Role of SOX9 and Hif-1α expression in placentas of patients with HELLP.

PURPOSE: In this study, we investigated the immunohistochemical staining of SRY-box transcription factor 9 (SOX9) and Hif-1α expression in placentas of pregnant woman with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. METHODS: Placentas of 20 normotensive and 20 women with HELLP syndrome were processed for routine histological tissue processing. The biochemical and clinical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and SOX9 and Hif-1α immunostaining. RESULTS: Normotensive placentas showed normal histology of placenta, however placentas of HELLP syndrome showed intense thrombosis, thinning of the villi membrane and vascular dilatation. In placentas of normotensive patients, SOX9 reaction was immunohistochemically negative, however placentas of HELLP group showed SOX9 expression in decidual cells, and syncytial regions of floating villi and inflammatory cells. In placentas of normotensive patients, Hif-1α reaction was mainly negative in vessels and connective tissue cells. Placentas of HELLP group showed increased Hif-1α expression in decidual cell and especially inflammatory cells in the maternal region. CONCLUSIONS: Hif-1α and SOX9 proteins can be used as a marker to show severity of preeclampsia and regulation of cell proliferation and angiogenesis during placental development.

Role of cited-1 and caspase-6 expression in HELLP syndrome.

OBJECTIVE: In this study, we investigated the immunohistochemical staining of cited-1 and caspase-6 expression in the placentas of pregnant women with HELLP syndrome. PATIENTS AND METHODS: Placentas of 20 normotensive patients and 20 women with HELLP syndrome were processed for routine histological tissue processing. The biochemical and clinical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and cited-1 and caspase-6 immunostaining. RESULTS: Placentas of normotensive patients showed normal histology. Placentas of women with HELLP syndrome showed degenerated cells, hyalinization and vacuolization. Cited-1 expression was negative in normotensive group; however, it was increased in HELLP group, especially in decidual cells, endothelial cells and other placental cells. Caspase-6 expression was negative in placental structures of normotensive groups. However, it was intense in decidual cells, vacuolar and hyalinized areas, inflammatory cells and connective tissue cells in HELLP group. CONCLUSIONS: Cited-1 and caspase-6 are a marker in determining the severity of HELLP syndrome.

Angiotensin-1 and vimentin expression and ultrastructural examination in severe preeclampsia complicated by HELLP syndrome changes in the structure of the umbilical cord.

OBJECTIVE: The purpose of this study was to examine the histopathologic, ultrastructural and immunohistochemical changes in the umbilical cord in women diagnosed with HELLP syndrome. MATERIALS AND METHODS: Postpartum umbilical cords of 40 patients at the 35-38th week of pregnancy were included. 20 severe preeclamptic (HELLP) and 20 normal umbilical cords were used. After the follow-up of tissue parts of 10% formaldehyde solution for histopathology and immunohistochemistry, histopathological and angiopoietin-1 and vimentin antibodies were examined as immunohistochemical after routine paraffin follow-up. For electron microscope analysis, umbilical cord samples were taken into 2.5% glutaral aldehyde solution. RESULTS: In the statistical comparison, mean difference in increased diameter and additional anomaly on the ultrasound of preeclamptic patients was statistically different compared to control patients. In the HELLP group, hyperplasia and degenerative changes, pyknosis of the endothelial cell nuclei of the vessels and apoptotic changes in some regions were observed. Immunohistochemical analysis showed that endothelial cells, basal membrane and fibroblast cells in the HELLP group expressed high levels of vimentin. Angiotensin-1 expression was increased in amniotic epithelial cells, endothelial cells and some pericyte cells. CONCLUSIONS: As a result, it was observed that the signaling that started with trophoblastic invasion with the effect of hypoxia in severe preeclampsia and continued with dysfunction in endothelial cells was parallel to the increase in angiotensin and vimentin receptors. It is thought that the ultrastructural change in endothelial cells may cause disruption of the collagenized structure in Wharton gel, which supports this, and may cause adverse effects in fetal development and nutrition.

Comparison of clinical features and pregnancy outcomes in early- and late-onset preeclampsia with HELLP syndrome: a 10-year retrospective study from a tertiary hospital and referral center in China.

