The Promise of Angiogenic Markers for the Early Diagnosis and Prediction of Preeclampsia

Renal Division, Department of Medicine and Centre for Molecular Medicine, University of Cologne, Cologne, Germany.
Clinical Chemistry (Impact Factor: 7.91). 03/2012; 58(5):837-45. DOI: 10.1373/clinchem.2011.169094
Source: PubMed


An imbalance in circulating factors that regulate blood vessel formation and health, referred to as angiogenic factors, plays a central role in the pathogenesis of preeclampsia.
Several studies have demonstrated a strong association between altered circulating angiogenic factors and preeclampsia. These factors include circulating antiangiogenic proteins such as soluble fms-like tyrosine kinase 1 and soluble endoglin and proangiogenic protein such as placental growth factor. Abnormalities in these circulating angiogenic factors are not only present during clinical disease, but also antedate clinical signs and symptoms by several weeks. These alterations are particularly prominent in patients who present with preeclamptic signs and symptoms prematurely and/or in patients with severe preeclampsia. The availability of automated platforms for the rapid measurement of circulating angiogenic proteins in blood samples has now allowed researchers and clinicians to evaluate the utility of these assays in the diagnosis of the disease, in the stratification of patients in clinical trials, or in the monitoring of therapies. In this review we highlight the various studies that have been performed, with a focus on large validation studies.
Measurement of circulating angiogenic proteins for the diagnosis and prediction of preeclampsia is still at an early stage but is rapidly evolving. Standardization across the various automated platforms and prospective studies that demonstrate clinical utility are needed.

19 Reads
  • Source
    • "Early termination of pregnancy is one of the main treatments for the patients with severe preeclampsia (Haddad et al. 2010). The efficient diagnosis and prediction method for preeclampsia is still unavailable (Hagmann et al. 2012). The high efficient and safe way for precise diagnosis of preeclampsia is needed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preeclampsia is a pregnancy-specific disorder characterized by hypertension and proteinuria, but the exact cause of preeclamptic hypertension remains unknown. ATP-binding cassette subfamily A member 1 (ABCA1) reverses cholesterol transport and eliminates excess cholesterol from tissues, whereas higher levels of cholesterol may lead to hypertension. Thus, ABCA1 affects the blood lipid profile. We have hypothesized that serum ABCA1 levels may influence the onset of hypertension and increase the risk of preeclampsia. To test this hypothesis, we measured serum ABCA1 levels in 50 normal pregnancies, 36 preeclamptic pregnancies, and 24 small-for-gestational-age (SGA) pregnancies during three trimesters. We also measured the concentrations of serum ABCA1 in non-pregnant women (n = 60), showing its normal ranges of 0.16 to 0.52 ng/ml. Importantly, the serum levels of ABCA1 were similar among non-pregnant women, normal pregnancies and SGA pregnancies. In contrast, the serum ABCA1 levels were significantly lower in preeclamptic pregnancies (0.06 ± 0.03 ng/ml) than those in non-pregnant women, and normal and SGA pregnancies (P < 0.05). Low serum ABCA1 levels were associated with the increases in the concentrations of blood lipid (low density lipoprotein cholesterol, total cholesterol and triglycerides) and with the decrease in the concentration of high-density lipoprotein cholesterol (P < 0.01), all of which may contribute to the onset of hypertension and eventually preeclampsia. Moreover, the preeclamptic pregnancy was diagnosed with high sensitivity from the nulliparous pregnancies if the cutoff value for serum ABCA1 was 0.06 ng/ml. Thus, low serum levels of ABCA1 are predictive of preeclampsia.
    The Tohoku Journal of Experimental Medicine 05/2015; 236(2):89-95. DOI:10.1620/tjem.236.89 · 1.35 Impact Factor
  • Source
    • "PE complicates up to 10% of all pregnancies and is a leading worldwide cause of maternal – fetal morbidity and mortality [11 – 14] . Maternal serum markers that predict the subsequent development of PE include elevated levels of angiogenesis mediators such as endoglin and sFlt-1 in the 2 nd or 3 rd trimester [15] . The disorder has long been associated with evidence of both maternal and uteroplacental inflammation including elevated levels of inflammatory cytokines in maternal serum and in the decidua. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Higher 1 st trimester maternal serum levels of interferon-induced protein 10 (IP-10) and interferon inducible T-cell alpha chemoattractant (ITAC) are reported in gestations complicated with preeclampsia. However, parallel results in the fetal circulation are lacking. Objective: To compare IP-10 and ITAC levels in neonatal cord blood from gestations complicated by severe preeclampsia vs. gestational age-matched controls. Method: Umbilical cord vessels were sampled following delivery of women with severe preeclampsia (n = 30) ≥ 36 weeks to measure plasma IP-10 and ITAC levels and compared to corresponding controls matched for parity as well as maternal and gestational age. Chemokines were measured by specific ELISAs and expressed as pg/mL. Rho Spearman ’ s coefficients were calculated to establish correlations between chemokine values and various numeric variables. Results: Preeclamptic cases displayed significantly lower median plasma umbilical artery and vein levels of both chemokines when compared to controls (IP-10: 23.4 vs. 31.4 and 2.0 vs. 24.6 pg/mL, P < 0.05; and ITAC: 2.0 vs. 13.9 and 11.9 vs. 31.6 pg/mL, P < 0.05, in artery and vein, respectively). There was a significant correlation between levels of both chemokines (r 2 = 0.616, P = 0.0001), but not with other variables. Conclusion: In contrast to elevated 1 st trimester levels of IP-10 previously found in the maternal serum of women who later developed preeclampsia, this study found lower umbilical cord IP-10 and ITAC plasma levels in near-term gestations with established severe preeclampsia.
    Journal of Perinatal Medicine 05/2015; DOI:10.1515/jpm-2014-0371 · 1.36 Impact Factor
  • Source
    • "Measurements of circulating angiogenic factors such as sFlt-1 and PlGF are rapidly evolving as tests for aid in diagnosis of preeclampsia [6]. There is a large body of evidence that these biomarkers may help not only in the early diagnosis of preeclampsia, but also help with prediction of adverse maternal and fetal outcomes [4], [5], [9], [34]–[39]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.
    PLoS ONE 01/2014; 9(1):e85258. DOI:10.1371/journal.pone.0085258 · 3.23 Impact Factor
Show more