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Anemia at the Extremes of Life: Congenital Hemolytic Anemia

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Anemia in the Young and Old

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Abstract

Congenital hemolytic anemia is an important etiology to consider in the differential diagnosis of pediatric anemia, especially in patients presenting with neonatal hyperbilirubinemia requiring phototherapy or exchange transfusion. It results from inherited or de novo genetic defects that affect the function, shape, or stability of the red blood cell, resulting in red blood cell destruction, primarily via extravascular mechanisms. The main categories of congenital hemolytic anemia include the hemoglobinopathies, red blood cell membrane defects, and red blood cell enzyme defects. Clinical manifestations range from mild, compensated, asymptomatic anemia to transfusion-dependent anemia with extramedullary hematopoiesis. Laboratory evaluation usually reveals a reticulocytosis and negative direct antiglobulin testing, with or without abnormal red blood cell morphology. The typical findings of acute hemolysis, including decreased haptoglobin and increased LDH, might not always be present. Diagnosis depends on family history, drug or infection exposure, and the constellation of clinical findings. Treatment is dictated by the diagnosis, the degree of anemia, and the overall clinical status of the patient.

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References

  1. Noronha SA. Acquired and congenital hemolytic anemia. Pediatr Rev. 2016;37(6):235–46.

    Article  PubMed  Google Scholar 

  2. Dhaliwal GC, Cornett PA, Tierney LM. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599–606.

    PubMed  Google Scholar 

  3. Robertson JJ, Brem E, Koyfman A. The acute hemolytic anemias: the importance of emergency diagnosis and management. J Emerg Med. 2017;53(2):202–11.

    Article  PubMed  Google Scholar 

  4. Forde DG, Cope A, Stone B. Acute parvovirus B19 infection in identical twins unmasking previously unidentified hereditary spherocytosis. BMJ Case Rep. 2014;2014:pii: bcr2013202957.

    Article  Google Scholar 

  5. Musallam KM, et al. Clinical experience with fetal hemoglobin induction therapy in patients with beta-thalassemia. Blood. 2013;121(12):2199–212; quiz 2372

    Article  CAS  PubMed  Google Scholar 

  6. Origa R, Moi P. Alpha-thalassemia. In: Adam MP, et al., editors. GeneReviews(R). Seattle, WA: University of Washington, Seattle University of Washington; 1993. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.: Seattle, WA.

    Google Scholar 

  7. Hatton CS, et al. Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster. Blood. 1990;76(1):221–7.

    CAS  PubMed  Google Scholar 

  8. Farashi S, Harteveld CL. Molecular basis of alpha-thalassemia. Blood Cells Mol Dis. 2018;70:43–53.

    Article  CAS  PubMed  Google Scholar 

  9. Thein SL. Molecular basis of beta thalassemia and potential therapeutic targets. Blood Cells Mol Dis. 2018;70:54–65.

    Article  CAS  PubMed  Google Scholar 

  10. Daikeler T, et al. New autoimmune diseases after cord blood transplantation: a retrospective study of EUROCORD and the Autoimmune Disease Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2013;121(6):1059–64.

    Article  CAS  PubMed  Google Scholar 

  11. Karakas Z, et al. Evaluation of alpha-thalassemia mutations in cases with hypochromic microcytic anemia: the Istanbul perspective. Turk J Haematol. 2015;32(4):344–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Harteveld CL, Higgs DR. Alpha-thalassaemia. Orphanet J Rare Dis. 2010;5:13.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Flint J, et al. High frequencies of alpha-thalassaemia are the result of natural selection by malaria. Nature. 1986;321(6072):744–50.

    Article  CAS  PubMed  Google Scholar 

  14. Modiano G, et al. Protection against malaria morbidity: near-fixation of the alpha-thalassemia gene in a Nepalese population. Am J Hum Genet. 1991;48(2):390–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Vichinsky EP. Clinical manifestations of alpha-thalassemia. Cold Spring Harb Perspect Med. 2013;3(5):a011742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Vichinsky EP, et al. Changes in the epidemiology of thalassemia in North America: a new minority disease. Pediatrics. 2005;116(6):e818–25.

    Article  PubMed  Google Scholar 

  17. Chui DH, Fucharoen S, Chan V. Hemoglobin H disease: not necessarily a benign disorder. Blood. 2003;101(3):791–800.

    Article  CAS  PubMed  Google Scholar 

  18. Farashi S, Najmabadi H. Diagnostic pitfalls of less well recognized HbH disease. Blood Cells Mol Dis. 2015;55(4):387–95.

    Article  CAS  PubMed  Google Scholar 

  19. Fucharoen S, Viprakasit V. Hb H disease: clinical course and disease modifiers. Hematology Am Soc Hematol Educ Program. 2009:26–34.

    Article  Google Scholar 

  20. Galanello R, et al. HbH disease in Sardinia: molecular, hematological and clinical aspects. Acta Haematol. 1992;88(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  21. Chui DH. Alpha-thalassemia: Hb H disease and Hb Barts hydrops fetalis. Ann N Y Acad Sci. 2005;1054:25–32.

    Article  CAS  PubMed  Google Scholar 

  22. Blouin P, et al. Evans’ syndrome: a retrospective study from the ship (French Society of Pediatric Hematology and Immunology) (36 cases). Arch Pediatr. 2005;12(11):1600–7.

    Article  CAS  PubMed  Google Scholar 

  23. Yaegashi N, et al. Parvovirus B19 infection induces apoptosis of erythroid cells in vitro and in vivo. J Infect. 1999;39(1):68–76.

    Article  CAS  PubMed  Google Scholar 

  24. Songdej D, Babbs C, Higgs DR. An international registry of survivors with Hb Bart's hydrops fetalis syndrome. Blood. 2017;129(10):1251–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Caocci G, et al. Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. Am J Hematol. 2017;92(12):1303–10.