BACKGROUND: Early-onset preeclampsia (EO-PE) and late-onset preeclampsia (LO-PE) are different subtypes of preeclampsia. We conducted this study to analyze the similarities and differences in the clinical features and pregnancy outcomes in EO- and LO-PE with HELLP syndrome. METHODS: This was a retrospective study in a tertiary hospital. Eighty-three parturients with HELLP syndrome were allocated into two groups based on the timing of preeclampsia onset: EO-PE with HELLP (n = 47) and LO-PE with HELLP (n = 36). RESULTS: In total, 31.9% and 63.9% of women in the EO-PE with HELLP and LO-PE with HELLP groups, respectively, were asymptomatic at diagnosis (P = 0.004, OR = 0.265 (0.106-0.662)). Headache or visual symptoms were more frequent in the EO-PE group than in the LO-PE group (48.9% vs. 25%, P = 0.026, OR = 0.348 (0.135-0.896)). Women in the EO-PE with HELLP group had higher SBP and DBP than those in the LO-PE with HELLP group. Laboratory tests, including platelets, liver function, and hemolysis, which are the main indicators for the diagnosis of HELLP syndrome, showed almost no significant differences between the two groups, with kidney function being the only difference observed. Women in the EO-PE with HELLP group had higher Scr than those in the LO-PE with HELLP group. The degree of proteinuria was higher in the EO-PE group than in the LO-PE with HELLP group. The incidence of severe maternal complications was significantly higher in the EO-PE group than in the LO-PE with HELLP group (25.5% vs. 5.6%, P = 0.016, OR = 0.172 (0.036-0.824)). In total, 57.4% and 8.3% of neonates in the EO-PE and LO-PE with HELLP groups were admitted to the NICU, and the difference was statistically significant, even after adjustment for the delivery week (P = 0.009, OR = 0.830 (0.729-0.944)). Postpartum HELLP syndrome was more common in the LO-PE group than in the EO-PE group (30.6% vs. 4.3%, P = 0.001, OR = 9.9 (2.031-48.256)). CONCLUSIONS: Compared with LO-PE with HELLP patients, EO-PE with HELLP patients have more obvious kidney damage, higher blood pressure and a higher risk of adverse maternal and neonatal outcomes. Patients with LO-PE need to be alerted to the occurrence of HELLP syndrome after delivery.

Identification of Differential Expression Cytokines in Hemolysis, Elevated Liver Enzymes, and Low Platelet Syndrome by Proteome Microarray Analysis and Further Verification.

To screen the differential expression cytokines (DECs) in hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, establish its differential cytokines spectra, and provide the clues for its diagnosis and pathogenic mechanism researches. Sera from four HELLP syndrome patients and four healthy controls were detected by proteome microarray. Then the analysis of Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network were performed and possible hub proteins were selected out, further verified by Enzyme Linked Immunosorbent Assay (ELISA) in sera from 21 HELLP syndrome patients and 21 healthy controls. Thirty DECs were defined according to P-value and fold change between HELLP group and control group. GO enrichment analysis showed that DECs were mainly involved in the regulation of inflammatory response and have relationship to growth factor binding, transmembrane receptor protein kinase, and cytokine receptor activity. Seven possible hub proteins were defined by PPI analysis, including IGFBP-3/Follistatin-like 1/FLRG/Fetuin A and MMP-13/Thrombospondin-5/Aggrecan. ELISA showed higher serum levels of Fetuin A/IGFBP-3/FLGR/MMP-13/Thrombospondin-5 in HELLP group than those in controls, while the levels of Follistatin-like 1 and Aggrecan were lower in HELLP patients (all P < 0.05 or <0.01).The serological DECs spectra of HELLP syndrome was established and seven possible hub proteins that may be more closely related to the disease have been verified, providing new clues for its pathogenesis, diagnosis, and clinical treatment.

Síndrome HELLP: controversias y pronóstico / HELLP syndrome: controversies and prognosis

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Clinical characteristics and pregnancy outcomes of atypical hemolysis, elevated liver enzymes, and low platelets syndrome: A case series.

