Download Postmenopausal Hormone Replacement Therapy Increases

Postmenopausal Hormone Replacement Therapy Increases
Coagulation Activity and Fibrinolysis
Helena J. Teede, Barry P. McGrath, Joseph J. Smolich, Erica Malan, Dimitra Kotsopoulos,
Yu-Lu Liang, Roger E. Peverill
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Abstract—Hormone replacement therapy (HRT) appears to be cardioprotective in postmenopausal women; however,
concerns exist over its thrombogenic effects. To address the effects of combined HRT on coagulation and fibrinolysis,
we have measured circulating markers of these processes in a double-blind placebo-controlled trial. Forty-two healthy
postmenopausal women aged 50 to 75 years received continuous combined HRT with 2 mg estradiol⫹1 mg
norethisterone or placebo for 6 weeks. Hormone profiles were measured at baseline, and lipid and hemostatic parameters
were measured at baseline and after 6 weeks of therapy. Baseline characteristics were similar in the 2 groups. With
change from baseline the main outcome measure, HRT increased the markers of coagulation (prothrombin fragments
1⫹2, 0.20⫾0.06 versus 0.06⫾0.04 nmol/L, P⫽0.0005; soluble fibrin, 2.3⫾0.4 versus 0.25⫾0.3 ␮g/mL, P⫽0.0004),
reduced plasma fibrinolytic inhibitory activity (plasminogen activator inhibitor-1, ⫺0.67⫾0.16 versus 0.24⫾0.21
U/mL, P⫽0.002), and increased fibrinolysis (D-dimer, 24⫾12 versus ⫺6⫾8 ng/mL, P⫽0.04) compared with placebo.
Increases in soluble fibrin and D-dimer were positively correlated (r⫽0.59, P⫽0.02), but changes in plasminogen
activator inhibitor-1 and D-dimer were unrelated. Although baseline hemostatic and lipid parameters were correlated,
there were no associations between changes in hemostatic markers and lipids after treatment. Short-term oral combined
continuous HRT (estradiol and norethisterone) increased thrombin and fibrin generation, reduced plasma fibrinolytic
inhibitory activity, and increased fibrinolysis. Enhanced fibrinolysis was related to increased fibrin generation but not
reduced plasma fibrinolytic inhibitory activity. Coagulation activation may partly explain the increases in venous
thrombosis and cardiovascular events reported with the use of combined HRT. (Arterioscler Thromb Vasc Biol.
2000;20:1404-1409.)
Key Words: thrombosis 䡲 coagulation 䡲 fibrinolysis 䡲 hormone replacement therapy 䡲 hemostatic markers
P
ostmenopausal hormone replacement therapy (HRT) reduces menopausal symptoms and protects against osteoporosis.1 Epidemiological studies have also consistently suggested that postmenopausal women using HRT have a
reduced risk of coronary artery disease.2,3 This reduced risk of
coronary events is believed to be mediated by an inhibition of
the atherosclerotic process, a hypothesis that is consistent
with the beneficial effects of HRT in humans on plasma
lipids4 and supported by animal studies showing that HRT
reduces the severity of atherosclerosis.5,6 However, thrombosis is also an important component of coronary events, and
concerns have been raised about the potential thrombogenic
effects of estrogen in the venous and arterial vasculature.
