ADVANCES IN CLINICAL CHEMISTRY, VOL.

53

BIOCHEMISTRY OF HELLP SYNDROME

Chiara Benedetto,1 Luca Marozio, Annalisa Tancredi,
Elisa Picardo, Paola Nardolillo, Anna Maria Tavella,
and Loredana Salton
Department of Obstetrics and Gynaecology, University of
Torino, Torino, Italy

1. Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Clinical Features of HELLP Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Laboratory Findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Maternal and Perinatal Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Pathogenesis of HELLP and Preeclampsia: The Role of Placenta . . . . . . . . . . . . . . . .
4. Inflammatory Response in HELLP Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. HELLP Syndrome, Complement Pathway, and the Coagulation System . . . . . . . . .
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Abstract
The HELLP syndrome is a serious complication of pregnancy characterized by hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP)
count that occurs in 0.20.6% of all pregnancies and in 1020% of cases with
severe preeclampsia and frequently leads to adverse maternal and perinatal
outcome. The exact pathobiology of HELLP syndrome has not been clearly
defined. As it is considered a form or a complication of severe preeclampsia,
it likely has its origin in aberrant placental development and function resulting in ischemia-producing oxidative stress. However, there is still a debate on
whether HELLP must be considered a severe form of preeclampsia or a
separate disease entity. It can be described as a placenta-induced disease, as
is preeclampsia itself, but with a more acute and predominant inflammatory
1

Corresponding author: Chiara Benedetto, e-mail: chbened@tin.it

85

0065-2423/11 $35.00
DOI: 10.1016/S0065-2423(11)53004-5

Copyright 2011, Elsevier Inc.

All rights reserved.

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BENEDETTO ET AL.

process typically targeting the liver and with a greater activation of the
coagulation system. This occurs during a disordered immunologic process
and may be due to a genetic predisposition. In this review, we discuss the
main biochemical characteristics of HELLP syndrome, particularly focusing
on molecular aspects of placental involvement and maternal systemic
responses.

2. Introduction
The HELLP syndrome is a serious complication of pregnancy characterized by hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP)
count occurring in 0.20.6% of all pregnancies and in 1020% of cases with
severe preeclampsia [1]. In about 70% of the cases, the HELLP syndrome
develops before delivery with a peak frequency between the 27th and 37th
gestational weeks; 10% occur before the 27th week, and 20% beyond the 37th
gestational week [2,3]. In some cases, it develops in the postpartum period,
usually within the first 48h in women who have had proteinuria and
hypertension prior to delivery [2].
2.1. CLINICAL FEATURES OF HELLP SYNDROME
The majority of women with the HELLP syndrome have had hypertension
and proteinuria, which may be absent in 1020% of the cases [4]. The more
common symptom at presentation is right upper abdominal quadrant or
epigastric pain, nausea, and vomiting being less frequent [4]. Up to 3060%
of women have headache; about 20% have visual disturbances and other
features of severe preeclampsia or impending eclampsia [4]. The clinical
symptoms often precede the laboratory findings. In some cases, however,
the HELLP syndrome may present with nonspecific viral syndrome-like
symptoms or malaise [4].
The syndrome, which is considered a complication of preeclampsia, is
characterized by prominent endothelial cell damage within the liver.
Hypovolemia is suggested with a decrease in the liver blood flow on Doppler
examination in patients with preeclampsia, who have subsequently developed HELLP syndrome [5]. Hepatic ischemia may cause infarction, subcapsular haematomas, and intraparenchymatous hemorrhage, resulting in
hepatic rupture, a rare but severe and life-threatening complication [6].
Recurrent episodes of hepatic haematoma and rupture in subsequent pregnancies have been reported, suggesting that there may be a specific predisposition to this condition [7]. On liver biopsy, periportal hemorrhage, focal
parenchymatous necrosis, and macrovesicular steatosis may be observed in