RATIONALE: Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome is a serious and rare disease, which is secondary to preeclampsia in most cases. Hypertension is usually considered as a premonitory symptom of HELLP syndrome. In some patients with HELLP syndrome; however, they develop hypertension very late, even after liver enzymes are elevated or platelet count is decreased. This condition is known as atypical HELLP syndrome. PATIENT CONCERNS: We screened and identified 4 cases of atypical HELLP syndrome in our hospital database from January 2007 to December 2018. All patients had a history of nonspecific symptoms for a few days before hospital admission, such as dizziness, nausea, and vomiting. They developed hypertension after abnormalities were noted in liver enzymes and platelet count. DIAGNOSES: They were diagnosed with atypical HELLP syndrome. INTERVENTIONS: These patients received same treatments as those with HELLP syndrome. Two patients took oral antihypertensive treatment to normalize the blood pressure. OUTCOMES: In our patients, both mothers and neonates had favorable outcomes. In follow-ups, they reported no incidences of high blood pressure after recovery from atypical HELLP syndrome. LESSONS: These cases provided additional clinical evidences of atypical HELLP syndrome. The incidence of atypical HELLP syndrome is extremely low. Hypertension is not essential for the diagnosis of HELLP syndrome, and can even appear after the onset of laboratory abnormalities. Advanced age, multiple pregnancies, hepatitis B virus infection, and obesity may be potential risk factors for atypical HELLP syndrome. Blood pressure should be monitored closely after delivery.

Copper and ceruloplasmin levels are closely related to the severity of preeclampsia.

Objective: The aim of this study was to investigate the maternal serum concentrations of copper (Cu) and ceruloplasmin (CP) in patients with mild preeclampsia, severe preeclampsia, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and to determine their association with the severity of the disease.Methods: This study was carried out at the largest tertiary care health center in the southeast region in Turkey and Department of Obstetrics and Gynecology, Dicle University Hospital. A total of 179 pregnant women, including 58 healthy pregnant women and 71 mild preeclampsia, 26 severe preeclampsia, and 24 HELLP syndrome cases classified according to the American College of Obstetricians and Gynecologists' 2013 guidelines were included in this prospective study. Blood samples were taken from all the pregnant women to evaluate the serum Cu and CP levels. The Cu level was determined via atomic absorption/emission spectroscopy, while the serum CP level was assessed with a nephelometric assay using an automatic image analyzer. Spearman's rank correlation tests were used to determine the correlations between the serum levels of the antioxidative markers and the preeclampsia severity.Results: The mean ± SD of the Cu was 81.2 ± 11.84 µg/dl in the mild preeclampsia cases and 160.2 ± 20.89 µg/dl in the severe preeclampsia cases (p < .001). The mean ± SD of the CP was 33.0 ± 4.81 mg/dl in the mild preeclampsia cases and 65.3 ± 9.17 mg/dl in the severe preeclampsia cases (p < .001). The Cu and CP levels were significantly higher in the patients with HELLP syndrome, which is an advanced and more severe form of severe preeclampsia, than in the mild and severe preeclampsia patients (p < .001 and p < .001, respectively). Therefore, the serum Cu and CP levels were correlated with the severity of preeclampsia (r = 859, p < .001 and r = 786, p < .001, respectively). In addition, there was a positive correlation between the serum Cu and CP levels and the systolic and diastolic blood pressure values and aspartate amino transferase levels (AST), and a negative correlation between the serum Cu and CP levels and the platelet count.Conclusion: This was the first study in which the ceruloplasmin and Cu levels were investigated in HELLP syndrome patients. When considering the results obtained in the present study, there were significant relationships between the Cu, CP levels which are the markers of oxidative stress and the preeclampsia severity.

Recurrent Placental Transcriptional Profile With a Different Histological and Clinical Presentation: A Case Report.

Statistically, patients with severe pregnancy complications are at risk of recurrent complications, but it is less understood if patients present with similar or different placental pathologies in subsequent pregnancies. In this case report, we describe 2 consecutive adverse pregnancies in the same woman 4 years apart. The first pregnancy was diagnosed as early-onset preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, with placental maternal vascular malperfusion features, such as syncytial knots and accelerated villous maturity. In contrast, the second pregnancy was associated with normotensive fetal growth restriction and placental "immunological" lesions, such as massive perivillous fibrin deposition and chronic intervillositis. However, based on the expression of FLT1, LIMCH1, and TAP1 by quantitative polymerase chain reaction, the placentas from both pregnancies were found to exhibit an "immunological" transcriptional signature. This suggests that this small panel of gene expression markers may be able to predict the future reoccurrence of an immunological placental pathology despite no histological evidence within the first pregnancy. These results call for more studies looking at paired pregnancies of individuals with recurrent obstetric complications and confirm the importance of assessing matched transcriptional and histopathological placental information.

Increased placental expression of Placental Protein 5 (PP5) / Tissue Factor Pathway Inhibitor-2 (TFPI-2) in women with preeclampsia and HELLP syndrome: Relevance to impaired trophoblast invasion?

