**[Women]{.underline}[']{.underline}[s Issues in Venous
Thromboembolism]{.underline}**

**[Suman Rathbun, MD, MS]{.underline}**

**[Associate Professor of Medicine]{.underline}**

**[Associate Director of the Vascular Medicine Program]{.underline}**

**[University of Oklahoma Health Sciences Center]{.underline}**

**[April 7, 2006]{.underline}**

**[Department of Medicine]{.underline}**

**[Cardiovascular section]{.underline}**

**[University of Oklahoma Health Sciences Center]{.underline}**

**[920 Stanton. L. Young Blvd. WP 3120]{.underline}**

**[Oklahoma City, OK 73104]{.underline}**

**[Phone: 405-271-4742]{.underline}**

**[Fax: 405-271-2679]{.underline}**

**[E-mail: ]{.underline}**

[The risk of ]{.underline}***[venous thromboembolism
(VTE)]{.underline}***[ throughout a woman's life has been found to vary
chronologically. Hormonal exposure in large part underlies this risk.
Early, a woman may be exposed to ]{.underline}***[oral contraceptive
therapy (OCPs)]{.underline}***[, later pregnancy, and finally with
menopause, a woman may choose to receive ]{.underline}***[hormone
replacement therapy]{.underline}**[ (HRT)]{.underline}***[. This varying
risk may be related to the duration of estrogen exposure. In addition,
the risk of VTE in women is inherently influenced by age, race, weight,
and ]{.underline}***[inherited ]{.underline}**[predisposition to
clotting (thrombophilia)]{.underline}***[. Externally, this risk is
influenced by the formulation, dose and duration of estrogen and
progestin administration. Taken together, these factors may pose
significant risk of VTE throughout a woman's life and should be
thoughtfully considered as an important women's health
issue.]{.underline}

[While most studies report the overall risk of VTE similar in men
compared with women, there are several reports of specific trends
related to gender. For example, evaluation of risk factors for VTE in
men versus women in a study of general surgery patients performed in
Italy found that women possessed more significant risk factors for VTE
than men, the most common being varicose veins, obesity and estrogen
treatment (1). Overall, 80% of women and 67% of men had at least one
risk factor, whereas, 51% of women and 35% of men had at least two risk
factors. A recent retrospective case control study has found that
lifetime estrogen exposure may be related to overall risk of VTE (2).
After adjustment for other common risk factors for VTE in women, it was
found that the risk of VTE increased by 6% for each year's delay in
menopause. Moreover, women with more than two children had a two-fold in
lifetime VTE risk compared with women with two or less children. The
combination of late menopause and oral estrogen use had the highest risk
of VTE. Other studies have confirmed the association of late menopause
and increased parity with risk of VTE (3,4). ]{.underline}

[A large study has found that, although the risk of first episode VTE
may be equal in men compared with women, men are at higher risk for
recurrent VTE (5). ]{.underline}

**[Assessment of VTE risk wi]{.underline}[th oral contraceptive
use]{.underline}**

[Over the past 10 years, there have been numerous evaluations of the
risk of VTE associated with the use of oral contraceptive preparations.
This risk has been further stratified by presence of thrombophilia, age,
weight, estrogen dose and route of administration, and progestin
preparation. The best estimates are that among all users of OCPs, the
risk of VTE is increased 2 to 8-fold compared with non-users (6-11).
While this elevation in risk with OCP use warrants discussion, it must
be put in the context of the very low overall risk of VTE with OCP use.
For example, women of fertile age have a risk of VTE of 1 per 10,000
persons per year that may be increase to 2 to 8 per 10,000 person-years
with the use of OCPs (12,13). Compared with the risk of pregnancy that
is associated with an even greater risk of VTE and the social and
economic consequences thereafter, the low risk of VTE with effective OCP
contraceptive use must be noted.]{.underline}

[The biological effects of OCPs on clotting factors include increased
levels of clotting proteins, and decreased levels of clotting inhibitors
(14). OCP use also leads to an acquired activated protein C resistance
thereby preventing the breakdown of clot. Recently it has been found
that this resistance may be more pronounced with use of the newer
third-generation OCPs compared with second-generation OCPs, and less
pronounced in those using progestin-only OCPs (15).]{.underline}

