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УДК
618.3:616-008.311.1-07
Agababyan Larisa Rubenovna
Candidate of Medical Sciences, Associate Professor
at the Chair of Obstetrics and Gynecology
of the Faculty of Postgraduate Education
Samarkand State Medical Institute,
Samarkand, Uzbekistan
Makhmudova Sevara Erkinovna
Assistant of the Department of Obstetrics and
Gynecology, Faculty of Postgraduate Education
Samarkand State Medical Institute,
Samarkand, Uzbekistan
COMPARISON OF PLACENTAL PATHOLOGY BETWEEN SEVERE PREECLAMPSIA AND HELLP SYNDROME(REVIEW)
For citation:
Agababyan Larisa Rubenovna, Makhmudova Sevara Erkinovna, Comparison of placental pathology between severe preeclampsia
and hellp syndrome(review), Journal of reproductive health and uro-nephrology research. 2020, vol. 1, issue 1, pp.
http://dx.doi.org/10.26739/2181-0990-2020-1-6
Агабабян
Лариса
Рубеновна
к
.
м
.
н
.,
доцент
кафедры
Акушерства
и
гинекологии
Факультета
последипломного
образования
Самаркандского
государственного
медицинского
института
,
Самарканд
,
Узбекистан
Махмудова
Севара
Эркиновна
Ассистент
кафедры
Акушерства
и
гинекологии
Факультета
последипломного
образования
Самаркандского
государственного
медицинского
института
,
Самарканд
,
Узбекистан
СРАВНЕНИЕ
ПЛАЦЕНТАРНОЙ
ПАТОЛОГИИ
МЕЖДУ
ТЯЖЁЛОЙ
ПРЕЭКЛАМПСИЕЙ
И
HELLP
СИНДРОМОМ
(
ОБЗОР
)
Agababyan Larisa Rubenovna
Tibbiyot fanlari nomzodi, dotsent,
Samarqand Davlat Tibbiyot instituti
Diplomdan keying ta’lim fakulteti
Akusherlik va ginekologiya kafedrasi,
Samarqand, O'zbekiston
Makhmudova Sevara Erkinovna
Samarqand Davlat Tibbiyot instituti
Diplomdan keying ta’lim fakulteti
Akusherlik va ginekologiya kafedrasi assistenti,
Samarqand, O'zbekiston
OG’IR PREEKLAMPSIYA VA HELLP SINDROMI O'RTASIDAGI PLATSENTA PATOLOGIYASINI SOLISHTIRISH
(ADABIYOTLAR TAHLILI)
Preeclampsia (PE) is a syndrome of polyorganic failure that occurs
during pregnancy and is based on an increase in the permeability of the
vascular wall and other membranes, resulting in volemic and
hemodynamic disorders. Preeclampsia, as a major cause of perinatal
and maternal morbidity and mortality worldwide, still remains an
important medical and social problem. About 8.5 million preeclampsia
cases are reported worldwide each year, accounting for 2-8% of all
pregnancies (14% of women die annually) and showing no decreasing
trend [7,9]. In terms of maternal mortality, preeclampsia along with its
further complications, ranked the second to the fourth. In Uzbekistan,
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PE is found in about 11-16% of pregnant women, taking the third
place among the causes of maternal mortality [2, 11]. Among children
born alive to mothers who have suffered from PE, one in four children
lag behind in their physical development [7]. In Russia, according to
various sources, PE is found in 5-30% of all pregnancies which
makes more than one third of severe obstetric pathology. Over the
recent years, , an increase in PE cases, has been observed in some of
developed countries, particularly in the USA. Specialists believe that
the reason for such a growing tendency is the presence of such
diseases as diabetes mellitus (AD), obesity, chronic arterial
hypertension (CAH). Remote prognosis of women who have
experienced PE during pregnancy is also associated with the
development of cardiovascular complications later in life.
