Evaluation of Pallor in Children

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Evaluation of pallor in children

Authors: Char Witmer, MD, MSCE, Catherine S Manno, MD
Section Editors: Gary R Fleisher, MD, Jan E Drutz, MD
Deputy Editor: James F Wiley, II, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2021. | This topic last updated: Mar 17, 2020.
INTRODUCTION
This topic will review the differential diagnosis and approach to children with pallor.
The approach to the child with anemia is discussed separately. (See "Approach to the child with anemia".)
BACKGROUND
The development of pallor can be acute and associated with a life-threatening illness, or it can be chronic and subtle, occasionally first noted by
someone who sees the child less often than the parents. The onset of pallor can provoke anxiety for parents who are familiar with the
descriptions of the presentation of leukemia in childhood. In some instances, only reassurance may be needed, as in the case of a light
complexioned or fair-skinned, non-anemic child. In other instances, pallor may occur in patients with nonhematologic conditions such as shock,
anaphylaxis, respiratory failure, or hypoglycemia. Even if there is a hematologic cause for the pallor, it often is a temporary condition readily
amenable to therapy. However, pallor can portend a serious disease, and when onset is acute, it can herald a true pediatric emergency for which
rapid diagnosis and treatment are needed.
CAUSES
Any condition that decreases the concentration of hemoglobin or alters the distribution of blood away from the body's surface may present as
pallor ( table 1). Clinically, pallor caused by anemia usually can be appreciated when the hemoglobin concentration is below 8 to 9 g/dL (4.96 to
5.56 mmol/L), although the complexion of the child and the rapidity of onset may influence this value.
The concentration of hemoglobin in the blood can be lowered by three basic mechanisms:
● Decreased erythrocyte production

