Soluble fms-like tyrosine kinase 1, placental growth factor and procalcitonin as biomarkers of gram-negative sepsis

Abstract Background Preeclampsia is a leading hypertensive disorder in pregnant women. The angiogenic biomarkers, soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio, have been shown to be associated with diagnosis and prediction of preeclampsia. The objective of this study is to validate the analytical performance of sFlt-1 and PlGF on the Cobas e602 system (Roche Diagnostics Corporation). Method Intra-day and inter-day precisions for both sFlt-1 and PlGF assays were assessed using quality control materials provided from Roche Diagnostics. The accuracies for both assays were assessed by running 60 patient samples, which have been previously analyzed on the Elecsys 411 analyzer (Roche Diagnostics Corporation) at the Beth Israel Deaconess Medical Center. Linearity studies for both assays were performed using patient plasma spiked with recombinant sFlt-1 and PlGF proteins (R&D systems). Hemolysis, icterus, lipemia and biotin interference studies were performed by spiking hemolysate, bilirubin, intralipid or biotin into either pooled patient plasma with detectable levels of sFlt-1 and PlGF or otherwise, patient plasma spiked with recombinant sFlt-1 and PlGF proteins. Results Total precisions for both assays demonstrated CVs of <5.0%. The sFlt-1 and PlGF assays demonstrated analytical measuring ranges of 3060,000 pg/mL and 79,000 pg/mL, respectively (r2 > 0.98). Lower limit of quantitation (10% CV) was 30 pg/mL for sFlt-1 and 7 pg/mL for PlGF, respectively. Interference studies showed sFlt-1 and PlGF were not significantly affected by hemolysis up to H-indices of 500 and 1000 respectively; both assays were not affected by bilirubin up to an I-index of 60, and lipemia up to an L-index of 2800. Biotin at concentrations >30 ng/mL caused significant negative bias for both sFlt-1 and PlGF assays. Comparison studies showed the following: Cobas e602 sFLT-1 = 1.09 [Elecsys 411 sFLT-1] +203 (r2=0.97, Sy/x=1234, n=58); Cobas e602 PlGF = 1.10 [Elecsys 411 PlGF] +47 (r2=0.99, Sy/x=22.1, n=58); Cobas e602 sFLT-1/PlGF ratio = 0.94 [Elecsys 411 sFLT-1/PlGF ratio] +3.5 (r2=0.91, Sy/x=50, n=58). Conclusion sFlt-1 and PlGF measured on Roche Diagnostics Cobas e602 system demonstrated excellent analytical performance and are acceptable for clinical use once approved in the US.

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Applying the concept of uncertainty to the sFlt-1/PlGF cut-offs for diagnosis and prognosis of preeclampsia

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2020-0477 ◽

2021 ◽

Vol 59 (4) ◽

pp. 681-686

Author(s):

Pacifique Lévy ◽

Safouane Hamdi ◽

Jean Guiboudenche ◽

Marie Clothilde Haguet ◽

Sophie Bailleul ◽

...

Keyword(s):

Quality Control ◽

Growth Factor ◽

Tyrosine Kinase ◽

Error Propagation ◽

Placental Growth Factor ◽

Internal Quality ◽

Diagnosis And Prognosis ◽

Diagnosis By Exclusion ◽

Using Data ◽

Plgf Ratio

Abstract Objectives Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) assays and the corresponding ratios (sFlt-1/PlGF) have been proposed to aid in the diagnosis by exclusion and/or prognosis of preeclampsia (PE). A method for evaluating ratio uncertainties (RUs), based on the theory of error propagation, was applied to the sFlt-1/PlGF ratio. Methods RUs were calculated using data derived from sFlt-1 and PlGF Internal Quality Control (IQC) results collected from four centers using Elecsys (Roche) or Kryptor (Thermo Fisher) sFlt-1 and PlGF assays. The corresponding ratio uncertainties were defined for each ratio value. Results The RUs increased linearly with the sFlt-1/PlGF ratio values. The Elecsys RUs were lower than the Kryptor RUs. Although RUs cannot eliminate differences in ratio values observed among various immunoassays, it can affect interpretation of the sFlt-1/PlGF ratio, especially when results are within the range of predefined PE diagnosis or prognosis cut-offs. Conclusions Since RUs are only a function of PlGF and sFlt-1 precision, they can be calculated for each assay from each laboratory to adjust the interpretation of sFlt-1/PlGF ratio results in the context of PE.