    Article  CAS  PubMed  Google Scholar 

  26. Taher AT, et al. Optimal management of beta thalassaemia intermedia. Br J Haematol. 2011;152(5):512–23.

    Article  CAS  PubMed  Google Scholar 

  27. Galanello R, Cao A. Relationship between genotype and phenotype. Thalassemia intermedia. Ann N Y Acad Sci. 1998;850:325–33.

    Article  CAS  PubMed  Google Scholar 

  28. Vehapoglu A, et al. Hematological indices for differential diagnosis of Beta thalassemia trait and iron deficiency anemia. Anemia. 2014;2014:576738.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Cappellini MD, et al. Coagulopathy in beta-thalassemia: current understanding and future perspectives. Mediterr J Hematol Infect Dis. 2009;1(1):e2009029.

    PubMed  PubMed Central  Google Scholar 

  30. Ben Salah N, et al. Revisiting beta thalassemia intermedia: past, present, and future prospects. Hematology. 2017;22(10):607–16.

    Article  CAS  PubMed  Google Scholar 

  31. Haddad A, et al. Beta-thalassemia intermedia: a bird’s-eye view. Turk J Haematol. 2014;31(1):5–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Manfre L, et al. MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease. AJR Am J Roentgenol. 1999;173(6):1477–80.

    Article  CAS  PubMed  Google Scholar 

  33. Badens C, et al. Variants in genetic modifiers of beta-thalassemia can help to predict the major or intermedia type of the disease. Haematologica. 2011;96(11):1712–4.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Danjou F, et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica. 2015;100(4):452–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Galanello R, et al. Amelioration of Sardinian beta0 thalassemia by genetic modifiers. Blood. 2009;114(18):3935–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Spanos T, et al. Red cell alloantibodies in patients with thalassemia. Vox Sang. 1990;58(1):50–5.

    CAS  PubMed  Google Scholar 

  37. Taher A, et al. Prevalence of thromboembolic events among 8,860 patients with thalassaemia major and intermedia in the Mediterranean area and Iran. Thromb Haemost. 2006;96(4):488–91.

    Article  CAS  PubMed  Google Scholar 

  38. Taher AT, et al. Splenectomy and thrombosis: the case of thalassemia intermedia. J Thromb Haemost. 2010;8(10):2152–8.

    Article  CAS  PubMed  Google Scholar 

  39. Cappellini MD, et al. Venous thromboembolism and hypercoagulability in splenectomized patients with thalassaemia intermedia. Br J Haematol. 2000;111(2):467–73.

    Article  CAS  PubMed  Google Scholar 

  40. Karimi M, et al. Adverse effects of hydroxyurea in beta-thalassemia intermedia patients: 10 years’ experience. Pediatr Hematol Oncol. 2010;27(3):205–11.

    Article  CAS  PubMed  Google Scholar 

  41. Bradai M, et al. Decreased transfusion needs associated with hydroxyurea therapy in Algerian patients with thalassemia major or intermedia. Transfusion. 2007;47(10):1830–6.

    Article  CAS  PubMed  Google Scholar 

  42. El-Beshlawy A, et al. Response to hydroxycarbamide in pediatric beta-thalassemia intermedia: 8 years’ follow-up in Egypt. Ann Hematol. 2014;93(12):2045–50.

    Article  CAS  PubMed  Google Scholar 

  43. Foong WC, et al. Hydroxyurea for reducing blood transfusion in non-transfusion dependent beta thalassaemias. Cochrane Database Syst Rev. 2016;10:Cd011579.

    PubMed  Google Scholar 

  44. Rutjanaprom W, et al. Heart rate variability in beta-thalassemia patients. Eur J Haematol. 2009;83(5):483–9.

    Article  PubMed  Google Scholar 

  45. Cazzola M, et al. A moderate transfusion regimen may reduce iron loading in beta-thalassemia major without producing excessive expansion of erythropoiesis. Transfusion. 1997;37(2):135–40.

    Article  CAS  PubMed  Google Scholar 

  46. Angelucci E, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008;93(5):741–52.

    Article  PubMed  Google Scholar 

  47. Borgna-Pignatti C, Marsella M. Iron chelation in thalassemia major. Clin Ther. 2015;37(12):2866–77.

    Article  CAS  PubMed  Google Scholar 

  48. Borgna-Pignatti C, et al. Myocardial iron overload in thalassaemia major. How early to check? Br J Haematol. 2014;164(4):579–85.

    Article  CAS  PubMed  Google Scholar 

  49. Bayanzay K, Khan R. Meta-analysis on effectiveness of hydroxyurea to treat transfusion-dependent beta-thalassemia. Hematology. 2015;20:469–76.

    Article  CAS  PubMed  Google Scholar 

  50. Baronciani D, et al. Hemopoietic stem cell transplantation in thalassemia: a report from the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Registry, 2000–2010. Bone Marrow Transplant. 2016;51(4):536–41.

    Article  CAS  PubMed  Google Scholar 

  51. Makis A, et al. 2017 Clinical trials update in new treatments of beta-thalassemia. Am J Hematol. 2016;91(11):1135–45.

    Article  CAS  PubMed  Google Scholar 

  52. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. 1910. Reprint from Arch Int Med. 1910;5:517. Yale J Biol Med. 2001;74(3):179–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Beet EA. The genetics of the sickle-cell trait in a Bantu tribe. Ann Eugenics. 1949;14(4):279–84.

    CAS  Google Scholar 

  54. Neel JV. The inheritance of sickle cell anemia. Science. 1949;110(2846):64–6.

    Article  CAS  PubMed  Google Scholar 

  55. Pauling L, Itano HA, et al. Sickle cell anemia a molecular disease. Science. 2865;1949(110):543–8.

    Google Scholar 

  56. Piel FB, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013;381(9861):142–51.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Gill FM, et al. Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative study of sickle cell disease. Blood. 1995;86(2):776–83.

