Advertisement

Update in Pediatric Hematology

  • Ziad Solh
  • Anthony K. C. Chan
  • Mihir D. Bhatt
Chapter

Abstract

This book chapter will address various aspects of pediatric hematology with regards to clinical and laboratory practice. Red blood cell disorders will be discussed including iron deficiency anemia, which is the most common form of anemia in children. The authors delve into novel advances in pediatric hemoglobinopathy therapies, such as hydroxyurea for sickle cell disease and iron chelation for thalassemia. Red cell transfusion controversies will be summarized including the question of hemoglobin thresholds in a variety of clinical scenarios and the recent age of blood trials. Immune cytopenias such as isolated thrombocytopenia, Evans syndrome, and autoimmune lymphoproliferative syndrome will be examined. The readers will also find an update about the management of other bleeding disorders in children such as hemophilia and disseminated intravascular coagulopathy. The challenges of oral anticoagulants in pediatric care, after their use in adults, are discussed in light of recent studies. Finally, an exploration of the various bone marrow failure syndromes, aplastic anemia, and neutropenia will conclude the chapter. Readers will gain an appreciation for new challenges that face the pediatric hematologist, and current prospects for improved care in pediatric patients with blood disorders.

Keywords

Pediatrics Hematology Thrombocytopenia Anemia Neutropenia Cytopenia Transfusion Thrombosis Hemostasis Anticoagulant Hemophilia Bleeding Coagulopathy Sickle cell disease Thalassemia Hemoglobinopathy Age of blood Aplastic anemia Lymphoproliferative 

