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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. Inammatory 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 dened. 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 inammatory

Corresponding author: Chiara Benedetto, e-mail: 85

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

Copyright 2011, Elsevier Inc. All rights reserved.



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 rst 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 ndings. In some cases, however, the HELLP syndrome may present with nonspecic 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 ow 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 specic predisposition to this condition [7]. On liver biopsy, periportal hemorrhage, focal parenchymatous necrosis, and macrovesicular steatosis may be observed in



up to one-third of patients. Fibrin and hyaline deposits are seen by immunouorescence at the level of liver sinusoids. However, there is little correlation between histological ndings and clinical presentation [8]. Hemolysis, one of the major characteristics of the disorder seen on a microangiopathic blood smear, reects 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 reect 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 specic 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 reect 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 dene 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 difcult. AFLP is a rare but life-threatening complication mainly of the third trimester. The patient usually presents with



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 ndings may include hypertension, proteinuria, low-grade fever, ascites, and bleeding from severe coagulopathy [18]. Common laboratory ndings in AFLP are hemoconcentration, elevated white blood count, and normal or reduced platelet count. The production of antithrombin, brinogen, and coagulation factors by the liver is signicantly 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 sufciently sensitive to conrm or exclude the diagnosis, and the gold standard for conrming the diagnosis of AFLP is the liver biopsy with special stains for fat, such as red oil: histopathological ndings 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].



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 dened. 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 conned to the inner layer of the myometrium so that a low resistance, high ow uteroplacental circulation typical of normal pregnancy cannot be established, and placental ischemia will develop [40,41]. The insufcient 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 ow 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 signicantly increase during PE, even before the clinical onset of the disease, and endogenous antioxidants sharply decrease [4749].



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 inammatory 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, rst, comparison of serial analysis of gene expression proles of 28 weeks control placenta (from idiopathic preterm delivery) to a HELLP/preeclampsia matched for gestational age identied 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 classication method determined the HELLP-specic 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 specically 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% misclassication 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 nding 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 specic expression of placental genes different from those activated in preeclampsia, leading to enhanced local and



systemic inammatory 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 signicantly 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 signicant impact on clinical laboratory parameters of women with HELLP syndrome, as the AST, LDH, and ALP levels were signicantly higher, whereas the platelet count tended to be lower in BclI carriers than in noncarriers. There were no signicant 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 nding 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 prole 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



HELLP, with episodic exacerbations together with the sensitivity to corticosteroids, suggest a key role for an immune-mediated and prominent inammatory 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 inammatory activity involving a maternal endothelial cell dysfunction. In many cases, the severity of HELLP syndrome uctuates, 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 signicantly 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. Signicant differences were found in IL-6 and IL-1Ra levels. During a HELLP exacerbation, plasma levels of both cytokines were signicantly increased as compared with preeclampsia and normal pregnancy. During HELLP exacerbation, median GSTA1-1 levels were signicantly higher as compared with preeclampsia and normal pregnancy. The authors concluded that these ndings conrm that the development of HELLP syndrome is associated with a further intensied inammatory 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 benecial effect on the liver damage commonly seen in HELLP exacerbation, as reected by an unaltered course



of plasma levels of AST, ALT, and GSTA1-1 during prednisolone therapy. A possible explanation of this nding 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 inammatory response typical of HELLP syndrome has been recently investigated by Tranquilli et al. [73]. They analyzed the expression of 96 genes involved in inammatory 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 inammatory response such as transforming growth factor (TGF)-b, interleukin (IL)-6 Ra, IL-10, IL-16, and CCL-18 and CXCL5 chemokines. Macroarray analysis identied 14 genes encoding differentially expressed cytokines. Gene expression measurement (HELLP vs. healthy) revealed a signicant upregulation for IL-10, IL-6 receptor, and TGF-b3 in HELLP placenta, while the expression of CCL18, CXCL5, and IL-16 was signicantly downregulated. IL-10 has a powerful anti inammatory effect. It is important in regulating immune function, by inhibiting macrophages, reducing antigen-specic 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 inammation, and it downregulates matrix metalloprotease (MMP)-9 [74]. Its overexpression in HELLP placenta may be regarded as a compensatory mechanism against excessive inammatory 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 inammatory response. It is known that dysregulation of IL-6-type cytokine signaling contributes to the onset and maintenance of several inammatory and autoimmune diseases, such as rheumatoid arthritis, inammatory bowel disease, osteoporosis, and multiple sclerosis [75]. The TGF-b family is involved in cellular proliferation and differentiation, extracellular matrix modication, 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



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 trafcking 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 inammation in response to allergens [78], the decrease of IL-16 expression in HELLP placenta suggests a role of the cytokine in the immune and inammatory features of the syndrome. In preeclampsia, there is exacerbation of physiological changes associated with pregnancy such as insulin resistance, altered immune responses, and inammatory 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 ndings 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 specically aimed to investigate the link between insulin resistance and HELLP syndrome [80].



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 classied into three main subtypes: ADAMTS-13 deciency-related TMA, complement dysregulation-related TMA, and indeterminate TMA [85]. Previous studies have shown that HELLP is not associated with a deciency 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 identied 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 ndings suggest that an abnormal genetic control of the CAP may be a risk factor for the occurrence of HELLP syndrome and open new elds of investigation.



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 inammation and thrombosis. Mice decient 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 specicity 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 brinolytic system is necessary for clot dissolution, and in a recent study, Guven et al. investigated the role of brinolytic and antibrinolytic activities in the pathophysiology of HELLP syndrome [97]. They measured the levels of plasma tissue-type plasminogen activator (tPA), thrombin-activatable brinolysis 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 signicantly increased in HELLP patients, suggesting an involvement of brinolytic system in HELLP, possibly as a response to the activation of coagulation system.



Moreover, components of brinolytic 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 specic 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 ndings, 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 ow. 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



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 myolament 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 specic features of HELLP [46].

6. Conclusion Although the cause of tissue injury in HELLP syndrome is multifactorial, a key role for prominent inammatory 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 inammation responses conrm this hypothesis. Further studies are needed to explain placental-induced disease, as in preeclampsia, since it involves a more acute and predominant inammatory 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 inammatory response, and the sensitivity to glucocorticoids. REFERENCES
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