W Schaarschmidt

Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Background— Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm (<32 weeks) preeclampsia. Methods and Results— We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. Conclusions— This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Removal of Soluble Fms-Like Tyrosine Kinase-1 by Dextran Sulfate Apheresis in Preeclampsia

Preeclampsia is a devastating complication of pregnancy. Soluble Fms-like tyrosine kinase-1 (sFlt-1) is an antiangiogenic protein believed to mediate the signs and symptoms of preeclampsia. We conducted an open pilot study to evaluate the safety and potential efficacy of therapeutic apheresis with a plasma-specific dextran sulfate column to remove circulating sFlt-1 in 11 pregnant women (20-38 years of age) with very preterm preeclampsia (23-32 weeks of gestation, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, new onset protein/creatinine ratio >0.30 g/g, and sFlt-1/placental growth factor ratio >85). We evaluated the extent of sFlt-1 removal, proteinuria reduction, pregnancy continuation, and neonatal and fetal safety of apheresis after one (n=6), two (n=4), or three (n=1) apheresis treatments. Mean sFlt-1 levels were reduced by 18% (range 7%-28%) with concomitant reductions of 44% in protein/creatinine ratios. Pregnancy continued for 8 days (range 2-11) and 15 days (range 11-21) in women treated once and multiple times, respectively, compared with 3 days (range 0-14) in untreated contemporaneous preeclampsia controls (n=22). Transient maternal BP reduction during apheresis was managed by withholding pre-apheresis antihypertensive therapy, saline prehydration, and reducing blood flow through the apheresis column. Compared with infants born prematurely to untreated women with and without preeclampsia (n=22 per group), no adverse effects of apheresis were observed. In conclusion, therapeutic apheresis reduced circulating sFlt-1 and proteinuria in women with very preterm preeclampsia and appeared to prolong pregnancy without major adverse maternal or fetal consequences. A controlled trial is warranted to confirm these findings.

Serum levels of the adipokine chemerin are increased in preeclampsia during and 6 months after pregnancy.

UNLABELLED Preeclampsia is a serious cardiovascular complication in pregnancy which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Recently, chemerin was introduced as a novel adipokine inducing insulin resistance in vitro and in vivo. In the current study, we investigated serum concentrations of chemerin by ELISA in control and preeclampsia patients during pregnancy ( CONTROL n=37, preeclampsia: n=37) and 6 months after delivery ( CONTROL n=35, preeclampsia: n=36). Furthermore, the association between chemerin and markers of renal function, glucose and lipid metabolism, as well as inflammation was studied in pregnant patients. Median maternal chemerin concentrations were significantly elevated in preeclampsia patients (249.5 [range: 123.1-366.9] μg/l) as compared to controls (204.8 [138.5-280.8] μg/l) (p<0.001). Furthermore, chemerin serum levels positively correlated with blood pressure, creatinine, free fatty acids, cholesterol, triglycerides (TG), leptin, adiponectin, and C-reactive protein in univariate analyses. In multivariate analyses, TG and leptin remained independently associated with circulating chemerin. Interestingly, median chemerin concentrations 6 months after delivery remained significantly higher in former preeclampsia patients (196.0 [119.8-368.7] μg/l) as compared to controls (152.2 [102.8-216.4] μg/l). Taken together, maternal chemerin serum concentrations are significantly increased in preeclampsia during and after pregnancy. Furthermore, TG and leptin are independent predictors of circulating chemerin during pregnancy.

The course of angiogenic factors in early- vs. late-onset preeclampsia and HELLP syndrome

Abstract Aims: Preeclampsia (PE) is considered a uniformly progressive disease, however, it shows a different pattern of clinical progression in patients with early (<34 weeks) or late (≥34 weeks) onset of the disease. Angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) are closely related to the clinical course of PE. We evaluated sFlt-1 and PlGF levels in the clinical course of PE in women admitted with a diagnosis of PE at different gestational ages. Methods: This retrospective study included 34 patients with PE, of which 11 patients had HELLP syndrome (over a period of 3 years). Serial measurements of sFlt-1 and PlGF were completed from admission until delivery. Values are presented as mean±standard deviation. Results: Mean gestational age of admission among women with early onset PE was significantly lower, at 29±3 weeks compared to 37±1 weeks among patients with late onset disease. Mean prolongation of pregnancy was 6 days, which was similar within the two groups. Compared to women with late onset PE, women with early-onset PE had a greater increase in sFlt-1 (11% vs. 3% per day, P<0.05), greater decrease in PlGF levels (21% vs. 10% per day, P=0.30), resulting in a much higher increase in sFlt-1/PlGF ratio (23% vs. 8% per day, P<0.05). Patients with HELLP syndrome showed comparable progression patterns. Conclusion: In a similar way to the progressively worsening clinical course observed in women with early onset PE, there were changes in the angiogenic profile that leads to a more anti-angiogenic state in these women with each passing day. These findings may have implications in identification of the women for appropriate patient management and possible future therapies based on the reduction of sFlt-1 levels.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia

BACKGROUND Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

Serum levels of the adipokine zinc-α2-glycoprotein are increased in preeclampsia

Background: Preeclampsia (PE) is associated with facets of the metabolic syndrome and an increased future metabolic and cardiovascular risk for mother and newborn. Recently, zinc-α2-glycoprotein (ZAG) has been proposed as a new adipokine involved in the pathogenesis of obesity. Aim: In the current study, we investigated ZAG serum levels in PE patients as compared to healthy gestational age-matched controls. Subjects and methods: We quantified serum concentrations of ZAG in patients with PE (no.=37) as compared to healthy gestational age-matched controls (no.=37) by enzyme-linked immunosorbent assay. Furthermore, association of this adipokine with renal function, glucose and lipid metabolism, as well as inflammation was studied. Results: Median serum ZAG levels were 1.4-fold higher in PE patients (58.8 mg/l) as compared to controls (41.9 mg/l) (p<0.01). Furthermore, circulating ZAG was positively correlated to systolic and diastolic blood pressure, creatinine, triglycerides, and leptin in univariate analyses. In multiple regression analysis, creatinine remained independently associated with ZAG. Conclusions: We demonstrate that maternal ZAG serum concentrations are significantly increased in PE. Furthermore, renal function is an independent predictor of circulating ZAG.

