Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome.

The complement system is critical to human health owing to its central role in host defense and innate immunity. During pregnancy, the complement system must be appropriately regulated to allow for immunologic tolerance to the developing fetus and placenta. Although some degree of complement activation can be seen in normal pregnancy, the fetus seems to be protected in part through the placental expression of complement regulatory proteins, which inhibit complement activation at different steps along the complement activation cascade. In women who develop preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, there is a shift toward increased complement activation and decreased complement regulation. There is an increase in placental deposition of C5b-9, which is the terminal effector of classical, lectin, and alternative complement pathways. C5b-9 deposition stimulates trophoblasts to secrete soluble fms-like tyrosine kinase-1, which sequesters vascular endothelial growth factor and placental growth factor. Pathogenic mutations or deletions in complement regulatory genes, which predispose to increased complement activation, have been detected in women with preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Before the disease, biomarkers of alternative complement pathway activation are increased; during active disease, biomarkers of terminal complement pathway activation are increased. Urinary excretion of C5b-9 is associated with preeclampsia with severe features and distinguishes it from other hypertensive disorders of pregnancy. Taken together, existing data link preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome with increased activation of the terminal complement pathway that, in some cases, may be influenced by genetic alterations in complement regulators. These findings suggest that the inhibition of the terminal complement pathway, possibly through C5 blockade, may be an effective strategy to treat preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome, but this strategy warrants further evaluation in clinical trials.

Investigation of FAS and IL-6 expression in placentas with HELLP syndrome / Investigación de la expresión de FAS e IL-6 en placentas con síndrome de HELLP

SUMMARY: The aim of our study was to investigate the effect of inflammation in the placenta on the pro-apoptotic development after severe preeclampsia. Placenta tissue samples of 15 HELLP syndrome and 15 healthy 35-38th week-pregnant women were involved in the study. Tissue samples were taken only from the maternal side of the placenta and fixed in 10 % formaldehyde, then blocked in paraffin wax and 4-6 mm-thick sections were cut and stained with Harris Hematoxylene-Eosin. Antigen retrieval was performed for sections, incubated with FAS antibody and anti-IL-6 antibody. After the application of streptavidin peroxidase followed by AEC chromogen solution, sections were counterstained with Harris hematoxylin. Significant thickening of the fibrinoid layer, degeneration and apoptotic change in decidua cells, marked increase in the hyalinized area, degenerative changes in the syncytial regions of the chorionic villus and an increase in syncytial nodes and bridges and IL- expression were observed as positive. FAS expression was positive in the pycnotic nuclei of decidual cells in the maternal region and in the syncytial regions. It was observed that the proapoptotic process increased as a result of severe preeclampsia. It was concluded that the control of cytokine activity and reduction of pro-apoptotic signal during the inflammation process will slow down the development of HELLP syndrome.

RESUMEN: El objetivo de nuestro estudio fue investigar el efecto de la inflamación en la placenta sobre el desarrollo proapoptótico después de la preeclampsia severa. Se recogieron muestras de tejido de placenta de 15 mujeres con síndrome de HELLP y 15 mujeres sanas con un embarazo de 35 a 38 semanas. Se tomaron muestras de tejido solo del lado materno de la placenta y se fijaron en formaldehído al 10 %, luego se bloquearon en parafina y se cortaron secciones de 4-6 mm de espesor y se tiñeron con hematoxilena-eosina de Harris. La recuperación del antígeno se realizó para secciones, incubadas con anticuerpo FAS y anticuerpo anti-IL-6. Después de la aplicación de estreptavidina peroxidasa seguida de solución de cromógeno AEC, las secciones se contrastaron con hematoxilina de Harris. Se observó como positivo un engrosamiento significativo de la capa fibrinoide, degeneración y cambio apoptótico en las células de la decidua, aumento marcado en el área hialinizada, cambios degenerativos en las regiones sincitiales de la vellosidad coriónica y un aumento en los nódulos y puentes sincitiales y la expresión de IL-6. La expresión de FAS fue positiva en los núcleos picnóticos de las células deciduales en la región materna y en las regiones sincitiales. Se observó que el proceso proapoptótico se incrementó como consecuencia de la preeclampsia severa. Se concluyó que el control de la actividad de las citocinas y la reducción de la señal proapoptótica durante el proceso de inflamación ralentizarán el desarrollo del síndrome de HELLP.