    CAS  PubMed  Google Scholar 

  58. Noguchi CT, Schechter AN. Sickle hemoglobin polymerization in solution and in cells. Annu Rev Biophys Biophys Chem. 1985;14:239–63.

    Article  CAS  PubMed  Google Scholar 

  59. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120(18):3647–56.

    Article  CAS  PubMed  Google Scholar 

  60. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013;122(24):3892–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sheehan VA, et al. Genetic modifiers of sickle cell anemia in the BABY HUG cohort: influence on laboratory and clinical phenotypes. Am J Hematol. 2013;88(7):571–6.

    Article  CAS  PubMed  Google Scholar 

  62. Aleluia MM, et al. Comparative study of sickle cell anemia and hemoglobin SC disease: clinical characterization, laboratory biomarkers and genetic profiles. BMC Hematol. 2017;17:15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Meier ER, Wright EC, Miller JL. Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease. Am J Hematol. 2014;89(9):904–6.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Miller ST, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. 2000;342(2):83–9.

    Article  CAS  PubMed  Google Scholar 

  65. Quinn CT, et al. Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort. Blood. 2008;111(2):544–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Quinn CT, et al. Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia. Blood. 2007;109(1):40–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Serjeant GR, et al. The painful crisis of homozygous sickle cell disease: clinical features. Br J Haematol. 1994;87(3):586–91.

    Article  CAS  PubMed  Google Scholar 

  68. Gonzalez ER, et al. Intermittent injection vs patient-controlled analgesia for sickle cell crisis pain. Comparison in patients in the emergency department. Arch Intern Med. 1991;151(7):1373–8.

    Article  CAS  PubMed  Google Scholar 

  69. van Beers EJ, et al. Patient-controlled analgesia versus continuous infusion of morphine during vaso-occlusive crisis in sickle cell disease, a randomized controlled trial. Am J Hematol. 2007;82(11):955–60.

    Article  PubMed  CAS  Google Scholar 

  70. Campbell CM, et al. An evaluation of central sensitization in patients with sickle cell disease. J Pain. 2016;17(5):617–27.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States, 2016. MMWR Recomm Rep. 2016;65(1):1–49.

    Article  PubMed  Google Scholar 

  72. Haywood C Jr, et al. Perceived discrimination in health care is associated with a greater burden of pain in sickle cell disease. J Pain Symptom Manag. 2014;48(5):934–43.

    Article  Google Scholar 

  73. Haywood C Jr, et al. Perceived discrimination, patient trust, and adherence to medical recommendations among persons with sickle cell disease. J Gen Intern Med. 2014;29(12):1657–62.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Wakefield EO, et al. Perceived racial bias and health-related stigma among youth with sickle cell disease. J Dev Behav Pediatr. 2017;38(2):129–34.

    PubMed  Google Scholar 

  75. Schwartz LA, Radcliffe J, Barakat LP. Associates of school absenteeism in adolescents with sickle cell disease. Pediatr Blood Cancer. 2009;52(1):92–6.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Epping AS, et al. Academic attainment findings in children with sickle cell disease. J Sch Health. 2013;83(8):548–53.

    Article  PubMed  Google Scholar 

  77. Ladd RJ, Valrie CR, Walcott CM. Risk and resilience factors for grade retention in youth with sickle cell disease. Pediatr Blood Cancer. 2014;61(7):1252–6.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Pearson HA, et al. Developmental aspects of splenic function in sickle cell diseases. Blood. 1979;53(3):358–65.

    CAS  PubMed  Google Scholar 

  79. Gaston MH, et al. Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med. 1986;314(25):1593–9.

    Article  CAS  PubMed  Google Scholar 

  80. Quinn CT, et al. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115(17):3447–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ellison AM, et al. Pneumococcal bacteremia in a vaccinated pediatric sickle cell disease population. Pediatr Infect Dis J. 2012;31(5):534–6.

    Article  PubMed  Google Scholar 

  82. Santoro JD, et al. A case of invasive Streptococcus pneumoniae in an afebrile adolescent with sickle cell disease. Clin Pediatr (Phila). 2013;52(12):1173–5.

    Article  Google Scholar 

  83. Ellison AM, et al. Variation in pediatric emergency department care of sickle cell disease and fever. Acad Emerg Med. 2015;22(4):423–30.

    Article  PubMed  Google Scholar 

  84. Brousse V, et al. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012;156(5):643–8.

    Article  PubMed  Google Scholar 

  85. Switzer JA, et al. Pathophysiology and treatment of stroke in sickle-cell disease: present and future. Lancet Neurol. 2006;5(6):501–12.

    Article  PubMed  Google Scholar 

  86. Ohene-Frempong K, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood. 1998;91(1):288–94.

    CAS  PubMed  Google Scholar 

  87. Balkaran B, et al. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr. 1992;120(3):360–6.

    Article  CAS  PubMed  Google Scholar 

  88. Powars D, et al. The natural history of stroke in sickle cell disease. Am J Med. 1978;65(3):461–71.

    Article  CAS  PubMed  Google Scholar 

  89. Russell MO, et al. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood. 1984;63(1):162–9.

    CAS  PubMed  Google Scholar 

  90. Wang WC, et al. High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease. J Pediatr. 1991;118(3):377–82.

    Article  CAS  PubMed  Google Scholar 

  91. Fasano RM, Meier ER, Hulbert ML. Cerebral vasculopathy in children with sickle cell anemia. Blood Cells Mol Dis. 2015;54(1):17–25.

    Article  PubMed  Google Scholar 

  92. Griessenauer CJ, et al. Encephaloduroarteriosynangiosis and encephalomyoarteriosynangiosis for treatment of moyamoya syndrome in pediatric patients with sickle cell disease. J Neurosurg Pediatr. 2015;16(1):64–73.

    Article  PubMed  Google Scholar 

  93. Hankinson TC, et al. Surgical treatment of moyamoya syndrome in patients with sickle cell anemia: outcome following encephaloduroarteriosynangiosis. J Neurosurg Pediatr. 2008;1(3):211–6.

