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Ann Thorac Surg 2004;78:1884-1885
© 2004 The Society of Thoracic Surgeons

Correspondence

Pitfalls in the Measurement of Serum VEGF in Children With Congenital Heart Disease

Elisa Arena, MD

Di.S.C.A.T.University of GenoaLargo R. Benzi 816132 Genoa, Italy

Simone Ferrero, MD

Department of Obstetrics and Gynaecology, San Martino Hospital, University of Genoa, Largo R. Benzi 1, 16132 Genoa, Italy

elisaarena{at}hotmail.com
simone.ferrero{at}fastwebnet.it

To the Editor:

We read the article by Ootaki and colleagues [1] with interest. We bring to your attention some methodological concerns that might have caused relevant bias in the conclusion. The concentrations of vascular endothelial growth factor (VEGF) were measured in serum samples, but there has been no validation of serum VEGF as an indicator of the extracellular circulating VEGF levels at the time of sampling. Vascular endothelial growth factor is stored in circulating platelets and is released during clotting. Therefore, serum VEGF concentrations may reflect blood platelet degranulation in vitro rather than VEGF synthesis by peripheral tissues [2–4]. Small differences in the circulating extracellular VEGF concentration between the children with abnormal vessels and those without these vessels may have been masked by the measurement of VEGF released from the platelets. Moreover, even if a uniformity of clotting time was applied to all samples, the interpersonal variation in generation of VEGF in clotted samples could make the interpretation of any observed difference between diseased and control groups very difficult and could invalidate the results [4]. Citrated, EDTA (ethylene diamine tetraacetic acid)–treated, or heparinized plasma processed in glass tubes is the material of choice for the measurement of circulating VEGF. In plasma, platelet degranulation is minimized by adding anticoagulants to the blood samples, and as a consequence, plasma VEGF concentrations are up to 20 times lower than the matched serum VEGF concentrations [3].

Ootaki and co-workers reported increased serum VEGF levels in patients with asplenia syndrome. It is well known that congenital absence of the spleen can be associated with thrombocytosis. Platelet count was not reported in the study; we believe that thrombocytosis could justify the increased level of serum VEGF in the subgroup of patients with asplenia syndrome. When serum is used for VEGF measurement, it is advisable to correct the measurements to platelet count [5].

In light of these considerations, the authors' conclusion that there is "no significant relationship in VEGF levels between the patients with abnormal vessels and without these vessels" cannot be justified on the basis of the data presented. The study of plasma VEGF levels could allow more meaningful results to be obtained.

References

  1. Ootaki Y, Yamaguchi M, Yoshimura N, Oka S, Yoshida M, Hasegawa T. Vascular endothelial growth factor in children with congenital heart disease. Ann Thorac Surg. 2003;75:1523–1526[Abstract/Free Full Text]
  2. Verheul HM, Hoekman K, Luykx-de Bakker S, et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res. 1997;3(12 pt 1):2187–2190[Abstract/Free Full Text]
  3. Banks RE, Forbes MA, Kinsey SE, et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer. 1998;77:956–964[Medline]
  4. Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci (Lond). 1998;94:395–404[Medline]
  5. Hormbrey E, Gillespie P, Turner K, et al. A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful? Clin Exp Metastasis. 2002;19:651–663[Medline]




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