The effect of therapeutic plasma exchange on management of HELLP Syndrome: The report of 47 patients.

BACKGROUND AND OBJECTIVES: HELLP syndrome is a life-threatening condition that may potentially cause complications during pregnancy. If not diagnosed and treated quickly, HELLP syndrome may lead to serious complications both for the mother and the baby. The aim of this study was to determin the effectiveness of therapeutic plasma exchange (TPE) for treatment of Class-I HELLP syndrome. MATERIALS AND METHODS: Laboratory results from 47 patients with Class-I HELLP syndrome patients who underwent TPE between 2011 and 2020 were recorded before and after the procedure. A central venous catheter was inserted, and TPE was performed in patients who had not responded to delivery, steroid, and supportive therapy (blood products, anti-hypertensive therapy, intravenous fluid administration, and antibiotics) within 24 hours after the diagnosis of Class I HELLP syndrome according to the Mississippi Criteria. RESULTS: The average age of patients was 33 ± 4.7 years (range; 21-39 years). A mean of 5 (range; 4 to 6) TPE sessions were performed. There was a statistically significant decrease in total bilirubin, lactic dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels in all patients, whereas a significant increase in platelet count was observed (p < 0.05). Furthermore, clinical and laboratory improvement was achieved. CONCLUSION: In all patients with HELLP syndrome, a dramatically clinical and laboratory improvement occurred after TPE. Our study suggests that postpartum use of TPE within 24 hours is an efficient treatment option for Class-I HELLP syndrome.

Is the presence of antiphospholipid antibodies a poor prognostic factor for patients with hemolysis, elevated liver enzymes, and low platelet count syndrome?

BACKGROUND: The characteristics of antiphospholipid syndrome-associated hemolysis, elevated liver enzymes, and low platelet count syndrome are poorly described, likely because of the low frequency of this combination of syndromes. OBJECTIVE: This study aimed to compare the characteristics and prognosis of hemolysis, elevated liver enzymes, and low platelet count syndrome in patients with and without antiphospholipid syndrome. STUDY DESIGN: In this multicenter, case-control study, adult women diagnosed with hemolysis, elevated liver enzymes, and low platelet count syndrome before 34 weeks' gestation and who were also tested for antiphospholipid antibodies according to international diagnostic recommendations were included. Cases labeled "HELLP-APS+" were defined as patients who fulfilled the international classification criteria for antiphospholipid syndrome; they were retrospectively recruited by screening the 672 patients with antiphospholipid syndrome in our antiphospholipid syndrome database. Control cases labeled "HELLP-APS-" were defined as patients who did not fulfill the criteria for antiphospholipid syndrome; they were retrospectively recruited from our hospital admission database. RESULTS: Overall, 71 patients were included (mean age, 30±5 years), with 23 patients in the hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome group and 48 patients in the hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome group. The live birth rate was significantly lower for patients with hemolysis, elevated liver enzymes, and low platelet count with antiphospholipid syndrome than for those with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (43.5% vs 89.4%; P<.001). The patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome gave birth prematurely more often than the patients without antiphospholipid syndrome (24 weeks' gestation; 22.0-28.0 weeks vs 30 weeks' gestation; 27.0-33.0 weeks; P<.001). Among the patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome, 39% required an induced abortion owing to hemolysis, elevated liver enzymes, and low platelet count syndrome severity vs 8.5% of the patients with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (P=.006). The intensive care unit admission rate was 61.9% in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome with antiphospholipid syndrome, which was significantly higher than the rate of 27.7% in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome without antiphospholipid syndrome (P=.007). None of the mothers died. CONCLUSION: Our results suggest that the presence of antiphospholipid syndrome is a poor prognostic factor for both the mother and fetus in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome.

