First trimester prediction of HELLP syndrome

Abstract Introduction Plasma ADAMTS13 exists at least two forms, bound and unbound to vonWillebrandfactor (VWF), of which the former was assumed to be 3% of the total by the immunoprecipitation method (Feyset al., JTH 2009). We have shown that plasma ADAMTS13 consists of 3 group bands, by means of isoelectric focusing (IEF) analysis (Hori et al, Transfusion 2013). Band I (pI4.9-5.6) was assumed to be free ADAMTS13, unbound to VWF, and Band III (pI7.0-7.5) was a complex with high-molecular-weight VWFmultimers(HMW-VWFM). However, the feature of Band II (pI5.8-6.7) was undetermined. HELLP (hemolysis, elevated liver enzymes and low platelet counts) syndrome is a life-threatening thromboembolic complication during pregnancy, and its pathogenesis is not determined. The curative therapy of HELLP syndrome is a termination of pregnancy. It was reported that plasma VWF antigen (VWF: Ag) was remarkably increased (215-422% of the normal) with a mild reduction of ADAMTS13 activity (ADAMTS13: AC) (12-43 % of the normal), but without qualitative analysis of ADAMTS13 antigen (Lattuadaet al.,Haematologica2003). We here analyzed plasma ADAMTS13 antigen in 9 patients with HELLP syndrome using the IEF gel, and revealed a unique picture of severe reduction of Band I (free ADAMTS13), unbound to VWF, that was not seen in plasmas from normal pregnancy. Patients and Methods One hundred twenty-nine normal pregnant women and 9 patients with HELLP syndrome were analyzed under approval by the ethics committees of Nara Medical University. All individuals gave written informed consent to the study. Diagnosis of HELLP syndrome was made by all the following laboratory abnormalities: characteristics peripheral blood smear, serum LDH >600 IU/L (or total bilirubin >1.2 mg/dL), AST >70 IU/L, and platelet counts < 100,000/mm3 (Sibai et al., Am JObstetGynecol 1993). Plasma level of ADAMTS13: AC was determined by chromogenic ADAMTS13-act-ELISA, and VWF: Ag was measured by a sandwich ELISA using a rabbit polyclonal anti-human VWF antibody. As reported previously (Hori et al., Transfusion 2013), the IEF was performed using a large-pore agarose-acrylamide composing gel followed by detection with anti-ADAMTS13 monoclonal antibody. Results In normal women, plasma levels of VWF: Agweremarkedly increased during pregnancy, and the values of third trimester (median 223%) were almost two times higher than those of first trimester (119%). Contrarily,plasma levels ofADAMTS13: AC were significantly decreased in second (68.4%) and third (66.2%) trimester compared with first trimester (84.3%, p<0.01 and p<0.001, respectively). Of note, a reduction in ADAMTS13: AC was significantly prolonged in postpartum period (50.2%, p<0.001), while increased VWF: Ag was rapidly recovered after delivery. Further, the IEF analysis of normal pregnant women showed that Band I was slightly decreased in accord with progression of pregnancy. In puerperium, there was no difference in ADAMTS13: AC between normal pregnant women and patients with HELLP syndrome. However, the values of VWF: Ag of patients with HELLP syndrome (352%) were significantly higher than those of normal pregnant women (178%, p<0.001), in agreement with a previous report. Interestingly, however, here we have shown that 7 out of 9 patients with HELLP syndrome showed severe reduction of Band I in puerperium period by the IEF analysis of ADAMTS13 (Figure). Discussion In normal pregnant women, the decreased ADAMTS13:AC was assumed to reflect a consumption of the enzyme for cleavage of increased VWF. Interestingly, both Band II and III were almost unchanged during normal pregnancy, but Band I slightly decreased in third trimester, concomitantly with a mild reduction of ADAMTS13:AC. In contrast, Band I was severely reduced during the acute phase of HELLP syndrome in 7 out of 9 patients. Our previous report indicated that under high-shear-stress Band I inhibited the VWF-dependent platelet aggregation in a dose-response manner from the initial phase, whereas Band III (+II) worked from the later phase. This result indicates that ADAMTS13 lacking Band I neither readily binds to VWF nor efficiently blocks the heightened high-shear-stress induced platelet aggregation generated by newly produced HMW-VWFM. Our data suggest that ADAMTS13 preparation might be used as a therapeutic option for the treatment of HELLP syndrome, before termination of pregnancy. Disclosures No relevant conflicts of interest to declare.

