Plasma and Urinary FGF-2 and VEGF-A Levels Identify Children at Risk for Severe Bleeding after Pediatric Cardiopulmonary Bypass: A Pilot Study.

Main Article Content

Anthony A. Sochet, MD, MSc Elizabeth A. Wilson, MD, MSHS Jharna R. Das, PhD John T. Berger, MD Patricio E Ray, MD

Abstract

Severe bleeding after cardiothoracic surgery with cardiopulmonary bypass (CPB) is associated with increased morbidity and mortality in adults and children. Fibroblast Growth Factor-2 (FGF-2) and Vascular Endothelial Growth Factor-A (VEGF-A) induce hemorrhage in murine models with heparin exposure. We aim to determine if plasma and urine levels of FGF-2 and VEGF-A in the immediate perioperative period can identify children with severe bleeding after CPB. We performed a prospective, observational biomarker study in 64 children undergoing CPB for congenital heart disease repair from June 2015 - January 2017 in a tertiary pediatric referral center. Primary outcome was severe bleeding defined as ≥ 20% estimated blood volume loss within 24-hours. Independent variables included perioperative plasma and urinary FGF-2 and VEGF-A levels. Analyses included comparative (Wilcoxon rank sum, Fisher’s exact, and Student’s t tests) and discriminative (receiver operator characteristic [ROC] curve) analyses.


Forty-eight (75%) children developed severe bleeding. Median plasma and urinary FGF-2 and VEGF-A levels were elevated in children with severe bleeding compared to without bleeding (preoperative: plasma FGF-2 = 16[10-35] vs. 9[2-13] pg/ml; urine FGF-2= 28[15-76] vs. 14.5[1.5-22] pg/mg; postoperative: plasma VEGF-A = 146[34-379] vs. 53[0-134] pg/ml; urine VEGF-A = 132[52-257] vs. 45[0.1-144] pg/mg; all p < 0.05). ROC curve analyses of combined plasma and urinary FGF-2 and VEGF-A levels discriminated severe postoperative bleeding (AUC: 0.73-0.77) with mean sensitivity and specificity above 80%.  We conclude that the perioperative plasma and urinary levels of FGF-2 and VEGF-A discriminate risk of severe bleeding after pediatric CPB.

Keywords: Cardiopulmonary bypass surgery, heparin, Fibroblast Growth Factor 2, bleeding

Article Details

How to Cite
SOCHET, Anthony A. et al. Plasma and Urinary FGF-2 and VEGF-A Levels Identify Children at Risk for Severe Bleeding after Pediatric Cardiopulmonary Bypass: A Pilot Study.. Medical Research Archives, [S.l.], v. 8, n. 6, june 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2134>. Date accessed: 16 apr. 2024. doi: https://doi.org/10.18103/mra.v8i6.2134.
Section
Research Articles