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87

up to one-third of patients. Fibrin and hyaline deposits are seen by immunofluorescence at the level of liver sinusoids. However, there is little correlation
between histological findings and clinical presentation [8].
Hemolysis, one of the major characteristics of the disorder seen on a
microangiopathic blood smear, reflects the damage of the vascular endothelium. Red cell fragmentation represents the extent of small vessel involvement, and schizocytes and Burr cells are usually present [9]. Polychromatic
red cells are also seen in blood smears, and increased reticulocyte counts
reflect the compensatory release of immature red cells into peripheral blood.
Decreased PLT count in the HELLP syndrome is due to their increased
consumption. Platelets are activated and adhere to damaged vascular endothelial cells, resulting in increased platelet turnover with shorter lifespan [9].
2.2. LABORATORY FINDINGS
Hemolysis causes increased serum lactate dehydrogenase (LDH) levels and
decreased hemoglobin concentrations [10]. Free hemoglobin is converted to
unconjugated bilirubin in the spleen or may be bound by haptoglobin. The
hemoglobinhaptoglobin complex is cleared quickly by the liver, leading to
decreased haptoglobin plasma levels [10,11]. Low haptoglobin concentration
is the preferred marker of hemolysis [12]. Thus, the diagnosis of hemolysis is
supported by high LDH concentration and the presence of unconjugated
bilirubin, but the demonstration of low or undetectable haptoglobin concentration is a more specific indicator. Intravascular hemolysis is diagnosed by
abnormal peripheral blood smear, increased serum bilirubin (
20.5
mol/L
or
1.2 mg/100 mL), and elevated LDH levels (> 600 units/L (U/L)) [13,14].
However, according to Smulian et al., the threshold of normal LDH values
may be much lower than 600 U/L depending on the laboratory method
adopted [15].
Elevation of liver enzymes may reflect the haemolytic process as well as
liver involvement. Enhanced aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) levels are mostly due to liver injury [10]. Visser and
Wallenburg used ALT > 30 U/L to define abnormality (2 SD above mean)
[16], while Sibai suggests a cutoff value for ALT > 70 U/L [4].
Thrombocytopenia (platelets < 100,000/ml) is obligatory in the HELLP
syndrome. Reduced platelet count in pregnancy may be also caused by
gestational thrombocytopenia, immune thrombocytopenic purpura, and
preeclampsia [17], but in those cases, hemolysis and liver damage are usually
absent.
Sometimes, the differential diagnosis of HELLP from acute fatty liver of
pregnancy (AFLP) may be very difficult. AFLP is a rare but life-threatening
complication mainly of the third trimester. The patient usually presents with

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a 1- to 2-week history of malaise, nausea, vomiting, epigastric or right upper

quadrant pain, headache, or jaundice, more rarely with hepatic encephalopathy or coma. Signs of preterm labor and/or fetal demise may be present.
Other findings may include hypertension, proteinuria, low-grade fever,
ascites, and bleeding from severe coagulopathy [18]. Common laboratory
findings in AFLP are hemoconcentration, elevated white blood count, and
normal or reduced platelet count. The production of antithrombin, fibrinogen, and coagulation factors by the liver is significantly reduced, often
leading to disseminated intravascular coagulation. Serum electrolytes will
reveal evidence of metabolic acidosis with elevated creatinine and uric acid
values [19]. Blood sugar is usually low, but may be high in association with
pancreatitis. Liver enzymes (AST, ALT, alkaline phosphatase) and bilirubin
will be elevated. The increase in bilirubin is mainly of the conjugated form,
with levels usually higher than 5 mg/dL. Ammonia levels increase in the late
stage of the disease [20]. Ultrasonography, CT, and MRI are not sufficiently
sensitive to confirm or exclude the diagnosis, and the gold standard for
confirming the diagnosis of AFLP is the liver biopsy with special stains for
fat, such as red oil: histopathological findings reveal swollen, pale hepatocytes with central nuclei. However, liver biopsy is rarely used in the clinical
practice [18]. Prompt delivery, within 24 h from the diagnosis and after
maternal stabilization, is a reasonable approach. In general, most patients
with AFLP will start to improve 23 days after delivery. However, in some
cases, deterioration in liver and renal function, encephalopathy, and coagulopathy may continue, requiring life-supporting treatments. In rare cases,
liver transplantation will be required [21].

