ORIGINAL PAPERS

original papers
Adv Clin Exp Med 2010, 19, 2, 203–210
ISSN 1230-025X
© Copyright by Wroclaw Medical University
Barbara Ruszkowska1, Sławomir Manysiak2, Beata Małecka1, Grażyna Dymek2,
Danuta Rość1, Grażyna Odrowąż-Sypniewska2
Parameters of Fibrinolysis
in Postmenopausal Women Taking Oral
and Transdermal Hormone Replacement Therapy*
Parametry układu fibrynolizy u kobiet w okresie pomenopauzalnym
stosujących hormonalną terapię zastępczą drogą doustną i przezskórną*
Department of Pathophysiology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University
in Torun, Poland
2
Department of Laboratory Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University
in Torun, Poland
1
Abstract
Background. Postmenopausal women constitute approximately 30% of the world’s population. More than a third
of the life of contemporary women falls within the period after menopause. Women with considerable sex hormone deficiency should take an exogenous hormone replacement.
Objectives. The aim of the study was to assess selected parameters of fibrinolysis such as tissue plasminogen activator antigen (t-PA Ag), plasminogen activator inhibitor type 1 antigen (PAI-1 Ag), D-dimers, fibrinogen, and
antiplasmin (AP) activity in postmenopausal women who were taking oral or transdermal hormone replacement
therapy (HRT).
Material and Methods. The study was conducted on 76 healthy nonsmoking postmenopausal women. Forty-six
women aged 44–58 years were taking oral (26) or transdermal (20) HRT. The control group consisted of 30 women
aged 44–54 years who did not take HRT. The concentrations of t-PA Ag, PAI-1 Ag, D-dimers, and fibrinogen and
the activity of AP were determined in plasma.
Results. Women using transdermal HRT had significantly higher concentrations of t-PA Ag and PAI-1 Ag than
those taking oral HRT (p < 0.03 and p < 0.0001, respectively) and those of the control group (p < 0.03 and p < 0.02,
respectively). AP activity among the women taking oral or transdermal HRT was significantly lower (p < 0.03 and
p < 0.05, respectively) than in the control group. A lower concentration of fibrinogen was found in the women
taking oral HRT than in the control group (p < 0.05). The average concentrations of D-dimer were similar in all
the subjects.
Conclusions. The increased t-PA Ag concentration and decreased antiplasmin activity among the women taking
transdermal HRT can indirectly indicate an increased formation of plasmin. The increased PAI-1 Ag concentration in women taking transdermal HRT showed that PAI-1 participated in suppressing increased plasminogenesis.
Transdermal HRT is undoubtedly more physiological, but it seems to be less effective if one considers the beneficial
influence on hemostasis, although larger trials to confirm these results are needed (Adv Clin Exp Med 2010, 19,
2, 203–210).
Key words: menopause, fibrinolysis, hormone replacement therapy.
Streszczenie
Wprowadzenie. Kobiety po menopauzie stanowią 30% populacji osób żyjących na ziemi. Ponad 1/3 życia
współczesnej kobiety przypada na okres po menopauzie. Kobiety, u których występuje znaczny niedobór hormonów płciowych mogą otrzymywać egzogenną substytucję hormonalną.
* Source support: BR was supported by grant no. 73/04 from Collegium Medicum in Bydgoszcz, Nicolaus
Copernicus University in Torun, Poland.
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B. Ruszkowska et al.
Cel pracy. Ocena wybranych parametrów fibrynolizy, takich jak: antygen tkankowego aktywatora plazminogenu
(t-PA: Ag), antygen inhibitora aktywatora plazminogenu typu 1 (PAI-1: Ag), D-dimery, fibrynogen oraz aktywność
antyplazminy (AP) u kobiet w okresie pomenopauzalnym stosujących hormonalną terapię zastępczą (HTZ) drogą
doustną i przezskórną.
