Overview of hemolytic anemias in children
- Michael Recht, MD, PhD
Michael Recht, MD, PhD
- Associate Professor of Pediatrics and Medicine
- Oregon Health & Science University
Anemia is among the most frequent laboratory abnormalities seen by a practicing pediatrician. Approximately 20 percent of all children in the United States and 80 percent of children in developing countries will be anemic at some time before their 18th birthdays . Anemia is caused by one of three broad mechanisms: decreased production of red blood cells, increased loss of red blood cells, or destruction of red blood cells. Worldwide, the vast majority of childhood anemias are due to iron deficiency, due to either inadequate dietary intake or blood loss associated with gastrointestinal infections such as hookworm. However, the hemolytic anemias are associated with excessive morbidity and mortality.
The approach to a child with hemolytic anemia is discussed here. An overall approach to the anemic child, including the characteristics that suggest a hemolytic process, is discussed separately. (See "Approach to the child with anemia".)
The hemolytic process — After release from the bone marrow, mature, nonnucleated erythrocytes (red blood cells, RBCs) survive for 100 to 120 days in the circulation . In the steady state, approximately 1 percent of the circulating erythrocytes are destroyed daily (ie, senescent RBCs) and are replaced by an equal number of new erythrocytes released from the bone marrow (ie, reticulocytes) (picture 1 and picture 2). The basic pathophysiology of the hemolytic anemias is a reduced erythrocyte lifespan, ranging from nearly normal to remarkably shortened. (See "Red blood cell survival: Normal values and measurement".)
In compensation for a reduced RBC lifespan, the bone marrow increases its output of erythrocytes, a response mediated by increased production of erythropoietin. As an example, in adults with hereditary spherocytosis, the bone marrow can increase its output of erythrocytes six- to eight-fold. With this maximal response, erythrocyte survival can be reduced to a value as low as 20 to 30 days without the onset of anemia (ie, fully compensated hemolysis). The limits of erythrocyte production in other hemolytic states have not been determined, particularly in infants and children, but they probably are lower in infants than in adults. (See "Regulation of erythropoiesis".)
As a result of increased RBC production in response to hemolysis, the reticulocyte count often exceeds 2 percent, with an absolute reticulocyte count usually greater than 100,000/microL . When a chronic hemolytic process is present, hyperplasia of the erythropoietic marrow elements occurs, with reversal of the myeloid-to-erythroid ratio from the normal 3:1 to 1:1 or less (picture 3 and picture 4). In the severe, chronic hemolytic processes of childhood (eg, thalassemia major, congenital spherocytosis, sickle cell disease), hypertrophy of the marrow may expand the medullary spaces, producing bony changes, particularly in the skull and hands . (See "Diagnosis of hemolytic anemia in the adult" and "Clinical manifestations and diagnosis of the thalassemias", section on 'Skeletal changes' and "Overview of the clinical manifestations of sickle cell disease", section on 'Skeletal complications'.)
- Recht M, Pearson H. The hemolytic anemias. In: Oski's Pediatrics, McMillan JA, Deangelis CD, Feigin RD, Warshaw JB (Eds), Lippincott Williams and Wilkins, Philadelphia 1999. p.1453.
- Oski FA, Brugnara C, Nathan DG. A diagnostic approach to the anemic patient. In: Nathan and Oski's Hematology of Infancy and Childhood, 6th, Nathan DG, Orkin SH, Ginsberg D, Look AT (Eds), WB Saunders, Philadelphia 2003. p.409.
- Davis BH, Ornvold K, Bigelow NC. Flow cytometric reticulocyte maturity index: a useful laboratory parameter of erythropoietic activity in anemia. Cytometry 1995; 22:35.
- Olivieri N. Thalassaemia: clinical management. Baillieres Clin Haematol 1998; 11:147.
- Senaati S, Gumruk FU, Delbakhsh P, et al. Gallbladder pathology in pediatric beta-thalassemic patients. A prospective ultrasonographic study. Pediatr Radiol 1993; 23:357.
- Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA 1980; 243:1909.
- Gallagher PG, Forget BG. Hematologically important mutations: spectrin and ankyrin variants in hereditary spherocytosis. Blood Cells Mol Dis 1998; 24:539.
- Chilcote RR, Le Beau MM, Dampier C, et al. Association of red cell spherocytosis with deletion of the short arm of chromosome 8. Blood 1987; 69:156.
- Palek J. Hereditary elliptocytosis, spherocytosis and related disorders: consequences of a deficiency or a mutation of membrane skeletal proteins. Blood Rev 1987; 1:147.
- Eber SW, Gonzalez JM, Lux ML, et al. Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis. Nat Genet 1996; 13:214.
- Rescorla FJ. Laparoscopic splenectomy. Semin Pediatr Surg 1998; 7:207.
- Goss GA, Szer J. Pancytopenia following infection with human parvovirus B19 as a presenting feature of hereditary spherocytosis in two siblings. Aust N Z J Med 1997; 27:86.
- Fogel BJ, Shields CE, Altstatt LB, et al. Determining the. A method especially applicable to pediatrics. Clin Pediatr 1967; 6:247.
