I. Anemia

A. Screening for Anemia

1. 1. The American Academy of Pediatrics (AAP) recommends screening between 9 and 12 months with a repeat level in 6 months.
2. 2. Screen yearly in high-risk children: history of prematurity or low birth weight, exposure to lead, exclusive breastfeeding without supplemental iron beyond 4 months, diet without iron-fortified cereals or foods naturally rich in iron, feeding problems, poor growth, inadequate nutrition¹

B. Definition of Anemia

1. 1. Anemia is defined as a reduction in hemoglobin (Hb) two standard deviations below the mean, based on age-specific norms.
2. 2. See Table 14.1 at the end of the chapter for age-specific blood cell indices.

C. Causes of Anemia

1. 1. See Fig. 14.1 for approach to anemia based on red blood cell (RBC) production, as measured by reticulocyte count and cell size. Note that normal ranges for Hb and mean corpuscular volume (MCV) are age dependent.
2. 2. See ^{TABLE 14.2 TABLE 14.3} for more details regarding specific causes of nonhemolytic and hemolytic anemia.

1. 1. Useful equations in the evaluation of anemia:
   1. a. Mentzer index ² = MCV/RBC
      1. (1) Index >13 suggests iron deficiency anemia (IDA).
      2. (2) Index <13 suggests thalassemia trait.
   2. b. Reticulocyte index = % reticulocytes × patient hematocrit/normal hematocrit ³
      1. (1) >2 is indicative of increased RBC production in appropriate response to anemia.
      2. (2) <2 is evidence of hypoproliferative anemia.
2. 2. Other useful indices and tests
   1. a. RBC distribution width (RDW):
      1. (1) Normal RDW favors thalassemia but can also be elevated.
      2. (2) Increased in IDA and sideroblastic anemia
   2. b. Mean cell hemoglobin concentration (MCHC):
      1. (1) Allows for classification of anemia as hypochromic, normochromic, or hyperchromic
      2. (2) Low MCHC in iron deficiency and thalassemia
      3. (3) Elevated MCHC and spherocytes in hereditary spherocytosis and hemolytic disease of the newborn
   3. c. Serum ferritin:
      1. (1) Reflects total body iron stores after 6 months of age
      2. (2) It is the first value to fall in early iron deficiency and is elevated with inflammation or infection.
   4. d. Coombs test ⁴ :
      1. (1) Direct (direct antiglobulin testing [DAT]): Detects antibody/complement bound to patient’s RBCs by mixing prepared nonspecific antihuman globulin with patient’s blood. RBC agglutination = positive test
      2. (2) Indirect (indirect antiglobulin testing): Detects antibodies to RBC antigens in patient’s plasma by mixing reagent RBCs with patient’s serum. RBC agglutination = positive test
   5. e. Hemoglobin electrophoresis:
      1. (1) Involves separation of Hb variants based on molecular charge and size. All positive sickle preparations and solubility tests for sickle Hb (e.g., Sickledex) should be confirmed with electrophoresis or isoelectric focusing (component of mandatory newborn screening in many states).
      2. (2) See Table 14.4 for neonatal Hb electrophoresis patterns.
      3. (3) See Fig. 14.2 for changes in Hb polypeptide over time in a normal fetus/infant.
   6. f. Blood smear interpretation ³
      1. (1) Howell-Jolly bodies = Impaired splenic function, postsplenectomy
      2. (2) Target cells = Hemoglobinopathies (HbSS, HbSC, HbC, thalassemias), liver disease, postsplenectomy
      3. (3) Bite cells, Heinz bodies = G6PD deficiency (during hemolysis)
      4. (4) Toxic granulation of neutrophils, bandemia, atypical lymphocytes = Infection
      5. (5) Pencil poikilocytes = IDA, thalassemia
      6. (6) Basophilic stippling = Lead poisoning, sideroblastic anemia
      7. (7) Pappenheimer bodies = Sideroblastic anemia
      8. (8) Hypersegmented neutrophils = Vitamin B₁₂, folate deficiencies
      9. (9) Blasts = Leukemia, lymphoma
      10. (10) Schistocytes (RBC fragments) = Microangiopathic hemolytic anemia (MAHA), burns, valve hemolysis
      11. (11) Spherocytes = Autoimmune hemolytic anemia, hereditary spherocytosis, ABO incompatibility/hemolytic disease of the newborn
      12. (12) Elliptocytes = Hereditary elliptocytosis, severe IDA
      13. (13) Teardrop cells = Myelofibrosis (and other bone marrow infiltrating processes), thalassemia
      14. (14) Echinocytes (burr cells) = Frequent artifact finding; uremia, pyruvate kinase deficiency
      15. (15) Acanthocytes (spur cells) = Liver disease, abetalipoproteinemia, hypothyroidism, vitamin E deficiency, severe malnutrition
      16. (16) See ^{eFIGURE 14.1 eFIGURE 14.2 eFIGURE 14.3 eFIGURE 14.4 eFIGURE 14.5 eFIGURE 14.6 eFIGURE 14.7 eFIGURE 14.8 eFIGURE 14.9 eFIGURE 14.10 eFIGURE 14.11 eFIGURE 14.12} for examples of peripheral smears.