● Increased erythrocyte destruction
● Blood loss
Anemias may also be classified by the size of the red blood cell: microcytic, normocytic, or macrocytic. The most common causes of anemia seen
in the emergency department (ED) are iron deficiency, infection, and blood loss, but several less common diseases remain important
considerations.
Nonhematologic causes of pallor include complexion ("fair skin"), hypoperfusion from shock, respiratory distress, hypoglycemia, skin edema, and
pheochromocytoma.
Life-threatening causes — The conditions that are life-threatening and cause pallor can be divided into nonhematologic and hematologic
causes ( table 1).
Nonhematologic — Pallor may be associated with respiratory failure, poor tissue perfusion (shock), and hypoglycemia. Etiologies for shock
include sepsis, hypovolemia, traumatic brain or spinal cord injury, heart failure, arrhythmia, or anaphylaxis. These conditions require recognition
and intervention prior to knowing the results of hematologic studies ( algorithm 1).
Severe blood loss — Massive hemorrhage (eg, severe trauma) is accompanied by signs of hypovolemic shock and is considered an
emergency. Rapid fluid resuscitation is required to reverse the hemodynamic abnormalities. The initial hemoglobin and indices are typically
normal due to lack of equilibration. (See "Hypovolemic shock in children: Initial evaluation and management".)
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Autoimmune hemolytic anemia — Pallor caused by autoimmune hemolytic anemia (AIHA) is usually acute in onset and may be associated
with severe anemia. On physical examination, the child with AIHA often will be pale and jaundiced. Tachycardia is typically present, as is a systolic
flow murmur, reflecting a high-output anemic state. However, cardiovascular compromise (eg, congestive failure) is uncommon unless the
hemoglobin concentration is <5 g/dL (3.10 mmol/L). The liver and spleen may be palpable, but the presence of massive organomegaly or lymph
node enlargement should suggest another disorder such as malignancy (eg, leukemia, lymphoma) or infection (eg, HIV, malaria, tuberculosis).
The presence of only a moderate anemia (6 to 8 g/dL [3.72 to 4.96 mmol/L]) at diagnosis should not detract from consideration of this disease as
a hematologic emergency because brisk hemolysis may result in a sudden, additional fall in the hemoglobin level that could be life-threatening.
It is usually characterized by a positive direct anti-globulin test (DAT or direct Coomb test) and an increased reticulocyte count. Spherocytes are
commonly seen in the peripheral smear ( picture 1). (See "Autoimmune hemolytic anemia in children: Classification, clinical features, and
diagnosis", section on 'Clinical presentation'.)
The etiology and treatment of AIHA in children is discussed separately. (See "Overview of hemolytic anemias in children" and "Autoimmune
hemolytic anemia in children: Treatment and outcome", section on 'Treatment'.)
Sickle cell anemia with splenic sequestration — The sequestration episodes of sickle cell anemia and related hemoglobin disorders (SC
disease, S-beta (0) thalassemia, S-beta (+) thalassemia) result from acute pooling of red cells and plasma in the spleen.
The sudden and severe anemia and the hypovolemia associated with this complication constitute a true hematologic emergency and, if
untreated, may rapidly lead to death. The presence of increased pallor and acute enlargement of the spleen in a patient with a sickling disorder
should prompt immediate investigation of a possible sequestration crisis.
Although this complication rarely occurs in children with homozygous sickle cell disease or S-beta (0) thalassemia after the age of five years,
sequestration crises may occur much later in children with milder sickling disorders such as SC or S-beta (+) thalassemia, in which early splenic
infarction is uncommon. Additionally, patients with SC or S-beta (0) thalassemia started on disease modifying therapy at a young age (ie,
hydroxyurea or chronic red cell transfusions) could have persistence of splenic tissue and remain at risk for splenic sequestration after the age of
five years. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Splenic sequestration crisis'.)
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) — The red blood cell destruction in both of these
processes is secondary to fibrin deposition resulting in microangiopathic hemolysis with schistocytes, helmet cells, and RBC fragments on the
peripheral blood smear ( picture 2 and picture 3). Thrombocytopenia and uremia may lower the hemoglobin concentration even further by
causing bleeding, impaired red cell production, shortened red cell survival, and increased plasma volume. In some instances, the anemia may be
moderately severe when the uremia is only mild and thrombocytopenia is absent, leaving doubt about the correct diagnosis. In more typical
cases, however, the diagnosis is readily apparent from the findings of oliguria, central nervous system (CNS) abnormalities, increased blood urea
nitrogen (BUN), and thrombocytopenia. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic
uremic syndrome (HUS) in children", section on 'Clinical and laboratory manifestations' and "Acquired TTP: Clinical manifestations and
diagnosis".)
Disseminated intravascular coagulation (DIC) — In DIC, abnormal fibrin deposition within small blood vessels results in mechanical injury
to the erythrocytes. Thrombocytopenia and clotting abnormalities, which often herald the onset of DIC, also may contribute to the anemia by
causing diffuse bleeding. The main diagnostic findings are red cell fragments in the peripheral blood smear ( picture 2 and picture 3),
platelet and clotting abnormalities typical of a consumptive coagulopathy, and the clinical features of a disease such as septic shock, which is
associated with DIC. (See "Disseminated intravascular coagulation in infants and children", section on 'Clinical manifestations' and "Disseminated
intravascular coagulation in infants and children", section on 'Laboratory findings'.)
Malignancy — Hypoplastic anemia can be the presenting symptom of childhood malignancies. The pallor can be severe, and although all
three cell lines of the bone marrow usually are affected, anemia may be the only notable hematologic abnormality [1]. The diagnosis can be
suspected from the presence of other symptoms or findings such as lymphadenopathy, bruising, limb pain, gum bleeding, or an abdominal
mass. Malignancies that can present with anemia include leukemias, lymphomas, and other solid tumors that infiltrate the bone marrow (eg,
neuroblastoma). (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical
presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Presenting symptoms'.)
Common hematologic conditions — The common hematologic conditions that result in pallor can be divided into decreased RBC production,
increased RBC destruction, and blood loss ( table 1).
Decreased RBC production
● Iron deficiency anemia – Anemia from iron deficiency is usually seen in the first two years of life, at which time the dietary iron content is
often insufficient to meet the demands of the rapidly increasing red cell mass. It is the most common hematologic disorder in childhood,
affecting approximately 5 to 10 percent of young children. The typical presentation of iron deficiency anemia (IDA) is an otherwise
asymptomatic, well-nourished infant or child who has a mild to moderate microcytic, hypochromic anemia ( picture 4). Much less frequent
are infants with severe anemia, who present with lethargy, pallor, irritability, cardiomegaly, poor feeding, and tachypnea. (See "Iron
deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Clinical manifestations
of IDA'.)
For infants presenting with a mild microcytic anemia and a presumptive diagnosis of IDA, a therapeutic trial of iron is the most cost effective
