Main Article Content
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.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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.