[Investigation of the temporal relationship between OCP use and VTE risk
has revealed that the risk is increased in first time users of OCPs and
is especially elevated during the first six months of use revealing
those who may have inherited clotting tendencies (7,16-18). With
discontinuation of use, the risk returns to that of non-users within one
to three months. Duration of use or lifetime cumulative use does not
seem to alter the VTE risk associated with OCP use, nor does re-exposure
after a period of non-use (6,18,19). ]{.underline}

[It is known that the incidence of VTE is rare before puberty, and
increases with age (20). The risk in women over 40 may be more than
three times greater than in those less than 25 years of age. However,
there have been few quantitative studies that document the magnitude of
interaction between age and OCP use. Reasonable assessment dictates that
OCP use confers a higher risk of VTE with increasing age
(18).]{.underline}

[Similarly, while it is well known that smoking increases the risk of
cardiovascular events in women who use OCPs (21), the risk of VTE in OCP
users that smoke has not been well elucidated, but has been shown to be
increased approximately two-fold (6,7,22).]{.underline}

[The evaluation of elevated body mass index (BMI) in conjunction with
OCP use has shown that the risk of VTE is increased five to ten-fold,
and especially significant with BMI greater than 30kg/m2 (6.7,22,23).
This risk is further increased in the presence of smoking (7).
]{.underline}

[Risk by formulation]{.underline}

[After the introduction of OCPs in the 1960s, it became readily apparent
that use was associated with an elevated risk of cardiovascular disease.
This recognition prompted evaluation of the formulation of OCPs,
scrutinizing both the dose of estrogen used as well as the formulation
of the progestin component. Subsequently, the form of estrogen was
changed from mestranol to ethinyl estradiol, and the estrogen dose was
lowered from 100 micrograms
]{.underline}***[(first-generation)]{.underline}***[ to 50 micrograms
]{.underline}***[(second-generation)]{.underline}***[ with preparations
available containing 30 micrograms or less. This reduction was effective
in lowering the risk of both cardiovascular disease and VTE (16,24-28).
The progestin component was also reviewed, and studies were performed to
evaluate any differences in risk with levonorgestrel found in
second-generation OCPs compared with desogestrel or gestodene found in
the newer ]{.underline}***[third-generation]{.underline}***[
formulations. Early studies showed that the risk of venous thrombosis
associated with third generation OCPs was significantly higher by about
two-fold compared with second generation OCPs (6,7,16,27). While
initially disputed as due to confounding by age (8), two recent
meta-analyses confirmed the increased risk with third-generation OCPs
(18,29). Newer fourth-generation preparations containing cyproterone
acetate are also being evaluated, and preliminary studies reveal a
four-fold increased risk in VTE compared with second generation OCPs
(26,30). To date, no studies have been published that confirm the
increased risk of VTE with the
]{.underline}***[fourth-generation]{.underline}***[ progestin
drospirenone. In addition, there have been no apparent differences found
between monophasic OCPs giving a constant daily dose of estrogen and
progestin compared with multiphasic OCPs that vary the dose of the
components through the cycle (18). ]{.underline}

[Progesterone-only preparations containing injectable
medroxyprogesterone are infrequently used. Case-control studies have
found little effect on the risk of VTE when used for contraception
(18,31,32). Other progesterone-only products include an oral daily
tablet and an intrauterine device. Both these preparations carry less
risk of VTE compared with combination estrogen/progestin products, and
may be an option for women at high risk for VTE.]{.underline}

[The ]{.underline}***[transdermal]{.underline}**[
]{.underline}***[(through the skin) contraceptive patch containing a
combination of ethinyl estradiol and the progestin norelgestromin was
marketed in 2002. Since, then only one study has been published that
evaluated the risk of venous thromboembolism (33). This case-control
study compared the risk of non-fatal VTE in woman receiving the
transdermal contraceptive patch with monophasic or triphasic OCPs
containing norgestimate and 35 micrograms of ethinyl estradiol. Overall,
the risk of non-fatal VTE was no higher in those receiving the
transdermal patch compared with those receiving OCPs, although the
effect of duration of use could not be evaluated.]{.underline}