1. 1. Iron deficiency anemia
   1. a. Oral iron (ferrous sulfate)
      1. (1) Empirically treat children with microcytic anemia and history of poor dietary iron.⁵
      2. (2) In anemia of chronic disease, only use iron supplementation if evidence of absolute iron deficiency and ferritin <100 ng/mL.⁵
      3. (3) After initiation of iron supplementation, expect reticulocyte count to increase within the first week with a 1g/dL increase in Hb in 4 weeks (if severe anemia with Hb <9g/dL, a response should be seen in 2 weeks).¹
   2. b. Iron infusion (low-molecular-weight iron dextran⁶ or iron sucrose⁷) is appropriate for children with iron malabsorption (PPI use, short bowel syndrome, primary malabsorption), poor response to oral iron therapy, inability to tolerate oral iron therapy, and hemodialysis-dependent patients receiving erythropoietin.
2. 2. Sickle cell anemia
   1. a. Etiology: Caused by a genetic defect in β-globin that leads to HbS polymerization and RBC sickling with deoxygenation, leading to hemolysis, adherence to blood vessel endothelium, and vaso-occlusive ischemia.
   2. b. Most common subtypes: HbSS (sickle cell anemia) and HbSβ⁰ (sickle-β⁰-thalassemia) are most severe. HbSC (sickle-hemoglobin C disease) and HbSβ+ (sickle-β+-thalassemia) are often milder.
   3. c. Diagnosis: Often made on newborn screen with Hb electrophoresis. The sickle preparation and Sickledex are rapid tests that are positive in all sickle hemoglobinopathies. False-negative test results may be seen in neonates and other patients with a high percentage of fetal Hb.
   4. d. Complications: See Table 14.5. A hematologist should be consulted.
   5. e. Acute management of anemia in sickle cell disease⁸ :
      1. (1) Baseline lab values including CBC, reticulocyte, hemoglobin electrophoresis (percent HbF), creatinine, BUN, urinalysis, liver function tests, fractionated bilirubin should be collected to compare with those during acute illness.
      2. (2) RBC exchange transfusions: Indicated for patients with stroke, acute chest syndrome (ACS) with rapid progression or clinical deterioration, and multisystem organ failure. May be indicated for hepatic sequestration, intrahepatic cholestasis, and refractory priapism. Also indicated for children with prior stroke or transcranial Doppler reading >200 cm/sec.⁸ Replace with HbS-negative cells. Follow Hct carefully with goal Hct <30% to avoid hyperviscosity.⁹
      3. (3) Do not transfuse for asymptomatic anemia unless concern for aplastic crisis (low reticulocyte count).
   6. f. Chronic management and health maintenance⁸ : See Table 14.6. Ongoing consultation and clinical involvement with a pediatric hematologist and/or sickle cell program are essential. Bone marrow transplant is the only current curative therapy.
3. 3. Thalassemia
   1. a. Etiology: Defects in α- or β-globin production lead to precipitation of excess chains, causing ineffective erythropoiesis and shortened survival of mature RBCs.
   2. b. α-Thalassemia:
      1. (1) Silent carriers (α−/αα): Not anemic; Hb electrophoresis usually normal
      2. (2) α-Thalassemia trait (α−/α−) or (αα/−): Causes mild microcytosis with or without mild anemia from birth; Hb electrophoresis usually normal. Hb Barts can be seen transiently in infancy (e.g., on state newborn screens) in patients with α-thalassemia trait.
      3. (3) HbH disease (β₄) (α−/−−): Causes mild to moderate anemia from birth; higher levels of Hb Barts seen on newborn screen with transition to HbH (β-tetramer) on subsequent electrophoresis.
      4. (4) Hb Barts/hydrops fetalis (−−/−−): Hb Barts (γ₄) cannot deliver oxygen; usually fatal in utero or in neonatal period.
   3. c. β-Thalassemia: Ineffective erythropoiesis is more severe in β-thalassemia than α-thalassemia. Patients often develop more severe iron overload from increased enteral absorption and transfusions. Adult Hb electrophoresis with decreased Hb A, increased Hb A₂, and increased HbF.
      1. (1) Thalassemia trait/thalassemia minor (β/β+) or (β/β0): Mildly decreased β-globin production. Usually asymptomatic with mild anemia.
      2. (2) Thalassemia intermedia (β+/β+): Markedly decreased β-globin production. Presents by 2 years of age with moderate compensated anemia (Hb 7 to 10 g/dL). Wide variability in presentation that may include features noted in thalassemia major.
      3. (3) Thalassemia major/Cooley anemia (β0/β0, β+/β0, or β+/β+): Minimal to no β-globin production. Presence of anemia within first 6 months of life requiring regular transfusions. Overstimulation of bone marrow, ineffective erythropoiesis, and iron overload results in jaundice, growth failure, hypersplenism, gallstones, skeletal abnormalities, liver cirrhosis, and cardiac impairment.
   4. d. Management¹⁰
      1. (1) Patients with thalassemia major are transfusion dependent. Patients with thalassemia intermedia may need occasional transfusions.
      2. (2) Transfuse every 3 to 5 weeks to maintain Hb >9 to 10.5 mg/dL.
      3. (3) Avoid hypertransfusion to Hb >14 to 15 g/dL due to risk of hyperviscosity-related symptoms, including stroke.
      4. (4) Treat iron overload with chelation (deferasirox or deferiprone PO, deferoxamine SQ or rarely IV), which should be initiated in thalassemia major after 10 to 20 transfusions or when ferritin >1000 μg/L.
      5. (5) Bone marrow transplant is curative.