High-dose estrogen elevates the incidence of myocardial
infarction in men,7 whereas HRT in standard doses may
increase myocardial infarction and unstable angina in women
with significant preexisting atherosclerosis8,9 and has also
been associated with an increased incidence of venous
thromboembolism.8,10,11
Thrombosis results from inappropriate initiation and propagation of the hemostatic response and may occur as a result
of activation of coagulation or inhibition of fibrinolysis.12
That estrogen has a complex effect on the mechanisms
underlying thrombosis is suggested by clinical studies indicating that although it produces a dose-dependent increase in
plasma markers of thrombin and fibrin generation,13,14 it also
decreases plasma fibrinolytic inhibitory activity14 –18 by decreasing levels of plasminogen activator inhibitor-1 (PAI1).14,16 –18 However, there is considerable uncertainty regarding the effects of combined HRT with estrogen and progestin
on coagulation and fibrinolytic processes. First, findings
concerning the effects of combined HRT on coagulation
activation have been variable, with reports of an increase in
thrombin generation19,20 as well as no change in thrombin
generation16,21 or fibrin production.16 Second, the effect of
combined HRT on fibrinolysis is also controversial, with
reports of normal20 and increased18 levels of D-dimer, a
specific marker of fibrinolysis. Last, although elevation of
Received November 4, 1999; revision accepted January 28, 2000.
From the Cardiovascular Research Group and Centre for Heart and Chest Research, Department of Medicine, Monash University, Monash Medical
Centre, Clayton, Victoria, Australia.
Correspondence to Dr Roger Peverill, Cardiology Unit, Monash Medical Centre, 246 Clayton Rd, Clayton, Victoria, 3168 Australia. E-mail
[email protected]
© 2000 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
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Teede et al
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D-dimer levels with combined HRT has been considered to
reflect increased fibrinolysis secondary to reduced PAI-1
activity,18 an alternate possibility is that it may also be due to
a reactive increase in fibrinolysis arising from a rise in fibrin
production accompanying the activation of coagulation processes. However, this possibility has not been explored
because changes in fibrin production and fibrinolysis have
not been simultaneously assessed in previous studies of
combined HRT therapy on hemostatic processes.
Accordingly, the aim of this double-blind, randomized,
placebo-controlled study was to determine the hemostatic
effects of 6 weeks of treatment of oral combined HRT
treatment with estradiol and norethisterone in healthy postmenopausal women. Thrombin generation was assessed by
measuring plasma levels of prothrombin fragments 1⫹2
(F1⫹2); fibrin production, by plasma levels of soluble fibrin;
fibrinolysis, by plasma levels of D-dimer; and plasma fibrinolytic inhibition, by PAI-1 activity. In view of previous
evidence of a relation between cardiovascular risk factors and
hemostatic markers in other patient populations,22 the relation
between hemostatic markers and lipids before and after
treatment with HRT was also evaluated.
Methods
Study Design
Forty-two healthy postmenopausal women were enrolled in a
double-blind, placebo-controlled, randomized trial conducted over 6
weeks. Participants were aged 50 to 75 years, had not received any
hormone replacement therapy for 12 months, and had no history of
hysterectomy or oophorectomy. Postmenopausal status was defined
as absence of menses for at least 12 months, a follicle-stimulating
hormone level ⬎23 IU/L, and estradiol ⬍120 pmol/L. Women were
enrolled from the community after responding to an advertisement in
community newspapers. Exclusion criteria included smoking within
the past 10 years, a history of diabetes, body weight ⬎100 kg,
alcohol or illicit drug abuse, uncontrolled hypertension (blood
pressure ⬎180/100 mm Hg), history of venous thrombosis, breast or
endometrial cancer, abnormal uterine bleeding, abnormal cervical
smear or mammogram results, or the presence of a major illness.
Randomization was performed by an experienced researcher not
otherwise involved in the study who used computer-generated
random numbers, which resulted in the assignation of 22 women to
HRT and 20 to placebo. Women began either continuous combined
therapy with oral estradiol (2 mg) combined with continuous
norethisterone acetate (1 mg, Kliogest, Novo-Nordisk) or placebo
tablets, having an identical appearance.