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Maternal and Fetal Outcomes in a Cohort of Patients Exposed to Tumor Necrosis Factor Inhibitors throughout Pregnancy

The Journal of Rheumatology ◽

10.3899/jrheum.171152 ◽

2018 ◽

Vol 45 (8) ◽

pp. 1109-1115 ◽

Cited By ~ 6

Author(s):

Geneviève Genest ◽

Karen A. Spitzer ◽

Carl A. Laskin

Keyword(s):

Tumor Necrosis Factor ◽

Hellp Syndrome ◽

Tumor Necrosis ◽

First Trimester ◽

Tumor Necrosis Factor Inhibitors ◽

Fetal Outcomes ◽

Live Births ◽

Group 2 ◽

Adverse Pregnancy ◽

Necrosis Factor

Objective.Tumor necrosis factor inhibitors (TNFi) are increasingly used in pregnancy but are frequently withheld in the second or third trimesters. We evaluated the maternal and fetal outcomes of women who continued their TNFi throughout pregnancy compared to women who interrupted TNFi during pregnancy.Methods.We retrospectively analyzed the outcomes of women seen in clinic with rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis (JIA), or ankylosing spondylitis, who were exposed to TNFi during pregnancy. We separated pregnancies into 2 groups based on the level of TNFi exposure and compared outcomes.Results.In Group 1 (TNFi exposure in first trimester only), 11 women had 14 pregnancies and 12 live births. There were 2 first-trimester losses (2/14, 14%), one in the setting of active RA. Five pregnancies (5/14, 35.7%) were complicated by a disease flare. Eight patients (8/12, 66%) flared postpartum. In Group 2 (TNFi exposure throughout pregnancy), 29 women had 32 pregnancies and 34 live births. Three (3/28, 10.7%) adverse pregnancy outcomes were reported in 2 patients. One patient had a twin pregnancy and delivered at 33 weeks after developing preterm premature rupture of membranes at 32 weeks in the setting of a JIA flare. Her second pregnancy was complicated by active JIA before and throughout gestation, and hemolysis, elevated liver enzyme levels, and low platelet levels (HELLP) syndrome at 39 weeks. Another patient with comorbid antiphospholipid syndrome underwent a cesarean birth at 36 weeks for suspicion of HELLP syndrome. Six (6/32, 18.7%) postpartum flares occurred.Conclusion.Women who discontinued their TNFi during pregnancy had a higher risk of peri- or postpartum flare compared to those who continued their TNFi throughout pregnancy.

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Leptospirosis in COVID-19 Positive Pregnancy: A Rare Case Report Mimicking Hellp Syndrome

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i43b32567 ◽

2021 ◽

pp. 379-383

Author(s):

Aarshika Singh ◽

Surekha Tayade ◽

Ooha Thadiboina ◽

Cherukuri Srinidhi

Keyword(s):

Hellp Syndrome ◽

Neonatal Intensive Care ◽

First Trimester ◽

Lower Segment Caesarean Section ◽

Normal Limits ◽

Elevated Bilirubin ◽

Rare Case Report ◽

Acute Fatty Liver ◽

Elevated Transaminases ◽

High Degree

Leptospirosis in pregnancy is often underdiagnosed and not commonly reported due to its unusual appearance and rarity. It looks like HELLP syndrome, obstetric cholestasis, viral hepatitis & pregnancy-related acute fatty liver. Miscarriages in the first trimester, stillbirths, and neonatal leptospirosis are serious complications that necessitate a high degree of concern, heightened sensitivity, and prompt diagnosis and treatment. We have one such incidence of leptospirosis in a COVID-19 positive pregnant female. A 21-year-old Primigravida with a predisposition of serious anaemia & thrombocytopenia, presented with fever, haematemesis, malena and sore throat at 38 weeks and 2 days gestation, during the COVID-19 pandemic. She had pallor, oedema, and haematuria on catheterization, rest all investigations were within normal limits. Proteinuria, haemolysis, low platelets, and elevated bilirubin were discovered during the investigation. Due to the lack of hypertension and elevated transaminases, the working diagnosis was atypical haemolysis, low platelets (HELLP) syndrome. The patient was tested for COVID-19 RT-PCR, came out to be positive and the fever spikes continued, leading to further investigations for Dengue, Malaria, Scrub Typhus, and Leptospirosis due to the ongoing Covid-19 pandemic. After the EIA (Enzyme Immunoassay) IgM antibody (confirmatory for Leptospirosis) tested positive for Leptospirosis, the decision to start Doxycycline was made. Meanwhile, the patient's CTG (Cardio tocograph) revealed signs of foetal distress, and a decision for an emergency LSCS was taken (Lower Segment Caesarean Section). The histology of the placenta after the section revealed normal findings. Doxycycline was initiated with a neonatal feeding regimen that was acceptable. On day two of life, the newborn had no indications of inherited leptospirosis and was removed from Neonatal Intensive Care. Within one week, the patient's symptoms had disappeared, and her biochemistry had went back to normal within 2 weeks.