Materiał i metody. Badaniami objęto 76 zdrowych, niepalących kobiet po menopauzie. 46 kobiet w wieku
44–58 lat stosowało doustną (26), przezskórną (20) HTZ. Grupę kontrolną stanowiło 30 kobiet w wieku 44–54 lat
niestosujących HTZ. Materiałem do badań było osocze cytrynianowe, oznaczono następujące parametry hemostazy: stężenie t-PA: Ag, PAI-1: Ag, stężenie D-dimerów, fibrynogenu i aktywność AP.
Wyniki. W grupie kobiet stosujących HTZ drogą przezskórną uzyskano większe stężenie t-PA: Ag i PAI-1: Ag
w porównaniu do grupy kobiet stosujących HTZ drogą doustną. Różnice te były istotne statystycznie (p < 0,03;
p < 0,0001 – odpowiednio) i do grupy kontrolnej (p < 0,03; p < 0,02 – odpowiednio). Aktywność AP była mniejsza
u kobiet stosujących HTZ drogą doustną i przezskórną w porównaniu do grupy kontrolnej; różnice te były istotne
statystycznie (p < 0,03 i p < 0,05 – odpowiednio). W grupie kobiet stosujących HTZ drogą doustną zaobserwowano w porównaniu z grupą kontrolną mniejsze stężenie fibrynogenu (p < 0,05). Nie wykazano różnic w stężeniu
D-dimerów w żadnej z badanych grup.
Wnioski. Większe stężenie t-PA: Ag oraz obniżona aktywność AP u kobiet stosujących HTZ drogą przezskórną
mogą pośrednio wskazywać na wzmożone tworzenie plazminy. Większe stężenie PAI-1: Ag u kobiet stosujących
przezskórną hormonoterapię dowodzi udziału tego inhibitora w kompensacyjnym hamowaniu nasilonej plazminogenezy. Droga przezskórna HTZ, niewątpliwie bardziej fizjologiczna i łagodna, wydaje się jednak mniej skuteczna
z punktu widzenia korzystnego wpływu na proces hemostazy, wymaga to jednak potwierdzenia (Adv Clin Exp Med
2010, 19, 2, 203–210).
Słowa kluczowe: menopauza, fibrynoliza, hormonalna terapia zastępcza.
The most important physiological role of the
fibrinolytic system is to dissolve intravascular fibrin
deposits and maintain patency in the vascular bed [1].
The fibrinolytic system’s components are serine
proteases that exhibit very high activity [2]. Serine
proteases consist of two polypeptide chains linked
by disulfide bonds. Hydrolysis of the peptide bond
between amino acids Arg560 and Val561 causes
the conversion of plasminogen to plasmin [2, 3].
Various factors in the blood, tissues, and urine
which are part of endogenous and exogenous fibrinolysis can trigger the plasminogen-to-plasmin
conversion process. Endogenous fibrinolysis starts
with the coagulation process at the same time
through contact factors such as factor XII, prekallikrein (PK), and high-molecular-weight kininogen
(HMWK). Factor XII is activated to XIIa by contact
with a subendothelial collagen and sulfatide groups.
This stimulates the conversion of prekallikrein to
kallikrein (KK) [3, 4]. Kallikrein can directly or
indirectly activate plasminogen. Kallikrein influences the inactive precursor of urokinase-type plasminogen activator (pro-u-PA, single chain urokinase plasminogen activator: scu-PA) which is transformed into the two-chain urokinase plasminogen
activator (tcu-PA). tcu-PA activates plasminogen
[3, 4]. u-PA generates pericellular proteolytic activity. The degradation of extracellular matrix, basement membranes, and other barriers to cell migration and cell invasion is caused by the extravascular
effect of plasminogen activators. Tissue plasminogen activator (t-PA) is a protein involved in intravascular thrombolysis [2, 5].