    Article  PubMed  Google Scholar 

  94. Adams R, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992;326(9):605–10.

    Article  CAS  PubMed  Google Scholar 

  95. Adams RJ, et al. Long-term stroke risk in children with sickle cell disease screened with transcranial Doppler. Ann Neurol. 1997;42(5):699–704.

    Article  CAS  PubMed  Google Scholar 

  96. Adams RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5–11.

    Article  CAS  PubMed  Google Scholar 

  97. Adams RJ, Brambilla D, Optimizing Primary Stroke Prevention in Sickle Cell Anemia Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26):2769–78.

    Article  CAS  PubMed  Google Scholar 

  98. Ware RE, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016;387(10019):661–70.

    Article  CAS  PubMed  Google Scholar 

  99. Kwiatkowski JL, et al. Silent infarcts in young children with sickle cell disease. Br J Haematol. 2009;146(3):300–5.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Wang WC, et al. Abnormalities of the central nervous system in very young children with sickle cell anemia. J Pediatr. 1998;132(6):994–8.

    Article  CAS  PubMed  Google Scholar 

  101. Armstrong FD, et al. Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease. Neuropsychology Committee of the Cooperative Study of Sickle Cell Disease. Pediatrics. 1996;97(6 Pt 1):864–70.

    CAS  PubMed  Google Scholar 

  102. Bernaudin F, et al. Multicenter prospective study of children with sickle cell disease: radiographic and psychometric correlation. J Child Neurol. 2000;15(5):333–43.

    Article  CAS  PubMed  Google Scholar 

  103. DeBaun MR, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014;371(8):699–710.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Clarkson JG. The ocular manifestations of sickle-cell disease: a prevalence and natural history study. Trans Am Ophthalmol Soc. 1992;90:481–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Platt OS, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639–44.

    Article  CAS  PubMed  Google Scholar 

  106. Vichinsky EP, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Engl J Med. 2000;342(25):1855–65.

    Article  CAS  PubMed  Google Scholar 

  107. Strouse JJ, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006;118(5):1916–24.

    Article  PubMed  Google Scholar 

  108. Strouse JJ, et al. Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease. Pediatr Blood Cancer. 2008;50(5):1006–12.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Quinn CT, et al. Tapered oral dexamethasone for the acute chest syndrome of sickle cell disease. Br J Haematol. 2011;155(2):263–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sylvester KP, et al. Pulmonary function abnormalities in children with sickle cell disease. Thorax. 2004;59(1):67–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. MacLean JE, et al. Longitudinal decline in lung volume in a population of children with sickle cell disease. Am J Respir Crit Care Med. 2008;178(10):1055–9.

    Article  PubMed  CAS  Google Scholar 

  112. Rosen CL, et al. Obstructive sleep apnea and sickle cell anemia. Pediatrics. 2014;134(2):273–81.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Fonseca GH, et al. Pulmonary hypertension diagnosed by right heart catheterisation in sickle cell disease. Eur Respir J. 2012;39(1):112–8.

    Article  CAS  PubMed  Google Scholar 

  114. Mehari A, et al. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA. 2012;307(12):1254–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parent F, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011;365(1):44–53.

    Article  CAS  PubMed  Google Scholar 

  116. Gordeuk VR, Castro OL, Machado RF. Pathophysiology and treatment of pulmonary hypertension in sickle cell disease. Blood. 2016;127(7):820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gladwin MT, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350(9):886–95.

    Article  CAS  PubMed  Google Scholar 

  118. Karayalcin G, et al. Cholelithiasis in children with sickle cell disease. Am J Dis Child. 1979;133(3):306–7.

    CAS  PubMed  Google Scholar 

  119. Lachman BS, et al. The prevalence of cholelithiasis in sickle cell disease as diagnosed by ultrasound and cholecystography. Pediatrics. 1979;64(5):601–3.

    CAS  PubMed  Google Scholar 

  120. Mintz AA, Church G, Adams ED. Cholelithiasis in sickle cell anemia. J Pediatr. 1955;47(2):171–7.

    Article  CAS  PubMed  Google Scholar 

  121. Walker TM, Hambleton IR, Serjeant GR. Gallstones in sickle cell disease: observations from The Jamaican Cohort study. J Pediatr. 2000;136(1):80–5.

    Article  CAS  PubMed  Google Scholar 

  122. Shah R, Taborda C, Chawla S. Acute and chronic hepatobiliary manifestations of sickle cell disease: a review. World J Gastrointest Pathophysiol. 2017;8(3):108–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ahn H, Li CS, Wang W. Sickle cell hepatopathy: clinical presentation, treatment, and outcome in pediatric and adult patients. Pediatr Blood Cancer. 2005;45(2):184–90.

    Article  PubMed  Google Scholar 

  124. Buchanan GR, Glader BE. Benign course of extreme hyperbilirubinemia in sickle cell anemia: analysis of six cases. J Pediatr. 1977;91(1):21–4.

    Article  CAS  PubMed  Google Scholar 

  125. Aygun B, et al. Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia. Am J Hematol. 2013;88(2):116–9.

    Article  CAS  PubMed  Google Scholar 

  126. Falk RJ, et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med. 1992;326(14):910–5.

    Article  CAS  PubMed  Google Scholar 

  127. Yawn BP, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312(10):1033–48.

    Article  PubMed  CAS  Google Scholar 

  128. Falletta JM, et al. Discontinuing penicillin prophylaxis in children with sickle cell anemia. Prophylactic Penicillin Study II. J Pediatr. 1995;127(5):685–90.

    Article  CAS  PubMed  Google Scholar 

  129. Zhang D, et al. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127(7):801–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Platt OS, et al. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest. 1984;74(2):652–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Charache S, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive “switching” agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore). 1996;75(6):300–26.