A baseline medical review was conducted with cardiovascular risk
factor assessment, medication details, breast examination, and cervical smears and screening mammograms if indicated. Medical
follow-up was repeated at the 6-week visit with compliance checked
by counting returned tablets and by questionnaire. Ethics approval
was obtained from the Monash Medical Center Human Research and
Ethics Committee, and all participants gave written informed consent
before their enrollment in the study. These women represented a
consecutively recruited subgroup enrolled in an ongoing study of
HRT and cardiovascular disease. Two withdrawals occurred in the
active therapy group because of vaginal bleeding, and 1 withdrawal
occurred because of unforeseen overseas travel by the participant,
leaving 39 women who completed the entire study protocol. Compliance in the women who completed the study averaged 98%, with
the least compliant individual consuming 88% of medications
provided.
Blood Collection
Gonadotropins and serum estradiol were measured at baseline.
Fasting morning blood samples were collected via nontraumatic
phlebotomy by a single technician (D.K.) at baseline and at 6 weeks
HRT Effects on Coagulation and Fibrinolysis
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TABLE 1. Baseline Characteristics of the Participants:
HRT vs Placebo
Characteristics
HRT (n⫽22)
Age, y
Placebo (n⫽20)
P
61⫾1
62⫾1
0.5
Height, m
1.61⫾0.01
1.62⫾0.02
0.5
Weight, kg
67⫾3
72⫾2
0.1
BMI, kg/m2
25.5⫾1
28.0⫾1.5
0.09
Systolic BP, mm Hg
134⫾4
132⫾3
0.6
Diastolic BP, mm Hg
76⫾1
76⫾2
0.8
FSH, IU/L
68⫾8
74⫾6
0.5
LH, IU/L
26⫾3
31⫾2
0.6
Values are mean⫾SEM. BP indicates blood pressure; FSH, folliclestimulating hormone; and LH, luteal hormone. Values of P compare baseline
values in HRT group vs placebo.
for lipid profiles and hemostatic parameters. Venipuncture was
performed with a 19-gauge needle; samples were placed directly into
plain tubes for lipid and hormone assays and then into 2 3.8% citrate
tubes (9:1 ratio) for coagulation and fibrinolysis studies. After
immediate centrifugation of samples at 2500g for 12 minutes, plasma
was separated into 200 ␮L aliquots, stored at ⫺80°C, and thawed
immediately before analysis.
Hormone and Lipoprotein Assays
Gonadotropins and estradiol were measured by radioimmunoassay.
Total cholesterol and triglycerides were measured by using enzymatic reagents (DADE Diagnostics); HDL cholesterol (HDL-C) was
measured by homogeneous HDL-C assay techniques (HDLC-Plus,
DADE Diagnostics) adapted to a DADE Dimension RXL chemistry
analyzer (DADE Diagnostics); and LDL cholesterol (LDL-C) was
calculated by using the Friedewald equation, LDL-C⫽(total cholesterol⫺HDL-C)⫺(triglycerides⫻0.20), adapted to SI units.
Hemostatic Markers
All hemostatic markers were assayed by a single trained medical
scientist (E.M.), with all assays performed in duplicate and the
results averaged. All samples from each individual participant were
assayed in the same batch. Commercial immunoassays were used to
measure concentrations of F1⫹2 (Enzygnost F1⫹2, Behring), soluble fibrin (Enzymum FM, Boehringer-Mannheim) on an ES300
instrument (Boehringer-Mannheim), PAI-1 activity (Berichrom PAI,
Behring), and D-dimer (Dimertest Gold EIA, Agen Biomedical).
Statistics
Statistical calculations were performed by using the SPSS statistical
package, version 8. Assessments of treatment effects were based on
the mean change from baseline. Data from all participants was
included in the analysis, with the exception of 2 samples with soluble
fibrin and D-dimer levels ⬎10 SD above the mean, which were
excluded because of presumed activation occurring during blood
collection. Data were normally distributed, except for levels of
D-dimer, which have been expressed as median (25th to 75th
percentile). Change in D-dimer was analyzed by a Mann-Whitney U
test, and comparison of within-group treatment effects on D-dimer
was analyzed with a Wilcoxon signed rank test. Other parameters
have been expressed as mean⫾SEM and were analyzed by a Student
t test. Univariate analyses were calculated by Pearson (parametric
data) or Spearman (nonparametric data) correlation coefficients.
