Plasma Placental Growth Factor Levels Research Articles

Preeclampsia is associated with reduced renin, aldosterone, and PlGF levels, and increased sFlt-1/PlGF ratio, and specific angiotensin-converting enzyme Ins-Del gene variants

We investigated the association of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism with preeclampsia (PE) in Tunisian women. ACE I/D genotyping was done by PCR in 342 pregnant women with PE and 289 healthy pregnant women. The association between ACE I/D and PE and associated features were also evaluated. Decreased active renin concentration, plasma aldosterone concentration, and placental growth factor (PlGF) were observed in PE cases, while soluble fms-like tyrosine kinase-1 (sFlt-1)/PlGF ratio was significantly higher in the PE group. Distribution of ACE I/D alleles and genotypes were comparable between women with PE and control women. A significant difference in the frequency of the I/I genotype was seen between PE cases and control women according to the recessive model, with a trend towards association in the codominant model. Carriers of the I/I genotype had significantly higher infant birth weights compared to the I/D and the D/D genotype carriers. A dose-dependent relationship was also seen in VEGF and PlGF plasma levels and specific ACE I/D genotypes, with the lowest VEGF levels seen in the I/I genotype carriers compared to the D/D genotype carriers. Similarly, the I/I genotype carriers had the lowest PlGF levels compared to I/D and D/D genotype carriers. Furthermore, when studying the linkage between PE features, we found a positive correlation between PAC and PIGF. Our study suggests a role for ACE I/D polymorphism in the pathogenesis of PE, possibly through modulating VEGF and PlGF levels and infant birth weight, and highlights the relationship between PAC and PlGF.

Placental Growth Factor in First Trimester of Pregnancy for Prediction of Maternal and Perinatal Adverse Outcomes.

Placental growth factor (PLGF) is an angiogenic factor in pregnancy. To find out correlation of plasma levels of placental growth factor in first trimester of pregnancy in Indian women who develop maternal and perinatal adverse outcomes was the aim of the study. A prospective longitudinal noninterventional study was done in the department of Obstetrics and Gynecology after obtaining ethics approval. After enrolling patients in the first trimester (11weeks to 13weeks 6days), a questionnaire was filled for demographic characteristics. Uterine artery doppler was done for every patient and blood sample (5ml) was taken by venu puncture of median cubital vein. Serum levels of PLGF were measured by enzyme linked immunosorbent assay using Thermo Scientific Pierce Human PLGF kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Patients were followed for their whole antenatal period and delivery outcomes. Incidence of preeclampsia in our study was 9.3% (15/161) and fetal growth restriction (FGR) was 19.8% (32/161). Neither BMI nor nulliparity was found to have statistically significant correlation with development of preeclampsia. However, history of preeclampsia was found to be significant risk factor for prediction of preeclampsia (p value < 0.04). Plasma levels of PLGF were significantly lower in preeclampsia and FGR group and this difference was statistically significant (p value < 0.04). 7.5% still born occurred in complicated group and 10% needed NNU/NICU admission in this group. Measuring PLGF levels in first trimester of pregnancy can help in prediction of preeclampsia and FGR.

Vascular and inflammatory plasma biomarkers correlate with human post‐mortem cerebral vascular pathology