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Knockdown of Splicing Complex Protein PCBP2 Reduces Extravillous Trophoblast Differentiation Through Transcript Switching

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.671806 ◽

2021 ◽

Vol 9 ◽

Author(s):

Danai Georgiadou ◽

Souad Boussata ◽

Remco Keijser ◽

Dianta A. M. Janssen ◽

Gijs B. Afink ◽

...

Keyword(s):

Cell Cycle ◽

Hellp Syndrome ◽

Rna Splicing ◽

Ex Vivo ◽

First Trimester ◽

Cellular Growth ◽

Extravillous Trophoblast ◽

Placental Development ◽

Alternative Mrna Splicing

Mutations in the LINC-HELLP non-coding RNA (HELLPAR) have been associated with familial forms of the pregnancy-specific HELLP syndrome. These mutations negatively affect extravillous trophoblast (EVT) differentiation from a proliferative to an invasive state and disturb the binding of RNA splicing complex proteins PCBP1, PCBP2, and YBX1 to LINC-HELLP. In this study, by using both in vitro and ex vivo experiments, we investigate if these proteins are involved in the regulation of EVT invasion during placentation. Additionally, we study if this regulation is due to alternative mRNA splicing. HTR-8/SVneo extravillous trophoblasts and human first trimester placental explants were used to investigate the effect of siRNA-mediated downregulation of PCBP1, PCBP2, and YBX1 genes on the differentiation of EVTs. Transwell invasion assays and proliferation assays indicated that upon knockdown of PCBP2 and, to a lesser extent, YBX1 and PCBP1, EVTs fail to differentiate toward an invasive phenotype. The same pattern was observed in placental explants where PCBP2 knockdown led to approximately 80% reduction in the number of explants showing any EVT outgrowth. Of the ones that still did show EVT outgrowth, the percentage of proliferating EVTs was significantly higher compared to explants transfected with non-targeting control siRNAs. To further investigate this effect of PCBP2 silencing on EVTs, we performed whole transcriptome sequencing (RNA-seq) on HTR-8/SVneo cells after PCBP2 knockdown. PCBP2 knockdown was found to have minimal effect on mRNA expression levels. In contrast, PCBP2 silencing led to a switch in splicing for a large number of genes with predominant functions in cellular assembly and organization, cellular function and maintenance, and cellular growth and proliferation and the cell cycle. EVTs, upon differentiation, alter their function to be able to invade the decidua of the mother by changing their cellular assembly and their proliferative activity by exiting the cell cycle. PCBP2 appears to be a paramount regulator of these differentiation mechanisms, where its disturbed binding to LINC-HELLP could contribute to dysfunctional placental development as seen in the HELLP syndrome.

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Can First-trimester AST to Platelet Ratio Index Scores Predict HELLP Syndrome?

Journal of College of Physicians And Surgeons Pakistan ◽

10.29271/jcpsp.2021.02.188 ◽

2021 ◽

Vol 31 (02) ◽

pp. 188-192

Keyword(s):

Hellp Syndrome ◽

First Trimester

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Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio and Complete Blood Count Components in the First Trimester Do Not Predict HELLP Syndrome

Medicina ◽

10.3390/medicina55060219 ◽

2019 ◽

Vol 55 (6) ◽

pp. 219 ◽

Cited By ~ 3

Author(s):

Giovanni Sisti ◽

Andrea Faraci ◽

Jessica Silva ◽

Ruchi Upadhyay

Keyword(s):