Significance was accepted at a level of P⬍0.05.
Results
Baseline Hormone, Lipid, and
Hemostatic Parameters
Estradiol levels were below detectable limits in most women,
and all women had gonadotropin levels consistent with their
postmenopausal state (Table 1). The HRT and placebo groups
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May 2000
TABLE 2.
Lipid Profiles at Baseline and 6 wk: HRT vs Placebo
Time Point
HRT
Placebo
P
Total cholesterol,
mmol/L
Baseline
5.9⫾0.2
6.0⫾0.2
0.5
6 wk
5.2⫾0.2
5.8⫾0.2
0.03
LDL-C, mmol/L
Baseline
3.8⫾0.2
4.0⫾0.2
0.5
6 wk
3.4⫾0.2
3.8⫾0.2
0.2
HDL-C, mmol/L
Baseline
1.6⫾0.1
1.5⫾0.1
0.7
6 wk
1.4⫾0.1
1.5⫾0.1
0.3
Triglycerides, mmol/L
Baseline
1.1⫾0.1
1.2⫾0.2
0.6
6 wk
1.1⫾0.1
1.1⫾0.2
0.7
Lipids
Values are mean⫾SEM.
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were well matched for baseline characteristics, including lipid
profiles (Tables 1 and 2) and levels of hemostatic markers
(Table 3). Univariate analysis of the relations between hemostatic parameters and cardiovascular risk factors indicated
that F1⫹2 was positively correlated with age (r⫽0.47,
P⫽0.002), whereas soluble fibrin was positively correlated
with body mass index (BMI; r⫽0.51, P⫽0.001) and negatively correlated with HDL-C (r⫽⫺0.35, P⫽0.03). D-dimer
was negatively correlated with HDL-C (r⫽⫺0.37, P⫽0.02)
and showed a trend toward a positive correlation with LDL-C
(r⫽0.31, P⫽0.05), whereas PAI-1 was positively correlated
with triglycerides (r⫽0.61, P⫽0.0001) and BMI (r⫽0.37,
P⫽0.02) and negatively correlated with age (r⫽⫺0.46,
P⫽0.002) and HDL-C (r⫽⫺0.42, P⫽0.009). Total cholesterol levels did not correlate with any hemostatic parameters.
Assessment of relations between baseline levels of fibrin
and fibrinolytic markers indicated that the soluble fibrin level
was positively correlated with the D-dimer level (r⫽0.34,
P⫽0.03); however, no relation was evident between the
PAI-1 activity and D-dimer levels.
Effects of HRT on Lipid and
Hemostatic Parameters
No patient within this study had clinical evidence of thrombosis during the treatment period. After 6 weeks of treatment,
total cholesterol levels were lower in the group treated with
HRT compared with placebo, but there were no significant
differences in the other lipid parameters (Table 2). Table 3
gives the values of hemostatic markers by treatment group at
baseline and after 6 weeks of treatment. In the HRT group,
TABLE 3. Hemostatic Parameters at Baseline vs 6 wk in HRT
and Placebo Groups
Parameter
F1⫹2, nmol/L
Soluble fibrin, ␮g/mL
PAI-1, U/mL
D-dimer, ng/mL
Treatment
Stage
Baseline
6 wk
P
HRT
1.07⫾0.05
1.29⫾0.09
0.005
Placebo
1.00⫾0.07
0.94⫾0.06
0.1
HRT
3.1⫾0.7
5.3⫾0.7
0.0001
Placebo
2.7⫾0.4
3.1⫾0.4
0.4
HRT
2.0⫾0.3
1.5⫾0.2
0.0005
Placebo
2.2⫾0.3
2.5⫾0.4
0.1
HRT
22 (6–41)
42 (26–73)
0.03
Placebo
25 (16–41)
14 (7–47)
0.3
Values are mean⫾SEM except D-dimer, which is shown as mean (25th to
75th percentile).
levels of F1⫹2, soluble fibrin, and D-dimer increased significantly by ⬇20%, 75%, and 100%, respectively, whereas
there was a 25% fall in PAI-1 activity. In contrast, no
significant changes were observed in any of the hemostatic
parameters in the placebo group. The mean change from
baseline was significantly greater in the HRT group than in
the placebo group for F1⫹2, soluble fibrin, D-dimer, and
PAI-1 (Figure 1).