Abnormal expression of the costimulatory molecule B7-H4 in placental chorionic villous and decidual basalis tissues of patients with preeclampsia and HELLP syndrome.

BACKGROUND: B7-H4, a checkpoint molecule of the B7 family, regulates a broad spectrum such as T-cell activation, cytokine secretion, tumour progression, and invasion capacities. Our previous data revealed that soluble B7-H4 (sB7-H4) blood serum levels are elevated in women at high risk for the hypertensive pregnancy disorder preeclampsia (PE) in the first trimester, as well as in patients with confirmed early/late-onset PE. AIM: We here aim to investigate the expression pattern of B7-H4 in placental tissues of PE and HELLP Syndrome versus control group. METHODS: B7-H4 protein expression and localization were investigated by immunoblotting and co-immunohistochemistry in placental chorionic villous and decidual basalis tissues. RESULTS: B7-H4 protein was prominently expressed at the cell membrane, in the cytoplasm of the syncytiotrophoblast (STB) and interstitial extravillous trophoblast (EVT). B7-H4 protein levels in placental chorionic villous tissue were significantly higher in women with early-onset/late-onset PE and HELLP, while it was decreased in decidual basalis tissues of early-onset PE and HELLP compared with controls. CONCLUSION: B7-H4 was inversely expressed in placental chorionic villous and decidual basalis tissues of PE and HELLP patients. The increase in B7-H4 in the STB in PE and HELLP may lead to excessive apical expression and release of soluble B7-H4 in the maternal circulation. In contrast, the decrease in B7-H4 in decidual basalis tissues could be related to the decrease in invasion ability of the EVT in PE. Thus, the current results strongly suggest that B7-H4 is involved in the pathogenesis of PE and HELLP.

Fas ligand neutralization attenuates hypertension, endothelin-1, and placental inflammation in an animal model of HELLP syndrome.

Neutralization of FasL is linked to suppression of hypertension, placental inflammation, and endothelin system activation in an animal model of hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. During HELLP syndrome the placenta has been reported to serve as the primary source of Fas ligand (FasL), which has an impact on inflammation and hypertension during pregnancy and is dysregulated in women with severe preeclampsia and HELLP syndrome. We hypothesize that neutralization of FasL during pregnancy in an animal model of HELLP syndrome decreases inflammation and placental apoptosis, improves endothelial damage, and improves hypertension. On gestational day (GD) 12, rats were chronically infused with placental antiangiogenic factors sFlt-1 and sEng to induce HELLP syndrome. To neutralize FasL, MFL4 or FasL antibody was infused into a subset of HELLP or normal pregnant rats on GD13. IgG infusion into another group of NP and HELLP rats on GD13 was used as a control for FasL antibody, and all rats were euthanized on GD19 after blood pressure measurement. Plasma and placentas were collected to assess inflammation, apoptosis, and the degree of placental debris activation of endothelial cells. Administration of MFL4 to HELLP rats significantly decreased blood pressure compared with untreated HELLP rats and HELLP rats infused with IgG and improved the biochemistry of HELLP syndrome. Both circulating and placental FasL were significantly attenuated in response to MFL4 infusion, as were levels of placental and circulating TNFα when compared with untreated HELLP rats and HELLP rats infused with IgG. Endothelial cells exposed to placental debris and media from HP + MFL4 rats secreted significantly less endothelin-1 compared with stimulated endothelial cells from HELLP placentas. Neutralization of FasL is associated with decreased MAP and improvement in placental inflammation and endothelial damage in an animal model of HELLP syndrome.

Complement-Mediated Disorders in Pregnancy.