    Article  CAS  Google Scholar 

  132. Steinberg MH, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA. 2003;289(13):1645–51.

    Article  CAS  PubMed  Google Scholar 

  133. Voskaridou E, et al. The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS). Blood. 2010;115(12):2354–63.

    Article  CAS  PubMed  Google Scholar 

  134. Steinberg MH, et al. The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol. 2010;85(6):403–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Kinney TR, et al. Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood. 1999;94(5):1550–4.

    CAS  PubMed  Google Scholar 

  136. Thornburg CD, et al. Impact of hydroxyurea on clinical events in the BABY HUG trial. Blood. 2012;120(22):4304–10; quiz 4448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang WC, et al. Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics. 2013;132(4):677–83.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Badawy SM, et al. Adherence to hydroxyurea, health-related quality of life domains, and patients' perceptions of sickle cell disease and hydroxyurea: a cross-sectional study in adolescents and young adults. Health Qual Life Outcomes. 2017;15(1):136.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Badawy SM, et al. Health-related quality of life and adherence to hydroxyurea in adolescents and young adults with sickle cell disease. Pediatr Blood Cancer. 2017;64(6):e26369.

    Article  CAS  Google Scholar 

  140. Badawy SM, Thompson AA, Liem RI. Beliefs about hydroxyurea in youth with sickle cell disease. Hematol Oncol Stem Cell Ther. 2018; https://doi.org/10.1016/j.hemonc.2018.01.001.

    Article  PubMed  Google Scholar 

  141. Badawy SM, et al. Barriers to hydroxyurea adherence and health-related quality of life in adolescents and young adults with sickle cell disease. Eur J Haematol. 2017;98(6):608–14.

    Article  CAS  PubMed  Google Scholar 

  142. Haywood C Jr, et al. Examining the characteristics and beliefs of hydroxyurea users and nonusers among adults with sickle cell disease. Am J Hematol. 2011;86(1):85–7.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Oyeku SO, et al. Parental and other factors associated with hydroxyurea use for pediatric sickle cell disease. Pediatr Blood Cancer. 2013;60(4):653–8.

    Article  CAS  PubMed  Google Scholar 

  144. Morris CR, et al. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood. 2008;111(1):402–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Niihara Y, et al. Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol. 1998;58(2):117–21.

    Article  CAS  PubMed  Google Scholar 

  146. Embury SH, et al. The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood. 2004;104(10):3378–85.

    Article  CAS  PubMed  Google Scholar 

  147. Luo W, et al. P-selectin glycoprotein ligand-1 inhibition blocks increased leukocyte-endothelial interactions associated with sickle cell disease in mice. Blood. 2012;120(18):3862–4.

    Article  CAS  PubMed  Google Scholar 

  148. Ataga KI, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429–39.

    Article  CAS  PubMed  Google Scholar 

  149. Gluckman E. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematology Am Soc Hematol Educ Program. 2013;2013:370–6.

    Article  PubMed  Google Scholar 

  150. Shenoy S, et al. A trial of unrelated donor marrow transplantation for children with severe sickle cell disease. Blood. 2016;128(21):2561–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fitzhugh CD, et al. Cyclophosphamide improves engraftment in patients with SCD and severe organ damage who undergo haploidentical PBSCT. Blood Adv. 2017;1(11):652–61.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Brodsky RA, et al. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008;42(8):523–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Frangoul H, et al. Haploidentical hematopoietic stem cell transplant for patients with sickle cell disease using thiotepa, fludarabine, thymoglobulin, low dose cyclophosphamide, 200 cGy tbi and post transplant cyclophosphamide. Bone Marrow Transplant. 2018;53(5):647–50.

    Article  CAS  PubMed  Google Scholar 

  154. Pawlowska AB, et al. HLA haploidentical stem cell transplant with pretransplant immunosuppression for patients with sickle cell disease. Biol Blood Marrow Transplant. 2018;24(1):185–9.

    Article  PubMed  Google Scholar 

  155. Lidonnici MR, Ferrari G. Gene therapy and gene editing strategies for hemoglobinopathies. Blood Cells Mol Dis. 2018;70:87–101.

    Article  CAS  PubMed  Google Scholar 

  156. Andolfo I, et al. New insights on hereditary erythrocyte membrane defects. Haematologica. 2016;101(11):1284–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Tse WT, Lux SE. Red blood cell membrane disorders. Br J Haematol. 1999;104(1):2–13.

    Article  CAS  PubMed  Google Scholar 

  158. Narla J, Mohandas N. Red cell membrane disorders. Int J Lab Hematol. 2017;39 Suppl 1:47–52.

    Article  CAS  PubMed  Google Scholar 

  159. Da Costa L, et al. Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders. Blood Rev. 2013;27(4):167–78.

    Article  PubMed  CAS  Google Scholar 

  160. Dhermy D, Schrevel J, Lecomte MC. Spectrin-based skeleton in red blood cells and malaria. Curr Opin Hematol. 2007;14(3):198–202.

    Article  CAS  PubMed  Google Scholar 

  161. Gallagher PG. Hereditary elliptocytosis: spectrin and protein 4.1R. Semin Hematol. 2004;41(2):142–64.

    Article  CAS  PubMed  Google Scholar 

  162. Gallagher PG, Forget BG. Hematologically important mutations: spectrin variants in hereditary elliptocytosis and hereditary pyropoikilocytosis. Blood Cells Mol Dis. 1996;22(3):254–8.

    Article  CAS  PubMed  Google Scholar 

  163. Figueiredo S, et al. Transient pure red blood cell aplasia as clinical presentation of congenital hemolytic anemia: a case report. Cases J. 2009;2:6814.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Debray FG, et al. A particular hereditary anemia in a two-month-old infant: elliptocytosis. Arch Pediatr. 2005;12(2):163–7.