The World Health Organization reports that in developed
countries, hypertensive complications responsible for maternal
mortality account for up to 30 per cent of all factors [11]. For many
decades, scientists of different specialities (cardiologists, obstetricians,
gynecologists, genetics) have been paying close attention to the
problem of PE , but despite the results obtained, there is still no
accurate information about the causes and pathogenesis of the disease,
neither have reliable laboratory methods of diagnosis been developed
to provide effective preventive and treatment actions.
Along with early termination of pregnancy, delayed fetal
growth retardation and premature placenta abruption detachment, PE
refers to the so-called "Great Obstetrical Syndromes" associated with
placental pathology, which is due to a different degree of remodeling
disorder and obstruction of spiral arteries in the transition zone and
myometry .The major risk factors for this complication of pregnancy
on the maternal side include: age over 40 years, previous pregnancies
with PE, first birth, multiple pregnancies, antiphospholipid syndrome,
chronic arterial hypertension, autoimmune diseases, diabetes mellitus,
kidney diseases, dyslepidemia and obesity. Preeclampsia is believed to
be increasing since the 1990s, possibly associated with an increase in
obesity (91). Notably, together with obstetric haemorrhage and
infectious complications, PE is the so-called "lethal triad", which
causes the overwhelming number of maternal deaths. It is worth
mentioning that preeclampsia remains one of the main causes of
neonatal morbidity (640-780) and perinatal mortality. Preeclampsia is
also associated with stress and subsequent postnatal depression [7,17].
The exact prevalence of preeclampsia is unknown. A prevalence of
26 per 1,000 births has been reported in one study [1–4]. Preeclampsia
refers to the onset of hypertension and proteinuria after 20 weeks of
gestation in a previously normotensive woman. Its common effect on
fetus is intrauterine growth restriction [5, 6]. Some studies report
common pathological features in PE including small placentas with
decidual arteriopathy, infarcts in central portions, retroplacental
hematoma, and intervillous thrombosis [7]. HELLP syndrome refers to
a syndrome characterized by microangiopathic hemolysis, elevated
liver enzymes, and a low platelet count [8]. It complicates about 20%
cases of severe PE. This syndrome probably represents a severe form
of preeclampsia, but the relationship remains controversial. As much
as 15–20% of the affected patients do not have antecedent
hypertension or proteinuria. Coagulopathy is seen in HELLP patients,
but it is not a feature of PE [9]. These differences have led some
experts to consider HELLP syndrome as a distinct disorder [8, 10, 11].
It is well documented that placenta is the prerequisite for development
of HELLP syndrome and preeclampsia. Part of the different clinical
manifestations of severe preeclampsia and HELLP syndrome might be
explained by different histopathologic characteristics of placentas in
these two conditions. The aim of this study was to test this hypothesis
by investigating various macroscopic and microscopic features of
placenta in pregnancies complicated by preeclampsia or HELLP
syndrome
The modern prediction of PE is reduced to the study of the
concentration and ratio of proangiogenic and antiangiogenic factors, as
it is well known that the development of this multisystem disorder is
based on the imbalance of factors affecting angiogenesis [2,10].
Today, two mechanisms of formation of new vessels are known:
vasculogenesis - formation of the primary vascular network de novo
(embryo cardiovascular system) and angiogenesis - formation of new
vessels from existing ones. Both processes occur under the influence
of very clear physiological regulation, when stimulators and inhibitors
work in balance with each other [2,5.6,10]. Normally, angiogenesis
inhibitors predominate over proangiogenic molecules, which prevents
angiogenesis, and proliferation of endothelial cells lining the capillary
walls is very slow. The processes included in the concept of
angiogenesis were studied in detail and highlighted in a number of
reviews [2,10] and presented in the following sequence. Angiogenesis
begins with vasodilation and increase of vascular permeability. Then,
there is the secretion of soluble angiogenic factor that affects the
nearby blood vessel and leads to changes in the capillary wall in the
form of basal membrane degradation, mitotic division of
endotheliocytes, their subsequent migration into the stroma, and
proteolytic degradation of the extracellular matrix. At the next stage,
vascular endotheliocytes are organized into a tubular structure and the
blood flow in the newly formed area is initiated. A huge number of
soluble growth factors and inhibitors, cytokines and proteases, as well
as proteins of the extracellular matrix and adhesion molecules strictly
control this multistage process. The role of tissue hypoxia and
increased production of nitrogen oxide in angiogenesis initiation is
also widely known.