The fibrinolytic system’s components participate in several physiological and pathophysiologi-
cal processes such as spermatogenesis, ovulation,
embryo implantation, morphogenesis, cell migration, and invasion of cancer. Remaining a balance
between clotting and fibrinolysis is important for
the maintaining hemostasis. Disturbances in the
balance between thrombus formation and degradation, simultaneously with an increase in the
concentration of clotting factors and decrease in
coagulation inhibitors or a decrease in the concentration of plasminogen and plasminogen activators
and an increase in the concentration of fibrinolysis inhibitors, can lead to thrombotic and embolic
events [1, 2, 4].
Menopause is the time in a woman’s life when
the reproductive capacity ceases. The ovaries gradually and inevitably stop functioning and the production of steroid hormones falls. The cessation
of ovary function results in decreased estrogen
and progesterone production. The secretion of the
gonadotropins follicle-stimulating hormone (FSH)
and luteinizing hormone (LH) by the hypophysis is increased during and after menopause [6].
A woman has reached menopause when she has
not had a period for 12 months [7]. The basis of
hormonal imbalance in perimenopausal women
is disorders in the efficiency of the hypothalamushypophysis-ovary axis. Menopausal symptoms are
caused by declining and fluctuating hormone levels. The most common symptoms of menopause
are hot flashes, mood swings, nocturnal sweat, palpitation, insomnia, atrophy of the sexual-urinary
system, osteoporosis, insulin resistance, atherosclerosis, and a higher risk of ischemic heart disease
[8]. The chronic estradiol deficiency in postmenopausal women is connected with several hemosta-
205
Fibrinolysis in Postmenopausal Women Taking HRT
sis factors such as decreased levels of fibrinogen,
plasminogen activator inhibitor type 1, coagulation factor VIIa (FVIIa), and tissue plasminogen
activator. These disorders lead to decreased global
fibrinolytic capacity [8–10].
Postmenopausal women constitute approximately 30% of the world population. More than
a third of the life of contemporary women falls
within the period after menopause. Women with
considerable sex hormone deficiency should take
an exogenous hormone replacement. Hormone
replacement therapy replaces the natural hormonal activity of the ovaries. HRT contains estrogens
and progesterone or its derivatives (progestogens)
in minimal effective doses. The suitable kind of
hormone, dose, and route of administration may
relieve vasomotoric syndromes, changing mood,
atrophy of the sexual-urinary system, and sleep
disorders and prevent osteoporosis [11, 12]. HRT
containing small doses of progestogens may prevent cancerous proliferation (hyperplasia of the
endometrium, breast cancer) [12].
Using HRT demands an analysis of the benefits and risk of undesirable effects. Hypertension,
varicose veins, thrombotic and embolic events, diabetes mellitus, endometriosis, smoking, and other
enforcers are recognized as contraindications for
starting HRT [13]. The level of relieved perimenopausal symptoms and the character and intensity of
undesirable effects are different and depend on the
route of HRT administration (oral or transdermal).
The kind of hormone, the time of taking HRT, and
the route of administration are still widely debated
in medical circles. For now, it is not known whether
HRT stimulates or suppresses fibrinolysis. The aim
of the present study was to assess several parameters
of fibrinolysis in postmenopausal women taking
oral or transdermal HRT.
Material and Methods
The women were selected at the Outpatient
Gynecology Center of the University Hospital
in Bydgoszcz. Written informed consent was
obtained from each participant before entering the
study. The study was approved by the Bioethics
Committee of Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University in Torun (no.
KB/305/2004).
Study Groups
The study was conducted on 76 healthy nonsmoking postmenopausal women who were 1–2 years
after menopause. Forty-six women aged 44–58 years
(mean age: 52 years) were taking oral (26) or trans-
dermal (20) hormone replacement therapy. HRT
was taken daily during continuous treatment in
the form of a composite preparation, i.e. estrogenprogestogen combinations. Twenty-six women of
the study group used oral HRT [2 mg 17beta-estradiol (E2) and 1 mg norethisterone acetate (NETA);
Kliogest, Novo Nordisk Pharma, Poland] and
20 women transdermal HRT (50 µg E2 and 170 µg
NETA; SYSTEN® Conti, Janssen-Cilag, Warsaw,
Poland). The women had been taking HRT for 6–14
months. Persistent climacteric symptoms such as
heavy and regular hot flashes with drenching sweat
were the main conditions to start HRT. The control
group consisted of 30 healthy nonsmoking postmenopausal women aged 44–54 years (mean age:
49 years) who did not take HRT.