    Article  CAS  PubMed  Google Scholar 

  165. Barcellini W, et al. Hereditary red cell membrane defects: diagnostic and clinical aspects. Blood Transfus. 2011;9(3):274–7.

    PubMed  PubMed Central  Google Scholar 

  166. Gallagher PG, et al. Mutation of a highly conserved residue of betaI spectrin associated with fatal and near-fatal neonatal hemolytic anemia. J Clin Invest. 1997;99(2):267–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Gallagher PG, et al. Recurrent fatal hydrops fetalis associated with a nucleotide substitution in the erythrocyte beta-spectrin gene. J Clin Invest. 1995;95(3):1174–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bayhan T, Unal S, Gumruk F. Hereditary Elliptocytosis with Pyropoikilocytosis. Turk J Haematol. 2016;33(1):86–7.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Bogardus HH, et al. A de novo band 3 mutation in hereditary spherocytosis. Pediatr Blood Cancer. 2012;58(6):1004.

    Article  PubMed  Google Scholar 

  170. Konca C, et al. Hereditary spherocytosis: evaluation of 68 children. Indian J Hematol Blood Transfus. 2015;31(1):127–32.

    Article  PubMed  Google Scholar 

  171. Perrotta S, Gallagher PG, Mohandas N. Hereditary spherocytosis. Lancet. 2008;372(9647):1411–26.

    Article  CAS  PubMed  Google Scholar 

  172. Rencic J, et al. Circling back for the diagnosis. N Engl J Med. 2017;377(18):1778–84.

    Article  PubMed  Google Scholar 

  173. Mariani M, et al. Clinical and hematologic features of 300 patients affected by hereditary spherocytosis grouped according to the type of the membrane protein defect. Haematologica. 2008;93(9):1310–7.

    Article  CAS  PubMed  Google Scholar 

  174. Eber SW, Armbrust R, Schroter W. Variable clinical severity of hereditary spherocytosis: relation to erythrocytic spectrin concentration, osmotic fragility, and autohemolysis. J Pediatr. 1990;117(3):409–16.

    Article  CAS  PubMed  Google Scholar 

  175. Bolton-Maggs PH, et al. Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. Br J Haematol. 2012;156(1):37–49.

    Article  PubMed  Google Scholar 

  176. Bianchi P, et al. Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics. Haematologica. 2012;97(4):516–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Iglauer A, et al. Cryohemolysis test as a diagnostic tool for hereditary spherocytosis. Ann Hematol. 1999;78(12):555–7.

    Article  CAS  PubMed  Google Scholar 

  178. Streichman S, Gesheidt Y, Tatarsky I. Hypertonic cryohemolysis: a diagnostic test for hereditary spherocytosis. Am J Hematol. 1990;35(2):104–9.

    Article  CAS  PubMed  Google Scholar 

  179. Streichman S, Gescheidt Y. Cryohemolysis for the detection of hereditary spherocytosis: correlation studies with osmotic fragility and autohemolysis. Am J Hematol. 1998;58(3):206–12.

    Article  CAS  PubMed  Google Scholar 

  180. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64–74.

    Article  CAS  PubMed  Google Scholar 

  181. Glucose-6-phosphate dehydrogenase deficiency. WHO Working Group. Bull World Health Organ. 1989;67(6):601–11.

    Google Scholar 

  182. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(7):1277–82.

    PubMed  Google Scholar 

  183. Beutler E. G6PD deficiency. Blood. 1994;84(11):3613–36.

    CAS  PubMed  Google Scholar 

  184. Baehner RL, Nathan DG, Castle WB. Oxidant injury of caucasian glucose-6-phosphate dehydrogenase-deficient red blood cells by phagocytosing leukocytes during infection. J Clin Invest. 1971;50(12):2466–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Beutler E, Yeh M, Fairbanks VF. The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A. 1962;48:9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kaplan M, et al. Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. J Pediatr. 2001;139(1):137–40.

    Article  CAS  PubMed  Google Scholar 

  187. Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl). 1998;76(8):581–8.

    Article  CAS  Google Scholar 

  188. Nkhoma ET, et al. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009;42(3):267–78.

    Article  CAS  PubMed  Google Scholar 

  189. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency and severe neonatal hyperbilirubinemia: a complexity of interactions between genes and environment. Semin Fetal Neonatal Med. 2010;15(3):148–56.

    Article  PubMed  Google Scholar 

  190. Kaplan M, et al. Severe hemolysis with normal blood count in a glucose-6-phosphate dehydrogenase deficient neonate. J Perinatol. 2008;28(4):306–9.

    Article  CAS  PubMed  Google Scholar 

  191. Kaplan M, et al. Conjugated bilirubin in neonates with glucose-6-phosphate dehydrogenase deficiency. J Pediatr. 1996;128(5 Pt 1):695–7.

    Article  CAS  PubMed  Google Scholar 

  192. Edwards CQ. Anemia and the liver. Hepatobiliary manifestations of anemia. Clin Liver Dis. 2002;6(4):891–907, viii.

    Article  PubMed  Google Scholar 

  193. Corchia C, et al. Favism in a female newborn infant whose mother ingested fava beans before delivery. J Pediatr. 1995;127(5):807–8.

    Article  CAS  PubMed  Google Scholar 

  194. American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics. 2001;108(3):776–89.

    Article  Google Scholar 

  195. Moiz B, Ali SA. Fulminant hemolysis in glucose-6-phosphate dehydrogenase deficiency. Clin Case Rep. 2018;6(1):224–5.

    Article  PubMed  Google Scholar 

  196. Gellady AM, Greenwood RD. G-6-PD hemolytic anemia complicating diabetic ketoacidosis. J Pediatr. 1972;80(6):1037–8.

    Article  CAS  PubMed  Google Scholar 

  197. Lee DH, et al. Acute hemolytic anemia precipitated by myocardial infarction and pericardial tamponade in G6PD deficiency. Am J Hematol. 1996;51(2):174–5.

