Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • State of the Art
  • Published:

State-of-the-Art

Hematologic Abnormalities in Severe Neonatal Necrotizing Enterocolitis: 25 Years Later

Journal of Perinatology volume 23, pages 523–530 (2003)Cite this article

Abstract

Necrotizing enterocolitis (NEC), the most common surgical emergency in newborns, remains a therapeutic challenge for clinicians. The hematological manifestations associated with NEC were first described 25 years ago. This review discusses current knowledge of the pathophysiology involved in disturbances in megakaryocytopoiesis, coagulation, leukopoiesis, and erythropoiesis that accompany the clinical entity NEC. The discussion includes current understanding of and potential strategies for treating the hematopoietic disturbances that occur secondary to NEC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Kliegman RM . Models of the pathogenesis of necrotizing enterocolitis. J Pediatr 1990;117:S2–S5.

    Article  CAS  Google Scholar 

  2. Kosloske AM . A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis. J Pediatr 1990;117:S68–S74.

    Article  CAS  Google Scholar 

  3. Hutter JJ, Hathaway WE, Wayne ER . Hematologic abnormalities in severe neonatal necrotizing enterocolitis. J Pediatr 1976;88:1026–1031.

    Article  Google Scholar 

  4. Patel C . Hematologic abnormalities in acute necrotizing enterocolitis. Pediatr Clin N Am 1977;24:579–584.

    Article  CAS  Google Scholar 

  5. Mehta P, Vasa R, Neumann L, Karpatkin M . Thrombocytopenia in the high-risk infant. J Pediatr 1980;97:791–794.

    Article  CAS  Google Scholar 

  6. Sola M, Vecchio A, Rimsza L . Evaluation and treatment of thrombocytopenia in the neonatal intensive care unit. Neonatal Hematol 2000;27:655–679.

    CAS  Google Scholar 

  7. Aronis S, Platokouki H, Photopoulos S, Eftychia A, Xanthou M . Indications of coagulation and/or fibrinolytic systems activation in healthy and sick very low birth weight neonates. Biol Neonate 1998;74:337–344.

    Article  CAS  Google Scholar 

  8. Manco-Johnson M, Nuss R . Hemostasis in neonates. Neoreviews 2000;1:e191–e195.

    Article  Google Scholar 

  9. Caplan M, Sun X, Hsueh W . Hypoxia causes ischemic bowel necrosis in rats: the role of platelet-activating factor (PAF-Acether). Gastroenterology 1990;99:979–986.

    Article  CAS  Google Scholar 

  10. Caplan M, Kelly A, Hsueh W . Endotoxin and hypoxia-induced intestinal necrosis in rats: the role of platelet activating factor. Pediatr Res 1992;31:428–434.

    Article  CAS  Google Scholar 

  11. Caplan M, Lickerman M, Adler L, Dietsch G, Yu A . The role of recombinant platelet-activating factor acetylhydrolase in a neonatal rat model of necrotizing enterocolitis. Pediatr Res 1997;42:779–783.

    Article  CAS  Google Scholar 

  12. Muguruma K, Gray PW, Tjoelker LW, Johnston JM . The central role of PAF in necrotizing enterocolitis development. Eicosanoids and Other Bioactive Lipids in Cancer Inflammation and Radiation Injury 1997;3:379–382.

    Article  Google Scholar 

  13. Rabinowitz SS, Dzakpasu P, Piecuch S, Leblanc P, Valencia G, Kornecki E . Platelet-activating factor in infants at risk for necrotizing enterocolitis. J Pediatr 2001;138:81–86.

    Article  CAS  Google Scholar 

  14. Furukawa M, Narahara H, Yasuda K, Johnston J . Presence of platelet-activating factor-acetylhydrolase in milk. J Lipid Res 1993;34:1603–1609.

    CAS  PubMed  Google Scholar 

  15. Lucas A, Cole T . Breast milk and neonatal necrotising enterocolitis. Lancet 1990;336:1519–1523.

    Article  CAS  Google Scholar 

  16. Stohlawetz P, Folman C, Borne A et al. Effects of endotoxemia on thrombopoiesis in men. Thromb Haemost 1999;81:613–617.

