Circulating Angiogenic Factors and Preeclampsia
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《新英格兰医药杂志》
To the Editor: Levine et al. (Feb. 12 issue)1 have shown that increased levels of soluble fms-like tyrosine 1 (sFlt-1) and reduced levels of placental growth factor (PlGF) predict the development of preeclampsia, a few weeks before the onset of clinical symptoms. Circulating angiogenic factors produced by the placenta could therefore be used to predict preeclampsia. Since vascular endothelial growth factor (VEGF) levels did not differ significantly between the controls and the women who later had preeclampsia, attention has been focused on PlGF and sFlt-1 modifications. However, differences in free VEGF concentrations might have been underestimated because measurements were performed in serum samples, not in plasma samples.2 Serum samples do not reflect the placental production of VEGF, since they are "contaminated" by the release of VEGF from platelets and other blood cells during clotting, and it has been recommended that free VEGF be measured in plasma samples.3 We agree that prospective longitudinal studies are needed to assess the relevance of these markers (sFlt-1 and PlGF) for the prediction of preeclampsia. Such studies should also include VEGF measurements in maternal plasma.
Vassilis Tsatsaris, M.D.
H?pital Cochin
75014 Paris, France
vassilis.tsatsaris@cch.ap-hop-paris.fr
Frederic Goffin, M.D., Ph.D.
Jean Michel Foidart, M.D., Ph.D.
H?pital de la Citadelle
1030 Liege, Belgium
References
Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-683.
Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003;88:5555-5563.
Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem 2001;47:617-623.
The authors reply: We thank Dr. Tsatsaris and colleagues for pointing out that low free VEGF concentrations may have the potential to predict preeclampsia. We agree that measurements in serum, rather than plasma, may have reduced our ability to discriminate between women who subsequently had preeclampsia and those who did not. Perhaps even more important is the fact that the minimal detectable VEGF concentration with the immunoassay we used (R&D Systems) was about 5 pg per milliliter — not much lower than the mean serum concentration during clinical preeclampsia in the women in our study (6.4 pg per milliliter). It is likely that plasma VEGF concentrations are even lower, since the contribution from platelets is not included. In fact, Tsatsaris et al.1 reported that in their study, free VEGF was not detectable in most maternal plasma specimens, and we have been unable to detect free VEGF in fresh plasma obtained during preeclampsia (unpublished data). Regardless of whether plasma or serum is used, an assay must have a sensitivity of 1 pg or less of free VEGF per milliliter to be clinically useful. Unless such an assay is developed, it will be impossible to determine whether measurements of VEGF in plasma may be better than serum measurements for the prediction of preeclampsia.
Richard J. Levine, M.D., M.P.H.
National Institute of Child Health and Human Development
Bethesda, MD 20892
levinerj@mail.nih.gov
S. Ananth Karumanchi, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
sananth@bidmc.harvard.edu
References
Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003;88:5555-5563.
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H?pital Cochin
75014 Paris, France
vassilis.tsatsaris@cch.ap-hop-paris.fr
Frederic Goffin, M.D., Ph.D.
Jean Michel Foidart, M.D., Ph.D.
H?pital de la Citadelle
1030 Liege, Belgium
References
Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004;350:672-683.
Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003;88:5555-5563.
Jelkmann W. Pitfalls in the measurement of circulating vascular endothelial growth factor. Clin Chem 2001;47:617-623.
The authors reply: We thank Dr. Tsatsaris and colleagues for pointing out that low free VEGF concentrations may have the potential to predict preeclampsia. We agree that measurements in serum, rather than plasma, may have reduced our ability to discriminate between women who subsequently had preeclampsia and those who did not. Perhaps even more important is the fact that the minimal detectable VEGF concentration with the immunoassay we used (R&D Systems) was about 5 pg per milliliter — not much lower than the mean serum concentration during clinical preeclampsia in the women in our study (6.4 pg per milliliter). It is likely that plasma VEGF concentrations are even lower, since the contribution from platelets is not included. In fact, Tsatsaris et al.1 reported that in their study, free VEGF was not detectable in most maternal plasma specimens, and we have been unable to detect free VEGF in fresh plasma obtained during preeclampsia (unpublished data). Regardless of whether plasma or serum is used, an assay must have a sensitivity of 1 pg or less of free VEGF per milliliter to be clinically useful. Unless such an assay is developed, it will be impossible to determine whether measurements of VEGF in plasma may be better than serum measurements for the prediction of preeclampsia.
Richard J. Levine, M.D., M.P.H.
National Institute of Child Health and Human Development
Bethesda, MD 20892
levinerj@mail.nih.gov
S. Ananth Karumanchi, M.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
sananth@bidmc.harvard.edu
References
Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab 2003;88:5555-5563.