• Thorough history may help identify risk as well as cause.
• Diet can identify children most likely to develop iron-deficiency anemia.
• Signs of systemic illness (fever, weight loss) with anemia may indicate underlying systemic disease, such as an autoimmune disorder.
• Historical factors important for diagnosis of anemia
  • Age
    • Nutritional anemias are rare in term infants but more common in infants born preterm, school-age children, and adolescents.
    • Significant anemia diagnosed in the first 6 months of life in a term infant is most likely due to a congenital anemia.
  • Sex
    • Glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency are X-linked disorders.
  • Race/ethnicity
    • Thalassemias are more common in patients of African or Asian descent, whereas thalassemia syndromes are more common in patients of Mediterranean descent.
  • Nutrition
    • Sources of iron, folate, vitamin B₁₂, and vitamin E should be documented.
    • A history of pica suggests iron deficiency.
  • Medications
    • Phenytoin and methotrexate can induce a megaloblastic anemia.
    • Oxidants can induce hemolytic anemias
    • Sulfa drugs can produce a hemolytic anemia in patients with G6PD deficiency.
  • Family history
    • Anemia, jaundice, gallstones, cholecystitis, splenomegaly, splenectomy, or hemolytic crisis may suggest an inherited hemolytic anemia.
  • Infections
    • Infections may induce hemolysis or RBC hypoplasia or aplasia (parvovirus B19).
    • Hepatitis may induce aplastic anemia.
    • Common acute bacterial and viral infections may result in mild anemia from decreased RBC production or increased RBC destruction, or both.
      • These anemias are typically short-lived but commonly identified on routine screening.
  • Gastrointestinal
    • The gastrointestinal tract is a common source of blood loss.
    • Nutritional deficiencies may result from malabsorption syndromes.

• Most mild/moderate anemias are asymptomatic.
• Possible symptoms of anemia
  • Infants and toddlers
    • Fatigue
    • Irritability
    • Pallor
    • Increased sleep
    • Poor feeding
    • Failure to thrive
  • Older children and adolescents
    • Fatigue
    • Pallor
    • Exercise intolerance
    • Dizziness

• Headaches
• Shortness of breath
• Palpitations
• Pallor
  • Rare in mild anemias but common in children with moderate to severe anemia
  • Does not necessarily indicate a low hemoglobin level
  • Frequently only seen reliably with hemoglobin concentrations < 8 g/dL
  • May be more easily identified in nail beds, mucosa, conjunctiva, and palmar creases
• Signs of hemolytic anemia
  • Splenomegaly
  • Icterus

• Signs of chronic hemolytic anemia (e.g., thalassemia)
  • Frontal bossing
  • Maxillary prominence
• Leukemia or lymphoma may present with anemia with focal lymphadenopathy and hepatosplenomegaly.

• Cardiovascular signs
  • Mild to moderate decrease in RBC mass may result in pulmonary flow murmur.
  • More severe anemias may be associated with signs of congestive heart failure.

Utility of subclassification

• Subclassification of anemias as microcytic, normocytic, and macrocytic greatly reduces the differential diagnosis and limits the number of laboratory tests needed for diagnosis.

Anemia in newborns

• Classifying the cause into 1 of 3 broad classifications is helpful.
  • Blood loss
    • Twin-to-twin transfusions
    • Chronic blood loss throughout pregnancy
      • Infant may have pallor and microcytic, hypochromic anemia but appear otherwise well and hemodynamically stable.
    • Infants with acute blood loss
      • May have pallor, tachypnea, tachycardia, hypotension, and decreased tone
      • Normocytic, normochromic anemia with a reticulocytosis will be detectable soon after birth.
  • Hemolysis
    • Different maternal blood types or antigens, maternal drug use, or neonatal infections
    • Microangiopathic hemolysis may occur in infants with thrombi, disseminated intravascular coagulation, and Kasabach-Merritt syndrome (multiple cavernous hemangiomas).
  • Decreased production