Women in both groups had neither diabetes
mellitus nor glucose intolerance. They have never
had any incident of thrombosis or systemic illnesses. None of them had ever taken any medication
that might interfere with the fibrinolytic system.
All the women included in the study had a complete gynecological examination, cytology smear,
palpable breast examination, mammography, and
biochemical examinations (lipid profile and hormone profile).
Venous blood for hemostatic tests (4.5 ml)
was collected in a fasting state into cooled tubes
(Becton Dickinson Vacutainer® System, Plymouth,
UK) containing 0.13 mol/l trisodium citrate (final
blood:anticoagulant ratio: 9:1) after 30 minutes of
rest between 7:30 and 9:30 a.m. after a 12-hour
overnight fast. The blood samples were immediately mixed and centrifuged at 3000 × g at +4°C
for 20 minutes. The obtained platelet-poor plasma was divided into 200-µl Eppendorf-type tubes
and then the samples were frozen at –86°C until
assayed, but for no longer than 6 months.
Hemostatic Assays
The concentration of t-PA Ag was determined by enzyme-linked immunosorbent assay
(ELISA) ASSERACHROM®t-PA (Diagnostica
Stago, Asnieres, France), PAI-1 Ag by ELISA
ASSERACHROM®PAI-1 (Diagnostica Stago,
Asnieres, France), and D-dimers by ELISA
ASSERACHROM®D-DI (Diagnostica Stago,
Asnieres, France). The concentration of fibrinogen
and activity of antiplasmin were determined in an
automated CC-3003 coagulometer and reagents
produced by Bio-Ksel Co., Grudziądz, Poland.
Statistical Analysis
Statistical analysis was performed using
Statistica 6.0 software (StatStoft). The Shapiro-
206
B. Ruszkowska et al.
-Wilk test was used to assess the normality of the
distribution. The analyzed data followed a normal
distribution. Student’s t test was used to calculate
the mean differences between groups. Results are
presented as the mean (X) and standard deviation
(SD). p-values < 0.05 were considered statistically
significant.
Results
The average concentrations of t-PA Ag, PAI-1
Ag, D-dimers, and fibrinogen and the average AP
activity in the women taking oral or transdermal
HRT compared with the control group are shown
in Table 1. Increased t-PA Ag concentration was
observed among the women taking transdermal
HRT compared with those taking oral HRT and
the control group. These differences were statistically significant (p < 0.03 for both). Increased
PAI-1 Ag concentration was observed in the group
of women taking transdermal HRT compared with
those taking oral HRT and the control group. The
differences were statistically significant (p < 0.0001
and p < 0.02, respectively). A significant decrease
in AP activity was observed in the women taking
oral and transdermal HRT compared with the con-
trol group (p < 0.03 and p < 0.05, respectively). The
concentration of fibrinogen was found to be lower
in the women taking oral HRT than in the control
group (p < 0.05). The concentration of D-dimers
was similar in all groups.
Discussion
Persistent climacteric symptoms such as heavy
and regular hot flashes with drenching sweat, palpitation, and urinary incontinence, which lower
the women’s quality of life, were the main conditions for starting HRT. When qualifying a patient
for HRT, every doctor should consider the indications and contraindications for this kind of
therapy [6]. The most important aspects of HRT
are individualization of the dose, the kind of medicine, the route of HRT administration, and the age
of the patient [6, 14].
Oral estrogens enter the liver via the digestive tract and portal vein system. Estradiol (E2) is
transformed to estrone (E1) during gastrointestinal passage [13, 15]. The absorbed steroids are
transferred via the portal vein system to the liver.