[Risk with thrombophilia]{.underline}

[The interaction between inherited risk for venous thromboembolism and
OCP use has been extensively evaluated, in particular with respect to
the heterozygous (one gene of two abnormal) Factor V Leiden and
prothrombin G20210 mutations. First estimates of a synergistic
association were derived from the Leiden Thrombophilia Study (34) which
revealed a 37-fold increased risk of VTE in individuals with
heterozygous Factor V Leiden mutation using OCPs compared with
non-carriers who were non-OCP users. This translated into an estimated
annual incidence of VTE of 28.5 per 10,000 women-years. Further studies
confirmed the increased risk but estimates were lower in the 10-fold
range (35,36). Homozygous (both genes abnormal) Factor V Leiden mutation
confers even greater risk (37,38).These studies also found a synergistic
increase in risk in carriers of the prothrombin gene mutation of 16-fold
(35,37,38). Recent meta-analyses have further attested to the increased
risk (9). Carriage of the combination of these mutations results in a
17-fold increase in DVT compared with non-carrier, non-OCP users (12).
Further, it has been discovered that the risk with genetic thrombophilia
is highest during the first 6 months of use and declines thereafter
(17). Activated protein C resistance in the absence of Factor V Leiden
mutation also has been shown to be associated with an increased risk of
VTE, but not as great as that in carriers of the mutation (39). In
addition, those with genetic thrombophilia who use third-generation OCPs
may be at greater risk compared to second generation users, although the
magnitude is not known (24,35,40).]{.underline}

[Other inherited thrombophilias including protein C, S, and antithrombin
deficiency have also been evaluated in OCP users and found to confer
increased VTE risk in the magnitude of 2 to 6-fold compared with non-OCP
users (9,41). Elevated levels of clotting factors, most notably factor
VIII, have been found to be associated with a four-fold increase in VTE
risk in OCP users (42). Re-analysis of the Leiden Thrombophilia study
revealed associations between elevated levels of Factor II and Factor XI
with higher risk of VTE in OCP users compared with nonusers
(43).]{.underline}

[The risk of VTE at other sites including cerebral vein thrombosis,
portal vein thrombosis and superficial thrombophlebitis with OCP use has
been reported. Studies report an increased risk of cerebral vein
thrombosis in carriers of both Factor V Leiden mutation and protein G
mutation that may be further elevated in those receiving third
generation OCPs (44-47). Genetic thrombophilia has been found to be a
risk factor for portal vein thrombosis, but OCP use was not associated.
(48) Remote studies reported an association between OCP use and
superficial thrombophlebitis, however, more recent reports have refuted
this risk (49,50).]{.underline}

[Prevention]{.underline}

[No trial has assessed the benefit of medical prevention of VTE in women
using OCPs (10). Currently, there are no recommendations for
discontinuation of OCPs prior to surgery. Appropriate prophylactic
measures should be taken according to those recommended routinely for
surgical procedures. In addition, universal screening for thrombophilia
prior to use of OCPs in an otherwise healthy woman is not recommended.
]{.underline}

**[Assessment of VTE risk duri]{.underline}[ng pregnancy]{.underline}**

[The reported overall risk of venous thromboembolism during pregnancy is
variable, and though to be from 18 per 100,000 women during pregnancy to
1900 per 100,000 women post-partum (51), but generally the risk is five
times more likely in pregnant women compared with non-pregnant women.
Moreover, pulmonary embolism is the most common cause of maternal death
in developed countries (52). DVT occurs more commonly on the left side.
Acquired resistance to activated protein C as discussed above, and a
reduction in protein S as well as venous stasis (pooling of blood in the
veins) are the likely physiological predisposing causes of VTE during
pregnancy. Only recently has longitudinal data been presented that more
descriptively assesses the risk. In a 30 year population-based cohort
study in Olmstead County, Minnesota, it was found the relative risk of
VTE during pregnancy and in the post-partum period is four-fold compared
with those not pregnant (51). ]{.underline}

[Other notable findings were a relatively constant rate of VTE during
the last 20 weeks of pregnancy, and a much higher risk post-partum. The
incidence of VTE increased with age, but younger women age 15 to 19 had
the highest risk overall. The reasons for this finding are not clear.
Smoking was associated with a higher risk of VTE during pregnancy.
Previous studies have found that obesity, immobilization, increased
gestational age at delivery, and preeclampsia were associated with a
higher risk, but these findings were not confirmed in this study (53).
Only a history of VTE and thrombophilia were associated with higher
risk.]{.underline}

[The risk of pulmonary embolism, especially post-partum, decreased over
the study period. Although this study included mostly white patients,
other studies have found that pregnancy-associated VTE is more common in
blacks (54). There is no consistent data confirming an increased risk of
VTE after C-section (55).]{.underline}

