Protein Biomarkers Herald Onset of Preeclampsia

BETHESDA, Md., Sept. 7 -- Abnormally high circulating levels of two proteins produced by the placenta may be responsible for the development of preeclampsia, researchers reported.

Circulating soluble endoglin levels increased markedly as did soluble fms-like tyrosine kinase 1 (sFlt1) beginning two to three months before the onset of clinical disease, a finding that might prove helpful in predicting the development of preeclampsia, the investigators reported in the Sept. 7 issue of the New England Journal of Medicine.

Endoglin, highly expressed on cell membranes of vascular endothelium, is up-regulated in preeclampsia, releasing soluble endoglin, an antiangiogenic protein, into the maternal circulation, said Richard Levine, M.D., of the National Institute of Child Health and Human Development here, and S. Ananth Karumanchi, M.D., of Beth Israel Deaconess Medical Center in Boston, and colleagues.

The other antiangiogenic protein, sFlt1, which sequesters proangiogenic placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), also increases before the onset of clinical disease in the circulation of women with preeclampsia, the researchers added.

These findings, along with rodent studies, suggest that these two protein biomarkers, each of which causes endothelial dysfunction by a different mechanism, may contribute to preeclampsia. Prospective longitudinal studies are needed to assess whether these biomarkers can predict the imminent onset of clinical disease, the researchers concluded.

Possible treatments, Dr. Levine said, might involve reducing levels of these two antiangiogenic factors or adding more of the molecules they remove from the bloodstream. However, he cautioned, attempts to develop a drug treatment would need to proceed cautiously. It is possible, he said, that restoring normal blood pressure and blood flow to the mother's circulatory system might deprive the fetus of blood.

In a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial, there were 72 women who had preterm preeclampsia (less than 37 weeks). Others in the study included 480 randomly selected women: 120 women with preeclampsia at term (37 weeks or less), 120 women with gestational hypertension, 120 normotensive women who delivered infants small for gestational age, and 120 normotensive controls who delivered infants who were not small.

Circulating soluble endoglin levels increased markedly beginning two to three months before the onset of clinical disease, at which point the mean serum level in women with preterm preeclampsia was 46.4 ng/ml compared with 9.8 ng/ ml in the controls (P

Both soluble endoglin and the altered sFlt1:PlGF ratio appear to contribute to the development of preeclampsia, Dr. Levine said. The risk of preeclampsia was greatest among women in the highest quartile of the distribution for both biomarkers, but not for either biomarker alone, he added.

The prevailing theory, Dr. Levine said, is that when the placenta cannot absorb sufficient oxygen from the mother's blood, it secretes these two biomarkers into the mother's blood stream. The sFlt1 binds to vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), while soluble endoglin binds transforming growth factor beta (TGF beta,) diverting the compound from the mother's blood vessels. In response the mother's blood pressure rises, forcing more blood to the placenta.

Elevations in soluble endoglin were particularly pronounced, Dr. Levine said, and therefore would potentially be most useful for prediction of preeclampsia. In women with term preeclampsia, soluble endoglin levels were significantly higher beginning about three months before hypertension or proteinuria developed, whereas the sFlt1:PlGF ratio rose much closer to the onset of clinical disease.

Women who had a small-for-gestational-age infant had an early, sustained elevation in soluble endoglin, but without an increase in the ratio, the researchers noted.

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Drs. Maynard and Karumanchi reported being named coinventors on multiple provisional patents that have been filed by Beth Israel Deaconess Medical Center for the diagnosis and treatment of preeclampsia. These patents have been nonexclusively licensed to several companies. Dr. Karumanchi reported having served as a consultant to Abbott, Beckman Coulter, and Johnson & Johnson.

Among the co-authors, Dr. Ravi Thadhani reported being named a coinventor on a provisional patent for the role of sex hormone-binding globulin and PlGF for the prediction of preeclampsia that has been licensed to several companies and having served as a consultant to Abbott, Beckman Coulter, and Johnson & Johnson. Dr. Benjamin Sachs reported having served as a consultant to Johnson & Johnson.

In an editorial in the same NEJM issue Marshall Lindheimer, M.D., of the University of Chicago and Jason Umans, M.D., Ph.D., of Georgetown University in Washington, had some reservations about the study but described the findings as "exciting, since they direct the next critical steps in the research of preeclampsia-prospective observational studies-and research toward prevention and treatment."

The writers' reservations had to do with the retrospective nature of the study (similar to most of the related literature). The results, they said, came from samples stored for about 10 years, and there is little information about the sample stability and assay validation. Some might question the arbitrary post hoc breakdown of the analysis according to quartiles, and the conclusions on causality seem ambitious, they said, noting that correlation is weak evidence for causality.

There are still unknowns to be pursued, they wrote. For example, why is sFlt1 upregulated in the placentas of women with preeclampsia, and what is the mechanism behind the increased generation of soluble endoglin? Nevertheless, they concluded, "we can now confidently state that a disorder once considered a mysterious disease is sufficiently understood to permit mechanistically rational studies of its prediction, diagnosis, prevention, and treatment."