Study demonstrates altered angiogenic proteins in preeclampsia patients

02/03/04

BOSTON -- The discovery that a protein "marker" is sharply elevated approximately five weeks prior to the onset of preeclampsia could provide a warning sign to help doctors in diagnosing this potentially life-threatening complication of pregnancy. Led by researchers at Beth Israel Deaconess Medical Center (BIDMC) and the National Institute of Child Health and Development (NICHD), the study appears in the February 12 issue of The New England Journal of Medicine.

Preeclampsia typically develops after the 20th week of pregnancy and is characterized by high blood pressure, edema and protein in the urine. However, in severe cases, it can without warning rapidly escalate to eclampsia, a condition in which the mother suffers serious and potentially fatal seizures. There are currently no blood tests available to help physicians diagnose these patients prior to the onset of clinical symptoms.

"Our new findings might allow doctors to closely monitor these high-risk patients and identify preeclampsia at an earlier stage," explains co-senior author S. Ananth Karumanchi, MD, of the Renal Division at BIDMC and Assistant Professor of Medicine at Harvard Medical School (HMS). Also known as toxemia, preeclampsia occurs in an estimated five percent of all pregnancies, and affects approximately 200,000 women in the U.S. each year. Worldwide, it is one of the leading causes of maternal and infant mortality.

Last year, Karumanchi and colleagues identified the source of the disease as being a protein known as soluble fms-like tyrosine kinase 1 (sFlt1). Released by the mother's placenta, sFlt1 is believed to trigger the symptoms of preeclampsia when it binds to and "mops up" another group of proteins placental growth factor (PGF) and vascular endothelial growth factor (VEGF). PGF and VEGF exist to promote angiogenesis, the growth of small blood vessels.

"What appears to be happening [in cases of preeclampsia] is that blood vessels to the placenta become narrowed, which impedes the flow of blood and oxygen to the fetus," explains Karumanchi. This, he adds, apparently sets in motion the progression of potentially fatal complications involving the mother's liver, kidneys, lungs, blood and nervous system.

In this new study, the authors analyzed blood samples of pregnant women to determine if sFlt1 levels were indeed elevated among preeclampsia patients. The archived specimens were obtained in collaboration with Richard Levine, MD, the principal investigator of the Calcium for Preeclampsia Prevention Trial, a large cohort study based at the National Institute of Child Health and Development.

"Out of a collection of blood specimens from 12,000 pregnant women, we obtained 120 random samples from patients who had gone on to develop preeclampsia, as well as 120 control samples of patients who had healthy pregnancies," notes Karumanchi. "These consisted of three specimens per patient, taken at early-, mid-, and late-stages of pregnancy."

Analysis of the specimens confirmed the authors' hypothesis: Among patients who went on to develop preeclampsia, levels of sFlt1 rose sharply about five weeks prior to the onset of symptoms. At the same time, as predicted, PGF levels dropped.

"It seems that preeclampsia is actually an exacerbation of an angiogenic state that has been noted at term in normal pregnancies," explains Karumanchi. "The angiogenic 'brakes' are being applied too hard and too soon, resulting in an exaggeration of the normal process governing placental growth and function, and leading to poor outcomes for mother and infant."

Notes Benjamin P. Sachs, MBBS, DPH, Chairman of the Department of Obstetrics and Gynecology at BIDMC and an investigator on the study, "The hope we have is that intensive surveillance of women known to be at high risk for developing preeclampsia might allow us to predict who will go on to actually develop the condition. Although no therapy currently exists for the treatment of the disease, such advance knowledge could provide patients and their doctors with important information."

Down the road, the contemplated treatment would be through administration of drug therapies that neutralize the effects of sFlt1, explains coinvestigator Vikas P. Sukhatme, MD, PhD, Chief of the Renal Division at BIDMC and Victor Aresty Professor of Medicine at HMS. "One such approach might be to administer VEGF or PGF," he adds.

In a related study appearing in the February issue of The Journal of Clinical Endocrinology and Metabolism, it was shown that measurements of PGF, taken as early as 10 to 12 weeks of pregnancy, appear to be a specific marker for preeclampsia and no other adverse outcomes of pregnancy. This investigation was led by Massachusetts General Hospital investigator Ravi Thadhani, MD, MPH, in conjunction with Karumanchi. A coauthor of the NEJM paper, Thadhani is also an assistant professor of medicine at HMS.

BIDMC has filed patents on methods of diagnosing and treating preeclampsia.

In addition to Karumanchi, Sachs and Sukhatme, study coauthors include BIDMC researchers Sharon E. Maynard, MD, Franklin H. Epstein, MD, and Kee-Hak Lim, MD; Richard J. Levine, MD, MPH, Lucinda J. England, MD, MSPH, Kai F. Yu, PhD, and Enrique F. Schisterman, PhD, of the National Institute of Child Health and Development; Cong Qian, MS, of the Allied Technology Group, Rockville, Md.; Ravi Thadhani, MD, MPH, of Massachusetts General Hospital; and Baha M. Sibai, MD, of the University of Cincinnati College of Medicine.

Source: Eurekalert & others

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