INTRODUCTION: Placental Protein 5 (PP5)/Tissue Factor Pathway Inhibitor-2 (TFPI-2) is an extracellular matrix-associated protein mainly expressed by the syncytiotrophoblast that may regulate trophoblast invasion. Our aim was to study placental PP5/TFPI-2 expression and its relation to placental pathology in various forms of preeclampsia and HELLP syndrome. METHODS: Placental and maternal blood specimens were collected at the time of delivery from the same women in the following groups: 1) early controls; 2) early preeclampsia; 3) early preeclampsia with HELLP syndrome; 4) late controls; and 5) late preeclampsia. After histopathological examination, placental specimens were immunostained with polyclonal anti-PP5/TFPI-2 antibody on Western blot and tissue microarray immunohistochemistry. Placental PP5/TFPI-2 immunoscores were assessed manually and with a semi-automated method. Maternal sera were immunoassayed for PP5/TFPI-2. RESULTS: PP5/TFPI-2 was localized to the cytoplasm of syncytiotrophoblast. Manual and semi-automated PP5/TFPI-2 immunoscores were higher in early preeclampsia with or without HELLP syndrome but not in late preeclampsia than in respective controls. In patients with preeclampsia, the correlation of placental PP5/TFPI-2 expression with maternal vascular malperfusion score of the placenta was positive while it was negative with birthweight and placental weight. Maternal serum PP5/TFPI-2 concentration was higher in early preeclampsia and it tended to be higher in early preeclampsia with HELLP syndrome than in early controls. DISCUSSION: Our findings suggest that an increased placental PP5/TFPI-2 expression may be associated with abnormal placentation in early preeclampsia, with or without HELLP syndrome.

Expression of endothelin-1 and Ki-67 in normotensive and severe preeclamptic placentas / Expresión de endotelina-1 y Ki-67 en placentas normotensas y preeclampsia severa

SUMMARY: Severe preeclampsia (HELLP syndrome) is a life-threatening pregnancy complication, usually a severe form of preeclampsia. In this study, we aimed to examine histopathologic changes and Endothelin-1 and KI-67 expression levels by immunohistochemical methods in severe preeclamptic placentas. Severe preeclampsia and obstetric characteristics and biochemical and hematological characteristics of healthy subjects were compared. Placenta sections were stained with hematoxylin-eosin for histopathological examination. In the histopathological examination of severe preeclamptic placenta, degeneration in synaptic and cytotrophoblastic cells, increase in insidious knots, fibrinoid necrosis, degeneration in endothelial cells, calcification and hyaline villous stains were observed. In the severe preeclampsia group, Ki-67 expression increased in decidua cells and inflammatory cells, while endothelial cells in the vessel wall and inflammatory cells in the villus and intervillous spaces increased. It is thought that angiogenetic and cellular proliferation is induced in a co-ordinated manner and significantly influences fetal development.

RESUMEN: La preeclampsia severa (síndrome de HELLP) es una complicación del embarazo potencialmente mortal, generalmente una forma grave de preeclampsia. En este estudio, nuestro objetivo fue examinar los cambios histopatológicos y los niveles de expresión de Endotelina-1 y Ki-67 mediante métodos inmunohistoquímicos en placentas preeclámpsicas graves. Se compararon la preeclampsia grave y las características obstétricas, además de las características bioquímicas y hematológicas de pacientes sanas. Las secciones de placenta se tiñeron con hematoxilina-eosina para examen histopatológico. En el examen histopatológico de placenta preeclampsia severa, se observó la degeneración en células sinápticas y citotrofoblásticas, un aumento de nudos insidiosos, necrosis fibrinoide, degeneración en las células endoteliales,calcificación y manchas vellosas hialinas. En el grupo de preeclampsia grave, la expresión de Ki-67 aumentó en células deciduas y células inflamatorias, mientras que las células endoteliales en la pared del vaso, y las células inflamatorias en las vellosidades y los espacios intervellosos aumentaron. Se cree que la proliferación angiogenética y celular se induce de forma coordinada y que influye significativamente en el desarrollo fetal.