strategy. In children older than two years of age, dietary causes of iron deficiency are less likely, and other causes of anemia (eg, chronic
blood loss, chronic disease, celiac disease) need to be considered. (See "Iron deficiency in infants and children <12 years: Screening,
prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected IDA'.)
● Aplastic episodes in patients with a hemolytic anemia – Patients with inherited hemolytic anemias such as spherocytosis or sickle cell
disease may develop red cell aplasia, usually in association with parvovirus B19 infection. Decreased red cell production in the face of
ongoing hemolysis causes an exacerbation of the anemia. The usually elevated reticulocyte count falls to inappropriately low levels, often
less than 1 percent. Although the platelets and white cells are generally unaffected, they may be mildly decreased. Red cell transfusions are
appropriate if the anemia is associated with cardiovascular signs or symptoms or if continuing reticulocytopenia indicates that the anemia is
likely to become severe before the usual spontaneous recovery after three to seven days. (See "Clinical manifestations and diagnosis of
parvovirus B19 infection", section on 'Transient aplastic crisis'.)
● Transient aplastic episodes in patients with immunocompromise and parvovirus infection – Patients with an immunodeficiency from
either a congenital immune disorder or acquired immune dysfunction in the setting of chemotherapy for malignancy, immunosuppression
post-transplant or HIV infection can experience a parvovirus B19 related aplastic episode from an inability to clear the parvovirus infection
with resultant persistent reticulocytopenia. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient
aplastic crisis'.)
● Lead poisoning – Lead poisoning reduces heme synthesis, but significant anemia is unusual unless blood lead levels are markedly elevated.
Iron deficiency is common in children with increased lead levels and usually accounts for the microcytic anemia found in these patients. If a
concomitant hematologic disorder cannot be found in the anemic patient with plumbism, particular care should be given to the possibility of
severe lead intoxication. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Hematologic'.)
● Anemia of inflammation – Occasionally, pallor is the only presenting finding of a serious systemic inflammatory disorder. Chronic
inflammatory diseases are often accompanied by a normocytic or microcytic anemia that is multifactorial related to abnormal iron
homeostasis, impaired erythropoiesis, and a blunted erythropoietin response (see "Anemia of chronic disease/anemia of inflammation",
section on 'Differential diagnosis').
Inflammation increases hepcidin production, which is a negative regulator of iron, decreasing iron absorption in the gastrointestinal (GI)
tract; as well as sequestration of macrophage iron, which results in iron restricted erythropoiesis. Laboratory results in anemia of
inflammation demonstrate a reduced serum iron and low total iron-binding capacity with a normal to high ferritin. (See "Anemia of chronic
disease/anemia of inflammation", section on 'Iron studies'.)
Increased RBC destruction
● Sickle cell syndromes – Patients with sickle cell disease have a baseline hemolytic anemia and pallor. Acute accentuation of the pallor can
result from an aplastic crisis, increased hemolysis, or acute pooling of red cells in the spleen. (See 'Sickle cell anemia with splenic
sequestration' above and 'Decreased RBC production' above.)
● Hereditary spherocytosis – Patients with hereditary spherocytosis, the most common of the red cell membrane disorders, typically present
with anemia, jaundice, and splenomegaly. However, the degree of anemia is extremely variable and may be absent, mild, moderate, or
severe to the point of threatening life.
Because hereditary spherocytosis often is inherited in an autosomal dominant fashion, a family history of anemia, splenomegaly,
splenectomy, or cholecystectomy may be helpful. However, a particularly severe form of spherocytosis occurs as an autosomal recessive
disorder, and some children with more typical disease lack an informative family history. Consequently, the diagnosis should not be
dismissed in the absence of other affected family members, in that only 75 percent will have a family history. The red cell morphology often
permits the diagnosis of spherocytosis to be made from the peripheral smear ( picture 1). (See "Hereditary spherocytosis", section on
'Clinical presentation'.)
Chronic blood loss — Although sudden, massive hemorrhage usually is accompanied by signs of hypovolemic shock, the repeated loss of
smaller amounts of blood may be associated with few findings other than pallor. The finding of iron deficiency anemia despite normal dietary
iron intake or iron supplementation may be a clue to the presence of chronic blood loss from the GI tract (eg, Meckel diverticulum, peptic ulcer,
variceal bleeding), heavy menstrual bleeding in females, or within the lungs (eg, pulmonary hemosiderosis).
Other conditions that cause pallor
● Decreased red blood cell production
• Acquired aplastic anemia – The clinical presentation of aplastic anemia (AA) is variable and includes symptoms and signs related to
cytopenia in each of the three cell lineages including fatigue, pallor, and cardiovascular complaints caused by progressive anemia;
hemorrhagic manifestations secondary to thrombocytopenia; and/or fever, mucosal ulcerations, and bacterial infections resulting from
neutropenia. A diagnosis of AA is suggested by the presence of pancytopenia with absolute reticulocytopenia, suggestive of bone
marrow failure. The condition is often idiopathic but has been associated with exposure to certain drugs and chemicals
(chloramphenicol, benzene, pesticides), radiation, and viral infections (especially hepatitis). (See "Acquired aplastic anemia in children
and adolescents".)
• Transient erythroblastopenia of childhood (TEC) – TEC is a condition often associated with a recent viral illness, and it is characterized
by moderate to severe anemia caused by diminished red cell production. The mean corpuscular volume (MCV) usually is normal at the
time of diagnosis. The white cell count is normal or moderately decreased; the platelet count is normal. The reticulocyte count is
decreased, and the direct antiglobulin test (direct Coomb test) is negative. Bone marrow examination shows reduction or absence of
erythrocyte precursors initially, followed by erythroid hyperplasia during recovery. TEC that occurs in the first six months of life may be
difficult to distinguish from Diamond-Blackfan anemia. Spontaneous recovery ultimately confirms the diagnosis of TEC. (See "Overview
of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.).
• Folic acid and vitamin B12 deficiency or other associated abnormalities – These nutritional anemias are uncommon in children in the
United States and rarely develop in the absence of a grossly altered diet, extended hyperalimentation, intestinal resection, celiac disease,
or chronic diarrhea. Unusual alterations of B12 and folic acid absorption and metabolism may cause symptoms similar to those of the
nutritional megaloblastic anemias. Megaloblastic anemia is rarely severe enough to be life-threatening. (See "Treatment of vitamin B12
and folate deficiencies".)
The condition is characterized by normochromic, macrocytic red blood cells, elevated red cell distribution width (RDW), hypersegmented
neutrophils, and an elevated serum level of lactate dehydrogenase (LDH). Leukopenia and thrombocytopenia may be present, but a
bone marrow aspirate demonstrates hypercellularity with megaloblastic changes. The diagnosis of folate deficiency is confirmed by the
finding of low red cell folate levels and an elevated homocysteine. B12 deficiency is confirmed by a low serum vitamin B12 and/or an