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Maternal Serum Placental Growth Factor, Soluble Fms-Like Tyrosine Kinase-1, and Soluble Endoglin in Twin Gestations and the Risk of Preeclampsia—A Systematic Review

Journal of Clinical Medicine ◽

10.3390/jcm9010183 ◽

2020 ◽

Vol 9 (1) ◽

pp. 183 ◽

Cited By ~ 1

Author(s):

Katarzyna Kosinska-Kaczynska ◽

Magdalena Zgliczynska ◽

Szymon Kozlowski ◽

Lukasz Wicherek

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Serum Levels ◽

Maternal Serum ◽

Placental Growth Factor ◽

Cochrane Library ◽

Original Research ◽

Multiple Gestation ◽

Soluble Endoglin ◽

Twin Pregnancies

Multiple gestation is one of the key risk factors for the occurrence of preeclampsia (PE). Soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin are molecules involved in the process of angiogenesis with a proven role in the pathogenesis of PE. The aim of the review was to summarize available data on maternal serum levels of the above-mentioned factors and their usefulness in predicting PE in twin pregnancies. Only original research articles written in English were considered eligible. Reviews, chapters, case studies, conference papers, experts’ opinions, editorials, and letters were excluded from the analysis. No publication date limitations were imposed. The systematic literature search using PubMed/MEDLINE, Scopus, Embase, and Cochrane Library databases identified 338 articles, 10 of which were included in the final qualitative analyses. The included studies showed significant differences in maternal serum levels of the discussed factors between women with twin pregnancies with PE and those who did not develop PE, and their promising performance in predicting PE, alone or in combination with other factors. The identification of the most effective algorithms, their prompt introduction to the clinical practice, and further assessment of the real-life performance should become a priority.

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New Gestational Phase–Specific Cutoff Values for the Use of the Soluble fms-Like Tyrosine Kinase-1/Placental Growth Factor Ratio as a Diagnostic Test for Preeclampsia

Hypertension ◽

10.1161/hypertensionaha.113.01787 ◽

2014 ◽

Vol 63 (2) ◽

pp. 346-352 ◽

Cited By ~ 152

Author(s):

Stefan Verlohren ◽

Ignacio Herraiz ◽

Olav Lapaire ◽

Dietmar Schlembach ◽

Harald Zeisler ◽

...

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Diagnostic Test ◽

Placental Growth Factor ◽

Cutoff Values ◽

Factor Ratio

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Soluble fms-Like Tyrosine Kinase 1 Is Increased in Preeclampsia But Not in Normotensive Pregnancies with Small-for-Gestational-Age Neonates: Relationship to Circulating Placental Growth Factor

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1955 ◽

2005 ◽

Vol 90 (8) ◽

pp. 4895-4903 ◽

Cited By ~ 178

Author(s):

Eiji Shibata ◽

Augustine Rajakumar ◽

Robert W. Powers ◽

Robert W. Larkin ◽

Carol Gilmour ◽

...

