The Health Outcome

Venous thromboembolism (VTE) occurs in about 1 in 1000 persons per year and results in significant morbidity and mortality (1,2).  It is a multifactorial disease resulting from both acquired and genetic factors with deep vein thrombosis (DVT) and subsequent pulmonary embolism (PE) as the most common presentations (1).

In a previous analysis, Daly et al. (3) found a 3.5 increased risk for VTE among women taking hormone replacement therapy (HRT) with the highest risk occurring in the first year of use.  This is consistent with a number of other studies, which have shown the risk to be between twofold to threefold. (4).

Genetic mutations in the clotting cascade have been implicated in VTE.  Factor V Leiden, a guanine to adenine mutation in the Factor V gene that results in activated protein C resistance, has a prevalence of about 5% in Caucasian populations (5).  Heterozygosity for the mutation increases risk for VTE about sevenfold, while homozygosity can increase risk 80-fold (5,6).  Another common inherited thrombophilia is a mutation in Factor II, Prothrombin 20210A, which is found in about 2% of Caucasians.  This mutation results in increased prothrombin levels, and has been found to increase risk for thrombosis about twofold to threefold (1,7,8).

The Finding

In the current analysis (9), the authors reanalyzed the case-control study by Daly et al. (3), which was designed to investigate the association between idiopathic DVT or PE and HRT use.   A follow-up study invited all original study participants to participate to evaluate thrombophilia phenotypes and the risk for DVT in HRT users (10).   The current study went a step further to look at the two most prevalent mutations associated with VTE, Factor V Leiden and Prothrombin 20210A, to assess whether HRT users with variant genotypes were at greater risk than HRT users without the mutations for VTE.

Case and control participants for the original study were recruited from hospitals in the Oxford Regional Health Authority area during 1990-1994.   One hundred three women aged 45-64 years admitted for a first occurrence of idiopathic VTE (DVT or PE) were recruited as cases.  Up to two women per case, matched for age, district of admission, and date of admission, were enrolled for a total of 178 controls.  Control women were admitted to hospital for reasons unrelated to thrombosis and HRT use.  Case and control groups excluded women who had histories of stroke, myocardial infarction, or cancer, or who in the 6 weeks before hospitalization had been pregnant or had undergone surgery or immobilization.

In the follow-up study, all surviving participants were invited to participate.  A total of 80 case women and 171 control women consented to participate.   From these, DNA was available for 77 and 163, respectively.  Current HRT use was defined as use at any time in the month preceding admission to hospital.   Case and control women were genotyped for Factor V Leiden and Prothrombin 20210A variants.  None of the women were homozygous for either mutation, and only four women carried the prothrombin variant.

The authors found a threefold increase in risk for VTE associated with HRT use alone (odds ratio=3.3, 95% confidence interval 1.8, 5.8). Regardless of HRT use, the presence of the Factor V Leiden mutation increased risk fourfold (OR=4.0, 95% CI 1.6,10.2) while the Prothrombin mutation showed a twofold increase in risk (OR=2.2, 95% CI 0.2, 30.3).  Looking at the joint effect of HRT use and presence of the Factor V Leiden variant, the authors found a 15-fold increased risk for VTE (OR=15.5, 95% CI (3.1, 76.7)).  The authors stated that the joint effect clearly exceeded the expected additive effect of six-fold, indicating a gene-environment interaction.

The authors concluded that their study demonstrated that HRT use and prothrombotic mutations increased risk for venous thrombosis for women aged 45-64 years.  They suggest that efforts be taken to limit prescription of HRT to women with heritable thrombophilia.

The findings from this study are compelling.  Consistent with current literature, the authors found an increased risk for VTE among HRT users as well as among the women with prothrombotic mutations.  Showing the synergistic effect of two strong risk factors, this study raises an already heightened concern regarding HRT use.  With the recent publicity from the results of the Women's Health Initiative, doctors and patients are already weighing the risk-to-benefit ratio of HRT use (11,12). 

The results from this study raise additional concerns about prescription of HRT for women who are genetically predisposed to thrombosis.  The authors argue that screening for Factor V Leiden in postmenopausal women and the subsequent withholding of HRT in women tested positive would prevent 5-25 thrombotic events per year per 10,000 women.   However, because recent evidence suggests that HRT may not help prevent cardiovascular disease (11,13), withholding HRT may be more prudent and more cost-effective, as the authors point out, in women with other risk factors for VTE, such as obesity and familial risk.

Although these results are significant, the sample size is small, and larger studies are needed to confirm this association.  In addition, perhaps a more thorough look at the types of treatment used, i.e., estrogen only versus progesterone and estrogen, the dosage, and length of treatment may help elucidate the women at greatest risk for VTE when using HRT.

References

1. Rosendaal FR.  Venous thrombosis: a multicausal disease.  Lancet 1999; 353:1167-1173.
2. SIlverstein MD,  Heit JA, Mohr DN, et al.  Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.  Arch Intern Med 1998; 158:585-593.
3. Daly E, Vessey M, Hawkins M, et al.  Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996;348:977-980.
4. J, Chan BKS, Nelson H.  Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the US preventive services task force.  2002.  Ann Intern Med 2002;136:680-690.
5. WW, Griffin JH, Taylor AK, et al. American college of medical genetics consensus statement on factor V leiden mutation testing  Genet Med 2001;3:139-148.
6. FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance).  Blood 1995;85: 1504-1508.
7. SR, Rosendaal FR, Reitsma PH, et al.  A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3703.
8. Margaglione M, Brancaccio V, Giuliani N, et al.  Increased risk for venous thrombosis in carriers of the prothrombin G -->A20210 gene variant.  Ann Intern Med 1998;129:89-93.
9. Rosendaal FR, Vessey M, Rumley A, et al.  Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis.  Br J Haematol 2002;116:851-854.
10. Lowe G, Woodward M, Vessey M, et al.  Thrombotic variables and risk of idiopathic venous thromboembolism in women aged 45-64 years. Thromb Haemost 2000;83:530-535.
11. Writing Group for the Women's Health Imitative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women.  JAMA 2002;288:321-333.
12. Nelson H. Assessing benefits and harms of hormone replacement therapy; clinical applications.  JAMA 2002;288:882-884.
13. Nelson H, Humphrey L, Nygren P, et al. Postmenopausal hormone replacement therapy; scientific review.  JAMA 2002;288:872-881.