References

  1. Aladjidi N, Leverger G, Leblanc T, Picat MQ, Michel G, Bertrand Y, et al. New insights into childhood autoimmune hemolytic anemia: a French national observational study of 265 children. Haematologica. 2011;96(5):655–63.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians evidence-based clinical practice guidelines (8th edn). Chest. 2008;133(6 Suppl):160S–98S.CrossRefPubMedGoogle Scholar
  3. Bader-Meunier B, Aladjidi N, Bellmann F, Monpoux F, Nelken B, Robert A, et al. Rituximab therapy for childhood Evans syndrome. Haematologica. 2007;92(12):1691–4.CrossRefPubMedGoogle Scholar
  4. Baru M, Carmel-Goren L, Barenholz Y, Dayan I, Ostropolets S, Slepoy I, et al. Factor VIII efficient and specific non-covalent binding to PEGylated liposomes enables prolongation of its circulation time and haemostatic efficacy. Thromb Haemost. 2005;93(6):1061–8.PubMedGoogle Scholar
  5. Blanchette V, Carcao M. Approach to the investigation and management of immune thrombocytopenic purpura in children. Semin Hematol. 2000;37(3):299–314.CrossRefPubMedGoogle Scholar
  6. Bleesing JJ. Autoimmune lymphoproliferative syndrome (ALPS). Curr Pharm Des. 2003;9(3):265–78.CrossRefPubMedGoogle Scholar
  7. Bussel JB, de Miguel PG, Despotovic JM, Grainger JD, Sevilla J, Blanchette VS, et al. Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study. Lancet Haematol. 2015;2(8):e315–25.CrossRefPubMedGoogle Scholar
  8. Canadian Haemoglobinopathy Association. Consensus statement on the care of patients with sickle cell disease in Canada. Ottawa, ON: Canadian Haemoglobinopathy Association; 2014.Google Scholar
  9. Chasse M, Tinmouth A, English SW, Acker JP, Wilson K, Knoll G, et al. Association of blood donor age and sex with recipient survival after red blood cell transfusion. JAMA Intern Med. 2016;176(9):1307–14.CrossRefPubMedGoogle Scholar
  10. Chou ST, Schreiber AD. Autoimmune Hemolytic Anemia. In: Orkin SH, Fisher DE, Look T, Lux SE, Ginsburg D, Nathan DG, editors. Nathan and Oski’s hematology and oncology of infancy and childhood. 8th ed. Philadelphia, PA: WB Saunders; 2015. p. 411.Google Scholar
  11. Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014;124(26):3880–6.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Cooper N. A review of the management of childhood immune thrombocytopenia: how can we provide an evidence-based approach? Br J Haematol. 2014;165(6):756–67.CrossRefPubMedGoogle Scholar
  13. Davies JK, Guinan EC. An update on the management of severe idiopathic aplastic anaemia in children. Br J Haematol. 2007;136(4):549–64.CrossRefPubMedGoogle Scholar
  14. De Falco L, Sanchez M, Silvestri L, Kannengiesser C, Muckenthaler MU, Iolascon A, et al. Iron refractory iron deficiency anemia. Haematologica. 2013;98(6):845–53.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Dumont JA, Liu T, Low SC, Zhang X, Kamphaus G, Sakorafas P, et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood. 2012;119(13):3024–30.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fergusson DA, Hebert P, Hogan DL, LeBel L, Rouvinez-Bouali N, Smyth JA, et al. Effect of fresh red blood cell transfusions on clinical outcomes in premature, very low-birth-weight infants: the ARIPI randomized trial. JAMA. 2012;308(14):1443–51.CrossRefPubMedGoogle Scholar
  17. Galanello R, Agus A, Campus S, Danjou F, Giardina PJ, Grady RW. Combined iron chelation therapy. Ann N Y Acad Sci. 2010;1202:79–86.CrossRefPubMedGoogle Scholar