Complement-mediated disorders in pregnancy span a large spectrum and have been implicated in all three complement pathways: classical, lectin, and alternative. Our understanding of these disorders in recent years has advanced due to a better understanding of complement regulatory proteins, such as complement factor H, complement factor I, membrane cofactor protein, and thrombomodulin that particularly affect the alternative complement pathway. Enthusiasm in genotyping for mutations that encode these proteins has allowed us to study the presence of genetic variants which may predispose women to develop conditions such as pregnancy-associated hemolytic uremic syndrome (P-aHUS), thrombotic thrombocytopenic purpura, preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP), systemic lupus erythematosus/antiphospholipid syndrome, and peripartum cardiomyopathy. The advent of the anti-C5-antibody eculizumab to quench the complement cascade has already proven in small case series to improve maternal kidney outcomes in complement-mediated obstetric catastrophes such as P-aHUS and HELLP. In this review, we will detail the pathogenesis behind these complement-mediated pregnancy disorders, the role of complement variants in disease phenotype, and the most up-to-date experience with eculizumab in this population.

Innate and Adaptive Immune Responses in HELLP Syndrome.

Innate and adaptive immune involvement in hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome is an understudied field, although it is of high clinical importance. This syndrome implies a risk of serious morbidity and mortality to both the mother and the fetus during pregnancy. It was proposed that HELLP syndrome occurs in a circulatory inflammatory milieu, that might in turn participate in a complex interplay between the secreted inflammatory immunomodulators and immune cell surface receptors. Meanwhile, reported immune cell attenuation during HELLP may consequently lead to a prolonged immunoactivation and tissue damage. In this regard, learning more about the immune components of this syndrome should widen the understanding of the HELLP pathophysiology and eventually enable development of novel immune-based therapeutics. This review aims to summarize and discuss the recent and previous findings of the innate and adaptive immune responses during HELLP in order to update the current knowledge of the immune involvement in HELLP pathogenesis.

Complement Activation and Thrombotic Microangiopathies.

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.

Placental sFLT1 is associated with complement activation and syncytiotrophoblast damage in preeclampsia.

The immune complement system protects against pathogens; however, excess activation results in disease like hemolytic uremic syndrome, a clinical imitator of preeclampsia. Vascular endothelial factor (VEGF) protects against aberrant complement activation and is inhibited by soluble fms-like tyrosine kinase-1 (sFLT1) in other organs. We hypothesize that sFLT1 promotes complement-mediated placental damage through VEGF inhibition in preeclampsia. Objective: Quantify placental complement activity and sFLT1 expression in preeclampsia, and the subgroup of preeclampsia with hemolysis elevated liver enzymes low platelets (HELLP) syndrome. Methods: Placental complement activation marker C4d, membrane attack complex (MAC), and sFLT1 expression was quantified using immunofluores cence microscopy. Results: Placentas from 18 controls, 25 preeclampsia, including 6 cases of HELLP syndrome were identified. Placental C4d expression was greater in PE (median 6.4 [IQR: 5.1, 8.3]) compared to controls (4.4 [3.6, 5.5]; p = 0.003). MAC expression was also increased in preeclampsia compared to controls (6.5 [5.8, 8.7]; 5.4 [2.9, 5.9], p = 0.001). Placental sFLT1 expression was also higher in preeclampsia (p <0.0001). C4d and MAC were strongly correlated with sFLT1 levels in the placenta (R = 0.72; p < 0.0001 and R = 0.59; p = 0.01, respectively). Complement and sFLT1 expression was elevated in HELLP compared to preeclampsia without laboratory abnormalities, but this difference did not reach statistical significance. Conclusion: Increased placental complement activation and damage was seen in preeclampsia and correlates with sFLT1 expression. Our findings support the importance of the complement pathway in preeclampsia.

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.

Eculizumab in pregnancy: a narrative overview.