2.3. MATERNAL AND PERINATAL OUTCOME

The HELLP syndrome is associated with both maternal and neonatal
complications. Spontaneous rupture of a subcapsular liver haematoma in
pregnancy is a rare but life-threatening complication that occurs in less than
1% of the cases with the HELLP syndrome. Rupture most often occurs in the
right liver lobe [4, 2224]. More common and serious maternal complications
are abruptio placentae, disseminated intravascular coagulation, and
subsequent severe postpartum bleeding, retinopathy, cerebral bleeding, and
stroke [2532]. In a large retrospective cohort study comprising 442 pregnancies complicated by the HELLP syndrome, the maternal mortality was
1.1% [2], which is in accordance with other reports [4,33,34]. Isler et al. found
cerebral hemorrhage or stroke to be the primary cause of death in 26% and
the most contributing factor in another 45% of the deaths [35]. Maternal
mortality rate in hepatic rupture ranges from 18% to 86% [8].

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Perinatal mortality and morbidity are considerably high in the HELLP

syndrome and are primarily dependent on the gestational age at onset
[36,37]. The perinatal mortality rate related to the HELLP syndrome is
between 7.4% and 34% [4,38,39]. Neonates delivered before completion of
32 weeks gestation have the highest risk of perinatal death [36,37].

3. Pathogenesis of HELLP and Preeclampsia: The Role

of Placenta
The exact pathobiology of HELLP syndrome has not been clearly defined.
As it is considered a form or a complication of severe preeclampsia, it likely
has its origin in aberrant placental development and function resulting in
ischemia-producing oxidative stress. An abnormal interaction between maternal and placental tissue at the time of trophoblast implantation is thought
to play a key role in the pathogenesis of preeclampsia. In preeclamptic
pregnancies, trophoblast invasion of the spiral arteries at the time of placentation is confined to the inner layer of the myometrium so that a low
resistance, high flow uteroplacental circulation typical of normal pregnancy
cannot be established, and placental ischemia will develop [40,41]. The
insufficient trophoblast invasion is believed to be the consequence of the
abnormal interaction between decidual immune cells and paternally derived
antigens on trophoblasts surface [42]. Owing to generalized vasoconstriction, microthrombi formation in small vessels, and plasma volume reduction,
blood flow is impaired in every organ and tissue. The maternal vascular
endothelium is an early target of placental ischemia, and its activation is
responsible for the generalization of damage [43,44]. The clinical manifestations of preeclampsia begin with the loss of vascular refractoriness to vasoconstrictors typical of normal pregnancy, with a subsequent increase in
peripheral resistances. The mechanisms underlying the impaired vascular
reactivity in preeclampsia are not fully understood, but they might be attributed to the systemic endothelial dysfunction [43,45,46].
The link between abnormal trophoblast invasion, placental ischemia, and
maternal vascular endothelium activation is still unclear. Oxidative stress
following immune rejection of the trophoblast in the decidua seems to play a
key role. The features of endothelial damage in PE are similar to those
observed in other diseases in which the impact of oxidative stress is known,
such as atherosclerosis, diabetes, septic shock, and ischemiareperfusion
syndrome. In PE, oxidative agents are released into the intervillous spaces
by activated leukocytes and the ischemic placenta itself. Several markers of
oxidative stress significantly increase during PE, even before the clinical onset
of the disease, and endogenous antioxidants sharply decrease [4749].