  18. Guinan EC. Acquired aplastic anemia in childhood. Hematol Oncol Clin North Am. 2009;23(2):171–91.CrossRefPubMedGoogle Scholar
  19. Hartung HD, Olson TS, Bessler M. Acquired aplastic anemia in children. Pediatr Clin N Am. 2013;60(6):1311–36.CrossRefGoogle Scholar
  20. Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409–17.CrossRefPubMedGoogle Scholar
  21. Heddle NM, Cook RJ, Arnold DM, Liu Y, Barty R, Crowther MA, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med. 2016;375(20):1937–45.CrossRefPubMedGoogle Scholar
  22. Janus J, Moerschel SK. Evaluation of anemia in children. Am Fam Physician. 2010;81(12):1462–71.PubMedGoogle Scholar
  23. Jimenez K, Kulnigg-Dabsch S, Gasche C. Management of iron deficiency anemia. Gastroenterol Hepatol (NY). 2015;11(4):241–50.Google Scholar
  24. Kelly N. Thalassemia. Pediatr Rev. 2012;33(9):434–5.CrossRefPubMedGoogle Scholar
  25. Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, et al. The premature infants in need of transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149(3):301–7.CrossRefPubMedGoogle Scholar
  26. Lacroix J, Hebert PC, Hutchison JS, Hume HA, Tucci M, Ducruet T, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med. 2007;356(16):1609–19.CrossRefPubMedGoogle Scholar
  27. Lacroix J, Hebert PC, Fergusson DA, Tinmouth A, Cook DJ, Marshall JC, et al. Age of transfused blood in critically ill adults. N Engl J Med. 2015;372(15):1410–8.CrossRefPubMedGoogle Scholar
  28. Madkaikar M, Mhatre S, Gupta M, Ghosh K. Advances in autoimmune lymphoproliferative syndromes. Eur J Haematol. 2011;87(1):1–9.CrossRefPubMedGoogle Scholar
  29. Magerus-Chatinet A, Stolzenberg MC, Lanzarotti N, Neven B, Daussy C, Picard C, et al. Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. J Allergy Clin Immunol. 2013;131(2):486–90.CrossRefPubMedGoogle Scholar
  30. Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014;123(3):317–25.CrossRefPubMedPubMedCentralGoogle Scholar
  31. McDonagh MS, Blazina I, Dana T, Cantor A, Bougatsos C. Screening and routine supplementation for iron deficiency anemia: a systematic review. Pediatrics. 2015;135(4):723–33.CrossRefPubMedGoogle Scholar
  32. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet. 2000;355(9220):2051–2.CrossRefPubMedGoogle Scholar
  33. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357–65.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Nathwani AC, Reiss UM, Tuddenham EG, Rosales C, Chowdary P, McIntosh J, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994–2004.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Negrier C, Knobe K, Tiede A, Giangrande P, Moss J. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood. 2011;118(10):2695–701.CrossRefPubMedGoogle Scholar
  36. Neunert CE. Current management of immune thrombocytopenia. Hematology Am Soc Hematol Educ Program. 2013;2013:276–82.PubMedGoogle Scholar
  37. Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De SL, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798–807.CrossRefPubMedGoogle Scholar
  38. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35–40.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Olivieri N, Brittenham G. Final results of the randomised trial of deferiprone and deferoxamine. Blood. 1997;90:264a.Google Scholar
  40. Thalassaemia International Federation. Guidelines for the management of transfusion dependent thalassaemia (TDT). 3rd ed. Nicosia: Thalassaemia International Federation; 2014.Google Scholar