Differential diagnosis of specific pathologic RBC features

• Target cells: surface-to-volume ratio is increased.
  • Thalassemia
  • Hemoglobinopathies
  • Hemoglobin C disease
  • Hemoglobin E disease
  • Hyposplenism or postsplenectomy
  • Hepatic disease
  • Severe iron-deficiency anemia
  • Abetaproteinemia
  • Lecithin or cholesterol acyltransferase deficiency
• Spherocytes: hyperdense cells with a decreased in surface-to-volume ratio and an increased mean corpuscular hemoglobin concentration
  • Hereditary spherocytosis
  • Hemolytic anemia (autoimmune, ABO incompatibility, water dilution)
  • Microangiopathic hemolytic anemia
  • Hemoglobin SS disease
  • Hypersplenism
  • Burns
  • After RBC transfusions
  • Pyruvate kinase deficiency
• Acanthocytes (spur cells): cells with 10–15 spicules that are typically irregular in length, spacing and width; cells usually smaller than normal RBCs
  • Disseminated intravascular coagulation
  • Microangiopathic hemolytic anemia
  • Hyposplenism or postsplenectomy
  • Hepatic disease
  • Hypothyroidism
  • Vitamin E deficiency
  • Abetalipoproteinemia
  • Malabsorption
• Echinocytes (burr cells): cells with 10–30 spicules that are typically of similar size and distributed evenly
  • Dehydration
  • Renal disease
  • Hepatic disease
  • Pyruvate kinase deficiency
  • Peptic ulcer disease
  • After RBC transfusion
• Pyknocytes: hyperchromic RBCs with decreased volume and distorted shape
  • Similar to acanthocytes and echinocytes
• Blister cells: contain a clear area in RBCs that contains no hemoglobin
  • Hemoglobin SS disease
  • G6PD deficiency
  • Pulmonary emboli
• Basophilic stippling: retention of RNA, resulting in fine blue inclusions in the cytoplasm
  • Iron-deficiency anemia
  • Lead poisoning
  • Hemolytic anemias
  • Pyrimidine 5’-nucleotidase deficiency
• Elliptocytes: elliptical-shaped cells
  
  • Hereditary elliptocytosis
  • Iron-deficiency anemia
  • Thalassemia
  • Hemoglobin SS disease
  • Sepsis
  • Megaloblastic anemia
  • Malaria
  • Leukoerythroblastic reaction
• Teardrop cells: microcytic and hypochromic cells that are teardrop-shaped
  
  • Normal finding in newborns
  • Thalassemia
  • Myeloproliferative diseases
  • Leukoerythroblastic reaction
• Schistocytes: RBC fragments that result from trauma
  
  • Disseminated intravascular coagulation
  • Hemolytic anemia and microangiopathic hemolytic anemia
  • Kasabach-Merritt syndrome
  • Purpura fulminans
  • Hemolytic-uremic syndrome
  • Uremia, glomerular nephritis, acute tubular necrosis
  • Cirrhosis
  • Malignant hypertension
  • Thrombosis
  • Thrombotic thrombocytopenia purpura
  • Amylosis
  • Chronic relapsing schistocytic hemolytic anemia
  • Burns
  • Connective tissue disorders
• Stomatocyte: area of central pallor is more slitlike than round
  
  • Stomatocytosis (hereditary)
  • Thalassemia
• Nucleated RBCs: normal on peripheral blood smear in the first week of life only
  
  • Significant bone marrow stimulation
  • Congenital infections
  • Hyposplenism or postsplenectomy
  • Leukoerythroblastic reaction, particularly with severe infections and leukemias or metastatic tumors in the bone marrow
  • Megaloblastic anemia
  • Dyserythropoietic anemia

• Tests to perform
  • Hemoglobin level and hematocrit
  • RBC morphology (see Differential Diagnosis)
  • MCV
  • Reticulocyte count
    • Elevated count implies bone marrow compensation for chronic blood loss or hemolysis.
    • Low count may suggest impaired RBC production or acute blood loss.
  • Stool guaiac tests for occult blood should be performed at several different times to capture intermittent bleeding.
  • The following tests are not necessary in initial diagnosis but help identify cause.
    • Iron studies
    • Erythrocyte sedimentation rate
    • Serum bilirubin
    • Serum lactate dehydrogenase
• Normal values for hemoglobin (g/dL)/hematocrit (%)/MCV (fL), by age
  • Cord blood: 15.3/49/112
  • 1 day: 19.0/61/119
  • 1 week: 17.9/56/119
  • 1 month: 17.3/54/112
  • 2 months: 10.7/33/100
  • 3 months: 11.3/33/88
  • 6 months - 2 years: 12.5/37/77
  • 2–4 years: 12.5/38/79
  • 5–7 years: 13/39/81
  • 8–11 years: 13.5/40/83
  • 12–14 years
    • Girls: 13.5/41/85
    • Boys: 14/43/84
  • 15–17 years
    • Girls: 14/41/87
    • Boys: 15/46/86
• Black children on average have normal hemoglobin values that are approximately 0.5 g/dL lower than those in white and Asian children.

• Chest radiograph may be required if pulmonary hemosiderosis needs to be ruled out.

• Bone marrow aspiration and biopsy may be required in patients with anemia suspected of having bone marrow involvement or abnormalities.