Most of the estrogens are metabolized and inactivated before they are transferred to the systemic
Table 1. Mean concentrations of t-PA Ag, PAI-1 Ag, D-dimers, fibrinogen, and AP activity in women taking oral HRT,
transdermal HRT, and no HRT (controls)
Tabela 1. Średnie stężenie t-PA: Ag, PAI-1: Ag, D-dimerów, fibrynogenu oraz aktywność antyplazminy u kobiet stosujących
HTZ drogą doustną, przezskórną i w grupie kontrolnej
Assessed parameters
– units
(Wskaźniki – jednostki)
Oral HRT (I)
(Droga doustna HRT)
X ± SD
Transdermal HRT (II)
(Droga przezskórna HRT)
X ± SD
Control group (III)
(Grupa kontrolna)
X ± SD
Significance level
(Poziom istotności
statystycznej)
p
t-PA Ag
[ng/ml]
4.3 ± 2.7
6.1 ± 2.7
4.4 ± 2.4
I vs. III NS
II vs. III p < 0.03
I vs. II p < 0.03
PAI-1 Ag
[ng/ml]
31.9 ± 20.8
58.2 ± 20.4
41.8 ± 26.1
I vs. III NS
II vs. III p < 0.02
I vs. II p < 0.0001
AP
[%]
84.5 ± 18.9
83.7 ± 20.4
95.5 ± 17.9
I vs. III p < 0.03
II vs. III p < 0.05
I vs. II NS
Fibrinogen
[g/l]
3.4 ± 0.7
3.7 ± 0.6
3.7 ± 0.5
I vs. III p < 0.05
II vs. III NS
I vs. II NS
D-dimers
[ng/ml]
378.4 ± 184.3
392.6 ± 197.0
369.2 ± 145.6
I vs. III NS
II vs. III NS
I vs. II NS
Abbreviations: NS – not significant, X – mean, SD – standard deviation, HRT – hormone replacement therapy.
Objaśnienia skrótów: NS – nieistotne statystycznie, X – średnia, SD – odchylenie standardowe, HRT – hormonalna terapia
zastępcza.
Fibrinolysis in Postmenopausal Women Taking HRT
circulation. This is the so-called first-pass effect on
the liver, which is largely avoided by the transdermal delivery route of estrogens [15]. In connection
with the first-pass effect during oral replacement
therapy, the doses of estrogens should be higher
than during parenteral replacement therapy [13].
Moreover, taking transdermal HRT ensures a relatively fixed level of sex hormones, without fluctuations in hormone concentration, which is characteristic of oral HRT [14].
The study results showed increases in the
concentrations of t-PA Ag and PAI-1 Ag in the
transdermal HRT users compared with the control group and the women taking oral HRT. The
main activator of the fibrinolytic system is t-PA.
It is synthesized and released by endothelial cells
and it has intravascular activity. Increased activity and concentration of t-PA, which is a marker
of endothelial damage in vascular diseases, is
observed in obliterative atheromatosis and diabetic microangiopathy of the lower extremities [16].
A high concentration of PAI-1 and an unexpectedly high t-PA concentration are associated with
an increased risk of myocardial infarction [17].
The present study showed a difference in the
concentrations of t-PA Ag in oral and transdermal HRT users. The reason for this difference is
probably the disparate influence of lower (transdermal HRT) and higher (oral HRT) hormone
doses in the women’s bodies. Transdermal HRT is
similar to the physiological concentration of estrogens in women. Endothelial cells are stimulated to
increase the synthesis of t-PA and its secretion into
the blood by exogenous estrogens. Wojnowska et
al. and Kanda et al. showed that estrogens stimulate endothelial cells. They reported the participation of receptors on the endothelium which
are sensitive to estrogens’ effects [12, 18]. On the
other hand, the liver metabolism is intensified by
the high doses of hormones in oral HRT. This
could increase t-PA clearance from the blood in
women using oral HRT, which was reported by
Stachowiak et al. and Soszka, demonstrating that
estrogen-progestogen replacement therapy caused
a decrease in t-PA concentration in the blood of
women taking HRT [19, 20].