PP052. The course of sFlt-1 and PLGF reflects different progression pattern in early- versus late-onset preeclampsia and HELLP syndrome

INTRODUCTION Preeclampsia (PE), a serious multisystem disorder in pregnancy, is a leading cause of maternal and fetal morbidity and mortality worldwide and angiogenic factors like sFlt-1 and PlGF are closely related to the clinical course of preeclampsia. OBJECTIVES We wondered, if these factors and the sFlt-1/PlGF ratio are a tool to differentiate the clinical progression pattern between early and late-onset PE and HELLP syndrome. METHODS This retrospective study included 30 patients with PE out of which 7 patients had HELLP syndrome. Early onset PE was defined as patients with gestational age <34 weeks. Serial measurements of sFlt-1 and PlGF using the automated Elecsys platform (Roche®) were done from admission until delivery. RESULTS Early-onset PE is characterized by an increase of sFlt-1 of 66% leading to an 137% increase of the sFlt-1/PlGF ratio. Late-onset PE shows a slower progression with an increase of the sFlt-1/PlGF ratio of only 39%. Patients with HELLP syndrome show comparable progression pattern. CONCLUSION Angiogenic factors characterize PE and HELLP syndrome as continuously progressive diseases with a uniform development towards an antiangiogenic state. Early-onset subtypes show a more aggressive progression with a faster sFlt-1 increase.

Effect of steroids on angiogenic factors in pregnant women with HELLP syndrome

No abstract available

Cerebroplacental ratio and fetal response to maternal extracorporeal soluble fms‐like tyrosine kinase‐1 removal

Preeclampsia (PE) is a serious complication in obstetrics that affects approximately 3-5% of all pregnancies and it constitutes the leading cause of maternal mortality and morbidity worldwide. Although PE appears to be a maternal disease, iatrogenic preterm birth shifts the burden on the neonate after delivery. Impaired throphoblast invasion and differentiation in the first trimester with high placental impedance is considered to be the pathogenetic pathway of early and severe PE. Maternal rise of blood pressure represents the counter-regulation to maintain fetal supply. The excessive release of anti-angiogenics by the preeclamptic placenta creates an angiogenic imbalance leading to endothelial damage and its consequences.

Reply to: hepatic rupture - a rare but serious complication of HELLP syndrome.

Hepatic rupture is a rare but serious complication of HELLP syndrome (hemolysis elevated liver enzymes and low platelets) with an incidence of nearly 0.05%; most of the ruptures occur during weeks 32–34 of gestation [1]. In a “Letter to the Editor”, Kapoor [2] gives a short and highlighting overview regarding this complication. Although hepatic rupture will never be totally avoidable, the identification of patients at risk is a clinical goal of paramount importance. The key seems to be the prediction of preeclampsia (PE) and HELLP syndrome. Prediction should become more efficient, as our understanding on the origin and pathophysiology of the disease has improved drastically over the last decade. Multiple studies have shown that an imbalance in angiogenic factors plays a crucial role in the development of PE and HELLP syndrome. The measurement of plasma sFlt-1 and PlGF in pregnant women is used as a diagnostic and predictive test for PE [5, 6]. The sFlt-1/PlGF ratio correlates closely to the severity and progression speed of the disease [2, 6]. Recently our group has found that PE and HELLP show comparable progression patterns regarding the course of sFlt-1/PlGF ratio and that early-onset subtypes show more aggressive progression with a faster sFlt-1 increase [3]. New cut-off values for earlyand late-onset PE enhance the diagnostic accuracy of the sFlt-1/PlGF ratio as a diagnostic tool [6]. Moreover, the automated measurement (Elecsys® assay, Roche Diagnostics, Mannheim, Germany) of sFlt-1 and PlGF in clinical routine allows an early detection and furthermore a prediction of PE/HELLP [5, 6] which might also determine patients at risk for hepatic rupture and, therefore, affect clinical management resulting in possibly reduced rates of hepatic rupture. Although Kapoor does not refer to angiogenic factors in context of hepatic rupture, we may assume that this condition is clearly characterized by a high sFlt-1/ PlGF ratio indicating an altered angiogenic state in fullblown HELLP syndrome. This emphasizes the role of new potential treatments for PE and HELLP syndrome by extracorporeal apheresis of sFlt-1 [3]. In a pilot study, Thadhani et al. [4] found that apheresis treatment can lower sFlt-1 up to 34% in patients with early-onset PE resulting in a stable clinical condition of the patient and prolongation of pregnancy. Thus, early detection and prediction of PE and HELLP syndrome by measurement of sFlt-1 and PlGF might lead to a quicker and more efficient identification of patients at risk for PE in general and thereby avoid complications of end-stage diseases such as hepatic rupture and others.