Haemophagocytic lymphohistiocytosis presenting as HELLP syndrome: a diagnostic and therapeutic challenge.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, haematological disorder, which can be clinically challenging to diagnose and manage. We report a case of HLH in a previously healthy 33-year-old primigravida. The patient presented at 22 weeks gestation with dyspnoea, abdominal pain, anaemia, thrombocytopenia and elevated liver enzymes suggestive of HELLP syndrome.HELLP, a syndrome characterised by haemolysis, elevated liver enzymes and low platelets is considered a severe form of pre-eclampsia. Despite delivery of the fetus, her condition deteriorated over 3-4 days with high-grade fever, worsening thrombocytopenia and anaemia requiring transfusion support. A bone marrow biopsy showed haemophagocytosis and a diagnosis of HLH was made. Partial remission was achieved with etoposide-based chemotherapy and complete remission following bone marrow transplantation. Eleven months post-transplant, the disease aggressively recurred, and the patient died within 3 weeks of relapse.

Complementopathies.

The complement system is an essential part of the innate immune system that requires careful regulation to ensure responses are appropriately directed against harmful pathogens, while preventing collateral damage to normal host cells and tissues. While deficiency in some components of the complement pathway is associated with increased susceptibility to certain infections, it has also become clear that inappropriate activation of complement is an important contributor to human disease. A number of hematologic disorders are driven by complement, and these disorders may be termed "complementopathies". This includes paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), cold agglutinin disease (CAD) and other related disorders, which will be the focus of this review. A better understanding of the central role of the complement system in the pathophysiology of these disorders may allow for application of therapies directed at blocking the complement cascade.

Color vision abnormality as the sole manifestation of posterior reversible encephalopathy due to post-partum HELLP syndrome.

Posterior reversible encephalopathy syndrome (PRES) is associated with several symptoms; of those, visual acuity loss, light oversensitivity (photophobia), and light flashes (photopsia) are known as PRES-related eye symptoms. We report a post-partum woman with PRES associated with hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP), in whom color vision abnormality (achromatopsia) was the sole manifestation. Cesarean section was performed at 28 weeks due to headache, epigastralgia, and severe hypertension. HELLP became evident after delivery. On post-partum day 1, she complained of achromatopsia, stating: "all things look brownish-gray". Ophthalmologic examination was normal, but brain magnetic resonance imaging showed occipital lobe lesions, indicative of PRES, and, interestingly, also color vision center (area V4) lesions, suggesting that the achromatopsia had been caused by brain damage. It may be prudent to question HELLP patients concerning achromatopsia.

The placental component and obstetric outcome in severe preeclampsia with and without HELLP syndrome.

OBJECTIVE: We aimed to compare obstetric outcome and placental-histopathology in pregnancies complicated by preeclampsia with severe features with and without HELLP syndrome. METHODS: Labor, maternal characteristics, neonatal outcome and placental histopathology of pregnancies complicated with severe preeclampsia during 2008-2015 were reviewed. Results were compared between those without signs of HELLP syndrome (severe preeclampsia group) and those with concomitant HELLP syndrome (HELLP group). Placental lesions were classified to maternal vascular lesions consistent with malperfusion, fetal vascular lesions consistent with fetal thrombo-occlusive disease, and inflammatory lesions. Small-for-gestational-age (SGA) was defined as birth-weight ≤10th% and ≤5th%. Composite adverse neonatal outcome was defined as one or more early neonatal complications. RESULTS: Compared to the severe preeclampsia group (n = 223), the HELLP group (n = 64) was characterized by earlier gestational-age, 34.1 ± 2.7 vs. 35.3 ± 3.4 weeks, p = 0.010, higher rates of multiple pregnancies (p = 0.024), and thrombophilia (p = 0.028). Placentas in the HELLP group had higher rates of vascular and villous lesions consistent with maternal malperfusion (p = 0.023, p = 0.037 respectively). By multivariate logistic regression analysis models, vascular and villous lesions of maternal malperfusion were independently associated with HELLP syndrome (aOR 1.9, aOR 1.8, respectively). SGA was also more common in the HELLP group, both below the 10th percentile (p = 0.044) and the 5th percentile (p = 0.016). Composite adverse neonatal outcome did not differ between the groups. CONCLUSION: Severe preeclampsia and HELLP syndrome have similar placental histopathologic findings. However, HELLP syndrome is associated with higher rates of placental maternal vascular supply lesions and SGA suggesting that the two clinical presentations share a common etiopathogenesis, with higher placental dysfunction in HELLP syndrome.

Are there any additional mechanisms for haemolysis in HELLP syndrome?