It is believed that research into factors that are important to
preeclampsia will help foresee the severity and extent of pathological
changes. Direct study of endothelium structures, which was one of the
first to be damaged in preeclampsia, is now available (58). The
problem is that meta-analyses are not sufficient to assess biomarkers
predicting preeclampsia. It is difficult to compare studies of individual
biomarkers.
To date, several dozens of the factors under discussion have been
described. It has been established that the following substances
deserve special attention:
1. Proangiogenic factors, one of the main representatives of
which family is vascular-endothelial growth factor (VEGF);
Antiangiogenic factors, including the soluble fms-like tyrosine
kinase-1 (sFlt-1);
3. Soluble adhesion molecules: intercellular adhesion molecule 1
(ICAM-1) and vascular adhesion molecule 1 (VCAM-1).
Hypoxia is the main stimulant of angiogenesis. When the action of
proangiogenic factors exceeds the action of antiangiogenic factors,
endothelial cells go into an active state, which is called "angiogenesis
inclusion". Endometrium, deciduous shell and placenta are sources of
angiogenic growth factors that trigger angiogenesis through a complex
system of mediators with the involvement of transmembrane receptors
with tyrosine kinase activity [10]. It was found that about 20
stimulating and 30 inhibiting angiogenesis factors take part in the
process of vascular formation [4,7]. "Survival" and apoptosis of
endothelial cells are opposite but necessary processes for angiogenesis,
regulated by the balance of proangiogenic and antiangiogenic factors
[6, 4]. The list of pathological conditions and diseases characterized by
excessive and incorrect angiogenesis includes: oncopathology,
retinopathy, arthritis, atherosclerosis, psoriasis, endometriosis and
many others. Diseases such as coronary heart disease, diabetes
mellitus, arterial hypertension and, finally, PE are characterized by
insufficient angiogenesis[10]. The studies have proved the
participation of altered production of numerous growth factors in the
development of PE, as they are the main carriers of the mitogenic
signal of cells, capable of stimulating or inhibiting the growth of
tissues and blood vessels [1,3,6]. Since soluble factors involved in the
processes of vascular formation are more accessible for research in the
maternal bloodstream, and the change in their content in the mother's
blood also reflects changes in the circulation and tissues of the fetus,
the study of these factors in the blood of a pregnant woman is key to
understanding and predicting the disturbance of vascular
morphogenesis processes [4,9]. The most studied and of particular
interest in studying PE pathogenesis are proangiogenic agents:
vascular endothelial growth factor (VEGF) and placental growth factor
(PlGF). The role of other growth factors and active substances in the
formation of uterine and placental blood flow is insufficiently studied,
because the overwhelming mass of studies is performed in late
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pregnancy, and the fundamental events determining the further course
take place at the very beginning of pregnancy [4].
The vascular endothelial growth factor, previously known as the
vascular permeability factor (VPR), was first isolated and described in
the experiment in 1983 by Senger and belongs to the family of platelet
growth factors, its basis is glycoprotein [2,3,5]. At present, several
forms of VEGF are known - A, B, C, D, and E [118]; the most studied
is VEGF-A. VEGF is the only specific mitogen of endothelial cells, it
stimulates their growth, migration, proliferation, and proteolytic
activity, increases the permeability of blood vessels in many tissues
and promotes vasculogenesis and angiogenesis [4, 5,7], thus playing
an important role in the physiological growth of the placenta and the
vascular network of stroma naphtha, as well as regulating the invasive
properties of the cytotrophblast [7]. One of the main functions of
VEGF in the placenta at late stages of pregnancy is to provide
increased viability of endothelial cells and stabilization of the vascular
channel. In addition, VEGF is essential for maintaining a "healthy"
endothelial phenotype of vessels in the kidneys, liver and brain [5,9].