Hellp Syndrome ◽

Blood Count ◽

Complete Blood Count ◽

First Trimester ◽

Neutrophil To Lymphocyte Ratio ◽

Sudden Increase ◽

Care Hospital ◽

Platelet To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Elevated Liver Enzymes

Background and Objectives: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and other components of the routine complete blood count (CBC) were found to be sensitive biomarkers of preeclampsia and other inflammatory obstetric conditions in previous studies, with conflicting results. We speculated that the same associations existed with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome in the first trimester of pregnancy. Materials and Methods: We conducted a retrospective case–control study at a tertiary care hospital in NY (USA), in the time frame between January 2016 and December 2018. Our population consisted of pregnant women in the first trimester: We compared patients with HELLP syndrome (cases) with healthy patients (controls) matched by age, body mass index (BMI), parity, and race. Patients with preeclampsia, infection, and fever were excluded. Venous blood samples were obtained as part of the routine work-up during the first prenatal visit in the first trimester, which includes a CBC. The main outcomes were NLR and PLR, and the secondary outcomes were hemoglobin, RDW, platelet count, MPV, neutrophils, and lymphocytes. Results: There were 10 patients in each group. There were no differences in NLR and PLR levels and other CBC components between the two groups. Conclusions: In our study NLR, PLR, and other CBC components did not predict HELLP syndrome. We speculate that HELLP syndrome has a sudden increase of tissue inflammation in the third trimester that is not manifested during the early phases of placentation. Larger studies are needed to evaluate the true ability of NLR, PLR, and CBC components to predict HELLP syndrome in the first trimester.

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Proteomic identification of membrane-associated placental protein 4 (MP4) as perlecan and characterization of its placental expression in normal and pathologic pregnancies

PeerJ ◽

10.7717/peerj.6982 ◽

2019 ◽

Vol 7 ◽

pp. e6982 ◽

Cited By ~ 3

Author(s):

Nikolett Lilla Szenasi ◽

Eszter Toth ◽

Andrea Balogh ◽

Kata Juhasz ◽

Katalin Karaszi ◽

...

Keyword(s):

Hellp Syndrome ◽

Core Protein ◽

Placental Tissue ◽

First Trimester ◽

Virtual Microscopy ◽

Third Trimester ◽

Diagnostic Significance ◽

Ischaemic Injury ◽

Tissue Samples ◽

Placental Protein

BackgroundMore than 50 human placental proteins were isolated and physico-chemically characterized in the 70–80s by Hans Bohn and co-workers. Many of these proteins turned to have important role in placental functions and diagnostic significance in pregnancy complications. Among these proteins was membrane-associated placental protein 4 (MP4), for which identity or function has not been identified yet. Our aim was to analyze the sequence and placental expression of this protein in normal and complicated pregnancies including miscarriage, preeclampsia and HELLP syndrome.MethodsLyophilized MP4 protein and frozen healthy placental tissue were analyzed using HPLC-MS/MS. Placental tissue samples were obtained from women with elective termination of pregnancy (first trimester controls,n= 31), early pregnancy loss (EPL) (n= 13), early preeclampsia without HELLP syndrome (n= 7) and with HELLP syndrome (n= 8), late preeclampsia (n= 8), third trimester early controls (n= 5) and third trimester late controls (n= 9). Tissue microarrays were constructed from paraffin-embedded placentas (n= 81). Slides were immunostained with monoclonal perlecan antibody and evaluated using light microscopy and virtual microscopy. Perlecan was also analyzed for its expression in placentas from normal pregnancies using microarray data.ResultsMass spectrometry-based proteomics of MP4 resulted in the identification of basement membrane-specific heparan sulfate proteoglycan core protein also known as perlecan. Immunohistochemistry showed cytoplasmic perlecan localization in syncytiotrophoblast and cytotrophoblasts of the villi. Perlecan immunoscore decreased with gestational age in the placenta. Perlecan immunoscores were higher in EPL compared to controls. Perlecan immunoscores were higher in early preeclampsia without and with HELLP syndrome and lower in late preeclampsia than in respective controls. Among patients with preeclampsia, placental perlecan expression positively correlated with maternal vascular malperfusion and negatively correlated with placental weight.ConclusionOur findings suggest that an increased placental perlecan expression may be associated with hypoxic ischaemic injury of the placenta in miscarriages and in early preeclampsia with or without HELLP syndrome.

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