In the HRT group, there were no observed correlations
between changes in lipid and hemostatic parameters. There
was a positive correlation between the increase in soluble
fibrin and D-dimer levels (r⫽0.59, P⫽0.02; Figure 2) but no
correlation evident between the decrease in PAI-1 activity
and the increase in D-dimer levels (Figure 2).
Discussion
The main finding of this placebo-controlled double-blind
study is that 6 weeks of treatment with oral estradiol and
norethisterone significantly increased plasma levels of F1⫹2,
soluble fibrin, and D-dimer, indicative of an increase in
thrombin generation, fibrin generation and breakdown, and
decreased PAI-1 activity, suggestive of a reduction in plasma
fibrinolytic inhibitory activity. Furthermore, an association
was evident between the increases in fibrin production and
fibrinolysis but not between the changes in plasma fibrinolytic inhibitory activity and fibrinolysis.
F1⫹2 is a peptide generated as a result of the conversion of
prothrombin to thrombin. Marked elevations of F1⫹2 occur
with established venous thromboembolism23 and myocardial
infarction,24 whereas lesser elevations have been reported in
subjects at risk of these conditions,25,26 possibly heralding a
prothrombotic state. Our finding of a 20% increase in F1⫹2
indicates that short-term treatment with estradiol and norethisterone increases in vivo thrombin generation. Elevated
levels of F1⫹2 have also been reported with estrogen alone.
An open crossover study showed a 25% increase after 6
weeks of treatment with 0.625 mg conjugated equine estrogen
(CEE),14 and a randomized crossover study involving treatment for 3 months with CEE (either 0.625 or 1.25 mg)
demonstrated a 40% and 98% increase in F1⫹2, respectively.13 On the other hand, results of placebo-controlled trials of
combined estrogen and progestin therapy have been inconsistent. Six months of treatment with estradiol (2 mg/d)
combined with cyclical micronized progesterone (200 mg/d
from days 14 to 25) resulted in a 14% increase in F1⫹2
levels.20 However, 3 months of treatment with estradiol (1 or
1.5 mg) combined with cyclical nomegestrol acetate (2.5 mg,
days 1 to 24)27 did not increase F1⫹2, whereas Walsh et al16
found a 16% increase in F1⫹2 after 3 to 6 months of
treatment with CEE (0.625 mg) and continuous medroxyprogesterone acetate (2.5 mg/d), but this change was not statistically significant.
The formation of fibrin occurs via cleavage of fibrinogen,
catalyzed by free thrombin. Yet free thrombin is subject to
inhibitory control by protein binding.28 Thus, thrombin generation may occur without stimulating fibrin production, a
situation previously defined as a prethrombotic state.28 Once
the thrombin inhibitory capacity is exceeded, however, soluble fibrin is formed, with increased levels noted with venous
thromboembolism29,30 and myocardial infarction.31 In the
present study, we observed a 76% increase in soluble fibrin in
Teede et al
HRT Effects on Coagulation and Fibrinolysis
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Figure 1. Mean change in prothrombin fragments (F 1⫹2), soluble fibrin, PAI-1, and D-dimer after 6 weeks of intervention with either
placebo or HRT.