elevated serum homocysteine and methylmalonic acid. In addition, the diagnosis is confirmed with a response to vitamin B12 or folate
replacement. (See "Treatment of vitamin B12 and folate deficiencies".)
• Diamond-Blackfan syndrome – Diamond-Blackfan syndrome is congenital hypoplastic anemia commonly detected in the first few
months of life. The anemia can be severe at the time of diagnosis. The red blood cells are normocytic or macrocytic. The reticulocyte
count is low. The white blood cell count is low in 10 percent of affected patients, but thrombocytopenia only occurs rarely. The diagnosis
is made by examination of a bone marrow aspirate that shows markedly reduced or absent erythrocyte precursors. (See "Overview of
causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)
• Dyskeratosis congenita – Dyskeratosis congenita is an inherited bone marrow failure syndrome secondary to accelerated telomere
shortening. It is characterized by oral leukoplakia, hyper and hypopigmentation, and dystrophic nails. Patients are at risk for developing
aplastic anemia, myelodysplastic syndrome or leukemia. (See "Dyskeratosis congenita and other short telomere syndromes".)
• Fanconi anemia – Fanconi anemia is characterized by pancytopenia and associated abnormalities, including hyperpigmentation and
hypopigmentation, microcephaly, strabismus, small stature, intellectual disability (mental retardation), and abnormalities of the thumbs
and radii. Unlike Diamond-Blackfan, all three cell lines of the bone marrow are affected, and the hematologic abnormalities rarely
develop before three to four years of age. The anemia is normochromic and macrocytic. (See "Inherited aplastic anemia in children and
adolescents".)
• Sideroblastic anemia – Sideroblastic anemia is a disorder of hemoglobin synthesis resulting in hypoproductive state. This disorder is
characterized by a microcytic, hypochromic anemia. Sideroblastic anemia may be inherited (sex-linked) or acquired. Iron use within the
developing red cell is abnormal, accounting for the presence of diagnostic ringed sideroblasts in the bone marrow. The serum iron and
ferritin levels usually are markedly elevated. (See "Sideroblastic anemias: Diagnosis and management".)
• Thalassemia – The production of the globin portion of the hemoglobin molecule is reduced or absent resulting in a compensating
increase of other globin chains and reduced or absent production of adult hemoglobin A. Beta-Thalassemia major (Cooley's anemia)
presents with severe pallor usually between 6 and 12 months of age, as the fetal hemoglobin level declines but the normal rise in the
adult hemoglobin (HbA) production fails to occur because of reduced or absent beta-globin production. Although beta-thalassemia is
often associated with Mediterranean ancestry, this disease and related disorders (eg, E-beta thalassemia, HgH disease) also are seen
commonly in children of Southeast Asian, Indian, Pakistani, and Chinese ancestry. The presence of hepatosplenomegaly and
characteristic red cell morphology, including marked variation in red cell shape, makes this diagnosis readily apparent. (See "Clinical
manifestations and diagnosis of the thalassemias".)
● Increased red blood cell destruction
• Erythrocyte membrane defects – Elliptocytosis, stomatocytosis, and pyknocytosis describe other erythrocyte membrane defects that
are less common than hereditary spherocytosis. Moderate or severe anemia is less common in these disorders. Elliptocytosis and
stomatocytosis have characteristic findings on peripheral blood smear ( picture 5 and picture 6). Infantile pyknocytosis is a
hemolytic anemia seen during the first few months of life and is characterized by distorted and contracted erythrocytes and burr cells.
The disorder may be associated with pallor and hyperbilirubinemia. Spontaneous recovery usually occurs by six months of age. (See
"Hereditary elliptocytosis and related disorders".)
• Erythrocyte enzyme defects – Erythrocyte enzyme defects such as pyruvate kinase deficiency and certain variants of glucose-6-
phosphate dehydrogenase (G6PD), may be associated with pallor from increased red blood cell destruction. In G6PD deficiency, pallor
may be accentuated by acute hemolytic crises after exposure to oxidant stress (eg, naphthalene-containing mothballs, drugs, acidosis).
Although alterations in red cell morphology sometimes are found in these enzyme disorders, assays of specific enzymes or substrates
are required for definitive diagnosis. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and
"Pyruvate kinase deficiency".)
• Kasabach Merritt syndrome – The abnormal proliferation of blood vessels within vascular tumors (most commonly tufted angioma or
hemangioendothelioma) may trap red cells or may initiate a localized consumptive coagulopathy, causing erythrocyte destruction.
Anemia is rarely severe unless the thrombocytopenia, that is more typical of the disorder, causes blood loss. (See "Tufted angioma,
kaposiform hemangioendothelioma, and the Kasabach-Merritt phenomenon".)
● Chronic blood loss – Blood loss can occur in conjunction with autoimmune disorders including inflammatory bowel disease and anti-
glomerular basement membrane disease (Goodpasture syndrome). Idiopathic pulmonary hemosiderosis results from slow but intractable
hemorrhage into the bronchioles and alveoli resulting in iron deficiency anemia. (See "Idiopathic pulmonary hemosiderosis".)
EVALUATION
Initial assessment of a child with pallor should include an immediate determination of the degree of illness. The acute onset of pallor consistent
with life-threatening hemorrhage or hemolysis requires emergency evaluation and treatment. (See "Hypovolemic shock in children: Initial
evaluation and management", section on 'Management' and "Autoimmune hemolytic anemia in children: Treatment and outcome", section on
'Severe or life-threatening anemia'.)
If the child with pallor is not acutely ill, a deliberate search for the cause of pallor should be undertaken.
History — Initial assessment of a child with pallor should include an immediate determination of the degree of illness. If the child with pallor is
not acutely ill, a deliberate search for the cause of pallor should be undertaken. A thorough yet relevant history should be obtained with
particular attention to the type of onset of pallor. The slow development of pallor, which may be noticed by a family member or friend who sees
the child only occasionally, suggests diminished red cell production, as is found in iron deficiency or bone marrow aplasia.
However, the acute onset of pallor is consistent with the brisk hemolysis found in autoimmune hemolytic anemia and often is accompanied by
jaundice, dark urine, and cardiovascular changes.
After establishing the type of onset of anemia, the history can be directed toward more narrow categories of anemia or specific diseases (
table 2). A detailed dietary history, with particular attention to milk intake, is important in young children with suspected iron deficiency.
Vitamin B12 deficiency may accompany strict vegetarian diets from which meat and egg products are excluded for many years and may occur in
breast fed infants of vegetarian mothers or mothers with pernicious anemia. Sources of internal or external blood loss should be carefully
sought. Chronic gastrointestinal (GI) bleeding may escape detection until iron deficiency anemia develops.
Similarly, small pulmonary hemorrhages associated with idiopathic pulmonary hemosiderosis are often mistaken for other pulmonic processes
until several recurrences of iron deficiency anemia suggest a hidden site of blood loss. If increased bruising or bleeding accompanies pallor,
multiple blood elements are probably affected. The circulation time for platelets is short in comparison with that of red cells. Clinical findings of
