Historical data to be obtained include diet, infection or chronic
disease, medications and other environmental exposures, and ethnicity.3 The
diet during infancy is particularly relevant to iron deficiency. Infants
who have been fed only whole cow’s milk or non-iron-fortified
cow’s milk formulas are at risk for developing iron deficiency.4 Although
the iron present in human milk appears to be better absorbed than
that in cow’s milk, it is insufficient to meet the requirements
for rapid growth in the first year of life, and infants consuming only
breast milk may develop iron deficiency after 9 to 12 months of age.
Vitamin B12 deficiency may occur in breast-fed babies of
strict vegetarian mothers (vegans).5 Infants exclusively
fed goat’s milk are at risk for developing folic acid deficiency.6
The age of the child at recognition of anemia may be diagnostically important
and aid in differentiation of a congenital disorder from an acquired
disorder. Intrinsic abnormalities of the RBC membrane and RBC enzymopathies
may present in the newborn period with anemia and jaundice, whereas
major β-globin chain hemoglobin disorders such
as sickle cell disease and thalassemia major usually have normal
hematologic values in the neonatal period and do not become evident
until 3 to 6 months of age or later.
Many hemolytic anemias are genetically determined therefore a
family history is important to determine a potential pattern of inheritance. An inherited
anemia such as hereditary spherocytosis may be suggested by a family history
of neonatal hyperbilirubinemia, anemia, jaundice, splenomegaly,
splenectomy, or gallstones. A family history indicating dominant inheritance
suggests a defect of the erythrocyte membrane, whereas recessive
inheritance is characteristic of many hemoglobinopathies and enzymopathies.
In the differential diagnosis of anemia in children, the relative frequencies
of various etiologies should also be considered. Iron deficiency
and the anemia of acute and chronic infections are by far the most
common causes of anemia in children. Next in frequency are genetic
conditions such as hereditary spherocytosis. Sickle cell diseases
are prevalent in African Americans, and thalassemia is common in
people of Mediterranean or Southeast Asian ethnicity. Other causes
of anemia are relatively unusual.
The most important physical finding of anemia is pallor, but
this is often a subtle finding that is evident only when the degree
of anemia is relatively severe (Hb < 70–80 g/L).
Anemia is best appreciated by pallor of the mucous membranes and
conjunctivae, particularly in dark-skinned children. The red color
of the palmar creases in the hand disappears when the hemoglobin
falls below 70 to 80 g/L.7 Children tolerate even
fairly severe anemia quite well when it develops slowly. Some children with
iron-deficiency anemia have few symptoms even when the hemoglobin
is 50 to 60 g/L.8 Children with sickle
cell anemia who chronically have hemoglobin levels of 65 to 80 g/L
often have normal activity and few symptoms. Tachycardia is present
only when anemia is severe or develops suddenly. Jaundice, best
appreciated as yellow sclerae, suggests a hemolytic process, although
some children with chronic hemolytic anemias are not clinically
jaundiced.1 Lymphadenopathy, hepatosplenomegaly,
and signs and symptoms of systemic diseases should be ascertained.
In the workup of a child with presumed anemia, it is necessary
to confirm that anemia is actually present according to age- and
gender-appropriate standards (Table 429-1).
Hemoglobin concentrations in those of African American ancestry
are about 5 g/L lower than in Caucasians, a difference
that is not explained by iron deficiency or thalassemia.9
Next, an evaluation is made of whether the anemia is a result
of decreased RBC production (aregenerative) or increased destruction/loss (hemolysis).
This is most easily assessed by the reticulocyte count. Reticulocytosis
reflects increased erythroid activity of the bone marrow; a sustained
reticulocytosis is very suggestive of a hemolytic process, whereas
reticulocytopenia is characteristic of an aregenerative process. Next,
the average size and hemoglobin content of the RBCs should be determined
by measuring the mean corpuscular volume (MCV) and mean corpuscular
hemoglobin (MCH) by automated cell analyzers. Finally, the morphology of
the RBCs should be assessed on a stained peripheral blood smear
(Fig. 430-1). These readily available determinations
permit a presumptive diagnosis of most anemias in children.
Hematocrit, and Red Blood Cell Indices
Modern automated cell analyzers accurately and directly measure white
blood cell (WBC), RBC, and platelet numbers as well as hemoglobin
(Hb) level, MCV, and MCH.3,10 The hematocrit (Hct)
and mean corpuscular hemoglobin concentration (MCHC) are calculated from
the directly measured values. Most automated cell analyzers also
measure RBC distribution width (RDW), which assesses the variability
of size of the RBCs, described as anisocytosis on the peripheral
blood smear. For office-based screening, Hb can also be measured
by point-of-care spectrophotometers, and Hct by microcentrifuges.
Hematocrit values can be estimated by multiplying the Hb value by
0.3, and Hb level is estimated by dividing Hct by 0.3.
The MCV, directly measured by automated cell analyzers, provides
a basis for deciding whether the RBC population is macrocytic, normocytic,
or microcytic. However, age-related norms must be employed to make
this decision because erythrocytes of the fetus and newborn are
very macrocytic, whereas during the first 2 to 3 years of life they
are distinctly microcytic compared to adult values (Table
429-1). The MCH reflects RBC hemoglobin content and gives a
quantitative assessment of hypochromia evident on the blood smear.