Pregnancy can be a dangerous trigger for patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), or hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome. Due to the possibility of several serious complications, pregnancy is somewhat discouraged in the presence of the above diseases. Eculizumab is a humanized antibody that may dramatically change the clinical course of PNH, aHUS and HELLP syndrome. However, data on the safety of eculizumab in pregnancy are scarce. In this narrative overview, we summarize current evidence on the use of eculizumab during pregnancy in women with PNH, aHUS and HELLP syndrome. Eculizumab is not present in breast milk, and the levels observed in umbilical cord blood samples are not sufficient to affect the concentrations of complement in newborns. Therefore, eculizumab may be regarded as safe in pregnancy. Nonetheless, given that data on eculizumab in pregnancy are limited, it is not possible to completely exclude risks for both mother and fetus in treating PNH, aHUS and HELLP syndrome.

The Complement Alternative Pathway and Preeclampsia.

PURPOSE OF REVIEW: Significant and intricate immune adaptations are essential for the establishment and maintenance of normal pregnancy. Preeclampsia is a morbid, potentially life-threatening disease for both mother and neonate that occurs uniquely in pregnancy, at least in part, due to maternal immune maladaptation. We aim to review the literature that focuses on case reports, diagnostic approaches, and treatment strategies for disorders of the complement alternative pathway (CAP) as related to preeclampsia. RECENT FINDINGS: There is evidence of complement dysregulation in preeclampsia and HELLP syndrome, similar to that observed in a few rare types of thrombotic microangiopathies. Complement dysregulation may be identified with functional laboratory testing as well as genetic testing. Increased utilization of a standardized diagnostic approach to establish whether persistent and/or severe cases of preeclampsia and HELLP syndrome are complement-mediated may lead to development of future treatment strategies, such as complement-targeted therapy.

10 workshops on Immunology of preeclampsia.

For the 10th issue of the « island workshops ¼, now the Reunion Workshops, organised by Pierre Yves Robillard since the first one in Tahiti challenging the "vascular disease only" theory of pre eclampsia and introducing the primipaternity concept, we examined the reasons for considering an Immunological approach to the disease. This (brief) overview thus examines several important topics in an Immunological framework. I have chosen to present here the evolution of the main themes rather than a purely chronological vision.

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.

Inhibition of T-cell activation attenuates hypertension, TNFα, IL-17, and blood-brain barrier permeability in pregnant rats with angiogenic imbalance.

PROBLEM: Angiogenic imbalance during pregnancy is associated with immune activation, hypertension, increased T cell infiltration, and neurological insults. METHOD OF STUDY: On gestational day (GD) 12, timed-pregnant rats were infused with anti-angiogenic factors sFlt-1 and sEndoglin (4.7 and 7 µg/kg) to create HELLP syndrome via mini-osmotic pumps for 8 days, with a subset of these rats having Orencia (2 mg/kg) infused on GD13. On GD19, blood-brain barrier (BBB) permeability was evaluated via Evan's Blue infusion, blood was collected for T-cell measurements, inflammatory cytokine secretion. Brain tissues were also collected to examine inflammatory cytokine infiltration. RESULTS: T-cell attenuation with Orencia decreased circulating CD4(+) and CD8(+) T cells, circulating tumor necrosis factor alpha (TNFα) and IL-17, BBB permeability and significantly decreased biochemical evidence of HELLP compared to untreated HELLP rats. CONCLUSIONS: These data support the hypothesis that T cells have a critical role in contributing to the pathophysiology that is seen in angiogenic imbalance during pregnancy.

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.

Elevated systemic galectin-1 levels characterize HELLP syndrome.

Galectin-1 (gal-1), a member of a family of conserved ß-galactoside-binding proteins, has been shown to exert a key role during gestation. Though gal-1 is expressed at higher levels in the placenta from HELLP patients, it is still poorly understood whether systemic gal-1 levels also differ in HELLP patients. In the present study, we evaluated the systemic expression of gal-1, together with the angiogenic factors, placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in conjunction with HELLP syndrome severity. Systemic levels of gal-1 and sFlt-1 were elevated in patients with both early- and late-onset HELLP syndrome as compared to healthy controls. In contrast, peripheral PlGF levels were decreased in early- and late-onset HELLP. A positive correlation between systemic gal-1 levels and sFlt-1/PlGF ratios was found in early onset HELLP patients. Our results show that HELLP syndrome is associated with increased circulating levels of gal-1; integrating systemic gal-1 measurements into the diagnostic analyses of pregnant women may provide more effective prediction of HELLP syndrome development.