PAI-1 is a glycoprotein which is produced in
endothelial cells, hepatocytes, smooth muscle cells,
and adipocytes. It can be found in plasma and
thrombocytes [4]. Increased PAI-1 concentration
in plasma has been associated with diabetes mellitus type 2, obesity, coronary heart disease, and
heart attack [4, 16, 21]. A high level of PAI-1 is an
independent risk factor of coronary heart disease
or venous thromboembolism [22]. PAI-1 may be
produced by cancer cells such as breast cancer, fibrosacroma, and hepatoma [4].
207
Many recent studies confirmed that HRT stimulates the fibrinolytic system through increased
t-PA concentration and decreased PAI-1 level.
Stachowiak et al. showed that estrogens taken during HRT have a direct influence on the biosynthesis and secretion of PAI-1. However, progestogen’s
component can decrease the beneficial influence
of estrogen on the fibrinolytic system [4, 22].
The available data show that the route of HRT
administration has an effect on PAI-1 concentration in the blood. Higher PAI-1 concentration was
found in women taking transdermal HRT than
oral HRT. The results of this study are in accord
with the data of Stachowiak et al., who showed that
PAI-1 concentration decreased significantly in oral
HRT (by even 50%), but they did not report significant differences when taking transdermal HRT
(tHT) [4, 23]. Post et al. also did not observe significant differences when taking tHT [17]. Taken
together, the data of Stachowiak et al. and Post
et al. demonstrated a lower influence on PAI-1
concentration in transdermal than in oral HRT.
This explains the present authors’ speculation that
the increase in PAI-1 concentration in the present
study in the women taking tHT compared with the
control group was caused by the stimulating effect
of t-PA on PAI-1 secretion [4, 17, 23]. Post et al.
showed an increase in liver clearance in women
taking oral HRT [17]. The lower concentrations of
both t-PA and PAI-1 in women using oral HRT
observed in the present study were probably the
result of intensified liver metabolism and blood
clearance from active factors of the fibrinolytic
system [17, 24].
The present data as well as research by
Stachowiak et al. and Post et al. suggest that the
route of administration HRT can have an important role in maintaining the balance between
coagulation and fibrinolysis [4, 17]. The decreased
AP activity in the oral and transdermal HRT users
compared with the control group probably had an
influence on the strong activation of the fibrinolytic system.
Antiplasmin is produced in the hepatocytes
and consists of one polypeptide chain. It is not
a specific inhibitor of substrate. It suppresses plasmin and also kallikrein, thrombin, and factors XIIa,
XIa, and Xa [25]. Increased AP activity was found
after surgical procedures and in inflammation,
thrombosis, and pregnancy whereas its decreased
activity is observed in disseminated intravascular
coagulation (DIC), liver diseases (such as hepatic
cirrhosis), hepatitis viral infection, hepatocarcinoma, during labor, and during thrombolytic treatment [26].
AP is used during intensified plasminogenesis. This enzyme reacts with plasmin by form-
208
ing a stable plasmin-antiplasmin (PAP) complex
that irreversibly inhibits the catalytic site of plasmin. Decreased antiplasmin activity stimulates
the liver to make up for the lack of antiplasmin.
In some diseases, such as cirrhosis and hepatocarcinoma, the liver cannot compensate rising AP
deficiency [27]. The present data showed that the
decreased AP activity in the women taking HRT
was independent of the HRT administration route.
Decreased AP activity can be an effect of antiplasmin consumption in connecting the antiplasmin
with the plasmin process, decreased AP synthesis
in the liver, or both these processes at the same
time. Taking high doses of estrogens which are
contained in HRT can lead to the activation of
hepatocytes and intensifies the synthesis of several
proteins. Therefore one would expect increased
AP activity and fibrinogen concentration. The
decreased AP activity found in the present study
was probably an effect of antiplasmin consumption in the plasmin inactivation process.
