per 10,000 women aged 15 to 19 years to 6.59 per 10,000 for women aged 45 to 49 years with current users, former users, and never users combined. With all types of OCs combined, the overall absolute rate of deep vein thrombosis was 6.29 per 10,000 woman-years for current OC users compared to 3.01 among nonusers, giving an adjusted rate ratio of 2.83 (95% confidence interval [CI], 2.65–3.01) (Table 10.6). This is a higher absolute risk than the 3 per 10,000 woman-years previously estimated and may reﬂect, among other things, the use of better means for diagnosis of deep vein thrombosis (131). This population-based study includes all Danish women aged 15 to 49, excluding only women with a diagnosis of cancer or of cardiovascular disease diagnosed before the study interval. Thrombosis risk was highest during the first year of use and decreased thereafter (Table 10.6).
Thrombophilia Changes in the coagulation system are detectable in all women, including those taking lower-dose OCs; some women are genetically predisposed to thrombosis when challenged by pregnancy or administration of exogenous estrogen. Women with inherited deficiencies of antithrombin III, protein C, or protein S are at very high risk for thrombosis with pregnancy or estrogen therapy, but they make up a very small proportion of potential OC users. A much more common variation, factor V Leiden exists in 3% to 5% of the