Jewish Hospital Cholesterol Center, Charles J. Glueck MD, Director, James E. Lang MD, Associate Director, LeAnn Coberly MD
Assistant Medical Director. Jewish Hospital Cholesterol Center, 3200 Burnet Ave, Cincinnati, Ohio 45229.
I. Background 1:Frequency of the Mutation:
About 6% of Caucasians and 3% of African-Americans are heterozygous for the Factor V Leiden mutation, which is,
however, very rare to absent in Asians. The gene mutation is in coagulation factor V which makes it resistant to inhibition by protein C. In the
coagulation cascade, Factor V is always "turned on", promoting thrombosis, but is inhibited by proteins C and (to a lesser degree) S. Hence,
the gene mutation produces "resistance to activated protein C" in which Factor V is poorly inhibited, if at all. The coagulation disorder
can be measured by a relatively simple, relatively inexpensive (~$75) clotting test (resistance to activated protein C), or by a more exact, more
expensive (~$150) gold standard, cDNA-PCR test of the V Leiden gene. Exogenous estrogen often (usually) produces acquired resistance to
activated protein C; hence, this serologic (blood) test can be abnormal even if the genotype is normal. Estrogen's ability to produce "acquired
resistance to protein C", when superimposed on Familial resistance to protein C (the Factor V Leiden mutation), vastly increases resistance to
activated protein C, and leads to both venous and arterial thrombi. The cDNA-PCR test is unaffected by exogenous estrogen.
Frequency of the Prothrombin gene mutation:
The prothrombin gene mutation exists in about 6% of Caucasians. It can be measured by a gold standard, cDNA-PCR test of
the prothrombin gene ($150). The serologic measurement of prothrombin is not sensitive or specific enough to identify the trait. When present,
heterozygosity for the prothrombin gene mutation vastly increases risk of venous thrombosis (about 10 fold), but with exogenous estrogen, the risk
increases 100 fold, and risk of arterial thrombosis also is then present, about twice as high as normal.
II. Background 2: Which test to use for screening:
In women not on exogenous estrogen and not pregnant and in men, the less expensive, serologic test is appropriate for
resistance to activated protein C. There is no sensitive and specific test for the prothrombin gene mutation, which requires the cDNA-PCR test.. In
women on exogenous estrogen or pregnant (physiologic hyperestrogenemia), only the cDNA-PCR test is appropriate for the Factor V Leiden
determination.
III. Background 3: Venous thrombosis:
The mutant Factor V Leiden is the most common cause (>50% of cases) of venous thrombosis (phlebitis, pulmonary
embolus, retinal vein thrombosis, osteonecrosis), and is a major cause of first trimester miscarriage, producing placental insufficiency. Being
heterozygous for the V Leiden trait as associated with a 10 fold increase in risk of venous thrombosis in both men and women. Being heterozygous for
the prothrombin gene mutation is also associated with about a 10 fold increase in risk of venous thrombosis in both men and women. When
exogenous estrogen is given to women, heterozygous for the V Leiden trait or heterozygous for the prothrombin gene mutation, then the risk of venous
thrombosis skyrockets, increasing to 100 fold the usual population risk, and arterial thrombosis risk is increased two-fold. Exogenous estrogen is
rarely, if ever, given to men. However, in the VA prostate cancer trial, when estrogen was given to men, there was a highly significant increase in
atherothrombotic myocardial infarction and stroke in the estrogen-treated men vs placebo, and we speculate that much of this was accounted by venous
and arterial thromboembolism in men who were heterozygous for either the V Leiden trait or for the prothrombin gene mutation.
IV. Background 4: Arterial thrombosis:
In men, heterozygosity for the Factor V Leiden mutation is a major cause of venous thrombosis, but is not associated with arterial thrombosis, probably because men have very low endogenous estrogen levels, do not have physiologic hyperestrogenemia
(pregnancy), and almost never receive exogenous estrogens or estrogen agonists. In women, however, heterozygosity for the V Leiden mutation, independent
of exogenous estrogen is associated with an (estimated) 2 fold increased risk of atherothrombosis, and an estimated 10 fold increase when
exogenous estrogen is given.
V. Background 5: Scientific Update, 9/27/2000. Failure of estrogen replacement therapy (ERT) to reduce coronary heart disease, coupled with an increase in atherothrombotic events.
Recently, the first major, placebo-controlled clinical trial of estrogen
replacement therapy (ERT) in the secondary prevention of coronary heart disease (CHD) has been reported (the HERS study).1 Over an
average 4.1 years of followup, ERT failed to reduce the overall rate of CHD events, but increased thromboembolic events by 289% and gall bladder
disease by 38%.1 In the Estrogen and Atherosclerosis (ERA) trial,2 309 postmenopausal women with at least 1 coronary artery
stenosis >30% were randomized to premarin 0.625 mg/day (n=100), premarin plus medroxyprogesterone acetate 2.5 mg/day (n=104), or placebo (n=105).