AbstractBackgroundVascular Cognitive Impairment and Dementia (VCID) is a common cause of dementia in Western populations. Small‐vessel disease (SVD), a VCID subtype, can present as arteriolosclerosis and microinfarcts. Currently, identifying this pathology clinically is limited to MRI, which is expensive, limited in terms of small vessel resolution and not widely available. Therefore, a more accessible screening tool is needed to clinically evaluate SVD. Here, we evaluate the relationships between vascular and inflammatory plasma biomarkers with global levels of SVD pathology in human brain.MethodPlasma and brain tissue samples were obtained from the University of Kentucky Alzheimer’s Disease Research Center (UK‐ADRC) Brain Bank. Cases were selected from participants who had an available plasma sample from within two years of death. These plasma samples were analyzed using a digital immunoassay (Quanterix Simoa) to determine biomarker levels of placental growth factor (PlGF), matrix metalloproteinase 9 (MMP9), and tumor necrosis factor α (TNFα). Biomarker levels were categorized by quartiles. Pathological evaluation was performed by UK‐ADRC neuropathologists, blind to clinical data. The association of plasma markers with neuropathology was estimated via multinomial and binary logistic regressions adjusted for age and sex. Global arteriosclerosis was examined using a scale of none/mild/moderate/severe, with none being the reference. Presence or absence of microinfarcts was also examined.ResultIncluded cases (n=93) were age 82.0±9.2 years at death; 46.7% were female. Higher plasma placental growth factor (PlGF) levels were associated with less severe arteriolosclerosis: odds ratio (OR)=0.8 (95% CI 0.5‐1.3), 0.8 (0.5‐1.5), and 0.6 (0.2‐1.7); higher plasma MMP9 levels were associated with more severe arteriolosclerosis (OR=1.0 (0.5‐2.1), 0.7 (0.3‐1.5), 0.7 (0.2‐2.4), comparing odds of mild, moderate, and severe to none, respectively), though these results were not statistically significant. Lower plasma PlGF and MMP9, and higher TNFa, were associated with higher odds of microinfarction: OR=0.59 (0.33‐1.02), 0.74 (0.38‐1.42), and 2.28 (0.84‐6.20), respectively.ConclusionOur results, while based on a small sample, suggest plasma PlGF and MMP9 levels have an inverse relationship with global SVD pathology, while plasma TNFa is positively correlated with increased global SVD pathology. These results provide support for potential use of plasma biomarkers as a clinical screening tool for SVD pathology.

Genetics of PlGF plasma levels highlights a role of its receptors and supports the link between angiogenesis and immunity

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family and is involved in bone marrow-derived cell activation, endothelial stimulation and pathological angiogenesis. High levels of PlGF have been observed in several pathological conditions especially in cancer, cardiovascular, autoimmune and inflammatory diseases. Little is known about the genetics of circulating PlGF levels. Indeed, although the heritability of circulating PlGF levels is around 40%, no studies have assessed the relation between PlGF plasma levels and genetic variants at a genome-wide level. In the current study, PlGF plasma levels were measured in a population-based sample of 2085 adult individuals from three isolated populations of South Italy. A GWAS was performed in a discovery cohort (N = 1600), followed by a de novo replication (N = 468) from the same populations. The meta-analysis of the discovery and replication samples revealed one signal significantly associated with PlGF circulating levels. This signal was mapped to the PlGF co-receptor coding gene NRP1, indicating its important role in modulating the PlGF plasma levels. Two additional signals, at the PlGF receptor coding gene FLT1 and RAPGEF5 gene, were identified at a suggestive level. Pathway and TWAS analyses highlighted genes known to be involved in angiogenesis and immune response, supporting the link between these processes and PlGF regulation. Overall, these data improve our understanding of the genetic variation underlying circulating PlGF levels. This in turn could lead to new preventive and therapeutic strategies for a wide variety of PlGF-related pathologies.

Circulating levels of angiogenic factors and their association with preeclampsia among pregnant women at Mulago National Referral Hospital in Uganda.

Preeclampsia (PE) is a major cause of maternal and new-born morbidity and mortality. Angiogenic factors contribute a major role in the vascular dysfunction associated with PE. We investigated the circulating levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and soluble Feline McDonough Sarcoma (fms)-like tyrosine kinase-1 (sFlt1), their association with PE and diagnostic performance of disease among pregnant women in Uganda. Using a case-control study design, 106 women with PE and 106 with normal pregnancy were enrolled. Demographic and clinical characteristics, and anticoagulated blood samples were collected from participants. Plasma VEGF, PlGF and sFlt1 levels were measured using Luminex and enzyme linked immunosorbent assays (ELISA). Conditional logistic regression was used to explore association of angiogenic factors with PE and receiver operating characteristic analysis was performed to investigate PE diagnostic performance. Levels of VEGF and PIGF were significantly lower in cases compared to controls (VEGF: median = 0.71 pg/ml (IQR = 0.38-1.11) Vs 1.20 pg/ml (0.64-1.91), p-value<0.001 and PlGF: 2.20 pg/ml (1.08-5.86) Vs 84.62 pg/ml (34.00-154.45), p-value<0.001). Plasma levels of sFlt1 were significantly higher in cases than controls (median = 141.13 (71.76-227.10) x103 pg/ml Vs 19.86 (14.20-29.37) x103 pg/ml). Increasing sFlt1 levels were associated with increased likelihood of PE (aOR = 4.73; 95% CI, 1.18-19.01; p-value = 0.0287). The sFlt1/PlGF ratio and sFlt1 had a better performance for diagnosis of PE, with AUC = 0.95 (95% CI, 0.93-0.98) followed by PlGF with AUC = 0.94 (95% CI, 0.91-0.97). Therefore, sFlt1, sFlt1/PlGF ratio and PlGF are potential candidates for incorporation into algorithms for PE diagnosis in the Ugandan population.