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Moreover, the placental release and the activity of angiogenic and endotheliumprotecting agents, such as the vascular endothelial growth factor and the
placental growth factor are deeply impaired [5053].
HELLP syndrome has many features in common with preeclampsia and
can be described as a placenta-induced disease, as is preeclampsia itself, but
with a more acute and predominant inflammatory process typically targeting
the liver and with a greater activation of the coagulation system. This occurs
during a disordered immunologic process and may be due to a genetic
predisposition [8,54,55]. There is still a debate on whether HELLP must be
considered a severe form of preeclampsia or a separate disease entity.
It is well documented that the placenta is a prerequisite for the development of both preeclampsia and HELLP syndrome, and it has been thought
that differences in placental gene expression may account for clinical and
molecular differences between the two syndromes. In a recent study, Buimer
et al. investigated differences in gene expression between placental tissue
obtained from normotensive pregnant women and women with preeclampsia
or HELLP syndrome [56]. In their study, first, comparison of serial analysis
of gene expression profiles of 28 weeks control placenta (from idiopathic
preterm delivery) to a HELLP/preeclampsia matched for gestational age
identified 404 differentially expressed transcripts. Second, using semiquantitative real-time PCR, the expression levels of 37 of these transcripts
were analyzed in placentas from normal pregnant women and from patients
with HELLP or preeclampsia. Third, nearest centroid classification method
determined the HELLP-specific molecular signature consisting of the
upregulated expression of genes encoding the vascular endothelial growth
factor receptor (Flt1), leptin, pappalysin2, and WW domain containing
transcription regulator 1 (WWTR1), combined with downregulated expression of the genes encoding cadherin-associated protein (CTNNAL), glutathione S-transferase-p1 (GSTP1), and calgranulin A (S100A8). Four of these
seven genes (Flt1, GSTP1, leptin, and pappalysin2) have been previously
associated with preeclampsia, although not specifically to HELLP syndrome
[5760]. The altered expression of WWTR1, CTNNAL1, and S100A8 has not
been associated with placental function or dysfunction previously. The
authors found that this set of seven genes expression discriminates HELLP
placenta from control and preeclamptic placenta with a 24% misclassification
rate (95% CI 8.341.9), independent from known risk factors like parity and
ethnicity. Although it is not known the exact role of the placental expression
of these genes in the pathogenesis of preeclampsia and HELLP syndrome,
this finding might suggest that HELLP is not a variant of preeclampsia but a
separate disease entity. It might be suggested that the abnormal placentation
in HELLP syndrome may trigger a specific expression of placental genes
different from those activated in preeclampsia, leading to enhanced local and

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systemic inflammatory response and endothelium activation, with a particular involvement of the liver and the coagulation system probably due to
maternal predisposition.
At this regard, it has been recently observed that the allelic and carrier
frequencies of the BclI polymorphism of the glucocorticoid receptor
(GR) gene were significantly higher in women with HELLP syndrome
compared to healthy pregnant women (p 0.004, OR 2.89) and to those
with severe preeclampsia (p 0.013, OR 2.56) [61]. Moreover, the BclI
carrier status had a significant impact on clinical laboratory parameters of
women with HELLP syndrome, as the AST, LDH, and ALP levels were
significantly higher, whereas the platelet count tended to be lower in
BclI carriers than in noncarriers. There were no significant differences in
carrier and allelic frequencies of the N363S and ER22/23EK polymorphisms of GR gene between groups [61]. Previous studies have demonstrated
that the BclI polymorphism of GR gene results in increased glucocorticoid
sensitivity in vivo and is associated with cardiovascular risk factors and with
autoimmune diseases [62,63]. The finding suggests that BclI polymorphism
of the GR gene may play a role in the pathogenesis of HELLP syndrome
and may account for clinical characteristics of the syndrome, such as EL
enzymes, LP count, and sensitivity to corticosteroids. Since preeclampsia
and HELLP syndrome develop exclusively in human, it seems particularly
interesting that alignment analysis of DNA sequences obtained from
database indicated the absence of the BclI site in six animal vertebral
species [61].
The difference between HELLP and preeclampsia is underlined also by
clinical aspects. For example, women with preeclampsia and no HELLP
proved to have more often a profile consistent with the metabolic syndrome.
Moreover, preeclamptic patients have a fourfold higher prevalence of thrombophilia as compared to those who had experienced HELLP [64]. Certain
maternal features known as risk factors for preeclampsia, such as obesity,
have not been associated with the HELLP syndrome [65]. Furthermore,
women with preeclampsia differ from those with HELLP by the presence
of a smaller placenta with more infarcts, and this data support the view of a
longer subclinical disease period preceding preeclampsia as compared to
HELLP [66]. Sep et al. postulate that preeclampsia differs from HELLP by
a more gradual course in early pregnancy due to unfavorable constitutional
conditions for placental growth and development [64]. Eventually, intervillous hypoxia results in the placental release of toxic substances pushing the
subclinical condition into the well-known clinical symptomatology. Conversely, an abnormal immune response to the placental allograft with nonappreciable negative impact on placental function is thought to characterize
the subclinical phase of HELLP. The acute course and appearance of

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HELLP, with episodic exacerbations together with the sensitivity to

corticosteroids, suggest a key role for an immune-mediated and prominent
inflammatory response [67].