- Judkiewicz L, Bartosz G, Oplatowska A, Szczepanek A. Modified osmotic fragility test for the laboratory diagnosis of hereditary spherocytosis. Am J Hematol 1989; 31:136.
- Rice HE, Englum BR, Rothman J, et al. Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry. Am J Hematol 2015; 90:187.
- Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187.
- American Academy of Pediatrics. Pneumococcal infections. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.626.
- Buchanan GR. Chemoprophylaxis in asplenic adolescents and young adults. Pediatr Infect Dis J 1993; 12:892.
- Silveira P, Cynober T, Dhermy D, et al. Red blood cell abnormalities in hereditary elliptocytosis and their relevance to variable clinical expression. Am J Clin Pathol 1997; 108:391.
- Lux SE, Wolfe LC. Inherited disorders of the red cell membrane skeleton. Pediatr Clin North Am 1980; 27:463.
- Palek J, Jarolim P. Clinical expression and laboratory detection of red blood cell membrane protein mutations. Semin Hematol 1993; 30:249.
- Eyssette-Guerreau S, Bader-Meunier B, Garcon L, et al. Infantile pyknocytosis: a cause of haemolytic anaemia of the newborn. Br J Haematol 2006; 133:439.
- Baronciani L, Bianchi P, Zanella A. Hematologically important mutations: red cell pyruvate kinase (2nd update). Blood Cells Mol Dis 1998; 24:273.
- McMullin MF. The molecular basis of disorders of red cell enzymes. J Clin Pathol 1999; 52:241.
- Necheles TF, Finkel HE, Sheehan RG, Allen DM. Red cell pyruvate kinase deficiency. The effect of splenectomy. Arch Intern Med 1966; 118:75.
- BOYER SH, PORTER IH, WEILBACHER RG. Electrophoretic heterogeneity of glucose-6-phosphate dehydrogenase and its relationship to enzyme deficiency in man. Proc Natl Acad Sci U S A 1962; 48:1868.
- Oppenheim A, Jury CL, Rund D, et al. G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet 1993; 91:293.
- Hollán S, Fujii H, Hirono A, et al. Hereditary triosephosphate isomerase (TPI) deficiency: two severely affected brothers one with and one without neurological symptoms. Hum Genet 1993; 92:486.
- Jacob HS. Mechanisms of Heinz body formation and attachment to red cell membrane. Semin Hematol 1970; 7:341.
- Habibi B, Homberg JC, Schaison G, Salmon C. Autoimmune hemolytic anemia in children. A review of 80 cases. Am J Med 1974; 56:61.
- Izui S. Autoimmune hemolytic anemia. Curr Opin Immunol 1994; 6:926.
- Buchanan GR, Boxer LA, Nathan DG. The acute and transient nature of idiopathic immune hemolytic anemia in childhood. J Pediatr 1976; 88:780.
- Burkart PT, Hsu TC. IgM cold-warm hemolysins in infectious mononucleosis. Transfusion 1979; 19:535.
- Wilkinson LS, Petz LD, Garratty G. Reappraisal of the role of anti-i in haemolytic anaemia in infectious mononucleosis. Br J Haematol 1973; 25:715.
- Heddle NM. Acute paroxysmal cold hemoglobinuria. Transfus Med Rev 1989; 3:219.
- van den Heuvel-Eibrink MM, Bredius RG, te Winkel ML, et al. Childhood paroxysmal nocturnal haemoglobinuria (PNH), a report of 11 cases in the Netherlands. Br J Haematol 2005; 128:571.
- Tomita M. Biochemical background of paroxysmal nocturnal hemoglobinuria. Biochim Biophys Acta 1999; 1455:269.
- Kanai N, Vreeke TM, Parker CJ. Paroxysmal nocturnal hemoglobinuria: analysis of the effects of mutant PIG-A on gene expression. Am J Hematol 1999; 61:221.
- Rosse WF. Treatment of paroxysmal nocturnal hemoglobinuria. Blood 1982; 60:20.
- Bemba M, Guardiola P, Garderet L, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999; 105:366.
- Flotho C, Strahm B, Kontny U, et al. Stem cell transplantation for paroxysmal nocturnal haemoglobinuria in childhood. Br J Haematol 2002; 118:124.
- Walshe JM. The acute haemolytic syndrome in Wilson's disease--a review of 22 patients. QJM 2013; 106:1003.
- Steindl P, Ferenci P, Dienes HP, et al. Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 1997; 113:212.
- The hemolytic process
- Diagnostic principles
- INTRINSIC HEMOLYTIC ANEMIAS
- Hereditary spherocytosis
- Hereditary elliptocytosis
- Hereditary stomatocytosis
- Abnormalities of erythrocyte glycolytic enzymes
- - Pyruvate kinase deficiency
- - Glucose-6-phosphate dehydrogenase deficiency
- - Other glycolytic enzymes
- - Other pentose phosphate pathway enzymes
- EXTRINSIC HEMOLYTIC ANEMIAS
- Autoimmune hemolytic anemias
- - Warm-reactive hemolytic anemia
- - Cold-agglutinin hemolytic anemia
- - Paroxysmal cold hemoglobinuria
- Paroxysmal nocturnal hemoglobinuria
- Wilson disease