Soluble fms-like tyrosine kinase 1 and placental growth factor ratio for predicting preeclampsia in elderly gravida

ABSTRACT Objective To determine the predictive value of plasma soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) ratio for detection of preeclampsia in elderly gravida at 16–18 weeks of gestation and to identify whether abnormalities of this ratio are associated with any other pregnancy complications or not. Methods Blood samples of 300 cases were collected. Plasma sFlt-1 and PlGF levels were measured using an automated immunoassay. Results Sensitivity and specificity for plasma sFlt-1/PlGF ratio above 9.8 for preeclampsia prediction were 85.7% and 61.2%, respectively. The sensitivity and specificity to predict early onset preeclampsia were 100% and 61.1%, respectively. Women with abnormal plasma sFlt-1/PlGF ratio were not associated with any other pregnancy complications. Conclusion sFlt-1/PlGF ratio at 16–18 weeks of gestation in elderly gravida has a high sensitivity for predicting preeclampsia, especially early onset preeclampsia.

Plasma VEGF-D and PlGF levels according to prior use of biologics among metastatic colorectal cancer: Preliminary results from GI-SCREEN CRC-Ukit study.

178 Background: Plasma vascular endothelial growth factor-D (VEGF-D) level is a potential predictor for ramucirumab efficacy in patients (pts) with metastatic colorectal cancer (mCRC), while a high VEGF-A and placental growth factor (PlGF) level in bevacizumab naïve pts receiving 2nd-line FOLFIRI plus aflibercept may suggest relatively higher activity. However, there are a few data associating 1st-line antiangiogenic treatments as well as anti-EGFR with angiogenic factors. Methods: This prospective longitudinal study aims to investigate an association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. Serial plasma collections were done at time points of pre- and post-treatments of either 1st- or 2nd-line. Comprehensive measurements of 17 mediators were analyzed by the multiplex assay with Luminex technology. Here we report an association between levels of VEGF-D, PlGF and patient backgrounds. Results: From Sep 2017 to Aug 2019, 375 samples from 317 pts were enrolled in this analysis. Baseline characteristics were follows; 169 samples at pre-1st-line (pre-1L), 151 with prior bevacizumab treatment (post-bev) and 55 with prior anti-EGFR antibody (post-EGFR); median age, 66 years; male gender, 58%; RAS mutant, 46%; left-sided primary, 76%. In pre-1L, the median values of VEGF-D/ PlGF were 264/ 7.21 pg/mL without a clear association between the two in each patient (r = 0.094) and any baseline characteristics. Compared to pre-1L, the values of VEGF-D/ PlGF showed significantly higher in post-bev (median VEGF-D/ PlGF; 346/ 23.5 pg/mL, respectively). Moreover, there was no clear relationship between the two cytokines in each patient (r = 0.190). In 37 pts with serial blood collection, VEGF-D/ PlGF levels showed similar trends. In addition, VEGF-D/ PlGF levels in post-EGFR tended to be higher than those in pre-1L (median VEGF-D/ PlGF; 395/ 9.11 pg/mL, respectively). Conclusions: The VEGF-D/ PlGF may be separately induced by bev treatment as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting a better antiangiogenic inhibitor by measuring baseline VEGF-D/ PlGF. Clinical trial information: UMIN000028616.

Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis.

BACKGROUNDClinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.AIMTo determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension.METHODSA cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals.RESULTSPeripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH.CONCLUSIONPlasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.

To Accelerate the Diagnosis of Preeclampsia, Consider Measuring Maternal Placental Growth Factor

Placental growth factor (PlGF) regulates angiogenesis in the developing placenta, and low plasma PlGF levels have been implicated in the etiology of

Assessing the sensitivity of placental growth factor and soluble fms-like tyrosine kinase 1 at 36\xa0weeks\u2019 gestation to predict small-for-gestational-age infants or late-onset preeclampsia: a prospective nested case-control study

BackgroundFetal growth restriction is a disorder of placental dysfunction with three to four-fold increased risk of stillbirth. Fetal growth restriction has pathophysiological features in common with preeclampsia. We hypothesised that angiogenesis-related factors in maternal plasma, known to predict preeclampsia, may also detect fetal growth restriction at 36 weeks’ gestation. We therefore set out to determine the diagnostic performance of soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and the sFlt-1:PlGF ratio, measured at 36 weeks’ gestation, in identifying women who subsequently give birth to small-for-gestational-age (SGA; birthweight <10th centile) infants. We also aimed to validate the predictive performance of the analytes for late-onset preeclampsia in a large independent, prospective cohort.MethodsA nested 1:2 case-control study was performed including 102 cases of SGA infants and a matched group of 207 controls; and 39 cases of preeclampsia. We determined the diagnostic performance of each angiogenesis-related factor, and of their ratio, to detect SGA infants or preeclampsia, for a predetermined 10% false positive rate.ResultsMedian plasma levels of PlGF at 36 weeks’ gestation were significantly lower in women who subsequently had SGA newborns (178.5 pg/ml) compared to normal birthweight controls (326.7 pg/ml, p < 0.0001). sFlt-1 was also higher among SGA cases, but this was not significant after women with concurrent preeclampsia were excluded. The sensitivity of PlGF to predict SGA infants was 28.8% for a 10% false positive rate. The sFlt-1:PlGF ratio demonstrated better sensitivity for preeclampsia than either analyte alone, detecting 69.2% of cases for a 10% false positive rate.ConclusionsPlasma PlGF at 36 weeks’ gestation is significantly lower in women who subsequently deliver a SGA infant. While the sensitivity and specificity of PlGF currently limit clinical translation, our findings support a blood-based biomarker approach to detect late-onset fetal growth restriction. Thirty-six week sFlt-1:PlGF ratio predicts 69.2% of preeclampsia cases, and could be a useful screening test to triage antenatal surveillance.

A clinical evaluation of placental growth factor in routine practice in high-risk women presenting with suspected pre-eclampsia and/or fetal growth restriction.

To evaluate the use of plasma Placental Growth Factor (PlGF), recommended by the recent NICE guidance, in women with suspected pre-eclampsia (PE) and/or fetal growth restriction (FGR). Non-randomised prospective clinical evaluation study in high-risk antenatal clinics in a tertiary maternity unit. PlGF testing was performed in addition to routine clinical assessment in 260 women >20 weeks' gestation with chronic disease (hypertension, renal disease ± diabetes) with a change in maternal condition or in women with suspected FGR to determine the impact on clinical management. Results were revealed and standardised care pathways followed. Outcome of pregnancies with a low PlGF (<12 pg/ml and 13-100 pg/ml), impact on clinical service and the diagnostic accuracy of alternative PlGF cut-offs. 206/260 (79.2%) women had an adverse outcome (PE/birthweight < 10th centile/preterm birth). In our cohort, a low PlGF (<12 pg/ml) was associated with a shorter test-birth interval and universally (100% PPV) with an adverse pregnancy outcome, although 29/61 (47.5%) of women with PlGF < 12 pg/ml continued their pregnancy >14 days. The PlGF result altered clinical management (surveillance or timing of birth) in 196/260 (75.4%) cases. Alternative PlGF thresholds did not significantly improve diagnostic performance. Our evaluation confirms the value of PlGF as a diagnostic tool for placental dysfunction. However, low PlGF in isolation should not trigger iatrogenic delivery. Further research linking placental pathology, maternal disease and maternal PlGF levels is urgently needed before this test can be implemented in routine clinical practice.