Jojovi
ć
M. et al. have shown that adding VEGF to mouse cell culture
stimulates the development of placental tissue and increases the
placenta area [1,5]. VEGF is produced by endothelial cells, fibroblasts,
smooth muscle cells, and inflammatory cells [1,3,4]. Along with
angiogenesis induction it has been found to increase vascular
permeability, this ability is approximately 1000 times higher than that
of histamine [2,4]. Deciduous NK cells produce VEGF already at early
stages of pregnancy, at the stage preceding the invasion of trophoblast
cells into mother arteries [4,9]. Its action on cells is mediated by 3
types of specific membrane receptors: VEGF-R1 (fms-like tyrosine
kinase-1, Flt-1), VEGF-R2 (Flk-1/KDR) and VEGF-R3 (Flt-4), and
the soluble form of the first of them - sFlt-1 - is considered as an
antiangiogenic one [2,7]. It is known that the most intensive
expression of VEGF-A and VEGFR-2 is observed at early gestational
age, and the formation of VEGF-R1 is more intensively closer to the
donor term [4].
Vascular endothelial growth factor receptor 1.
Vascular
endothelium growth factor receptor 1 (VEGFR1) is a high-affinity
receptor for tyrosine kinase. In patients with PE the serum level of
sVEGFR1 was increased, with a correlation between sVEGFR1
concentration and proteinuria level, the number of platelets in the
mother and clinical criteria for PE classification [1,2,7]. Both early and
late PE are associated with increased sVEGFR1. However, in patients
with early PE the serum concentration of sVEGFR1 increases earlier
and to a greater extent than in late PE patients. Moreover, sVEGFR1 is
able to predict early PE with greater sensitivity and specificity than
late PE.
Endostatin.
Specific inhibition of endothelial cell proliferation
and migration, ability to induce apoptosis, and preclinical increase of
endostatin serum concentration in PE have been shown [7,9].
However, studies comparing early and late PE have shown a change in
circulating endostatin levels only for early PE and not for late PE [6,7],
which supports the view that early PE is associated with pathological
placentalism.
Epidermal growth factor.
Epidermal growth factor (EGF) and
growth transforming factor-
β
(TGF-
β
) are two important angiogenic
factors that participate in PE pathogenesis. EGF has been shown to be
a trigger for trophoblast syncytization, while TGF-
β
inhibits it in vitro
[5]. Accordingly, a balance between these two factors is necessary for
adequate trofoblast syncytization. Low concentrations of EGF and
high TGF-
β
are determined in PE patients [10]; heparin-binding EGF
also reduces trofoblast apoptosis, which develops in response to
hypoxia; its level is reduced in PE patients [4,9]. TGF-
β
1 is one of the
most studied types of TGF-
β
. Early studies did not find any difference
in TGF-
β
levels between PE patients and healthy pregnant women,
later studies found an increase in TGF-
β
in women with PE and a
genetic predisposition to high TGF-
β
levels in women with PE in the
history [1,3]. To date, there are no data on TGF-
β
and EGF
concentrations in early and late PE.
Endoglin is mainly expressed on the endothelial cell surface as
well as on the placenta syncyotrofoblast and is a coreceptor for TGF-
β
1 and TGF-
β
2. The increase in the level of the soluble form of
endoglin (sEng) was studied as a prognostic marker of PE, as a
noticeable increase in sEng concentration in women with PE was
shown in some cases 2-3 months before the signs of pathology
appeared [9]. There are conflicting data on sEng levels in early and
late PE. Thus, some authors noted the absence of reliable differences
[10], while others reported a significant increase in sEng concentration
in women with early PE compared to late PE [1,4]. Increased sEng and
sFlt1 levels were also shown in the first trimester in women who
subsequently developed late PE [5]. According to the researchers, a
combination of sEng and sFlt1 can be a reliable prognostic marker of
PE, especially for the development of early PE with a sensitivity of
about 100% and specificity of about 95% [2,5] in a study at 13 and 20
weeks of pregnancy.