    Article  CAS  PubMed  Google Scholar 

  198. Ninfali P, Bresolin N. Muscle glucose 6-phosphate dehydrogenase (G6PD) deficiency and oxidant stress during physical exercise. Cell Biochem Funct. 1995;13(4):297–8.

    Article  CAS  PubMed  Google Scholar 

  199. Luzzatto L, Nannelli C, Notaro R. Glucose-6-phosphate dehydrogenase deficiency. Hematol Oncol Clin North Am. 2016;30(2):373–93.

    Article  PubMed  Google Scholar 

  200. Ringelhahn B. A simple laboratory procedure for the recognition of A – (African type) G-6PD deficiency in acute haemolytic crisis. Clin Chim Acta. 1972;36(1):272–4.

    Article  CAS  PubMed  Google Scholar 

  201. Minucci A, et al. Glucose-6-phosphate dehydrogenase laboratory assay: how, when, and why? IUBMB Life. 2009;61(1):27–34.

    Article  CAS  PubMed  Google Scholar 

  202. Lam R, Li H, Nock ML. Assessment of G6PD screening program in premature infants in a NICU. J Perinatol. 2015;35(12):1027–9.

    Article  CAS  PubMed  Google Scholar 

  203. Grace RF, et al. Erythrocyte pyruvate kinase deficiency: 2015 status report. Am J Hematol. 2015;90(9):825–30.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Zanella A, et al. Pyruvate kinase deficiency: the genotype-phenotype association. Blood Rev. 2007;21(4):217–31.

    Article  CAS  PubMed  Google Scholar 

  205. Fothergill-Gilmore LA, Michels PA. Evolution of glycolysis. Prog Biophys Mol Biol. 1993;59(2):105–235.

    Article  CAS  PubMed  Google Scholar 

  206. Zanella A, et al. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. 2005;130(1):11–25.

    Article  CAS  PubMed  Google Scholar 

  207. Bowman HS, Oski FA. Laboratory studies of erythrocytic pyruvate kinase deficiency. Pathogenesis of the hemolysis. Am J Clin Pathol. 1978;70(2):259–70.

    Article  CAS  PubMed  Google Scholar 

  208. Bowman HS, Procopio F. Hereditary non-spherocytic hemolytic anemia of the pyruvate-kinase deficient type. Ann Intern Med. 1963;58:567–91.

    Article  CAS  PubMed  Google Scholar 

  209. Matsumoto N, et al. Sequestration and destruction of reticulocyte in the spleen in pyruvate kinase deficiency hereditary nonspherocytic hemolytic anemia. Nihon Ketsueki Gakkai Zasshi. 1972;35(4):525–37.

    CAS  PubMed  Google Scholar 

  210. Mentzer WC Jr, et al. Selective reticulocyte destruction in erythrocyte pyruvate kinase deficiency. J Clin Invest. 1971;50(3):688–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Nathan DG, et al. Life-span and organ sequestration of the red cells in pyruvate kinase deficiency. N Engl J Med. 1968;278(2):73–81.

    Article  CAS  PubMed  Google Scholar 

  212. Satoh H, et al. The human liver-type pyruvate kinase (PKL) gene is on chromosome 1 at band q21. Cytogenet Cell Genet. 1988;47(3):132–3.

    Article  CAS  PubMed  Google Scholar 

  213. Nakashima K, et al. Characterization of pyruvate kinase from the liver of a patient with aberrant erythrocyte pyruvate kinase, PK Nagasaki. J Lab Clin Med. 1977;90(6):1012–20.

    CAS  PubMed  Google Scholar 

  214. Canu G, et al. Red blood cell PK deficiency: an update of PK-LR gene mutation database. Blood Cells Mol Dis. 2016;57:100–9.

    Article  CAS  PubMed  Google Scholar 

  215. van Wijk R, et al. Fifteen novel mutations in PKLR associated with pyruvate kinase (PK) deficiency: structural implications of amino acid substitutions in PK. Hum Mutat. 2009;30(3):446–53.

    Article  PubMed  CAS  Google Scholar 

  216. Warang P, et al. Molecular and clinical heterogeneity in pyruvate kinase deficiency in India. Blood Cells Mol Dis. 2013;51(3):133–7.

    Article  CAS  PubMed  Google Scholar 

  217. Zanella A, Bianchi P. Red cell pyruvate kinase deficiency: from genetics to clinical manifestations. Baillieres Best Pract Res Clin Haematol. 2000;13(1):57–81.

    Article  CAS  PubMed  Google Scholar 

  218. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. 2000;95(11):3585–8.

    CAS  PubMed  Google Scholar 

  219. Baronciani L, Beutler E. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995;95(4):1702–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Christensen RD, et al. Six children with pyruvate kinase deficiency from one small town: molecular characterization of the PK-LR gene. J Pediatr. 2011;159(4):695–7.

    Article  CAS  PubMed  Google Scholar 

  221. Machado P, et al. Pyruvate kinase deficiency in sub-Saharan Africa: identification of a highly frequent missense mutation (G829A;Glu277Lys) and association with malaria. PLoS One. 2012;7(10):e47071.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Min-Oo G, Gros P. Erythrocyte variants and the nature of their malaria protective effect. Cell Microbiol. 2005;7(6):753–63.

    Article  CAS  PubMed  Google Scholar 

  223. Ayi K, et al. Pyruvate kinase deficiency and malaria. N Engl J Med. 2008;358(17):1805–10.

    Article  CAS  PubMed  Google Scholar 

  224. Min-Oo G, et al. Pyruvate kinase deficiency: correlation between enzyme activity, extent of hemolytic anemia and protection against malaria in independent mouse mutants. Blood Cells Mol Dis. 2007;39(1):63–9.

    Article  CAS  PubMed  Google Scholar 

  225. Pissard S, et al. Pyruvate kinase (PK) deficiency in newborns: the pitfalls of diagnosis. J Pediatr. 2007;150(4):443–5.