Blockade of placental growth factor reduces vaso-occlusive complications in murine models of sickle cell disease

Vaso-occlusive crisis (VOC) is the most common and debilitating complication of sickle cell disease (SCD); recurrent episodes cause organ damage and contribute to early mortality. Plasma placental growth factor (PlGF) levels are elevated in SCD and can further increase under hypoxic conditions in SCD mice. Treatment with a PlGF-neutralizing antibody (anti-PlGF Ab) in SCD mice reduced levels of monocyte chemoattractant protein-3, eotaxin, macrophage colony-stimulating factor, and plasminogen activator inhibitor-1 significantly, and of macrophage-derived chemokine and macrophage inflammatory protein-3β moderately; this may contribute to inhibition of leukocyte recruitment, activation, and thrombosis. In subsequent experiments, anti-PlGF Ab treatment significantly reduced plasma lactate dehydrogenase levels, indicating possible reduction in cellular destruction and/or hemolysis. Histopathology studies revealed decreased incidence and severity of congestion in the lungs and spleen with repeated anti-PlGF Ab treatment. Furthermore, anti-PlGF Ab significantly reduced vaso-occlusion events under hypoxic conditions in a modified dorsal skinfold chamber model in SCD mice. Therefore, elevated PlGF levels may contribute to recruitment and activation of leukocytes. This can subsequently lead to increased pathology of affected organs in addition to mediating acute hypoxia/reoxygenation-triggered vaso-occlusion under SCD conditions. Thus, targeting PlGF may offer a therapeutic approach to reduce acute VOC and possibly alleviate long-term vascular complications in patients with SCD.

Placental Growth Factor in Bladder Cancer Compared to the Diagnostic Accuracy and Prognostic Performance of Vascular Endothelial Growth Factor A

To evaluate the diagnostic accuracy and prognostic performance of urinary and plasma levels of placental growth factor (PLGF) and provide their comparison with the results of vascular endothelial growth factor A (VEGF-A) in patients with primary and recurrent urinary bladder cancer. The enzyme-linked immunosorbent assay (ELISA) was used to assess urinary and plasma concentrations of PLGF and VEGF-A in 240 individuals. PLGF levels in urine and plasma were significantly higher in patients with primary bladder cancer than in healthy individuals (p=0.003, p=0.005, respectively). Area under the curve (AUC) of urinary PLGF was 0.68; AUC of plasma PLGF levels was 0.65. Patients with the urine levels of PLGF higher than 82.33 pg/ml had three times higher risk of recurrence. In patients with recurrent bladder cancer, the urinary concentrations of PLGF did not significantly differ from the concentrations in patients without current disease (p=0.61). However, plasma PLGF levels were significantly higher in patients diagnosed with tumor recurrence (p=0.001); AUC of plasma PLGF levels was 0.69. Moreover, patients with plasma levels higher than 10.09 pg/ml had a five-times higher risk of future tumor recurrence. The diagnostic accuracy of PLGF was comparable with VEGF-A. From a clinical point of view, PLGF could be considered a valid diagnostic test for the detection of primary and recurrent bladder cancer. In patients with recurrent bladder cancer, plasma PLGF levels can differentiate individuals at risk of tumor recurrence.

Obese Melanocortin‐4 Receptor (MC4R)‐Deficient Pregnant Rats Have Increased Blood Pressure With Reduced Circulating Placental Growth Factor Levels