References

1. Despotis G, Avidan M, Eby C. Prediction and management of bleeding in cardiac surgery. J Thromb Haemost. 2009;7 Suppl 1:111-117.
2. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood. 1990;76(9):1680-1697.
3. Guay J, Rivard GE. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg. 1996;62(6):1955-1960.
4. Despotis G, Eby C, Lublin DM. A review of transfusion risks and optimal management of perioperative bleeding with cardiac surgery. Transfusion. 2008;48(1 Suppl):2S-30S.
5. Butler J, Rocker GM, Westaby S. Inflammatory response to cardiopulmonary bypass. Ann Thorac Surg. 1993;55(2):552-559.
6. Kilbridge PM, Mayer JE, Newburger JW, et al. Induction of intercellular adhesion molecule-1 and E-selectin mRNA in heart and skeletal muscle of pediatric patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1994;107(5):1183-1192.
7. Wilson I, Gillinov AM, Curtis WE, et al. Inhibition of neutrophil adherence improves postischemic ventricular performance of the neonatal heart. Circulation. 1993;88(5 Pt 2):II372-379.
8. Gospodarowicz D, Ferrara N, Schweigerer L, et al. Structural characterization and biological functions of fibroblast growth factor. Endocr Rev. 1987;8(2):95-114.
9. Klagsbrun M, D'Amore PA. Vascular endothelial growth factor and its receptors. Cytokine Growth Factor Rev. 1996;7(3):259-270.
10. Andres G, Leali D, Mitola S, et al. A pro-inflammatory signature mediates FGF2-induced angiogenesis. J Cell Mol Med. 2009;13(8B):2083-2108.
11. Ray P, Acheson D, Chitrakar R, et al. Basic fibroblast growth factor among children with diarrhea-associated hemolytic uremic syndrome. J Am Soc Nephrol. 2002;13(3):699-707.
12. Jerebtsova M, Wong E, Przygodzki R, et al. A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice. Am J Physiol Heart Circ Physiol. 2007;292(2):H743-750.
13. Jerebtsova M, Das JR, Tang P, et al. Angiopoietin-1 prevents severe bleeding complications induced by heparin-like drugs and fibroblast growth factor-2 in mice. Am J Physiol Heart Circ Physiol. 2015;309(8):H1314-1325.
14. Ray PE, Liu XH, Xu L, et al. Basic fibroblast growth factor in HIV-associated hemolytic uremic syndrome. Pediatr Nephrol. 1999;13(7):586-593.
15. Starnes SL, Duncan BW, Kneebone JM, et al. Vascular endothelial growth factor and basic fibroblast growth factor in children with cyanotic congenital heart disease. J Thorac Cardiovasc Surg. 2000;119(3):534-539.
16. Eliceiri BP, Paul R, Schwartzberg PL, et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell. 1999;4(6):915-924.
17. Ferrara N, Bunting S. Vascular endothelial growth factor, a specific regulator of angiogenesis. Curr Opin Nephrol Hypertens. 1996;5(1):35-44.
18. Tassi E, Lai EY, Li L, et al. Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor-Binding Protein). Hypertension. 2018;71(1):160-167.
19. Granger JP. Vascular endothelial growth factor inhibitors and hypertension: a central role for the kidney and endothelial factors? Hypertension. 2009;54(3):465-467.
20. McBride WT, Armstrong MA, Crockard AD, et al. Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits. Br J Anaesth. 1995;75(6):724-733.
21. Himeno W, Akagi T, Furui J, et al. Increased angiogenic growth factor in cyanotic congenital heart disease. Pediatr Cardiol. 2003;24(2):127-132.
22. Seghaye MC, Grabitz RG, Duchateau J, et al. Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations. J Thorac Cardiovasc Surg. 1996;112(3):687-697.
23. Dirix LY, Vermeulen PB, Pawinski A, et al. Elevated levels of the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in sera of cancer patients. Br J Cancer. 1997;76(2):238-243.
24. Baghdady Y, Hussein Y, Shehata M. Vascular endothelial growth factor in children with cyanotic and acyanotic and congenital heart disease. Arch Med Sci. 2010;6(2):221-225.
25. Brogi E, Wu T, Namiki A, et al. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation. 1994;90(2):649-652.
26. Abrahamov D, Erez E, Tamariz M, et al. Plasma vascular endothelial growth factor level is a predictor of the severity of postoperative capillary leak syndrome in neonates undergoing cardiopulmonary bypass. Pediatr Surg Int. 2002;18(1):54-59.
27. Giuliano JS, Jr., Lahni PM, Bigham MT, et al. Plasma angiopoietin-2 levels increase in children following cardiopulmonary bypass. Intensive Care Med. 2008;34(10):1851-1857.
28. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12(2):235-239.
29. Parikh SM, Mammoto T, Schultz A, et al. Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med. 2006;3(3):e46.
30. Roviezzo F, Tsigkos S, Kotanidou A, et al. Angiopoietin-2 causes inflammation in vivo by promoting vascular leakage. J Pharmacol Exp Ther. 2005;314(2):738-744.
31. Koning NJ, Overmars MA, van den Brom CE, et al. Endothelial hyperpermeability after cardiac surgery with cardiopulmonary bypass as assessed using an in vitro bioassay for endothelial barrier function. Br J Anaesth. 2016;116(2):223-232.
32. Pierce RW, Zahr RA, Kandil S, et al. Sera From Children After Cardiopulmonary Bypass Reduces Permeability of Capillary Endothelial Cell Barriers. Pediatr Crit Care Med. 2018;19(7):609-618.
33. Das JR, Gutkind JS, Ray PE. Circulating Fibroblast Growth Factor-2, HIV-Tat, and Vascular Endothelial Cell Growth Factor-A in HIV-Infected Children with Renal Disease Activate Rho-A and Src in Cultured Renal Endothelial Cells. PLoS One. 2016;11(4):e0153837.
34. Whalen GF, Shing Y, Folkman J. The fate of intravenously administered bFGF and the effect of heparin. Growth Factors. 1989;1(2):157-164.
35. Wai K, Soler-Garcia AA, Perazzo S, et al. A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children. Pediatr Nephrol. 2013;28(11):2189-2198.
36. Nellis ME, Tucci M, Lacroix J, et al. Bleeding Assessment Scale in Critically Ill Children (BASIC): Physician-Driven Diagnostic Criteria for Bleeding Severity. Crit Care Med. 2019;47(12):1766-1772.
37. Karam O, Nellis ME, Zantek ND, et al. Criteria for Clinically Relevant Bleeding in Critically Ill Children: An International Survey. Pediatr Crit Care Med. 2019;20(3):e137-e144.
38. Soler-Garcia AA, Rakhmanina NY, Mattison PC, et al. A urinary biomarker profile for children with HIV-associated renal diseases. Kidney Int. 2009;76(2):207-214.
39. Lex DJ, Toth R, Cserep Z, et al. A comparison of the systems for the identification of postoperative acute kidney injury in pediatric cardiac patients. Ann Thorac Surg. 2014;97(1):202-210.
40. Gupta C, Massaro AN, Ray PE. A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy. Pediatr Nephrol. 2016;31(7):1167-1178.