Women, Hormones, and Thrombosis

By Zoe L. Larned, M.D.

The increased risk of thrombosis associated with hormonal factors and hormonal therapies has been well established although there is still much to be learned regarding the mechanisms, risks for recurrence and other associated risk factors that may contribute.

In today's Simultaneous Sessions, Dr. Mary Cushman and colleagues will provide the final results regarding the risk of venous thrombosis associated with hormone therapy from the Women’s Health Initiative Trial of Estrogen plus Progestin. This trial was terminated early with the recognition that the overall health risks associated with combined estrogen plus progestin exceeded the benefits of this therapy for postmenopausal women. They report a 2.1- fold increased risk for thrombosis (both DVT and PE) (95% CI: 1.6-2.7) in the postmenopausal women who received the combination hormonal therapy. An increased absolute risk of thrombosis for older women (subset of women 70-79) and obese women (BMI > 25 kg/m2) is also indicated. Older women assigned to hormones had an incidence rate of thrombosis of 6.2 per 1,000 person years, while this rate was 5.1 per 1,000 for obese women assigned to hormones. To evaluate genetic risk factors for thrombosis (Factor V Leiden, prothrombin gene mutation), Dr. Cushman and colleagues performed a nested case control study evaluating thrombosis. They found that heterozygous factor V Leiden was associated with a 2.5-fold increased risk of thrombosis. Compared to placebo-assigned women without factor V Leiden, women assigned to hormone therapy with factor V Leiden had a 6.7-fold increased risk of thrombosis (95% CI 3.1-14). The prothrombin variant was not common enough to draw firm conclusions. This study serves as an excellent reminder that not only are certain hormone therapies associated with increased thrombosis risk, but that other factors may further enhance this risk.

Dr. Mary Cushman and colleagues will also note the association of hormonal factors and recurrent venous thrombosis based on retrospective analysis of the data from the PREVENT trial. Given evidence that hormone factors (oral contraceptives, hormone replacement therapy, or pregnancy) are associated with an increased risk of first venous thrombosis, they evaluated the association of gender and hormones with risk of recurrent thrombosis. After adjusting for other thrombotic risk factors, they found that the overall risk of venous thrombosis recurrence was lower in women than in men in this trial (3.5% versus 6.3%/year). On further analysis of the women, much of this lower recurrence risk was attributed to a lower recurrence risk in the subset of women identified as having a hormone-related factor at the time of their index event (54.5% of participants were women: 34% on hormone replacement, 18% on oral contraceptives, and 2.5% were pregnant or postpartum). They learned that this subset of women were less likely to have recurrent venous thrombosis when compared to men (57% lower recurrence risk, HR 0.43) or even other women who did not have hormonal exposure at their index event (44% lower recurrence risk, HR 0.56). The reasons for this finding are not yet clear, although possibilities may include that these women were taken off of oral contraceptives and hormone replacement after their index event.

Specific issues regarding the diagnosis and treatment of pregnancy associated thrombosis, including risks associated with hormonal therapy for infertility, were highlighted by Dr. Barbara Konkle in the Education Session, Thrombotic Disorders: Diagnosis and Treatment.