Preeclampsia is a pregnancy‐specific disorder of hypertension, which significantly increases the immediate and long‐term morbidity of mother and offspring. Obesity is a major risk factor for preeclampsia, but the mechanisms linking obesity to this maternal disorder are unknown. Studies in humans have suggested that a greater angiogenic imbalance mediates this increased risk. Preeclampsia is thought to result from placental ischemia and release of anti‐angiogenic factors, such as sFlt‐1, into the maternal circulation where it reduces bioavailability of vascular protective and angiogenic factors, like placental growth factor (PlGF). We have shown previously, in two separate studies, the PlGF prevents placental ischemia‐induced hypertension in rats and that obese MC4R‐deficient rats have increased sFlt‐1 levels and blood pressure during pregnancy. Therefore, we tested the hypothesis that MC4R‐deficient pregnant rats have increased blood pressure with reduced circulating levels of PlGF. MC4R+/+ and MC4R+/− rats were maintained on a standard chow diet and timed‐pregnancies generated at 15 weeks of age using genotyped‐matched males. Carotid catheters were implanted on gestational day 18 for conscious mean arterial pressure (MAP) measurements and plasma collection on day 19. At day 19, absolute body weights were greater in MC4R+/− (n=13) over MC4R+/+ (n=10) pregnant rats (371±9 vs. 340±6 g, P&lt;0.05), as was retroperitoneal adipose tissue mass (13±1 vs. 9±1 g, P&lt;0.05). Circulating levels of leptin (6.7±1.0 vs. 3.5±0.4 ng/mL, P&lt;0.05) were also greater in the obese pregnant rats. MAP was greater in the obese pregnant rats (108±2 vs. 101±1, P&lt;0.05). In addition, circulating sFlt‐1 levels were doubled in the obese pregnant rats (440±128 vs. 252±106 ng/mL) but not in placental tissue (136±10 vs. 143±7 ng/mL). In contrast, the obese MC4R+/− pregnant rats had significantly reduced plasma levels of PlGF (45±10 vs. 121±34 pg/mL, P&lt;0.05) but not in the placenta (496±152 vs. 508±183). In conclusion, these data suggest that the increased blood pressure found in obese MC4R‐deficient pregnant rats is associated with reduced circulating PlGF, and that therapeutic strategies to restore PlGF levels may be a way to reduce the increased incidence of preeclampsia in obese pregnancies.Support or Funding InformationK99HL130577, HL51971, P20GM104357

Preeclampsia: Obstetric-neonatal risk stratification according to plasma placental growth factor levels

Introduction To evaluate the clinical utility of placental growth factor (PlGF) in the management of pregnancies complicated by preeclampsia (PE). Methods This prospective cohort study included women with a risk of developing PE. Blood samples were collected every 4–5 weeks from second trimester until delivery. Plasma levels of PlGF were stratified in very low ( 12 pg/mL but Results A total of 75 women were included, 20 developed PE: the ones with very low plasma levels (n = 12) had a significantly lower gestational age at delivery (p = 0.0003), lower birthweight (p = 0.0009), and higher rate of emergency C-section outside labour (p Conclusion Our data suggest that the decreasing of PlGF levels is associated with worse outcomes. Therefore the PlGF may be useful for risk stratification of pregnancies that require an intensive monitoring or delivery. This single biomarker would simplify the clinical management and would reduce costs. Download : Download high-res image (161KB) Download : Download full-size image

A new angiogenesis prognostic index with VEGFA, PlGF, and angiopoietin1 predicts survival in patients with advanced gastric cancer.

The role of angiogenic factors in gastric cancer is not clear. We aimed to assess the role of vascular endothelial growth factor A (VEGFA), angiopoietin 1 (Ang-1), and placental growth factor (PlGF) in the prognosis of patients with advanced gastric cancer. Thirty consecutive patients treated with a modified DCF (docetaxel, cisplatin, and fluorouracil) regimen were included in the study. The plasma VEGFA, Ang-1, and PlGF levels of the patients before treatment and following two cycles of chemotherapy were measured and evaluated as prognostic factors. Poor performance status and lower Ang-1 levels were correlated with poor overall survival (OS). No significant correlation between VEGFA or PlGF and OS was found. An angiogenesis prognostic index (API) based on the levels of VEGFA, Ang-1, and PlGF was found to be highly correlated with OS. Performance status and API were found as independent prognostic factors for OS. Furthermore, a decrease in VEGFA by 25% from the pretreatment level was also found as a prognostic factor for OS independent of response to DCF regimen. Our results support the use of the new API including VEGFA, Ang-1, and PlGF levels in patients with advanced gastric cancer as a predictor of survival.