Reference Type: Abstract

  1. Patel RM, Knezevic A, Shenvi N, Hinkes M, Keene S, Roback JD, et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA. 2016;315(9):889–97.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Pegels JG, Helmerhorst FM, van Leeuwen EF, Dalen P, Engelfriet CP, von dem Borne AE. The Evans syndrome: characterization of the responsible autoantibodies. Br J Haematol. 1982;51(3):445–50.CrossRefPubMedGoogle Scholar
  3. Peters RT, Low SC, Kamphaus GD, Dumont JA, Amari JV, Lu Q, et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood. 2010;115(10):2057–64.CrossRefPubMedGoogle Scholar
  4. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358(13):1362–9.CrossRefPubMedGoogle Scholar
  5. Porter JB, Elalfy MS, Taher AT, Aydinok Y, Chan LL, Lee SH, et al. Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy. Ann Hematol. 2013;92(2):211–9.CrossRefPubMedGoogle Scholar
  6. Powell JS, Ragni MV, White GC, Lusher JM, Hillman-Wiseman C, Moon TE, et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood. 2003;102(6):2038–45.CrossRefPubMedGoogle Scholar
  7. Powell JS, Josephson NC, Quon D, Ragni MV, Cheng G, Li E, et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in hemophilia A patients. Blood. 2012;119(13):3031–7.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013;369(24):2313–23.CrossRefPubMedGoogle Scholar
  9. Price S, Shaw PA, Seitz A, Joshi G, Davis J, Niemela JE, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989–99.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Price TH, Boeckh M, Harrison RW, McCullough J, Ness PM, Strauss RG, et al. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection. Blood. 2015;126(18):2153–61.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Rajagopal R, Thachil J, Monagle P. Disseminated intravascular coagulation in paediatrics. Arch Dis Child. 2017;102(2):187–93.CrossRefPubMedGoogle Scholar
  12. Rao VK, Oliveira JB. How I treat autoimmune lymphoproliferative syndrome. Blood. 2011;118(22):5741–51.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK, et al. Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. Br J Haematol. 2005;129(4):534–8.CrossRefPubMedGoogle Scholar
  14. Richardson M. Microcytic anemia. Pediatr Rev. 2007;28(1):5–14.CrossRefPubMedGoogle Scholar
  15. Rodeghiero F, Stasi R, Gernsheimer T, Michel M, Provan D, Arnold DM, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386–93.CrossRefPubMedGoogle Scholar
  16. Roth DA, Tawa NE Jr, O'Brien JM, Treco DA, Selden RF. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med. 2001;344(23):1735–42.CrossRefPubMedGoogle Scholar
  17. Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127(14):1761–9.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Scott DW, Lozier JN. Gene therapy for haemophilia: prospects and challenges to prevent or reverse inhibitor formation. Br J Haematol. 2012;156(3):295–302.CrossRefPubMedGoogle Scholar
  19. Segel GB, Halterman JS. Neutropenia in pediatric practice. Pediatr Rev. 2008;29(1):12–23.CrossRefPubMedGoogle Scholar
  20. Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood. 2010;115(11):2142–5.CrossRefPubMedGoogle Scholar
  21. Shapiro AD, Ragni MV, Valentino LA, Key NS, Josephson NC, Powell JS, et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood. 2012;119(3):666–72.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Siu AL. Screening for iron deficiency anemia in young children: USPSTF recommendation statement. Pediatrics. 2015;136(4):746–52.CrossRefPubMedGoogle Scholar
  23. Sleight BJ, Prasad VS, DeLaat C, Steele P, Ballard E, Arceci RJ, et al. Correction of autoimmune lymphoproliferative syndrome by bone marrow transplantation. Bone Marrow Transplant. 1998;22(4):375–80.CrossRefPubMedGoogle Scholar
  24. Solh Z, Taccone MS, Marin S, Athale U, Breakey VR. Neurological PRESentations in sickle cell patients are not always stroke: a review of posterior reversible encephalopathy syndrome in sickle cell disease. Pediatr Blood Cancer. 2016;63(6):983–9.CrossRefPubMedGoogle Scholar
  25. Soundar EP, Jariwala P, Nguyen TC, Eldin KW, Teruya J. Evaluation of the International Society on Thrombosis and Haemostasis and institutional diagnostic criteria of disseminated intravascular coagulation in pediatric patients. Am J Clin Pathol. 2013;139(6):812–6.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Spira J, Plyushch O, Andreeva T, Zorenko V, Zozulya N, Velichkoi I, et al. Safety and efficacy of a long-acting liposomal formulation of plasma-derived factor VIII in haemophilia A patients. Br J Haematol. 2012;158(1):149–52.CrossRefPubMedGoogle Scholar
  27. Steiner ME, Ness PM, Assmann SF, Triulzi DJ, Sloan SR, Delaney M, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med. 2015;372(15):1419–29.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Tarantino MD, Bussel JB, Blanchette VS, Despotovic J, Bennett C, Raj A, et al. Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10039):45–54.CrossRefPubMedGoogle Scholar
  29. Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood. 2005;105(6):2443–8.CrossRefPubMedGoogle Scholar
  30. Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010;148(2):205–16.CrossRefPubMedGoogle Scholar
  31. Vaglio S, Arista MC, Perrone MP, Tomei G, Testi AM, Coluzzi S, et al. Autoimmune hemolytic anemia in childhood: serologic features in 100 cases. Transfusion. 2007;47(1):50–4.CrossRefPubMedGoogle Scholar
  32. von Vajna E, Alam R, So TY. Current clinical trials on the use of direct oral anticoagulants in the pediatric population. Cardiol Ther. 2016;5(1):19–41.CrossRefGoogle Scholar
  33. Wada H, Thachil J, Di NM, Mathew P, Kurosawa S, Gando S, et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013;11(4):761–7.CrossRefGoogle Scholar
  34. Walkovich K, Boxer LA. How to approach neutropenia in childhood. Pediatr Rev. 2013;34(4):173–84.CrossRefPubMedGoogle Scholar
  35. Wang WC, Ware RE, Miller ST, Iyer RV, Casella JF, Minniti CP, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011;377(9778):1663–72.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509–19.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S119–25.CrossRefPubMedGoogle Scholar
  38. Zhu S, Hsu AP, Vacek MM, Zheng L, Schaffer AA, Dale JK, et al. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet. 2006;119(3):284–94.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ziad Solh
    • 1
    • 2
  • Anthony K. C. Chan
    • 3
  • Mihir D. Bhatt
    • 3
  1. 1.Department of Pathology and Molecular MedicineMcMaster UniversityHamiltonCanada
  2. 2.Medical Services and InnovationCanadian Blood ServicesHamiltonCanada
  3. 3.Division of Hematology/Oncology, Department of PediatricsMcMaster UniversityHamiltonCanada

Personalised recommendations