subjects given HRT, indicating that increased fibrin production accompanied the increased thrombin generation. Although effects of HRT on soluble fibrin have not been
previously examined, estrogen alone has been demonstrated
to cause a dose-dependent increase in fibrinopeptide A, a
peptide also generated during fibrinogen cleavage,13,19
whereas the only study to examine the effect of combined
HRT on fibrin production found no significant change in
fibrinopeptide A levels.16
Four factors potentially contributed to the variable findings
in the literature regarding the effects of combined HRT on
thrombin and fibrin formation. First, a variety of estrogens
have been previously used. With the coagulation effects of
conjugated estrogen demonstrated to be dose dependent,13 the
variety of estrogens used may have had different potencies
with regard to their effect on coagulation activity. Second, the
reported studies have differed in the type and pattern (continuous or cyclic) of progestin administration, with potential
implications because progestins may modify the actions of
estrogen,4 may vary in many respects, including their androgenicity and metabolic effects,32 and may differ in their
potential to cause venous thrombosis.33 Third, the duration of
therapy varied between studies. We examined HRT use over
6 weeks, but other studies have had a duration of up to 6
months.16,20 Given evidence suggesting that hemostatic effects of HRT may be early and transient,34 these longer
studies may have had a reduced power to detect any shortterm but resolving changes in hemostatic markers. Last, study
designs have varied, with single-center studies potentially
advantaged by uniformity in blood collection and sample
processing20 and larger multicenter studies having greater
statistical power.16
Under physiological circumstances, increases in fibrin
formation may not result in thrombosis because of an accompanying increase in fibrinolysis.35 Fibrinolysis involves plasminogen conversion to plasmin via plasminogen activators,
which are in turn inhibited by plasminogen activator inhibitors, including PAI-1. The role of PAI-1 as a fibrinolytic
inhibitor36 appears clinically important, with elevations asso-
ciated with venous thrombosis36 and myocardial infarction.37,38 In the present study, a 25% reduction in PAI-1
activity was observed after 6 weeks of combined HRT,
consistent with other prospective studies using either estrogen
alone or combined HRT14,16 –18,39 and indicating that HRT
with estradiol and norethisterone increases plasma fibrinolytic inhibitory activity.
The fibrinolytic process involves plasmin-mediated breakdown of cross-linked fibrin to produce D-dimer. D-dimer
levels are elevated in venous thrombosis,40 pulmonary embolism,41 stroke,42 and myocardial infarction,43 with additional
evidence that increased D-dimer levels may be a marker of
subsequent thrombotic events.44 Our finding of significantly
Figure 2. Correlation between changes in D-dimer and soluble
fibrin (top) and changes in D-dimer and PAI-1 (bottom) after
intervention.
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elevated D-dimer levels with HRT indicates that combined
estradiol and norethisterone increases fibrinolysis. Two previous studies addressed the effects of combined HRT on
fibrinolysis with divergent findings. Scarabin et al20 found no
increase in D-dimer after 6 months of treatment with estradiol
and micronized progesterone, whereas Koh et al18 recently
reported increased fibrinolysis associated with decreased
PAI-1 levels after 1 month of treatment with combined
continuous HRT (0.625 mg of CEE and 2.5 mg medroxyprogesterone acetate), although the actual change in D-dimer
levels in that study was not statistically significant.
We also aimed to investigate the effects of combined HRT
on the relation between coagulation activation, plasma fibrinolytic inhibitory activity, and fibrinolysis. We have demonstrated a relation between fibrin production and fibrinolysis, with a positive correlation between baseline levels of
soluble fibrin and D-dimer and also between the increases
observed in these markers after HRT treatment. Alternatively,
a relation between plasma fibrinolytic inhibitory activity and
fibrinolysis was not found as there was no correlation evident
between PAI-1 activity and D-dimer levels at baseline or after
treatment. Although a contribution from enhanced plasma
fibrinolytic inhibitory activity in the observed increase in
fibrinolysis in the subjects receiving HRT was not excluded,
an implication of these findings is that reactive fibrinolysis
secondary to elevation in fibrin is a more important factor. In
contrast, however, Koh et al18 found an inverse correlation
between baseline D-dimer levels and PAI-1 antigen and
between the increase in D-dimer and reduction in PAI-1 with
HRT; the authors concluded that increased fibrinolysis was
related to the enhanced plasma fibrinolytic inhibitory activity.