thrombocytopenia often are present by the time pallor develops in patients with acquired aplastic anemia, Fanconi anemia, and acute leukemia.
The family history helps in the diagnosis of hemoglobinopathies and inherited disorders of red cell membranes and enzymes. Because results of
previous hemoglobin testing may have been explained inadequately or recalled inaccurately, a negative family history or newborn screening for
hemoglobinopathies should not preclude evaluation of the patient's hemoglobin phenotype if a sickling disorder is suspected. A history of
splenomegaly, splenectomy, or early cholecystectomy in family members may help identify a hemolytic disorder such as hereditary spherocytosis
or pyruvate kinase deficiency. Finally, a well-directed review of systems is essential in looking for systemic disorders such as chronic renal disease,
hypothyroidism, or rheumatologic disorders.
Physical examination — In the examination of the severely anemic patient, pallor of the skin and mucous membranes usually is readily
apparent. When anemia is less severe or when the skin color is dark, pallor may be appreciated only in the nailbeds and palpebral conjunctivae.
● Vital signs – Blood pressure and pulse should be measured to be sure that hypovolemic shock and high output cardiac failure are neither
present nor imminent. If anemia or volume loss is mild to moderate, tachycardia may be present, but normal blood pressure is preserved.
● Eyes – Scleral icterus suggests shortened red cell survival with hemolysis. Conjunctival pallor, although insensitive, is often noted when the
hemoglobin falls below 10 grams/dL (6.21 mmol/L).
● Cardiac – A systolic flow murmur is often heard when the hemoglobin level falls below 8 to 9 grams/dL (4.96 to 5.56 mmol/L).
● Lymph nodes and abdomen – Lymphadenopathy and splenomegaly may suggest a malignancy or an infectious disease such as
mononucleosis. When splenomegaly occurs without lymphadenopathy, however, attention is drawn to hemolytic disorders such as
hereditary spherocytosis and autoimmune hemolytic anemia or hemoglobinopathies.
Careful auscultation of the abdomen may detect hemangiomas of the viscera. The finding of an unusually large and firm spleen in the
absence of increasing scleral icterus suggests that red cells are being sequestered.
● Skin – Lack of red color in the palmar creases is associated with a hemoglobin that is less than 7 grams/dL (4.34 mmol/L). The presence of
large hemangiomas suggests microangiopathic anemia.
● Musculoskeletal – Bony abnormalities associated with red cell disorders include frontal bossing from compensatory expansion of the bone
marrow in hemolytic disease and radial and thumb anomalies found in some patients with Fanconi anemia.
Laboratory studies — A complete blood cell count (CBC) with differential and a reticulocyte count is the first step in determining if pallor is due
to a hematologic abnormality and, in the anemic patient, the likely cause. The use of hemoglobin, hematocrit, mean corpuscular volume, and
reticulocyte count in the evaluation of pallor in a child is presented here. Additional discussion of other indices (eg, red cell distribution width
[RDW], mean corpuscular hemoglobin concentration, and peripheral smear) is presented separately. (See "Approach to the child with anemia",
section on 'Laboratory evaluation'.)
Hemoglobin and hematocrit — Anemia may be defined as a reduction in red blood cell mass or blood hemoglobin concentration below the
standard for age ( table 3). In practice, anemia most commonly is defined by reductions in one or both of the following (see "Approach to the
child with anemia", section on 'Definition of anemia'):
● Hemoglobin – This is a measure of the concentration of the red blood cell (RBC) pigment hemoglobin in whole blood, expressed as grams
per 100 mL (dL) of whole blood (or mmol/L). The normal value for HGB in a child age 6 to 12 years is approximately 13.5 g/dL (8.38 mmol/L).
● Hematocrit – The hematocrit is the fractional volume of a whole blood sample occupied by red blood cells; it is expressed as a percentage.
As an example, the normal HCT in a child age 6 to 12 years is approximately 40 percent (0.4 fraction).
Mean corpuscular volume — The mean corpuscular volume (MCV) is measured directly by automated blood cell counters and represents the
mean value (in femtoliters, fL) of the volume of individual RBCs in the blood sample. Values may be low (microcytic), normal (normocytic), or large
(macrocytic).
The MCV provides a quick, accurate, and readily available method of distinguishing the microcytic anemias (iron deficiency, thalassemia
syndromes) from the normocytic (membrane disorders, enzyme deficiencies, autoimmune hemolytic anemia, most hemoglobinopathies) or
macrocytic (bone marrow/stem cell failure, disorders of B12 and folic acid absorption or metabolism) anemias.
As with hemoglobin and hematocrit, the MCV varies with age, necessitating the use of age-adjusted normal values ( table 3). In addition, the
measured MCV represents an average value. If microcytic and macrocytic red cells are present in the peripheral blood as, for example, in a
patient with combined iron deficiency and B12 deficiency, the MCV may remain normal. Thus, the peripheral smear should be examined carefully
to determine whether the MCV reflects a single population of red cells of uniform size or two or more populations of distinctly different size. The
red cell distribution width (RDW) is elevated in the presence of increased variation in red cell size. (See "Approach to the child with anemia",
section on 'Red blood cell indices'.)
Reticulocyte count — Reticulocytes are the youngest red cells in the circulation, and are identified via the presence of residual RNA, which
gives them a blue tint on standard Wright-Giemsa stains ( picture 7). They are quantitated via staining with vital dyes, such as new methylene
blue or thiazole orange, and are reported as a percentage. The reticulocyte count can be performed rapidly and helps to distinguish the various
causes of impaired red cell production on the basis of decreased reticulocyte count versus increased reticulocyte count.
Correction — Because the reticulocyte count is expressed as a percent of total red cells, it must be corrected for the degree of the anemia.
The easiest way to make this correction is to multiply the reticulocyte count by the reported hemoglobin or hematocrit (HCT) divided by a normal
hemoglobin or hematocrit:
● Reticulocyte count x HCT(pt)/HCT(nL)
As an example, a reticulocyte count of 5 percent in a child with severe iron deficiency anemia and a hematocrit of 6 percent is not elevated when
corrected for the degree of anemia (5 percent x 6 percent/33 percent = 0.9 percent).
Interpretation — Once anemia is identified, the reticulocyte count and MCV help in the initial classification of anemia but leave the clinician
with broad categories of disease, rather than specific diagnoses. In many instances, the history and physical examination, when coupled with
these laboratory measurements, permit identification of a particular disorder ( table 4 and algorithm 2).
In addition, the reticulocyte count should be interpreted with caution. Disorders of shortened red cell survival are not always characterized by an
increased reticulocyte count. As an example, reticulocytopenia may occur in an autoimmune hemolytic anemia despite active hemolysis and
increased erythropoiesis in the bone marrow. Chronic hemolytic disorders, such as sickle cell anemia or hereditary spherocytosis, may first be
detected during an aplastic crisis when the reticulocyte count is low. Unless the underlying disorder is recognized, the clinician may be misled by
this finding.
APPROACH
The initial approach to a patient with pallor includes determining if the patient is seriously ill and requires immediate supportive measures (
algorithm 3). Afterward, the history should be taken to determine if the pallor was acute or insidious in onset. A complete blood count with