After mean followup of 3.2 years, there was no difference between the three groups in coronary artery disease progression measured by change in the
mean minimal lumen diameter by quantitative coronary angiography. Moreover, the change in mean minimal lumen diameter from baseline to
follow-up, a measure of disease progression, did not differ significantly among the 3 treatment groups. Preliminary data from the data and safety
monitoring board of a third prospective, placebo-controlled, randomized clinical trial, the Woman's Health Initiative Hormone Replacement Trial
(WHI-HRT),3,4 like HERS1 and ERA,2 revealed no cardiovascular benefit from ERT (Lenfant, NHLBI statement, 4/17/00).
The WHI-HRT included 16,609 postmenopausal women with a uterus taking estrogen combined with progestin, 10,739 women with a hysterectomy taking
estrogen alone, and a placebo group.3,4 During the first two years of the WHI-HRT there was a small increase in the number of myocardial
infarctions, strokes, and thromboemboli in women taking active hormones compared to placebos. These increased events, however, did not meet
statistical criteria for stopping the trial (Lenfant, NHLBI statement, 4/17/00). Along with HERS1 and ERA2, WHI-HRT3,4 was the third prospective, placebo-controlled, randomized clinical trial which suggested that ERT is not cardio-protective in postmenopausal women
with CHD, and substantially increases thromboembolism.
Our recent cross-sectional study5 of interactions between the
thrombophilic Factor V Leiden gene mutation, ERT, and ATCVD in 423 women referred for hyperlipidemic therapy may provide some insight into the
unexpected failure of ERT to reduce CHD in the HERS,1 ERA,2 and WHI-HRT3,4 studies. We reported an interaction
between ERT-mediated thrombophilia and the thrombophilic Factor V Leiden mutation for ATCVD.5 Independent of other risk factors for ATCVD,
ATCVD events were more likely in two subgroups of women, not taking ERT (ERT minus [-]) and without the Factor V Leiden gene mutation (Leiden gene
mutation minus [-]) or ERT users (ERT plus [+]) and Leiden gene mutation present (Leiden plus [+]).5 ERT was protective against ATCVD in
Leiden gene mutation - women; 24% of Factor V Leiden gene mutation - women on ERT had sustained ATCVD vs 43% of those not on ERT (p=.001).5 We speculated5 that when ERT-mediated thrombophilia is superimposed on the heritable thrombophilic Factor V Leiden mutation, ATCVD is
promoted, and any putative1-4 ERT associated reduction in ATCVD is overshadowed. We speculated5 that ERT might reduce ATCVD in
women without the Factor V Leiden gene mutation, and suggested,5-7 as have others,8-12 that women with the Factor V Leiden gene
mutation not be given ERT, so as to reduce thromboembolic events,1 and (speculatively) ATCVD.
Recently, we have shown that exogenous estrogen interacts with a common
heritable trait, the prothrombin gene mutation, which is present in at least 6% of American women.13
In a consecutive case series, cross-sectional study of 275 women referred
for therapy of hyperlipidemia, (75 [27%] on estrogen replacement therapy [ERT]), our specific aim was to determine whether ERT-mediated thrombophilia
and heterozygosity for the thrombophilic 20210 G/A prothrombin gene mutation interacted as risk factors for atherothrombotic cardiovascular disease
(ATCVD).13 Of the 275 women, 100 (36%) had ATCVD; 10 (3.6%) were heterozygous for the 20210 G/A prothrombin gene mutation. In women without
the 20210 G/A prothrombin gene mutation, 15 of 71 (21%) on ERT had ATCVD vs 78 of 194 (40%) not on ERT (X2 = 8.31, p=.004). By
stepwise logistic regression, in 261 women with ATCVD risk factor data, positive explanatory variables for ATCVD included the 20210 G/A prothrombin
mutation (risk odds ratio 5.8, 95% confidence intervals [CI] 1.4-30.2, p=.021) and a 20210 G/A prothrombin gene mutation*ERT interaction term (risk
odds ratio 2.70, 95% CI 1.4-5.4, p=.004). ATCVD events were more likely in two subgroups of women (ERT - and 20210 G/A prothrombin gene mutation -) or
(ERT + and 20210 G/A prothrombin gene mutation +), p=.004. Other positive explanatory variables for ATCVD events included age (p=.004), triglycerides
(p=.012), lipoprotein (a) (p=.03), and homocysteine (p=.032). ERT may be protective against ATCVD when the thrombophilic 20210 G/A prothrombin gene
mutation is absent, whereas the 20210 G/A prothrombin gene mutation may increase risk for ATCVD, particularly in the presence of ERT. We suggest that
the 20210 G/A prothrombin gene mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the
thrombophilic prothrombin gene mutation (4%) in whom ERT is contraindicated because of increased risk for ATCVD and thromboembolism, and a
second, much larger group of women without the 20210 G/A prothrombin gene mutation (96%) in whom ERT may possibly reduce risk for ATCVD.