[Risk with thrombophilia]{.underline}

[A rigorous meta-analysis reviewed the available data regarding the risk
of VTE with inherited thrombophilia (56). Heterozygous and homozygous
factor V Leiden confers a 34-fold and 8-fold increased in
pregnancy-associated VTE compared with non-pregnant women, although the
absolute risk remains low. Heterozygous prothrombin G mutation was
associated with a 6.8-fold elevation in risk. The less common
antithrombin, protein C, and protein S deficiencies carried about a 3 to
4-fold increase in VTE risk. Homozygous MTHRF mutation that is
associated with homocysteinemia was not found to confer increased risk.
The highest risk for VTE during pregnancy is in women with
antiphospholipid antibodies which commonly manifests as pregnancy loss
after 10 weeks gestation (57). Lupus anticoagulant antibodies confer
higher risk than anticardiolipin antibodies (57). One study has reported
a higher risk of VTE with A or AB blood groups compared with women with
the O blood group (58). Despite these associations, universal screening
for thrombophilia prior to pregnancy is not currently
recommended.]{.underline}

[Prevention and treatment]{.underline}

[The use of medical prevention with ]{.underline}***[unfractionated
heparin (]{.underline}**[UFH)]{.underline}***[ or ]{.underline}***[low
molecular weight heparin (LMWH)]{.underline}***[ in women with a history
of VTE or known thrombophilia is controversial (59). There are no large
randomized trials, and recommendations are based on small studies. Two
studies have evaluated the risk of recurrent thrombosis during pregnancy
in women with a history of VTE and found it to be between 2 and 6% in
women not receiving any pharmacological prophylaxis (60,61). Women with
known hereditary thrombophilia were at higher risk for recurrent VTE.
Consensus panel recommendations support use of prophylaxis with UFH or
LMWH for women with a single VTE and known thrombophilia, and
therapeutic dose UFH or LMWH in women with a history of recurrent VTE
(62). In women with a history of VTE associated with a risk factor that
is no longer present, watchful waiting without pharmacological treatment
is appropriate during pregnancy with medical prophylaxis post-partum for
6 weeks (63). For pregnant women with known antiphospholipid antibodies
and one or more fetal losses, a combination of heparin and low dose
aspirin is recommended. All women with a history of VTE, should wear
graduated compression stockings during pregnancy and post-partum
(62).]{.underline}

[The treatment of acute VTE during pregnancy with either UFH or LMWH has
shown to be effective during pregnancy (64). Either intravenous UFH or
adjusted-dose LMWH for 5 days followed by adjusted-dose UFH or LMWH for
the remainder of pregnancy is recommended (62). While LMWH may be
cleared through the kidneys more quickly in pregnancy, there are no
consistent guidelines regarding monitoring of clotting factor
(anti-factor Xa) levels during pregnancy (62,65). Warfarin may be
substituted post-partum and continued for at least 6 weeks. The use of
UFH and LMWH has been shown to be safe for use in pregnancy, both for
prevention and treatment of VTE. Major bleeding is rare and occurs with
similar incidence to that in non-pregnant women. Heparin-induced
thrombocytopenia (low platelets) and osteoporosis occur more commonly
after prolonged UFH use, but are much less common with LMWH use (62,64).
Anticoagulation should be discontinued 24 hours prior to elective
induction of labor (62). Heparin and LMWH do not cross the placenta and
are not secreted into breast milk. Warfarin use has also been found to
be safe for nursing mothers and their infants (62). For pregnant women
with contraindications to blood-thinning therapy, there is anecdotal
evidence that the use of retrievable inferior vena cava filters is safe
(66). ]{.underline}

**[Assessment of VTE risk with HRT]{.underline}**

[The benefits and risks of hormone replacement therapy (HRT) have been
the topic of rigorous meta-analyses, and large randomized controlled
trials, yet still is under great debate. Most oral preparations contain
conjugated estrogens derived from pregnant mare urine or micronized
estradiol and are given in combination with progesterone acetate to
negate the increased risk of endometrial cancer in those without
hysterectomy. In addition, phytoestrogens have recently been marketed as
a natural source of estrogen replacement.]{.underline}