differential, mean corpuscular volume (MCV), and reticulocyte count will help further delineate the cause of the anemia:
Increased reticulocytes and low MCV — The thalassemia syndromes associated with moderate or severe anemia can be recognized by
distinctive abnormalities of red cell morphology. In beta-thalassemia major, the red cells generally are small but vary markedly in size and shape.
Many cells appear to contain little or no hemoglobin; the central pallor extends to the cell membrane. Nucleated red cells, basophilic stippling,
and polychromasia reflect active erythropoiesis. The parents of an affected child usually have a low MCV characteristic of thalassemia trait. (See
"Clinical manifestations and diagnosis of the thalassemias".)
Children with HbS-beta-thalassemia have microcytic red cells, although the alterations of red cell morphology are not as dramatic as in beta-
thalassemia major. Sickled forms are often but not always present. Target cells are common. Hemoglobin electrophoresis reveals HbS and
reduced (less than 50 percent) or absent HbA.
Increased reticulocytes and normal MCV — Most membrane disorders can be readily identified by the characteristic changes in the red cell
shape that lend their names to the diseases (eg, spherocytosis, elliptocytosis, and stomatocytosis). When the diagnosis of a membrane disorder
is uncertain, examination of the parents' peripheral smears may be helpful because, in many cases, the inheritance pattern is autosomal
dominant. (See "Hereditary spherocytosis", section on 'Clinical presentation' and "Hereditary elliptocytosis and related disorders".)
Abnormalities of red cell morphology are less striking in erythrocyte enzymatic defects. Blister cells (cells with asymmetric distribution of
hemoglobin) may be found during episodes of active hemolysis in G6PD deficiency. If transfusion is necessary, a pretransfusion sample should
be saved for assay of specific enzymes. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
The reticulocyte count usually is markedly elevated in autoimmune hemolytic anemia, but it may be normal or only slightly elevated during the
first days of the disease. In rare instances, reticulocytopenia persists. Spherocytes usually are present on the peripheral smear. Clumping of red
cells from agglutination may be seen. This agglutination causes a falsely elevated MCV because the electronic counter measures the volume of
the red cell couplets or triplets. The direct Coombs test is positive in 90 percent of cases. Patients with a negative Coombs test present a
challenging diagnostic problem because the initial findings may be similar to those in hereditary spherocytosis. (See "Autoimmune hemolytic
anemia in children: Classification, clinical features, and diagnosis", section on 'Clinical presentation'.)
Homozygous sickle cell disease usually is recognized by the finding of sickled red cells on the peripheral smear. Rarely, however, such cells are
absent, even during an acute illness. Target cells are commonly found in sickle cell disease but are more prominent in HbSC. Hemoglobin
electrophoresis reveals the presence of the abnormal hemoglobin(s) and the absence of HgA. The broad application of newborn screening allows
for identification of most affected children prior to the onset of clinical signs and symptoms or RBC morphological abnormalities. (See "Diagnosis
of sickle cell disorders".)
Red cell fragments are found in those diseases characterized by microangiopathic hemolytic anemia. In HUS or TTP, thrombocytopenia is
present, renal or neurologic function is usually impaired, and thrombotic complications may be present. The platelet count also is low in DIC, and
clotting studies are abnormal. If intravascular hemolysis is severe, as in anemia associated with certain artificial cardiac valves, hemosiderin may
be detected in the urinary sediment. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic
syndrome (HUS) in children", section on 'Clinical and laboratory manifestations' and "Acquired TTP: Clinical manifestations and diagnosis" and
"Disseminated intravascular coagulation in infants and children", section on 'Clinical manifestations' and "Disseminated intravascular coagulation
in infants and children", section on 'Laboratory findings'.)
Low, normal, or slightly increased reticulocytes and low MCV — In severe iron deficiency anemia, red cells are markedly microcytic and show
substantial variation in size and shape. Elongated red cells (pencil forms) are common. Platelets are often increased. (See "Iron deficiency in
infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Clinical manifestations of IDA'.)
Anemia is uncommon in lead poisoning but, when present, resembles the anemia of iron deficiency in its red cell morphology. Basophilic
stippling is found in a small percentage of cases. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on
'Hematologic'.)
Low, normal, or slightly increased reticulocytes and normal or elevated MCV — With the exception of mild macrocytosis, red cell
morphology usually is normal in childhood disorders of bone marrow or stem cell failure. Thrombocytopenia and neutropenia are present in
aplastic anemia and Fanconi anemia. Although the platelet and white count are occasionally low in patients with Diamond-Blackfan syndrome,
the red cells are most severely affected. Erythropoiesis is most severely affected in TEC and acquired red cell aplasia, although neutropenia may
accompany the former disorder. (See "Overview of causes of anemia in children due to decreased red blood cell production" and "Inherited
aplastic anemia in children and adolescents".)
The clinical features at the onset of acute leukemia may closely resemble those of aplastic anemia. Examination of a bone marrow aspirate is
required to distinguish these disorders. This procedure is rarely performed in the emergency department. Therapy, such as corticosteroids,
which might interfere in the interpretation of the bone marrow aspirate, should be withheld until a definitive diagnosis has been made. (See
"Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)
The MCV is usually increased in megaloblastic anemias unless other nutritional disorders are present. Hypersegmentation of the
polymorphonuclear leukocytes is characteristic. In severe or long-standing megaloblastic anemia, neutropenia and thrombocytopenia also may
be found. In such cases, the findings in the peripheral blood may be similar to those of aplastic anemia or even acute leukemia; examination of
the bone marrow and measurement of specific nutrients (B12, folic acid) are necessary to distinguish these disorders. (See "Treatment of vitamin
B12 and folate deficiencies".)
SUMMARY
● Any condition that decreases the concentration of hemoglobin or alters the distribution of blood away from the body's surface may present
as pallor ( table 1). Clinically, pallor caused by anemia usually can be appreciated when the hemoglobin concentration is below 8 to 9 g/dL
(4.96 to 5.56 mmol/L). (See 'Causes' above and 'Physical examination' above.)
● The first priority in evaluating children with pallor is to determine if the patient is seriously ill (eg, life-threatening blood loss or hemolytic
anemia) and requires immediate supportive measures ( algorithm 3). (See 'Evaluation' above.)
● In stable children, a thorough history, physical exam, and simple laboratory studies (complete blood count with peripheral smear, mean
corpuscular volume, reticulocyte count, peripheral blood smear) usually identifies the underlying etiology ( algorithm 3 and table 1 and
algorithm 2). (See 'History' above and 'Physical examination' above and 'Laboratory studies' above.)
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Topic 6447 Version 19.0
GRAPHICS
Differential diagnosis for pallor in children
Decreased erythrocyte or hemoglobin production