References
VI. Health Outcomes and the Factor V Leiden and prothrombin gene mutations:
We have suggested that before giving ERT, the serologic or PCR-DNA assay for both the V Leiden and
prothrombin gene mutations be done, identifying a group of women (4-6% of Caucasians) who should not be given ERT because of a 100 fold increased risk
of venous thromboembolism and a 10 fold increase risk of atherothrombosis when the thrombophilic effects of ERT were superimposed on the underlying
thrombophilic V Leiden and prothrombin gene mutations. In women already on ERT, the screening test should be the cDNA-PCR assay.
I. Recommendation 1: Before EVER giving estrogen-containing oral
contraceptives or estrogen replacement therapy, or in women already on such therapy, screen using the serologic resistance to activated protein C assay,
and genotype for the prothrombin gene, or genotype for both the prothrombin and V Leiden mutations by cDNA-PCR assay (MDL lab [513-475-6631]). In women already on ERT, or pregnant, the assay of choice is the cDNA-PCR test, since it is not effected by exogenous estrogen, unlike the serologic
test.
II.Recommendation 2: In women, heterozygous for the Factor V Leiden mutation,
and/or heterozygous for the prothrombin gene mutation, exogenous estrogens are relatively to absolutely contraindicated.
III. References: Factor V Leiden Mutation, venous and arterial thrombosis, interactions with exogenous estrogen
(6/3/99):
- A major risk factor for osteonecrosis of the hip (adults and children) and jaw (adults). Venous thrombosis as
a pathoetiology of osteonecrosis. Factor V Leiden mutation has been shown to interact with ERT to promote osteonecrosis.
- A major risk factor for retinal vein thrombosis (adults). Venous thrombosis as a pathoetiology for retinal
vein thrombosis. Factor V Leiden mutation has been shown to interact with ERT to promote retinal vein thrombosis.
- A major risk factor for first trimester miscarriage and for major complications of pregnancy. Physiologic
hyperestrogenemia of pregnancy interacts with Factor V Leiden mutation.
- A major risk factor in men when interacting with other thrombophilic and hypofibrinolytic risk factors (atherothrombosis),
and in women, when interacting with estrogen, for venous and arterial thrombosis.
Osteonecrosis of the Hip
Osteonecrosis of the Jaws:
Atherothrombosis: Arterial thrombosis
Retinal Vein Thrombosis:
E-mail: glueckch@healthall.comor cglueck@fuse.net Fax: 513-924-8273
Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L, Lang JE. The thrombophilic factor V Leiden mutation (Resistance to
Activated Protein C) and estrogen therapy as risk factors for atherothrombotic cardiovascular disease in 423 hyperlipidemic women. Am J Cardiology, September
1, 1999
1. Specific aim:
In a cross-sectional study of 423 hyperlipidemic women (93
[22%] on estrogen replacement [estrogen replacement therapy]), we assessed whether heterozygosity for the Factor V Leiden mutation (LM) and/or
resistance to activated protein C (RAPC) and estrogen replacement therapy interacted as risk factors for atherothrombotic cardiovascular disease
(atherothrombotic cardiovascular disease).
Results 1: Of the 423 women, 168 (40%) had atherothrombotic cardiovascular
disease; 19 (4%) were heterozygous for LM or had RAPC <2 (LM+), 404 were wild type normal for the Factor V gene and/or had RAPC > 2
(LM-).
Results 2: By stepwise logistic regression, positive explanatory variables
for atherothrombotic cardiovascular disease included hypertension (p=.002), age (p=.003), relatives' atherothrombotic cardiovascular disease (p=.002),
anticardiolipin antibody IgM (p=.02), and an LM*estrogen replacement therapy interaction term where atherothrombotic cardiovascular disease events
were more likely in two subgroups of women (estrogen replacement therapy- and LM-) or (estrogen replacement therapy+ and LM+) (p=.02). HDLC was
inversely associated with atherothrombotic cardiovascular disease (p=.004).
Results 3: In a separate logistic regression model for the 213 women with PCR
measurement of the Factor V gene, estrogen replacement therapy was protective (p=.008); the LM was positively associated with atherothrombotic
cardiovascular disease (p=.050).
Results 4: The atherothrombotic cardiovascular disease risk odds ratio for
estrogen replacement therapy (yes vs no) was 0.36 with 95% confidence intervals (CI) 0.16-0.74, p=.007. The atherothrombotic cardiovascular disease
risk odds ratio in women heterozygous for LM (vs normal) was 2.00 with 95% CI 1.02-4.22, p=.05.
Conclusion 1: estrogen replacement therapy may be protective against
atherothrombotic cardiovascular disease when the LM is absent, whereas the LM may increase risk for atherothrombotic cardiovascular disease, particularly in the presence of estrogen replacement therapy.
Conclusion 2: We suggest that the LM be measured in all women already on estrogen replacement therapy or before beginning estrogen replacement therapy. This would identify women heterozygous or homozygous for LM (4%) in
whom estrogen replacement therapy is relatively or absolutely contraindicated because of increased risk for atherothrombotic cardiovascular disease
and thromboembolism, and a second, much larger group of women without LM (96%) in whom estrogen replacement therapy may reduce risk for
atherothrombotic cardiovascular disease.