Abstract 12903: Low-molecular Weight Heparin Improves Endothelial Function in Pregnant Women at High-risk of Preeclampsia

Introduction: Women who develop preeclampsia (PE) demonstrate cardiovascular abnormalities during pregnancy and postpartum. Low-molecular weight heparin (LMWH) significantly reduces the incidence of PE, although the mechanisms of action are unknown. Hypothesis: LMWH improves cardiovascular function in pregnant women at high-risk of PE. Methods: Pregnant women at high-risk of PE (n=25) and low-risk pregnant controls (n=20) at 22-26 weeks’ gestation underwent cardiovascular assessments. High-risk women were then randomized to LMWH or saline placebo (30mg IV bolus and 1mg/kg subcutaneous dose). Cardiovascular function was assessed 1 and 3 hours post-randomization. The in vitro endothelial effects of patient serum and LMWH on human umbilical venous endothelial cells (HUVEC) were determined through angiogenesis assays, gene expression and protein secretion. Results: High-risk women demonstrated a low-volume, high resistance hemodynamic profile with significantly impaired radial artery flow-mediated dilation (FMD) when compared to low-risk controls (6.5±0.9% vs 9.7±1.0%, P=0.03). Baseline plasma and urine levels of placental growth factor (PlGF) were significantly lower in high-risk women compared with controls (P=0.003 and P=0.01, respectively). LMWH significantly increased FMD in high-risk women following randomization compared to baseline (10.8±1.0% vs 7.6±1.0%, P=0.008). LMWH also significantly increased plasma levels of PlGF, soluble fms-like tyrosine kinase-1 and myeloperoxidase (P=0.006, P=0.03 and P=0.03, respectively). Serum from high-risk women significantly impaired HUVEC angiogenesis and significantly increased PlGF-1 and PlGF-2 transcription compared to serum from controls (0.79±0.05 vs 0.99±0.05, P=0.03; P=0.03 and P=0.01, respectively). Co-exposure of high-risk serum with LMWH improved the in vitro angiogenic response such that it was equivalent to that of control serum and promoted PlGF secretion. Conclusions: Our data indicate that LMWH improves maternal endothelial function in pregnant women at high-risk of developing PE, possibly mediated through increased PlGF bioavailability. Future trials are needed to assess the effectiveness of LMWH for the prevention of severe PE in screen-positive women.

PlGF in a clinical setting of pregnancies at risk of preeclampsia and/or intrauterine growth restriction

Placental growth factor (PlGF) is an angiogenic molecule produced by the placenta and implicated in the pathogenesis of preeclampsia (PE) and intrauterine growth restriction (IUGR). We have evaluated utility and applicability of the PlGF test in a clinical setting of pregnancies at risk of PE or complicated by IUGR in order to assess its relationship with pregnancy outcomes. Seventy-three pregnancies were enrolled between 19 and 35 weeks: 57 pregnancies at risk of PE and 16 at diagnosis of IUGR. Maternal circulating PlGF levels were measured by the Triage PlGF test (Alere, San Diego, CA). Pregnancy outcomes were evaluated in relation to three categories of plasma PlGF levels: very low (<12 pg/ml), low (12–100 pg/ml) and normal (≥100 pg/ml). Uterine artery Doppler velocimetry (UADV) pulsatility index (PI) was measured in the same patients on the day of maternal sampling. Pregnancies at risk with very low plasma PlGF levels had significantly lower gestational age at delivery than patients with low or normal PlGF. The rate of emergency C-section was significantly higher in the group with PlGF <12 pg/ml. IUGR pregnancies with very low and low PlGF delivered earlier than patients with normal PlGF. All IUGR with very low and low PlGF had UADV PI > 95th percentile. Our data indicate that PlGF may provide useful information to identify fetuses requiring increased surveillance and possibly urgent delivery in pregnancies at risk of adverse outcomes. Furthermore, in IUGR, PlGF can predict adverse pregnancy outcomes that may be secondary to placental insufficiency.