Because most microcytic anemias are also hypochromic, MCH is usually proportional
to the MCV and may be even more sensitive than the MCV in the diagnosis
of mild iron deficiency. The MCHC is a derived rather than a directly
measured value and is not useful in assessing hypochromia. A high MCHC,
however, is characteristic of membranopathies such as spherocytosis.
The number of new erythrocytes in peripheral blood reflects the
rate at which new reticulocytes, which contain stainable RNA, are
being produced and released from the erythroid bone marrow. Reticulocytosis
can be recognized by polychromatophilia on the blood smear and may
sometimes be accompanied by an increased MCV because reticulocytes
are larger than mature RBCs. Manual reticulocyte counts can be performed
on blood smear stained with new methylene blue by counting the percentage
of erythrocytes with visible blue staining of RNA reticulum mesh. This
rather tedious manual method has been virtually replaced by fluorescent
techniques performed by automated analyzers,11 which
provide accurate absolute reticulocyte counts. Reticulocytes contain
stainable reticulum for about 1 to 2 days, so the normal reticulocyte
count is 1.0% to 2.0%. The normal absolute reticulocyte count
is 40 to 75 × 109/L.
Low values (< 40 × 109/L)
indicate erythroid underproduction, and increased values (> 100 × 109/L)
suggest erythroid marrow hyperplasia often associated with hemolysis.
Transiently high reticulocyte counts are seen after acute blood
loss and after institution of specific therapy for nutritional deficiencies
of iron, folic acid, or vitamin B12.
Hemolysis refers to an increased rate of erythrocyte
destruction leading to a survival time that is less than the normal
100 to 120 days. In acute hemolysis with a rapid onset of anemia,
a compensatory increase in erythroid marrow activity mediated by
erythropoietin (EPO) takes place several days before peripheral
reticulocytosis appears.1 In chronic hemolytic
states, anemia is usually present because the rate of erythrocyte
destruction and production are not balanced. However, in some patients,
the rate of hemolysis is fully compensated by increased erythrocyte
production, resulting in a normal hemoglobin level. Such patients
will, however, have an elevated reticulocyte count.
In most chronic hemolytic states, erythrocytes are destroyed extravascularly in
the reticuloendothelial (RE) tissues of the spleen, liver, and bone marrow.
Within the RE cell, hemoglobin is catabolized to amino acids, the
heme metabolite bilirubin and iron recycled back to the marrow.
Most patients with chronic severe hemolysis are jaundiced and have
elevated serum levels of unconjugated (indirect) bilirubin. However,
hepatic conjugation and biliary excretion of bilirubin may result
in normal serum bilirubin levels, and hyperbilirubinemia and clinical
jaundice should not be considered essential findings to consider
a diagnosis of hemolysis. Chronically increased rates of bilirubin
excretion, characteristic of congenital and chronic hemolysis, often
result in gallstones, which are composed of calcium bilirubinate
and are usually multiple, faceted, and radiopaque.
Primarily intravascular hemolysis is characteristic
of some hemolytic anemias that are immune mediated, drug induced,
or microangiopathic.1 Free hemoglobin is released
into the plasma, where it combines with haptoglobin and is then cleared
by RE tissues. When the rate of haptoglobin-hemoglobin complex clearance
exceeds the rate of hepatic haptoglobin synthesis, the level of
serum haptoglobin decreases below the normal range (20–200
mg/dL) and is often undetectable in patients with significant hemolysis.
Low or absent levels of serum haptoglobin may also be seen in hemolytic
states where RBC destruction is primarily extravascular. In acute
intravascular hemolysis, the binding capacity of haptoglobin for
hemoglobin may be exceeded, and free hemoglobin is excreted by the
kidney, resulting in hemoglobinuria as indicated by a positive test
for occult blood without erythrocytes in the urinary sediment. In
chronic hemolytic states, hemosiderin may be present in the urinary
Aspiration and Biopsy
Bone marrow examination is painful, and for most common forms
of anemia, it should not be undertaken unless likely to provide
information that cannot be readily obtained from studies of peripheral
blood. For example, measurement of serum ferritin levels and other
iron studies almost always obviates the need for bone marrow aspiration
to assess reticuloendothelial iron stores (hemosiderin).12 Bone
marrow aspiration may be necessary for the diagnosis of pure RBC
aplasias or pancytopenias from marrow failure or invasion. The bone
marrow should usually be evaluated when a diagnosis of leukemia
is considered or when metastatic malignancy, bone marrow failure,
or storage diseases such as Gaucher and Niemann-Pick disease are
suspected. Overall cellularity, morphology, and maturation of the
hematopoietic cell lines can be evaluated. Needle biopsy, performed
at the same time as the aspirate, provides an intact specimen that
is especially useful for assessing marrow architecture and cellularity.
Marrow aspiration is often indicated in thrombocytopenic states
to assess the number of megakaryocytes, an indicator of platelet
production (Chapter 439). The most notable
bone marrow finding in infants and young children, compared to older
patients, is a predominance of mature lymphocytes.