    Article  CAS  PubMed  Google Scholar 

  226. Ferreira P, et al. Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency. Eur J Pediatr. 2000;159(7):481–2.

    Article  CAS  PubMed  Google Scholar 

  227. Hennekam RC, et al. Hydrops fetalis associated with red cell pyruvate kinase deficiency. Genet Couns. 1990;1(1):75–9.

    CAS  PubMed  Google Scholar 

  228. Olivier F, et al. Cholestasis and hepatic failure in a neonate: a case report of severe pyruvate kinase deficiency. Pediatrics. 2015;136(5):e1366–8.

    Article  PubMed  Google Scholar 

  229. Boivin P, Ottenwaelter T. Hereditary haemolytic anaemia due to pyruvate kinase deficiency. Prognosis of neonatal forms (author’s transl). Nouv Press Med. 1982;11(12):917–9.

    CAS  Google Scholar 

  230. Zanella A, et al. Iron status and HFE genotype in erythrocyte pyruvate kinase deficiency: study of Italian cases. Blood Cells Mol Dis. 2001;27(3):653–61.

    Article  CAS  PubMed  Google Scholar 

  231. Marshall SR, et al. The dangers of iron overload in pyruvate kinase deficiency. Br J Haematol. 2003;120(6):1090–1.

    Article  PubMed  Google Scholar 

  232. Andersen FD, et al. Unexpectedly high but still asymptomatic iron overload in a patient with pyruvate kinase deficiency. Hematol J. 2004;5(6):543–5.

    Article  PubMed  Google Scholar 

  233. Amankwah KS, Dick BW, Dodge S. Hemolytic anemia and pyruvate kinase deficiency in pregnancy. Obstet Gynecol. 1980;55(3 Suppl):42s–4s.

    Article  CAS  PubMed  Google Scholar 

  234. Esen UI, Olajide F. Pyruvate kinase deficiency: an unusual cause of puerperal jaundice. Int J Clin Pract. 1998;52(5):349–50.

    CAS  PubMed  Google Scholar 

  235. Fanning J, Hinkle RS. Pyruvate kinase deficiency hemolytic anemia: two successful pregnancy outcomes. Am J Obstet Gynecol. 1985;153(3):313–4.

    Article  CAS  PubMed  Google Scholar 

  236. Wax JR, et al. Pyruvate kinase deficiency complicating pregnancy. Obstet Gynecol. 2007;109(2 Pt2):553–5.

    Article  PubMed  Google Scholar 

  237. Dolan LM, Ryan M, Moohan J. Pyruvate kinase deficiency in pregnancy complicated by iron overload. BJOG. 2002;109(7):844–6.

    Article  PubMed  Google Scholar 

  238. Pincus M, Stark RA, O'Neill JH. Ischaemic stroke complicating pyruvate kinase deficiency. Intern Med J. 2003;33(9–10):473–4.

    Article  CAS  PubMed  Google Scholar 

  239. Muller-Soyano A, et al. Pyruvate kinase deficiency and leg ulcers. Blood. 1976;47(5):807–13.

    CAS  PubMed  Google Scholar 

  240. Chou R, DeLoughery TG. Recurrent thromboembolic disease following splenectomy for pyruvate kinase deficiency. Am J Hematol. 2001;67(3):197–9.

    Article  CAS  PubMed  Google Scholar 

  241. Oski FA, et al. The role of the left-shifted or right-shifted oxygen-hemoglobin equilibrium curve. Ann Intern Med. 1971;74(1):44–6.

    Article  CAS  PubMed  Google Scholar 

  242. Deeren D. Deferasirox in pyruvate kinase deficiency. Ann Hematol. 2009;88(4):397.

    Article  PubMed  Google Scholar 

  243. Vukelja SJ. Erythropoietin in the treatment of iron overload in a patient with hemolytic anemia and pyruvate kinase deficiency. Acta Haematol. 1994;91(4):199–200.

    Article  CAS  PubMed  Google Scholar 

  244. Zahid MF, Bains APS. Rapidly fatal Klebsiella pneumoniae sepsis in a patient with pyruvate kinase deficiency and asplenia. Blood. 2017;130(26):2906.

    Article  PubMed  Google Scholar 

  245. Morimoto M, et al. Pyruvate kinase deficiency of mice associated with nonspherocytic hemolytic anemia and cure of the anemia by marrow transplantation without host irradiation. Blood. 1995;86(11):4323–30.

    CAS  PubMed  Google Scholar 

  246. Tanphaichitr VS, et al. Successful bone marrow transplantation in a child with red blood cell pyruvate kinase deficiency. Bone Marrow Transplant. 2000;26(6):689–90.

    Article  CAS  PubMed  Google Scholar 

  247. Garcia-Gomez M, et al. Safe and efficient gene therapy for pyruvate kinase deficiency. Mol Ther. 2016;24(7):1187–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Steinberg MH. Sickle cell disease and other hemoglobinopathies. In: Goldman L, Shafer A, editors. Goldman-cecil medicine. 25th ed. Philadelphia, PA: Elsevier Saunders; 2016. p. 1095–104.

    Google Scholar 

  249. McAdam AJ, Milner DA, Sharpe AH. Red blood cell and bleeding disorders. In: Kumar V, Abbas AK, Aster JC, editors. Robbins and Cotran pathologic basis of disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015. p. 629–67.

    Google Scholar 

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  1. Division of Pediatric Hematology/Oncology, Golisano Children’s Hospital, University of Rochester Medical Center, Rochester, NY, USA

    Ariel L. Reinish MD & Suzie A. Noronha MD

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    Robert T. Means Jr.

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Reinish, A.L., Noronha, S.A. (2019). Anemia at the Extremes of Life: Congenital Hemolytic Anemia. In: Means Jr., R. (eds) Anemia in the Young and Old. Springer, Cham. https://doi.org/10.1007/978-3-319-96487-4_6

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