4. Inflammatory Response in HELLP Syndrome

The maternal signs of HELLP syndrome as hypertension, proteinuria,
intravascular coagulation, LPs, and hemolysis can all be explained by a
systemic inflammatory activity involving a maternal endothelial cell dysfunction. In many cases, the severity of HELLP syndrome fluctuates, resulting in
a pattern of exacerbations and remissions. During exacerbations, systemic
endothelial activation produces abnormalities due to thrombotic microangiopathic hemolysis, with periportal or focal parenchymal necrosis of hepatocytes [13]. This leads to increased plasma levels of AST and glutathione-Stransferase alpha 1-1 (GSTA1-1), a very sensitive marker for hepatocellular
damage [2,68]. Van Runnard Heimel et al. [55] recently observed that during
a HELLP exacerbation, plasma levels of C reactive protein were significantly
higher than those in normal pregnancy or in preeclampsia and decreased
during remission. In HELLP patients, plasma levels of IL-8 and tumor
necrosis factor-a (TNF-a) were below the detection limit, as in normal
pregnancy and preeclampsia. Plasma levels of IL-1b, IL-10, and sIL-6R
did not differ between groups, neither during exacerbations nor during
remissions of HELLP. Significant differences were found in IL-6 and
IL-1Ra levels. During a HELLP exacerbation, plasma levels of both cytokines were significantly increased as compared with preeclampsia and normal pregnancy. During HELLP exacerbation, median GSTA1-1 levels were
significantly higher as compared with preeclampsia and normal pregnancy.
The authors concluded that these findings confirm that the development of
HELLP syndrome is associated with a further intensified inflammatory
response. Moreover, they observed that prednisolone therapy in patients
with HELLP syndrome abolished the rise in plasma levels of the cytokine
IL-6 during exacerbation. Since the activated vascular endothelium is an
important source for circulating IL-6, it may be speculated that corticosteroids act by stabilizing the endothelium in patients with HELLP as previously
reported [6971]. These observations are in agreement with the results of
several randomized controlled trials [12] showing a rapid recovery of the
platelet count during corticosteroid therapy in patients with HELLP syndrome. This effect may be the result of the decrease of endothelial activation
following corticosteroids administration. In the study of van Runnard Heimel et al. [55], prednisolone had no beneficial effect on the liver damage
commonly seen in HELLP exacerbation, as reflected by an unaltered course

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of plasma levels of AST, ALT, and GSTA1-1 during prednisolone therapy.

A possible explanation of this finding is that prednisolone does not seem to
impede the formation of microthrombi, the main cause of hepatic damage.
However, a major pathogenic mechanism for liver disease in HELLP syndrome is Fas (APO-1, CD95)-mediated apoptosis of hepatocytes [54]. Fasligand was found to be produced in the placenta. Extracts of placenta were
cytotoxic for human hepatocytes and cytotoxic activity increased as HELLP
syndrome developed [72]. It is possible that corticosteroid is not able to
prevent the cytotoxic activity of placental microparticles on the liver.
The role of the placenta in triggering the inflammatory response typical of
HELLP syndrome has been recently investigated by Tranquilli et al. [73].
They analyzed the expression of 96 genes involved in inflammatory response
in the placenta from women with HELLP syndrome and from healthy
women at term and evaluated some cytokines probably involved in important steps of the inflammatory response such as transforming growth factor
(TGF)-b, interleukin (IL)-6 Ra, IL-10, IL-16, and CCL-18 and CXCL5
chemokines. Macroarray analysis identified 14 genes encoding differentially
expressed cytokines. Gene expression measurement (HELLP vs. healthy)
revealed a significant upregulation for IL-10, IL-6 receptor, and TGF-b3
in HELLP placenta, while the expression of CCL18, CXCL5, and IL-16 was
significantly downregulated. IL-10 has a powerful anti inflammatory effect.
It is important in regulating immune function, by inhibiting macrophages,
reducing antigen-specific T-cells proliferation, and diminishing the antigenpresenting capacity of monocytes via downregulation of class II major
histocompatibility complex expression [74]. It has also been reported that
IL-10 has an important inhibitory role in regulation of T-cell responses and
acute inflammation, and it downregulates matrix metalloprotease (MMP)-9
[74]. Its overexpression in HELLP placenta may be regarded as a compensatory mechanism against excessive inflammatory response. In HELLP
placenta, the expression of IL-6 receptor (IL-6 Ra) is increased. IL-6, a
cytokine normally produced at the maternalfetal interface, stimulates
MMP-2 and MMP-9. IL-6 Ra produces a signal transduction occurring
through two pathways: the Ras/mitogen-activated protein kinase (MAPK)
pathway and the Jak/Stat pathway, thus making it an important control in
the inflammatory response. It is known that dysregulation of IL-6-type
cytokine signaling contributes to the onset and maintenance of several
inflammatory and autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, and multiple sclerosis [75].
The TGF-b family is involved in cellular proliferation and differentiation,
extracellular matrix modification, tissue remodeling, and angiogenesis.
It has been observed that TGF-b3 is overexpressed in preeclamptic placentas, and its inhibition restores the invasive capability of extravillous