Iron deficiency
Folic acid
Vitamin B12 deficiency
Diamond-Blackfan anemia
Fanconi's anemia
Aplastic anemia
Transient erythroblastopenia of childhood (TEC)
Malignancy*
Thalassemias
Sideroblastic anemia
Lead poisoning
Anemia of chronic disease
Increased erythrocyte destruction

Hereditary spherocytosis
Elliptocytosis
Stomatocytosis
Pyknocytosis
G6PD deficiency
Pyruvate kinase deficiency
Sickle cell syndromes*
Unstable hemoglobins
Autoimmune hemolytic anemia* ¶
Isoimmune hemolytic anemia*
Disseminated intravascular coagulation*
Hemolytic uremic syndrome*
Thrombotic thrombocytopenic Purpura*
Cavernous hemangioma (Kasabach Merritt syndrome)
Blood loss
Severe trauma*
Meckel's diverticulum
Peptic ulcer
Idiopathic pulmonary hemosiderosis
Nonhematologic
Respiratory failure*
Shock*
Hypoglycemia*
Pheochromocytoma*
Skin edema
Fair skinned complexion
* Life threatening.
¶ Potential causes of autoimmune hemolytic anemia include idiopathic, viral infection (eg, mononucleosis, influenza, coxsackie, measles, varicella, cytomegalovirus), bacterial infection (eg, Escherichia coli,
Pneumococcus, Streptococcus, typhoid fever, mycoplasma), drugs, inflammatory and collagen vascular disease (eg, systemic lupus erythematosus), and malignancy.
Graphic 65774 Version 3.0
Initial shock management in children in settings with access to ICU care
ICU: intensive care unit; HR: heart rate; BP: blood pressure; HFNC: high-flow oxygen by nasal cannula; NIV: noninvasive ventilation; IV: intravenous; IO: intraosseous; US: ultrasound; ECHO:
echocardiography; PT: prothrombin time; INR: international normalized ratio; PTT partial thromboplastin time; ECG: electrocardiography; e-FAST: extended focused assessment with sonography
for trauma.
* A trial of HFNC or NIV, such as continuous positive airway pressure ventilation or bi-level positive airway pressure ventilation, may avoid the need for endotracheal intubation in selected
patients. Patients with hemodynamic instability should receive appropriate interventions to treat shock prior to or during intubation. Refer to UpToDate content on HFNC, NIV, and rapid sequence
intubation in children.
¶ Ancillary studies are determined by patient presentation and suspected type or types of shock present. Other laboratory and ancillary studies may also be indicated based upon the suspected
underlying condition that is causing shock.
Δ Fluid volume should be calculated based upon ideal body weight (eg, 50 th percentile for age).
◊ When performed by trained and experienced physicians, bedside ECHO can provide rapid evidence of myocardial dysfunction, including dysfunction due to obstructive shock.
§ Patients with signs of fluid overload who continue to receive fluid boluses warrant close monitoring for respiratory and cardiac failure. The clinician should have a low threshold for endotracheal
intubation and mechanical ventilation to treat pulmonary edema in these patients.
¥ Suggested vasoactive therapy depends upon type of shock and clinical findings; refer to UpToDate topics and graphics on management of shock in children.
Spherocytes
Peripheral blood smear shows multiple spherocytes, which are small, dark, dense
hyperchromic red cells without central pallor (arrows). These findings are compatible
with hereditary spherocytosis or autoimmune hemolytic anemia.
Courtesy of Carola von Kapff, SH (ASCP).
Peripheral smear in microangiopathic hemolytic anemia