Antiphospholipid antibodies and the risk of severe and non-severe pre-eclampsia: the NOHA case-control study.

BACKGROUND: pre-eclampsia (PEecl) can be defined as non-severe (NS-PEecl) or severe (S-PEecl). Our study aimed to determine the incidence of antiphospholipid antibodies (aPLs) in women with a past history of NS-PEecl or S-PEecl. PATIENTS AND METHODS: This case-control study includes 195 control women, 199 NS-PEecl patients and 143 S-PEecl patients whose plasma samples were collected 6 months after their first delivery. Each plasma was tested for lupus anticoagulant (LA), anticardiolipin (aCL) and antiß2GP1 antibodies, as well as antibodies against phosphatidylserine/prothrombin complex (aPS/PT) and domain I of the ß2GP1. RESULTS: When compared with the control group no significant associations were found for the NS-PEecl group after adjustment of confounding variables. For the S-PEecl group, there was an association with antiß2GP1 immunoglobulin G (IgG) (OR 16.91, 95% CI 3.71-77.06), as well as age, obesity, smoking and multiparity. Antiß2GP1-domain I IgG was associated with aCL, antiß2GP1 and aPS/PT IgG in the three groups. aPS/PT IgG was associated with aCL IgG, and aPS/PT IgM was associated with aCL and antiß2GP1 IgM in the three groups. CONCLUSION: S-PEecl is a distinct entity from NS-PEecl and is mainly associated with the presence of antiß2GP1 IgG. Antiß2GP1 domain I correlates with other aPL IgG tests, and aPS/PT may be promising in patients for whom LA tests cannot be interpreted.

Differentiation of ICOS+ and ICOS- recent thymic emigrant regulatory T cells (RTE T regs) during normal pregnancy, pre-eclampsia and HELLP syndrome.

Two different subsets of naturally occurring regulatory T cells (nTregs), defined by their expression of the inducible co-stimulatory (ICOS) molecule, are produced by the human thymus. To examine the differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(+) recent thymic emigrant (RTE) T regs during normal pregnancy and in the presence of pre-eclampsia or haemolysis elevated liver enzymes low platelet (HELLP)-syndrome, we used six-colour flow cytometric analysis to determine the changes in the composition of the ICOS(+) and ICOS(-) T reg pools with CD45RA(+) CD31(+) RTE T regs, CD45RA(+) CD31(-) mature naive (MN) T regs, CD45RA(-) CD31(+) and CD45RA(-) CD31(-) memory Tregs. With the beginning of pregnancy until term, we observed a strong differentiation of both ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE, but not CD45RA(+) CD31(-) MN T regs, into CD45RA(-) CD31(-) memory T regs. At the end of pregnancy, the onset of spontaneous term labour was associated with a significant breakdown of ICOS(+) CD45RA(-) CD31(-) memory T regs. However, in the presence of pre-eclampsia, there was a significantly increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE T regs into CD45RA(-) CD31(+) memory T regs, wherein the lacking differentiation into CD45RA(-) CD31(-) memory T regs was partially replaced by the increased differentiation of ICOS(+) and ICOS(-) CD45RA(+) CD31(-) MN Tregs into CD45RA(-) CD31(-) memory T regs. In patients with HELLP syndrome, this alternatively increased differentiation of CD45RA(-) CD31(-) MN T regs seemed to be exaggerated, and presumably restored the suppressive activity of magnetically isolated ICOS(+) and ICOS(-) T regs, which were shown to be significantly less suppressive in pre-eclampsia patients, but not in HELLP syndrome patients. Hence, our findings propose that the regular differentiation of both ICOS(+) and ICOS(-) CD45RA(+) CD31(+) RTE T regs ensures a healthy pregnancy course, while their disturbed differentiation is associated with the occurrence of pre-eclampsia and HELLP syndrome.