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trophoblasts [76]. In HELLP placenta, TGF-b3 was 2.5-fold upregulated as

compared to placenta from normal pregnancy, and this suggests an involvement in pathogenic mechanisms of HELLP syndrome. Chemokines are
implicated in angiogenesis, cell recruitment, and lymphoid trafficking and
can modulate innate and adaptive immune response [77]. The chemokines
decrease observed in HELLP placenta may be involved in the derangement
of immune activity control at the maternalfetal interface. Finally, since
IL-16 has been linked with modulation of Th2 cell-mediated inflammation
in response to allergens [78], the decrease of IL-16 expression in HELLP
placenta suggests a role of the cytokine in the immune and inflammatory
features of the syndrome.
In preeclampsia, there is exacerbation of physiological changes associated
with pregnancy such as insulin resistance, altered immune responses, and
inflammatory pathway activation. These exaggerated responses seen in preeclampsia are reminiscent of metabolic syndrome and also are evident in
gestational diabetes mellitus. Many features of the insulin resistance syndrome have been associated with this condition. These include hypertension,
hyperinsulinemia, glucose intolerance, obesity, and lipid abnormalities.
Other accompanying abnormalities may include elevated levels of leptin,
TNF-a, tissue plasminogen activator, plasminogen activator inhibitor-1
(PAI-1), and testosterone. The documentation of these features before the
onset of preeclampsia suggests that insulin resistance or associated abnormalities may have a role in this disorder. Furthermore, the recognition that
features of the insulin resistance syndrome persist many years after
pregnancy among women with preeclampsia raises the possibility that these
women may have increased risk for future cardiovascular disease. These
observations suggest that interventions to reduce insulin resistance may
reduce the risk of both hypertension in pregnancy and later life cardiovascular complications [79]. The link between insulin resistance and preeclampsia
is not clear but novel findings providing some insight have been reported
recently. Inositol phosphoglycan P-type (P-IPG) in preeclampsia has been
extensively investigated and increased production has been demonstrated.
This molecule acts as a second messenger of insulin, enhances the metabolic
effects of insulin, and is associated with insulin resistance. An increase
in urinary release of P-IPG during pregnancy may herald the onset of
preeclampsia. The overexpression of P-IPG during preeclampsia may be a
counter-regulatory mechanism to insulin resistance since these molecules
mimic insulin action. Further knowledge about the nature of the metabolic
syndrome during preeclampsia and the degree of association between its
components will help to inform future research efforts. To date, there are
no studies specifically aimed to investigate the link between insulin resistance
and HELLP syndrome [80].

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5. HELLP Syndrome, Complement Pathway, and