    CAS  PubMed  Google Scholar 

  17. Nakashima K, Taga T . gp130 and the IL-6 family of cytokines: signaling mechanisms and thrombopoietic activities. Semin Hematol 1998;35:210–211.

    CAS  PubMed  Google Scholar 

  18. Bruno E, Briddell RA, Cooper RJ, Hoffman R . Effects of recombinant interleukin 11 on human megakaryocyte progenitor cells. Exp Hematol 1991;19:378–381.

    CAS  PubMed  Google Scholar 

  19. Harris MC, Costarino AT, Sullivan JS et al. Cytokine elevations in critically ill infants with sepsis and necrotizing enterocolitis. J Pediatr 1994;124:105–111.

    Article  CAS  Google Scholar 

  20. Ledbetter DJ, Juul SE . Erythropoietin and the incidence of necrotizing enterocolitis in infants with very low birth weight. J Pediatr Surg 2000;35:178–182.

    Article  CAS  Google Scholar 

  21. Du X, Liu Q, Yang Z et al. Protective effects of interleukin-11 in a murine model of ischemic bowel necrosis. Am J Physiol 1997;272:G545–G552.

    CAS  PubMed  Google Scholar 

  22. Nadler EP, Stanford A, Zhang X-R et al. Intestinal cytokine gene expression in infants with acute necrotizing enterocolitis: interleukin-11 mRNA expression inversely correlates with extent of disease. J Pediatr Surg 2001;36:1122–1129.

    Article  CAS  Google Scholar 

  23. Oren H, Duman N, Abacioglu H, Ozkan H, Irken G . Association between serum macrophage colony-stimulating factor levels and monocyte and thrombocyte counts in healthy, hypoxic and septic term neonates. Pediatrics 2001;108:329–332.

    Article  CAS  Google Scholar 

  24. Kaushansky K . Thrombopoietin. N Engl J Med 1998;339:746–754.

    Article  CAS  Google Scholar 

  25. Ishiguro A, Nakahata T, Matsubara K et al. Age-related changes in thrombopoietin in children: reference interval for serum thrombopoietin levels. Br J Haematol 1999;106:884–888.

    Article  CAS  Google Scholar 

  26. Murray N, Watts T, Roberts I . Endogenous thrombopoietin levels and effect of recombinant human thrombopoietin on megakaryocyte precursors in term and preterm babies. Pediatr Res 1998;43:148–151.

    Article  CAS  Google Scholar 

  27. Sola M, Calhoun D, Hutson A, Christiansen R . Plasma thrombo-poietin concentrations in thrombocytopenic and non-thrombo-cytopenic patients in a neonatal intensive care unit. Br J Haematol 1999;104:90–92.

    Article  CAS  Google Scholar 

  28. Colarizi P, Fiorucci P, Caradonna A, Ficuccilli F, Mancuso M, Papoff P . Circulating thrombopoietin levels in neonates with infection. Acta Paediatr 1999;88:332–337.

    Article  CAS  Google Scholar 

  29. Gupta SK, Burke G, Herson VC . Necrotizing enterocolitis: laboratory indicators of surgical disease. J Pediatr Surg 1994;29:1472–1475.

    Article  CAS  Google Scholar 

  30. Schober PH, Nassiri J . Risk factors and severity indices in necrotizing enterocolitis. Acta Paediatr Suppl 1994;396:49–52.

    Article  CAS  Google Scholar 

  31. Ross MN, Wayne ER, Hanson JB, Burrington JD, Chang JHT . A standard of comparison for acute surgical necrotizing enterocolitis. J Pediatr Surg 1989;24:998–1002.

    Article  CAS  Google Scholar 

  32. Ververidis M, Kiely EM, Spitz L, Drake DP, Eaton S, Pierro A . The clinical significance of thrombocytopenia in neonates with necrotizing enterocolitis. J Pediatr Surg 2001;36:799–803.

    Article  CAS  Google Scholar 

  33. VanGeet C, Devriendt K, Eyskens B, Vermylen J, Hoylaerts MF . Velocardiofacial syndrome patients with a heterozygous chromosome 22q11 deletion have giant platelets. Pediatr Res 1998;44:607–611.