In the present study, a lower concentration
of fibrinogen in the oral HRT users was observed
compared with the control group. Fibrinogen is
produced in the liver and it belongs to the group of
acute-phase proteins. This protein is crucial in the
process of thrombus formation. It is the last target
of coagulation. Fibrinogen is a mediator of platelet
aggregation and a determinant of plasma viscosity. The concentration of fibrinogen increases with
age; moreover, it is higher during pregnancy and
menopause, in obese women, and in women taking contraceptives and also in patients with coronary disease. High concentrations of fibrinogen
were noted in habitual smokers. However, physical activity and moderate alcohol consumption
reduce fibrinogen concentration [23].
Oral as well as transdermal estrogens decrease
fibrinogen concentration, but in many studies
differences in fibrinogen concentration were not
found when using HRT [17, 19]. Results similar to
those of the present study were obtained during the
multicenter Postmenopausal Estrogen/Progestin
Interventions (PEPI) trial, where a slight decrease
in fibrinogen concentration was noted when taking estrogens only (horse estrogens of natural origin, conjugate estrogens in a dose of 0.625 mg/day)
[28]. However, Andersen et al. observed rapidly
decreasing fibrinogen level during estrogen-progestogen therapy consisting of estradiol valerianate
B. Ruszkowska et al.
in a dose of 2 mg/day and cyproterone acetate in
a dose of 1 mg/day, which were taken for 10 days in
the second phase of the menstrual cycle [29]. Oral
estrogen-progestogen therapy which contained
a mixture of horse estrogens of natural origin and
conjugate estrogens and medroxyprogesterone acetate in a dose of 2.5 mg/day caused a slight increase
in fibrinogen concentration [29].
The present study found simultaneous decreases in AP activity and fibrinogen concentration in
oral HRT users. These results show that a lower
fibrinogen concentration in the blood is an effect
of fibrinogen digestion by plasmin. When fibrin
is not in the blood, plasmin, which cannot connect with antiplasmin, digests plasma proteins and
also fibrinogen. If one takes into account the above
facts, one can explain the decreased fibrinogen
concentration in women taking oral HRT. A correct D-dimer concentration confirms the possible
digestion of fibrinogen through plasmin. D-dimers
are formed during the decomposition of fibrin and
are indicators of fibrin forming in the blood, and
follow its degradation through plasmin. A lower
fibrinogen concentration observed in women after
menopause taking oral HRT is a beneficial and
desirable effect because in this age group a higher
fibrinogen concentration was observed than in
younger women. Decreased fibrinogen concentration is an independent risk factor of atherosclerosis
[28]. The normal D-dimer concentration observed
in the present study showed that in both groups
there was no increase in thrombin and fibrin formation. Therefore dissolving stabilized fibrin was
not observed. These results show how important
the proper qualification of women to start taking
HRT is. Before taking HRT, risk of factors leading to the development of venous thrombosis such
as smoking, diabetes mellitus, and hypertension
should be eliminated.
The authors concluded that elevated t-PA concentration and decreased AP activity among women
taking transdermal HRT can indirectly indicate
increased formation of plasmin. Elevated PAI-1
concentration in women taking transdermal HRT
showed that PAI-1 participates in the suppression
of increased plasminogenesis. Transdermal HRT
is undoubtedly more physiological, but it seems
to be less effective if one considers the beneficial
influence on hemostasis, although larger trials are
needed to confirm these results.
Fibrinolysis in Postmenopausal Women Taking HRT
209
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B. Ruszkowska et al.
Address for correspondence:
Barbara Ruszkowska
Department of Pathophysiology, Collegium Medicum in Bydgoszcz
Marii Skłodowskiej-Curie 9
85-094 Bydgoszcz, Poland
Tel.: +48 52 585 35 91
E-mail: [email protected]
Conflict of interest: None declared
Received: 23.11.2009
Revised: 18.02.2010
Accepted: 7.04.2010