KRYPTOR-automated angiogenic factor assays and risk of preeclampsia-related adverse outcomes

ABSTRACTObjective: To evaluate KRYPTOR assays for circulating soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) in risk assessment of adverse outcomes in women with suspected preeclampsia. Methods: We studied 412 women carrying a singleton pregnancy from a previous study cohort who were evaluated for suspected preeclampsia. Another 434 nonpreeclamptic patients with plasma samples drawn throughout pregnancy were used to derive normative data. Plasma sFlt1 and PlGF levels were measured on the automated KRYPTOR platform and evaluated for prediction of adverse maternal and perinatal outcomes within 2 weeks. Normative values were used to create a ratio of markers and these values were reported as multiples of median (MoM) for women with and without adverse outcomes. The KRYPTOR assay results were also compared with previously reported measurements obtained using the automated Elecsys platform. Results: Among participants presenting at <34 weeks (N = 110), patients with subsequent adverse outcome had higher sFlt1, lower PlGF, and higher sFlt1/PlGF ratio compared with women without adverse outcomes: the median (25th, 75th centile) sFlt1 (pg/ml), 9030 (3197, 12,140) versus 1976 (1248, 2937); PlGF (pg/ml), 36 (16, 111) versus 318 (108, 629); and ratio, 285.6 (32.2, 758.5) versus 6.1 (2.3, 20.3) (all p < 0.0001). Higher sFlt1/PlGF ratio correlated negatively with timing of delivery (r = −0.60, p < 0.001) and the risk of adverse outcomes was markedly elevated among women in highest tertile compared with lower tertile (odds ratio, 14.77; 95% confidence interval (CI), 4.28–51.00). The addition of sFlt1/PlGF ratio (≥85) to hypertension and proteinuria significantly improved the prediction for subsequent adverse outcomes (AUC 0.89 (95% CI): 0.82, 0.95) for hypertension, proteinuria, and sFlt1/PlGF (AUC = 0.75 (0.65, 0.85)) for hypertension alone (p = 0.002). Compared with normative controls, women who were evaluated for preeclampsia without adverse outcomes had higher MoM for sFlt1/PlGF ratio; these values were further elevated in women with adverse outcomes. sFlt1/PlGF ratios measured on the KRYPTOR platform were highly correlated with measurements obtained using Elecys platform (r = 0.97, p < 0.001). Conclusions: In women with suspected preeclampsia presenting prior to 34 weeks of gestation, KRYPTOR assays for circulating sFlt1 and PlGF when used in conjunction with standard clinical evaluation performs well in the prediction of adverse maternal and perinatal outcomes occurring within 2 weeks of presentation.

Impact of Obstructive Sleep Apnea on the Levels of Placental Growth Factor (PlGF) and Their Value for Predicting Short-Term Adverse Outcomes in Patients with Acute Coronary Syndrome.

BackgroundPlacental growth factor (PlGF) induces angiogenesis and promotes tissue repair, and plasma PlGF levels change markedly during acute myocardial infarction (AMI). Currently, the impact of obstructive sleep apnea (OSA) in patients with AMI is a subject of debate. Our objective was to evaluate the relationships between PlGF levels and both the severity of acute coronary syndrome (ACS) and short-term outcomes after ACS in patients with and without OSA.MethodsA total of 538 consecutive patients (312 OSA patients and 226 controls) admitted for ACS were included in this study. All patients underwent polygraphy in the first 72 hours after hospital admission. The severity of disease and short-term prognoses were evaluated during the hospitalization period. Plasma PlGF levels were measured using an electrochemiluminescence immunoassay.ResultsPatients with OSA were significantly older and more frequently hypertensive and had higher BMIs than those without OSA. After adjusting for age, smoking status, BMI and hypertension, PlGF levels were significantly elevated in patients with OSA compared with patients without OSA (19.9 pg/mL, interquartile range: 16.6–24.5 pg/mL; 18.5 pg/mL, interquartile range: 14.7–22.7 pg/mL; p<0.001), and a higher apnea-hypopnea index (AHI) was associated with higher PlGF concentrations (p<0.003). Patients with higher levels of PlGF had also an increased odds ratio for the presence of 3 or more diseased vessels and for a Killip score>1, even after adjustment.ConclusionsThe results of this study show that in patients with ACS, elevated plasma levels of PlGF are associated with the presence of OSA and with adverse outcomes during short-term follow-up.Trial RegistrationClinicalTrials.gov NCT01335087