Placental Protein 13.
Placental Protein 13 (PP-13) is a placental-
specific marker that plays a role in normal implantation, placental
vessel development and spiral artery remodeling. Normally, the level
of PP-13 increases during pregnancy, and in women who subsequently
develop PE, its level is abnormally reduced [5]. Studies have shown
that the serum level of PP-13 in combination with the average
pulsation index of the uterine artery with high accuracy can be a
predictive marker of PE. Moreover, it has been shown that serum level
PP-13 itself in the first trimester, as well as its combination with the
pulsation index of the uterine artery according to ultrasound Doppler
in the second trimester, better predict the development of early PE than
the late form of the disease [4].
Plasma pentraxin 3
. Pentraxins is a superfamily of proteins,
which are mandatory components of the humoral immune system.
Plasma pentraxin 3 (PTX3) is expressed by a number of cells,
including endothelial cells of vessels, monocytes, macrophages and
fibroblasts. It is believed to bind the antigens of apoptotic cells in
order to limit their risk of initializing the immune response. An
association between PE and an increase in plasma RTX3 concentration
has been shown [7,9]. Moreover, serum RTX3 levels in 11-13 weeks
of pregnancy are significantly higher compared with controls, although
they do not differ in patients with subsequent development of early or
late PE. In addition to those discussed above, analysis of biochemical
and placental determinants revealed that "early" PE is characterized by
an increased ratio of plasminogen inhibitor of the first type to the
second (PAI-1/PAI2) - a marker of trofoblast dysfunction; a higher
concentration of 8-iso-prostaglandin F2
α
in the placenta - a marker of
oxidative stress [4,8]; higher concentration of elastase - a soluble
marker of neutrophil activation [1,5]; increased concentration of
retinol binding protein-4 - adipokin, involved in pathogenesis of
insulin resistance and inflammation [1,8]. At the same time the
increase of adiponectin - adipokin with anti-inflammatory action in
blood was revealed only in patients with late PE [3,7,8].
Soluble Fms-like tyrosine kinase
. Taking into account the
connection between PFR and SEFR and the development of the
trofoblast, it can be assumed that antiangiogenic factors play an
important role in the development of PE, which inhibit their functions.
PFR and SEFR bind to the receptor fms-like tyrosine kinase, which
undergoes an alternative splicing from Flt-1 to soluble Fms-like
tyrosine kinase (sFlt1), inducing endothelial dysfunction. Placental
expression of sFlt1 is increased in PE, in some works it is associated
with the degree of disease severity [4]. There are data that reliable
changes in PFR level in PE are observed already in the first or in the
beginning of the second trimester. The sFlt1 level rises 2-3 months
before clinical symptoms of PE occur [9]. Both early and late PE are
associated with changes in sFlt1 serum concentrations, with more
pronounced disorders in early disease development.
At present, in the conditions of practical obstetrics, the most
important measures to diagnose and prevent hypertensive disorders in
pregnancy, and especially PE, are carefully collected anamnesis,
identification of reliably associated with PE risk factors, early and
adequate laboratory diagnostics, including the study of the most
important parameters: proteinuria, hemostasis system, indicators of
clinical and biochemical blood tests, including hepatic enzymes,
determination of reliable prognostic markers of PE development in the
blood. Complex laboratory diagnostics, dynamic monitoring of the
patient under the control of instrumental methods of research, timely
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and rational tactics of management of pregnant women with
hypertensive disorders will contribute to the effective reduction of
maternal and perinatal morbidity and mortality, as well as improve the
remote prognosis for mother and fetus.
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