the Coagulation System
Evidence from the literature supports a role for the complement system in
the pathogenesis of preeclampsia/HELLP. Increased levels of the complement alternative pathway (CAP) activation fragment Bb early in pregnancy
were associated with the subsequent development of preeclampsia [81].
Complement activation was shown to induce dysregulation of angiogenic
factors and to cause fetal rejection and growth restriction in a murine model
of spontaneous miscarriage and intrauterine growth restriction [82]. Complement activation products, particularly C5a, stimulate monocytes to produce sVEGFR-1 (sFlt-1) and thereby sequester VEGF [80], and it is known
that increased release of sFlt-1 from ischaemic placenta is one of the key
pathogenic mechanisms in the development of preeclampsia/HELLP syndrome and in the endothelial activation typical of the diseases [50]. Moreover, it has been observed that some SNPs polymorphisms of VEGF,
particularly the VEGF  460TT and the 405CC genotypes, may increase
the risk for HELLP syndrome [83].
HELLP syndrome shares several clinical and biological features with
thrombotic microangiopathy (TMA). TMA is characterized by the occurrence of thrombi in the microvasculature of several organs, leading to
thrombocytopenia, mechanical haemolytic anemia, and end-organs failure
[84]. TMA may be classified into three main subtypes: ADAMTS-13
deficiency-related TMA, complement dysregulation-related TMA, and indeterminate TMA [85]. Previous studies have shown that HELLP is not associated with a deficiency in ADAMTS-13 activity [86], which is a disintegrin
and metalloprotease that cleaves the high molecular weight von Willebrand
factor oligomers secreted by endothelial cells, resulting in unusually large
multimers that can aggregate to form microvascular platelet thrombi [87].
In a recent study, Fakhouri et al. [88] evaluated the plasma concentration of
factor H (FH), factor I, C3, C4, and factor B in 11 patients with HELLP
syndrome. They also analyzed the expression of membrane cofactor protein
(MCP) and the coding sequences for complement factor H (CFH) and
complement factor I (CFI). They identified four patients with a mutation
in one of the genes coding for proteins involved in the regulation of the
alternative pathway of complement and linked with the C3b activity. Two
patients had low C3 and factor B levels, clearly indicating a dysfunctional
regulation of the CAP. Although obtained in a very small number of subjects, these findings suggest that an abnormal genetic control of the CAP may
be a risk factor for the occurrence of HELLP syndrome and open new fields
of investigation.

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Previous reports indicate that HELLP syndrome appears in a more severe

form in patients carrier of antiphospholipid antibodies, and in those patients
it may be refractory to standard treatment leading more frequently to the
development of hepatic infarcts [8991]. The role of the complement system
in antiphospholipid antibodies syndrome (APS) has been investigated in
murine models [92]. Passive transfer of human antiphospholipid antibodies
(aPL) resulted in complement activation and generation of split products
that induced placental injury and led to fetal loss/growth restriction [82,93].
The complement activation by aPL in other vascular areas may cause inflammation and thrombosis. Mice deficient in C3 or C5 are less susceptible to
aPL-induced thrombosis and endothelial cell activation. Inhibiting C5 activation prevents aPL-induced thrombocytopenia, and mice treated with inhibitors of complement activation are protected from fetal loss [92].
The complement and coagulation system are linked through both direct
and indirect interactions, and the vascular endothelium plays a key role in
this interaction. The complement increases blood clotting properties. C3a
and C5a induce platelet activation and aggregation, upregulation in PAI-1,
and tissue factor expression [94,95]. Complement also has thrombogenic
properties by decreasing protein S activity [96]. C3a and C5a contribute to
the regulation of the cytokine response, modulating production and secretion of TNF-a and IL-6 by macrophages [95], which may enhance TF
expression and platelet production and activity. A damage of the endothelial cell lining may activate the complement system and clotting, and the
thrombotic tendency of each organ varies depending on the local anticoagulant and procoagulant characteristics. This may explain the tissue specificity of the liver for HELLP syndrome, but the role of complement activation
in the pathogenesis of HELLP remains to be established.
The coagulation system seems to play a key role in HELLP syndrome.
Microthrombi formation, due to endothelial dysfunction and probably to
complement system activation, is essential in determining the clinical features
of the disease. The fibrinolytic system is necessary for clot dissolution, and in
a recent study, Guven et al. investigated the role of fibrinolytic and antifibrinolytic activities in the pathophysiology of HELLP syndrome [97]. They
measured the levels of plasma tissue-type plasminogen activator (tPA),
thrombin-activatable fibrinolysis inhibitor (TAFI), PAI-1, thrombin
antithrombin complex (TAT), and thrombomodulin (TM) in normal pregnant women, nonpregnant women, and women with HELLP syndrome.
Compared to the control groups, the mean tPA, PAI-1, TAFI, TAT, and
TM levels were significantly increased in HELLP patients, suggesting an
involvement of fibrinolytic system in HELLP, possibly as a response to the
activation of coagulation system.

