Risk Factors

The risk factors for VTE fit into a contemporary and extended version of Virchow’s triad (stasis, hypercoagulability, endothelial damage) changing the haemostatic balance towards clot formation (thrombophilia). The change can be achieved by decreasing blood flow and lowering oxygen tension, activation of the endothelium, inborn or acquired immune responses and blood platelets, increasing the number of platelets and red blood cells, or modifying the concentrations of pro- and anticoagulant proteins in the blood. Numerous genetic and acquired risk factors are known (Table 22.1). For details, see [6]. An extended multiple-hit hypothesis implies that more than one risk factor is present at any one time. Superficial vein thrombosis combined with an acquired thrombotic risk factor increases the risk of venous thrombosis 10–100-fold [7], but one of the most well-known acquired risk factors is the use of exogenous sex steroids such as COCs and MHT.

Gender Differences and Age

Younger women during the child-bearing years have higher incidence of VTE than men at similar age. With advancing age, however, risk is higher in men than women. A relative risk (RR) of 1.3 in men with an age between 60 and 69 years versus women in the same age group is reported. Also the risk of recurrent venous thrombosis is two-fold higher in men than in women [8]. Venous thromboembolism has an annual incidence of 1–3 per 10 000 individuals per year (global background rate). It is uncommon in young individuals, but becomes more frequent with advancing age. The risk is doubled between the ages of 20 and 40. The incidence is estimated to be approximately 5 per 10 000 per year in women in their forties, 6–12 per 10 000 per year in women in their fifties, 30–40 per 10 000 per year in women aged 70–80 years, and approximately 70 per 10 000 in women above 80 [9, 10]. Similarly, in the Women’s Health Initiative Study (WHI), users of combined MHT in the sixth, seventh and eighth decades of life had a two-, four- and seven-fold VTE risk, respectively [11]. An analogous though less pronounced effect of age was seen in the estrogen-only arm of the WHI [12].

Obesity

Obesity has been suggested to be a risk factor for fatal pulmonary embolism for a long time, but whether obesity is an independent risk factor for pulmonary embolism or VTE has not been fully determined until recently [13]. Investigations on increased risk because of obesity have been criticized because they failed to control for hospital confinement or other risk factors. Although high proportions of patients with venous VTE have been found to be obese, the importance of the association is diminished because of the high proportion of obesity in the general population. To date, however, there is notable and consistent evidence of an association of obesity with VTE, more so in women compared with men. The risk appears to be at least double that for normal weight subjects (BMI 20–24.9) [14]. In the WHI, VTE risk increased in both overweight and obese (BMI > 30) MHT users when compared with normal weight placebo users. The risk of venous thromboembolism may be additive when using MHT, and with the continuous and global rise in obesity, this interaction will become a more prevalent risk issue.

Specific Risk of MHT

A number of different estrogen and progestin preparations in both sequential and continuous combined products are available. They differ according to the chemical structure of the estrogen as well as the progestin component, daily dose and route of administration. The estrogen compound of combined MHT consists of either natural 17β-estradiol (E2), including estradiol valerate (E2V), or the conjugated equine estrogens (CEE). E2 can be administered orally or transdermally. CEE is always orally administered. CEE and E2, administered alone, are associated with different risks of major thrombotic events. Compared with current use of oral E2, current use of oral CEE is associated with a doubling of the risk of deep vein thrombosis (DVT) [15]. The association of VTE risk with the different pharmacological classes of progestins has not been elucidated in detail, despite many clinical and epidemiologic investigations. Progestins include progesterone, the physiologic molecule synthesized and secreted by the ovary, as well as synthetic compounds named progestins, derived from either progesterone or testosterone. To date, the only desired effect in relation to MHT is endometrial protection [16]. An indirect comparison within the WHI clinical trials showed that the combination of estrogens plus progestins was more thrombogenic than unopposed estrogens. Indeed, compared with placebo, the VTE risk was doubled in the opposed clinical trial and not significantly elevated among MHT users in the estrogen-alone clinical trial. Similarly, the WISDOM trial provided a direct comparison of the effect of CEE alone and CEE plus medroxyprogesterone (MPA) on VTE risk among postmenopausal hysterectomized women [3]. Users of CEE plus MPA had a doubling in thrombotic risk compared with women treated with CEE alone [17]. While MPA may have a thrombogenic effect among postmenopausal women using estrogens, micronized progesterone could be safe with respect to thrombotic risk [3]. The effects of the different types of progestins on VTE risk have to be further investigated.

Tibolone, a testosterone-derived progestin, has estrogenic, progestogenic and androgenic properties and can be used alone for treatment of climacteric symptoms. The available studies, although limited in types and number, show that tibolone is not associated with an increased risk of VTE [3, 18].

Route of Administration

In general, investigations of the relationship of venous thromboembolism and MHT have focused on oral administration. Orally administered estrogen may exert a pro-thrombotic effect through the hepatic induction of haemostatic imbalance, as observed with COCs. The pro-thrombotic effect is possibly related to high concentrations of estrogen in the liver due to the ‘first-pass’ effect. Studies comparing oral and transdermal estrogen administration have demonstrated that transdermally administered estrogen has little or no pro-thrombotic effect and may have beneficial effects on pro-inflammatory markers, including C-reactive protein. The EStrogen and THromboEmbolism Risk (ESTHER) Study Group demonstrated that oral but not transdermal estrogen is associated with a four-fold increased VTE risk. They also noted that norpregnane progestins may be thrombogenic, whereas micronized progesterone and pregnane derivatives appear safe with respect to thrombotic risk [19].

Smoking and Length of Use

No interaction between smoking and MHT was found in the WHI clinical trial [11], although smoking is a weak risk factor for incident VTE. Smoking further increases the risk of VTE in women using CHC [20].

The risk of VTE in users of MHT decreases with length of use. There is a marked increased risk of VTE during the first year of use with the odds ratio as high as 8 (‘the timing effect’) [21]. This is likely to be caused by the presence of pro-thrombotic/thrombophilic abnormalities in these women, as has been shown for COCs. Besides the type and route of administration, comparisons of the thrombosis risks between MHT regimens must therefore also account for length of use. With time, the risk of thrombosis decreases, but the risk remains always higher than in non-users. This VTE risk disappears during the first months after stopping treatment.

Thrombophilia

Thrombophilia describes conditions with increased tendency for excessive clotting, including inherited conditions, based on genetic mutation such as Factor V Leiden, antithrombin, protein C and S deficiencies and the prothrombin G20210A mutation; or an acquired condition, such as lupus anticoagulant or antiphospholipid syndrome. The presence of an inherited thrombophilia is a major modifier of thrombosis risk in users of both CHC and MHT. The absolute risk of venous thrombosis in factor V Leiden heterozygous carriers is estimated as being 0.15 per 100 person-years, whereas in antithrombin-, protein C– or protein S–deficient persons, these estimates range from 0.7 to 1.7 per 100 person-years, indicating a considerably higher degree of risk. Risk estimates for thrombophilic women using MHT are less precise compared with estimates performed in CHC users, because fewer women on MHT have been included in retrospective studies informative for this situation. In principle, the known relative risks for the various thrombophilias should be multiplied by the MHT baseline risk in the relevant age category. The route of administration as well as the progestin component has been clearly shown to modulate/decrease the risk. In general, thrombophilic women or women with a positive first-degree family history of VTE should refrain from oral MHT. However, as part of the shared decision-making process, the gynecologist should weigh the risks against the benefits when prescribing MHT and counsel the patient accordingly, taking into consideration the possible thrombosis-sparing properties of transdermal administration and tibolone.