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Gestational Age ◽

Small For Gestational Age ◽

Vascular Dysfunction ◽

Normal Pregnancy ◽

Maternal Serum ◽

Placental Growth Factor ◽

Gestational Age At Delivery ◽

Placental Protein

Context: An excess of the soluble receptor, fms-like tyrosine kinase 1 (sFlt-1) may contribute to maternal vascular dysfunction in women with preeclampsia by binding and thereby reducing concentrations of free vascular endothelial growth factor and placental growth factor (PlGF) in the circulation. The putative stimulus for increased sFlt-1 during preeclampsia, placental hypoxia due to poor perfusion, is common to both preeclampsia and idiopathic intrauterine growth restriction. However, the latter condition occurs without maternal vascular disease. Objective: We asked whether, as with preeclampsia, sFlt-1 is increased and free PlGF is decreased in villous placenta and maternal serum of normotensive women with small-for-gestational-age (SGA) neonates. Study Design: This was a case-control study using banked samples. Groups of women with SGA neonates (birth weight centile < 10th) and women with preeclampsia were matched to separate sets of normal pregnancy controls based on gestational age at blood sampling (serum) or gestational age at delivery (placenta). Results: sFlt-1 levels were higher in preeclamptics than controls (serum, P < 0.0001; placental protein, P = 0.03; placental mRNA, P = 0.007) but not increased in SGA pregnancies. PlGF was lower in both preeclampsia (serum, P < 0.0001; placental protein, P = 0.05) and SGA (serum, P = 0.0008; placental protein, P = 0.03) compared with their controls. PlGF in preeclampsia and SGA groups did not differ. Conclusions: These data are consistent with a role for sFlt-1 in the maternal manifestations of preeclampsia. In contrast to preeclampsia, sFlt-1 does not appear to contribute substantially to decreased circulating free PlGF in SGA pregnancies in the absence of a maternal syndrome.

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Letter: Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase-1 in Preeclampsia: A Novel Cut-Off Point?

Journal of Obstetrics and Gynaecology Canada ◽

10.1016/j.jogc.2020.11.014 ◽

2021 ◽

Vol 43 (4) ◽

pp. 435

Author(s):

Afshin Azimirad

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Placental Growth Factor

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Abstract 28: Omeprazole Administration To Women With Preterm Preeclampsia: Effects On Circulating Soluble Fms-like Tyrosine Kinase-1, Placental Growth Factor And Endothelin-1 Secretion.

Hypertension ◽

10.1161/hyp.78.suppl_1.28 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Rugina I Neuman ◽

Willy Visser ◽

Jan H Danser

Keyword(s):

Growth Factor ◽

Tyrosine Kinase ◽

Gestational Age ◽

Controlled Trial ◽

Placental Growth Factor ◽

Potential Treatment ◽

Perinatal Complications ◽

Longitudinal Course ◽

The Difference ◽

Circulating Levels

Low soluble Fms-like tyrosine kinase (sFlt-1) has been reported in women with suspected or confirmed preeclampsia (PE) coincidentally using proton pump inhibitors (PPIs), suggesting a role for these agents as potential treatment for PE. Here, we examined whether administration of omeprazole to women with PE could acutely reduce their circulating levels of sFlt-1 or enhance their placental growth factor (PlGF) concentrations. We performed a randomized controlled trial in which women (≥ 18 years) with confirmed preeclampsia and a gestational age between 20 +0 and 34 +6 weeks were allocated to receive 40mg omeprazole once daily or no omeprazole. Blood was collected at baseline and days 1,2,4,8 followed by twice-weekly until delivery. Primary outcome was specified as the difference in sFlt-1 or PlGF 4 days after omeprazole initiation compared to the non-omeprazole group. Secondary outcomes were defined as between-group differences in longitudinal course of sFlt-1 and PlGF and pregnancy outcomes. Between Dec 2018 and June 2021, 50 women with PE were randomized, of which 40 women remained pregnant after 4 days. Mean maternal age was 30 years, and median gestational age was 31 weeks. Baseline sFlt-1 levels did not differ between non-omeprazole (n=20) and omeprazole group (n=20) (10743 vs. 7110pg/mL, p=0.11), neither did the levels of PlGF (p=0.14). After 4 days, sFlt-1 levels remained similar in women receiving omeprazole compared to women not receiving omeprazole (8364 vs. 13017pg/mL, p=0.14), and the same was true for PlGF (90 vs. 55pg/mL, p=0.14). Using linear mixed models, no difference in longitudinal course of sFlt-1 or PlGF could be attributed to the treatment group, when adjusted for baseline values and GA at enrollment (p=0.47). Women receiving omeprazole had a similar length of pregnancy compared with those not receiving this drug (median 15 vs. 14 days, p=0.70). Except for a higher neonatal intubation rate in the non-omeprazole group (31% vs 4%, p=0.02) there were no differences in maternal/perinatal complications between the two groups. Our findings suggest that daily administration of 40mg in women with PE do not alter their circulating levels of sFlt-1 and PlGF, arguing against a role for this drug as a potential treatment for this syndrome.

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