HELLP syndrome is a microangiopathy that leads to severe maternal complications. The objective of this study was to identify any additional mechanisms that could have contributed to HELLP syndrome-induced haemolysis. This is a pilot, prospective and observational study that lasted 9months. All patients with HELLP syndrome treated at academic tertiary care women hospital accepted to participate. Sixteen patients were included. In ten patients (63%), schizocytes were detected following a blood smear test. Six patients (38%) were diagnosed with a partial expression deficiency of proteins regulating the complement system (CD 55 or CD 59). In nine patients (56%), an activation of the complement classical pathway was detected. In two patients (13%), an ADAMTS 13 activity below 30% was detected. Three patients (19%) were diagnosed with a folate deficiency and one (6%) with an antiphospholipid syndrome. All patients developed maternal or fetal morbidity including nine (56%) an acute kidney injury. All patients but one had at least one additional mechanism that could contribute to haemolysis, besides a simple physical injury. Larger studies should be promoted to understand haemolysis in HELLP syndrome.

CHOROIDAL MORPHOLOGY IN A PATIENT WITH HELLP SYNDROME.

PURPOSE: We report here, the morphological characteristics of the retina and choroid in a patient with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, who was not aware of her pregnancy before visiting our hospital. METHODS: Case report. RESULTS: The patient complained of visual disturbances in both eyes for a few days. Extensive serous retinal detachment and hyperreflective foci were observed in both eyes on spectral domain optical coherence tomography (SDOCT). Enhanced depth imaging technique using SDOCT revealed choroidal thickening and unclear choroidal vessel contour. Her blood pressure was 230/168 mmHg. Laboratory data showed hemolysis and liver dysfunction. Obstetrical examination disclosed her pregnancy. She was diagnosed as having HELLP syndrome. Because her general condition improved after prompt Cesarean delivery, the fundus lesions were rapidly resolved with choroidal thinning. CONCLUSION: The eyes in a patient with HELLP syndrome showed characteristic choroidal morphology. The choroidal morphology shown with SDOCT might be one of the pathognomonic signs for a diagnosis of HELLP syndrome.

Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome.

Preterm preeclampsia is associated with the failure of trophoblast invasion, placental hypoxic/ischemic injury and the release of toxic substances, which promote the terminal pathway of preeclampsia. In term preeclampsia, factors yet unknown trigger the placenta to induce the terminal pathway. The contribution of the villous trophoblast to these pathologic events has not been fully elucidated. Here we aimed to study how stress and signaling pathways influence trophoblastic functions in various subforms of preeclampsia. Tissue microarrays (TMAs) were constructed from placentas obtained from pregnant women in the following groups: 1-2) preterm preeclampsia with (n = 8) or without (n = 7) HELLP syndrome; 3) late-onset preeclampsia (n = 8); 4-5) preterm (n = 5) and term (n = 9) controls. TMA slides were stained for phosphorylated Akt-1, ERK1/2, JNK, and p38 kinases, and trophoblastic immunostainings were semi-quantitatively evaluated. BeWo cells were kept in various stress conditions, and the expression of FLT1, GCM1, LEP, and PGF was profiled by qRT-PCR, while Akt-1, ERK1/2, JNK, and p38 kinase activities were measured with phospho-kinase immunoassays. We found that: 1) Placental LEP and FLT1 expression was up-regulated in preterm preeclampsia with or without HELLP syndrome compared to controls; 2) Mean pp38 immunoscore was higher in preterm preeclampsia, especially in cases with HELLP syndrome, than in controls. 3) Mean pERK1/2 immunoscore was higher in preterm preeclampsia with HELLP syndrome than in controls. 4) In BeWo cells, ischemia up-regulated LEP expression, and it increased JNK and decreased ERK1/2 activity. 5) Hypoxia up-regulated FLT1 and down-regulated PGF expression, and it increased ERK1/2, JNK and p38 activity. 6) IL-1ß treatment down-regulated PGF expression, and it increased JNK and p38 activity. 7) The p38 signaling pathway had the most impact on LEP, FLT1 and PGF expression. In conclusion, hypoxic and ischemic stress, along with unknown factors, activates trophoblastic p38 signaling, which has a key role in villous trophoblastic functional changes in preterm preeclampsia. The activation of ERK1/2 signaling may induce additional trophoblastic functional changes in HELLP syndrome, while distinct mechanisms may promote late-onset preeclampsia.