    Article  CAS  Google Scholar 

  34. Andrew M, Castle V, Mitchell L, Paes B . Modified bleeding time in the infant. Am J Hematol 1989;30:190–191.

    Article  CAS  Google Scholar 

  35. Rennie JM, Gibson T, Cooke RW . Micromethod for bleeding time in the newborn. JPEN 1989;13:620–622.

    Article  Google Scholar 

  36. Michelson AD . Platelet function in the newborn. Semin Thromb Hemost 1998;24:507–512.

    Article  CAS  Google Scholar 

  37. Gitto E, Karbownik M, Reiter RJ et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001;50:756–760.

    Article  CAS  Google Scholar 

  38. Tapper H, Herwald H . Modulation of hemostatic mechanisms in bacterial infectious diseases. Blood 2000;96:2329–2337.

    CAS  PubMed  Google Scholar 

  39. Sonntag J, Wagner MH, Waldschmidt J, Wit J, Obladen M . Multisystem organ failure and capillary leak syndrome in severe necrotizing enterocolitis of very low birthweight infants. J Pediatr Surg 1998;33:481–484.

    Article  CAS  Google Scholar 

  40. Gopel W, Christiansen B, Reiss I, Moller J, Gortner L . Resistance to activated protein C in newborns with necrotizing enterocolitis. Eur J Pediatr 1999;158:608.

    Article  CAS  Google Scholar 

  41. Hathaway W, Corrigan J . Report of the scientific and standardization subcommittee on neonatal hemostasis. Thromb Haemost 1991;65:323–325.

    Article  CAS  Google Scholar 

  42. Andrew M, Paes B, Milner R et al. Development of the human coagulation system in the healthy premature infant. Blood 1988;72:1651–1657.

    CAS  PubMed  Google Scholar 

  43. Edstrom CS, Christensen RD, Andrew M . Developmental aspects of blood hemostasis and disorders of coagulation and fibrinolysis in the neonatal period. In: Christensen RD, editor. Hematologic Problems of the Neonate. Philadelphia: Saunders; 2000. p. 239–272.

    Google Scholar 

  44. Kreuz W, Veldmann A, Fischer D, Schlosser R, Volk WR, Ettinghausen CE . Neonatal sepsis: a challenge in hemostaseology. Semin Thromb Hemost 1999;25:531–535.

    Article  CAS  Google Scholar 

  45. Rintala E, Kauppila M, Seppala O-P et al. Protein C substitution in sepsis-associated purpura fulminans. Crit Care Med 2000;28:2373–2378.

    Article  CAS  Google Scholar 

  46. Bernard GR, Vincent J-L, Laterre P-F et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.

    Article  CAS  Google Scholar 

  47. White B, Livingstone W, Murphey C, Hodgson A, Rafferty M, Smith OP . An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. Blood 2000;96:3719–3724.

    CAS  PubMed  Google Scholar 

  48. Ettinghausen CE, Veldmann A, Beeg T, Schneider W, Jaeger G, Kreuz W . Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost 1999;25:537–541.

    Article  Google Scholar 

  49. Matthay MA . Severe sepsis — a new treatment with both anticoagulant and antiinflammatory properties. N Engl J Med 2001;344:759–763.

    Article  CAS  Google Scholar 

  50. Fuse S, Tomita H, Yoshida M, Hori T, Igarashi C, Fujita S . High dose of intravenous antithrombin III without heparin in the treatment of disseminated intravascular coagulation and organ failure in four children. Am J Hematol 1996;53:18–21.

    Article  CAS  Google Scholar 

  51. Schmidt B, Gillie P, Mitchel L, Andrew M, Caco C, Roberts R . A placebo-controlled randomized trial of antithrombin therapy in neonatal respiratory distress syndrome. Am J Respir Crit Care Med 1998;158:470–476.

    Article  CAS  Google Scholar 

  52. Kocherlakota P, La Gamma EF . Human granulocyte colony-stimulating factor may improve outcome attributable to neonatal sepsis complicated by neutropenia. Pediatrics 1997;100:e6.

    Article  CAS  Google Scholar 

  53. Bernstein HM, Pollock BH, Calhoun DA, Christensen RD . Administration of recombinant human granulocyte colony stimulating factor to neonates with septicemia: a meta-analysis. J Pediatr 2001;138:917–920.