BIOCHEMISTRY OF HELLP SYNDROME

97

Moreover, components of fibrinolytic system may be involved in the

control of trophoblast invasion and spiral artery remodeling at the time of
placentation. It is known that MMPs and their specific inhibitors are
involved in this process [98]. The invasive behavior of trophoblast cells
correlates with MMP-9 expression, and tissue inhibitor of MMPs (TIMPs)
inhibits their invasive capacity. MMP-2 and MMP-9 cooperate closely with
the urokinase-type plasminogen activator (uPA) system, mutually activating
their components [98]. Synergism of these proteolytic factors in placental
development has been shown in animal experiments [99]. PAI-1, expressed in
villous and extravillous trophoblasts, as well in maternal decidual tissue, is
suggested to be closely involved in control of trophoblast invasion [100].
Recently, Pildner von Steinburg et al. observed that in patients with HELLP
syndrome, mRNA placental expression of MMP-2 and TIMP-2 was decreased, and mRNA expression of MMP-9 and uPA receptor was undetectable [101]. These findings, although preliminary, suggest a decrease in matrix
remodeling in placentae from patients with HELLP syndrome.
Preeclampsia is characterized by an imbalance between two cyclooxygenase metabolites of arachidonic acid, thromboxane, and prostacyclin (PGI2)
that favors thromboxane. Because of the biologic actions of these two eicosanoids, this imbalance might explain major clinical symptoms of preeclampsia, such as hypertension, platelet aggregation, and reduced uteroplacental
blood flow. In the maternal circulation, this imbalance is primarily manifested
by decreased production of PGI2 by endothelial cells. Platelet thromboxane
synthesis is only increased in severe preeclampsia. In the placenta and leukocytes, the imbalance is exacerbated by increased production of thromboxane
coupled with decreased production of PGI2 in both mild and severe preeclampsia. Longitudinal measurements of urinary metabolites of thromboxane and PGI2 reveal that the thromboxane/PGI2 imbalance predates the onset
of clinical symptoms of preeclampsia. The imbalance between thromboxane
and PGI2 is most likely caused by oxidative stress, which is manifest in
preeclampsia by increased lipid peroxidation and decreased antioxidant protection. Oxidative stress may drive this imbalance because lipid peroxides
activate the cyclooxygenase enzyme to increase thromboxane synthesis, but at
the same time they inhibit PGI2 synthase to decrease PGI2 synthesis [102].
Furthermore, the endothelial cell dysfunction typical of preeclampsia leads to
alterations in the release of vasodilator substances such as nitric oxide (NO),
PGI2, and endothelium-derived hyperpolarizing factor, and thereby reductions of the NO-cGMP, PGI2-cAMP, and hyperpolarizing factor vascular
relaxation pathways. These alterations may also increase the release of or the
vascular reactivity to endothelium-derived contracting factors such as
endothelin, thromboxane, and angiotensin II. These contracting factors
could increase intracellular Ca2 concentrations ([Ca2]i) and stimulate

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BENEDETTO ET AL.

Ca2-dependent contraction pathways in vascular smooth muscle. The

contracting factors could also increase the activity of vascular protein
kinases such as protein kinase C, leading to increased myofilament force
sensitivity to [Ca2]i and enhancement of smooth muscle contraction. The
decreased endothelium-dependent mechanisms of vascular relaxation and
the enhanced mechanisms of vascular smooth muscle contraction represent
plausible causes of the increased vascular resistance and arterial pressure
associated with preeclampsia. It is reasonable to think that these mechanisms are involved in HELLP syndrome, but they are not specific features of
HELLP [46].

6. Conclusion
Although the cause of tissue injury in HELLP syndrome is multifactorial,
a key role for prominent inflammatory response to abnormal placentation
may be suggested. Maternal vascular endothelium activation, complement
system defective regulation, and coagulation system activation are important
features of the disease. HELLP is categorized as a gestational hypertensive
disorder and seen as the more severe variant of preeclampsia. However,
several reports suggest that it may be a separate disease entity: differences
in placental genes expression and maternal polymorphic alleles involved in
inflammation responses confirm this hypothesis. Further studies are needed
to explain placental-induced disease, as in preeclampsia, since it involves a
more acute and predominant inflammatory process that typically targets the
liver with greater activation of the coagulation system. This occurs during a
disordered immunologic process and may be due to a genetic predisposition
in the particular involvement of the liver in HELLP syndrome, the prominent
inflammatory response, and the sensitivity to glucocorticoids.
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