[Most agree that HRT improves the negative symptoms of menopause
including hot flashes, depression, and sleep disturbance, and increases
bone density, however, the overall cardiovascular benefit of HRT is
suspect. Further, these benefits must be balanced against the increase
risk of stroke, breast cancer and venous thromboembolism. Recent large
prospective trials, the Heart and Estrogen/progestin replacement study
(HERS) and Women's Health Initiative (WHI), have confirmed the 2 to
4-fold increase in VTE risk with HRT (3,67). The risk is greater with a
larger dose of estrogen administered \>1.25mg/day (68,69), and seems to
be greater within the first year returning to normal within months of
discontinuation of HRT (69-74). ]{.underline}

[There is emerging evidence that the timing of HRT after menopause may
influence the overall risk profile. One recent presentation (75) of the
Danish Osteoporosis Prevention Study (DOPS) reported no increased risk
of VTE on ten-year follow-up in women aged 45-58 years with HRT
administration. The participants in the large HERS and WHI trials were
significantly older with too few younger women enrolled to confirm this
possible lower risk in younger women. ]{.underline}

[Risk by formulation]{.underline}

[Women who have undergone hysterectomy are candidates for estrogen-only
HRT. Review of studies reporting estrogen-only HRT reveal a modest
increase of VTE risk of 1.3-fold, but there is large variability in
study design with small numbers of patients enrolled (76). Data from the
Women's Health Initiative study indicates the risk of VTE in women
receiving estrogen-only HRT is increased during the first two years of
use, but is still less than that with a progestin combination
(77).]{.underline}

[With the well-documented increase in VTE risk with oral HRT, recent
emphasis has been on evaluation of the risk associated with transdermal
(through the skin) HRT. Transdermal administration bypasses the
first-pass effect by the liver that may be responsible for induction of
a pro-clotting state. Studies evaluating this risk have conflicted.
Small studies initially also indicated increased VTE risk with
transdermal HRT, but more recent larger studies have shown no elevation
in risk (78,79). ]{.underline}

[To date, there have been no controlled studies on the risks of
nutritional supplements containing plant chemicals that have
estrogen-like properties known as
]{.underline}***[phytoestrogens]{.underline}***[. Many of these are
soy-based containing the isoflavones genistein and diadzein. Although
they may have found to have possible benefit in relieving
post-menopausal symptoms of hot flashes, the risks associated with their
use are unknown (80,81). The selective estrogen receptor modulators
tamoxifen and raloxifene used in the treatment of breast cancer and
osteoporosis, have a two to three-fold higher risk of VTE (82).
]{.underline}

[There are few studies evaluating the risk of HRT in women with a
previous history of VTE. One small study found a 5-fold increased risk
in recurrent VTE in women who used HRT compared with non-users (83).
This trend was also was seen the in WHI trials, but the number of women
with a history of VTE was too small to reach significance (67).
]{.underline}

[Risk with thrombophilia]{.underline}

[There are now several case-control studies that document the increased
risk of HRT use in woman with genetic thrombophilia. The most widely
studied is the interaction with Factor V Leiden mutation where the risk
is 7 to 17-fold higher in those with the genetic mutation who used oral
HRT compared with non-carrier, non-users (12,76,77,84). A less
significant elevated risk of VTE in those with the prothrombin mutation
and oral HRT has been shown (67,76,77). Notably, women with Factor V
Leiden or prothrombin G mutation who receive either estrogen-only or
transdermal estrogen HRT may not have additional risk of VTE above those
who carry these mutations and do not use HRT (76,77). Studies to date
show no increased risk with oral HRT in patients with
hyperhomocysteinemia, antiphospholipid antibodies or elevated factor XI
(85,86). However, levels of factor VIII correlated with risk of VTE in
both estrogen/progestin and estrogen-only HRT users (86).]{.underline}

[Prevention]{.underline}

[Prevention of VTE should be aimed at avoidance of HRT in high-risk
groups including those with a history of VTE. In women with genetic
thrombophilia who use HRT, the risk of VTE is elevated compared with
non-users, however, the overall incidence remains low. Use of
estrogen-only or transdermal estrogen may confer less risk of VTE. If
required, low-dose estrogen in younger woman for a short duration for
relief of post-menopausal symptoms likely is associated with the lowest
risk of VTE. To date, no studies have shown an increase in
post-operative risk in woman using HRT who undergo elective surgery
compared with non-users (87,88). Importantly, both mechanical and
pharmacological preventive measures should be used appropriately in
these patients. ]{.underline}

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