    Article  CAS  Google Scholar 

  54. Bilgin K, Yaramis A, Haspolat K, Tas A, Gunbey S, Derman O . A randomized trial of granulocyte–macrophage colony-stimulating factor in neonates with sepsis and neutropenia. Pediatrics 2001;107:36–41.

    Article  CAS  Google Scholar 

  55. Kling PJ, Sullivan TM, Leftwich ME, Roe DJ . Score for neonatal acute physiology predicts erythrocyte transfusions in premature infants. Arch Pediatr Adoles Med 1997;151:27–31.

    Article  CAS  Google Scholar 

  56. Ringer SA, Richardson DK, Sacher RA, Keszler M, Churchill WH . Variations in transfusion practice in neonatal intensive care. Pediatrics 1998;101:194–200.

    Article  CAS  Google Scholar 

  57. Hall N, Ong EGP, Ade-Ajayi N et al. T cryptantigen activation is associated with advanced necrotizing enterocolitis. J Pediatr Surg 2002;37:791–793.

    Article  CAS  Google Scholar 

  58. Jelkmann W, Wolff M, Fandrey J . Modulation of the production of erythropoietin by cytokines: in vitro studies and their clinical implications. Contrib Nephrol 1990;80:68–77.

    Article  Google Scholar 

  59. Jelkmann W, Pagel H, Wolff M, Fandrey J . Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci 1991;50:301–308.

    Article  Google Scholar 

  60. Juul SE, Joyce AE, Zhao Y, Ledbetter DJ . Why is erythropoietin present in human milk? Studies of eythropoietin receptors on enterocytes of human and rat neonates. Pediatr Res 1999;46:263–268.

    Article  CAS  Google Scholar 

  61. Kling PJ, Sullivan TM, Roberts RA, Philipps AF, Koldovsky O . Human milk as a potential enteral source of erythropoietin. Pediatr Res 1998;43:216–221.

    Article  CAS  Google Scholar 

  62. Obayashi H, Koshi S, Miyauchi Y, Inoue M . Inhibition of posthemorrhagic transfusion-induced gastric injury by a long-acting superoxide dismutase derivative. Proc Soc Exp Biol Med 1991;196:164–169.

    Article  CAS  Google Scholar 

  63. Strauss RG . Practical issues in neonatal transfusion practice. Am J Clin Pathol 1997;107:S5763.

    Google Scholar 

  64. Atkinson SA . Human milk feeding of the micropremie. Clin Perinatol 2000;27:235–247.

    Article  CAS  Google Scholar 

  65. Ledbetter DJ, Juul SE . Necrotizing enterocolitis and hematopoietic cytokines. Clin Perinatol 2000;27:697–716.

    Article  CAS  Google Scholar 

  66. Bauer CR, Morrison JC, Poole WK et al. A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy. Pediatrics 1984;73:682–688.

    CAS  PubMed  Google Scholar 

  67. Halac E, Halac J, Begue EF et al. Prenatal and postnatal corticosteroid therapy to prevent neonatal necrotizing enterocolitis: a controlled trial. J Pediatr 1990;117:132–138.

    Article  CAS  Google Scholar 

  68. Crowley P, Chalmers I, Keirse MJNC . The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11–25.

    Article  CAS  Google Scholar 

  69. Ihara Y, Frenkel RA, Johnston JM . Hormonal regulation of platelet-activating factor-acetyltransferase activity in rat tissue. Arch Biochem Biophys 1993;304:503–507.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Pamela J Kling: The Southwest Affiliate of American Heart Association SW-GS-16-98 and Program Project NIH HD 26013.

Authors and Affiliations

  1. Department of Pediatrics, University of Wisconsin, Madison, WI, USA

    Pamela J Kling MD

  2. Department of Pediatrics, Steele Memorial Children's Research Center, The University of Arizona Health Sciences Center, Tucson, AZ, USA

    John J Hutter MD

Authors
  1. Pamela J Kling MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John J Hutter MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kling, P., Hutter, J. Hematologic Abnormalities in Severe Neonatal Necrotizing Enterocolitis: 25 Years Later. J Perinatol 23, 523–530 (2003). https://doi.org/10.1038/sj.jp.7210983

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jp.7210983

This article is cited by

Search

Advanced search

Quick links