On the other hand, Scarabin et al20 noted no increase in
D-dimer despite the enhancement of plasma fibrinolytic
inhibitory activity, evidenced by decreased levels of both
PAI-1 antigen and activity and an increase in global fibrinolytic activity. Neither of these studies measured soluble fibrin
levels; therefore, Koh et al were unable to address whether
coagulation activation with a resultant increase in fibrin
production was an alternative stimulus to fibrinolysis in their
study, whereas Scarabin et al were unable to determine
whether the absence of an increase in D-dimer, despite the
observed elevation in F1⫹2 and thus thrombin generation,
was related to effective antithrombin mechanisms and an
absence of increase in fibrin in their study.
The mechanism of combined HRT effects on hemostatic
markers was further evaluated by assessing the relation
between changes in lipid and hemostatic parameters in the
HRT-treated group on the basis of the well-established
benefits of HRT on lipid profiles4 and the known association
between lipids and hemostatic markers.22,45 However, although significant associations of baseline hemostatic marker
levels with BMI and lipid subfractions were evident in the
present study, no significant correlations between changes in
lipids and hemostatic parameters were evident after treatment. This suggests that changes in hemostatic markers with
HRT may be independent of changes in lipids. Only total
cholesterol was lower in the HRT group after 6 weeks of
treatment, whereas LDL and HDL remained unchanged. This
was not unexpected, because on the basis of previous literature,46 the present study was underpowered to detect lipid
changes.
The effects of HRT on coagulation and fibrinolysis are of
clinical relevance in view of recent evidence suggesting that
HRT is associated with an increased risk of arterial and
venous thrombotic events. A 3-fold increase in venous
thromboembolism with HRT use has been observed in
case-control studies10,11 and in the recent Heart and EstrogenProgestin Replacement Study (HERS), a double-blind,
placebo-controlled, randomized study of combined oral HRT
in the secondary prevention of cardiovascular disease.8 The
HERS study also found an early increase in arterial vascular
events associated with HRT use. It was hypothesized that this
may be due to the prothrombotic effect of combined HRT, a
suggestion consistent with a retrospective study noting increased unstable angina in women starting HRT after myocardial infarction compared with women not given HRT.9
Our finding that combined estradiol and norethisterone increases coagulation activation provides mechanistic evidence
that this combination may also contribute to thrombosis in
susceptible individuals.
In the present study, we have demonstrated that oral
combined continuous HRT with estradiol and norethisterone
results in the activation of coagulation, increased fibrinolysis,
and reduced plasma fibrinolytic inhibitory activity. Increased
fibrinolysis with HRT was positively associated with increased fibrin production but not with reduction in plasma
fibrinolytic inhibitory activity. The finding of an increase in
thrombin and fibrin generation is consistent with an adverse
effect of combined HRT on thrombotic risk.
Acknowledgments
This study was supported by a grant-in-aid from the National Heart
Foundation of Australia (G95 M4418). Medications were provided
by Novo-Nordisk. We thank the Department of Biochemistry,
Monash Medical Center, for completing the hormone and
lipid assays.
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Downloaded from http://atvb.ahajournals.org/ by guest on May 3, 2017
Postmenopausal Hormone Replacement Therapy Increases Coagulation Activity and
Fibrinolysis
Helena J. Teede, Barry P. McGrath, Joseph J. Smolich, Erica Malan, Dimitra Kotsopoulos,
Yu-Lu Liang and Roger E. Peverill
Arterioscler Thromb Vasc Biol. 2000;20:1404-1409
doi: 10.1161/01.ATV.20.5.1404
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