Estrogen replacement therapy (ERT), which produces acquired resistance to activated
protein C when superimposed on heritable resistance to activated
protein C (the mutant
Factor V Leiden trait), may promote venous and arterial
thrombosis. In a cross-sectional study of 423 women referred for hyperlipidemic
therapy (93 of whom [22%] were on ERT), our specific aim was to determine whether ERT and heterozygosity for the
Factor V Leiden mutation and/or resistance to activated
protein C interacted as risk factors for
atherothrombosis. Of the 423 women, 168 (40%) had
atherothrombosis, 19 (4%) were heterozygous for
Factor V Leiden mutation or had resistance to activated
protein C <2 (
Factor V Leiden mutation+), and 404 were wild-type normal for the
Factor V gene and/or had resistance to activated
protein C > or =2 (
Factor V Leiden mutation-). By stepwise logistic regression, positive explanatory variables for
atherothrombosis included
hypertension (p = 0.002), age (p = 0.003), relatives with
atherothrombosis (p = 0.002),
anticardiolipin antibody immunoglobulin-M (p = 0.02), and
a Factor V Leiden mutation*ERT interaction term where
atherothrombosis events were more likely in 2 subgroups of women (ERT- and
Factor V Leiden mutation-) or (ERT+ and
Factor V Leiden mutation+) (p = 0.02).
High-density lipoprotein cholesterol was inversely associated with
atherothrombosis (p = 0.004). In a separate logistic regression model for the 213 women with a polymerase chain reaction measurement of the
Factor V gene, ERT was protective (p = 0.008); the
Factor V Leiden mutation was positively associated with
atherothrombosis (p = 0.05). The
atherothrombosis odds ratio risk for ERT (yes vs no) was 0.36 (95% confidence intervals [CI] 0.16 to 0.74, p = 0.007). The
atherothrombosis risk odds ratio in women heterozygous for the
Factor V Leiden mutation (vs normal) was 2.00 (95% CI 1.02 to 4.22, p = 0.05). ERT may be protective against
atherothrombosis when the
Factor V Leiden mutation is absent, whereas the
Factor V Leiden mutation may increase risk for
atherothrombosis, particularly in the presence of ERT. We suggest that the
Factor V Leiden mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the
Factor V Leiden mutation (4%), in whom ERT is relatively or absolutely contraindicated because of increased risk for
atherothrombosis and
thromboembolism. A second, much larger group of women will also be identified without the
factor V Leiden mutation (96%), in whom ERT may reduce the risk for
atherothrombosis.