showing presence of schistocytes
Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with
marked red cell fragmentation. The smear shows multiple helmet cells (arrows)
and other fragmented red cells (small arrowhead); microspherocytes are also seen
(large arrowheads). The platelet number is reduced; the large platelet in the center
(dashed arrow) suggests that the thrombocytopenia is due to enhanced destruction.
Normal peripheral blood smear
High-power view of a normal peripheral blood smear. Several platelets

(arrowheads) and a normal lymphocyte (arrow) can also be seen. The red cells are
of relatively uniform size and shape. The diameter of the normal red cell should
approximate that of the nucleus of the small lymphocyte; central pallor (dashed
arrow) should equal one-third of its diameter.
Helmet cells in microangiopathic hemolytic anemia
Peripheral smears from two patients with microangiopathic hemolytic anemia, showing a
number of red cell fragments (ie, schistocytes), some of which take the form of combat
(arrow), bicycle (arrowhead), or football (short arrow) "helmets." Microspherocytes are also
seen (dashed arrows), along with a nucleated red cell (thick arrow).

Peripheral blood smear in iron deficiency anemia showing

microcytic, hypochromic red blood cells
The same peripheral blood smear from a patient with iron deficiency is shown at two
different magnifications. Small (microcytic) red blood cells are shown, many of which
have a thin rim of pink hemoglobin (hypochromia). Occasional "pencil"-shaped cells
are also present. A small lymphocyte is shown for size comparison (arrow). Normal red
blood cells are similar in size to the nucleus of a small lymphocyte (arrow), and central
pallor in normal red blood cells should equal approximately one-third of the cell
diameter.
Kindly supplied by Dr. German Pihan, Department of Pathology, Beth Israel Deaconess Medical
Center, Boston, MA.

Elliptical red cells in hereditary elliptocytosis
Peripheral blood smear from a patient with hereditary elliptocytosis shows multiple
elliptocytes.

Stomatocytosis
Peripheral blood smear showing multiple stomatocytes characterized by a mouth-

shaped area of central pallor.

The medical history in the child with anemia: Elements associated with specific causes of childhood anemia
Patient characteristics Age:

In neonates and young infants, immune hemolytic disease, infection, and hereditary disorders are most common
Anemia detected at 3 to 6 months of age suggests a hemoglobinopathy
Nutritional iron deficiency is an unlikely cause of anemia before the age of 6 months in term infants
In older children, acquired causes of anemia are more likely, particularly iron deficiency anemia (dietary or due to blood loss)
Sex:
Some inherited causes of anemia are X-linked (eg, G6PD deficiency and X-linked sideroblastic anemia) and occur most commonly in males
Race/ethnicity:
Hemoglobin S and C are most commonly seen in Black and Hispanic populations
Thalassemia syndromes are more common in individuals of Mediterranean and Southeast Asian descent
G6PD deficiency is more common among Sephardic Jews, Filipinos, Greeks, Sardinians, Kurds, and Black populations
Symptoms Changes in urine color, scleral icterus, or jaundice suggest a hemolytic disorder
Bloody stools, hematemesis, severe epistaxis, or severe menstrual bleeding suggest anemia from blood loss and/or iron deficiency
Infectious symptoms (eg, fevers, cough) suggest an infectious etiology of anemia
History of anemia Prior episodes of anemia suggest an inherited disorder

Anemia in a patient with previously documented normal CBC suggests an acquired etiology
Hyperbilirubinemia in the newborn period suggests a hemolytic etiology; microcytosis at birth suggests chronic intrauterine blood loss or thalassemia
Underlying medical conditions Underlying renal disease, malignancy, or inflammatory/autoimmune disorders may be associated with anemia
Drugs and toxin exposure Anemia following exposure to oxidant drugs or fava beans suggests G6PD deficiency
Exposure to paint, home renovations, or use of imported or glazed ceramics suggest lead toxicity
Family history Family members with jaundice, gallstones, or splenomegaly suggests an inherited hemolytic anemia
Dietary history In infants and young children, iron deficiency is suggested by the following:
Use of low iron formula
Introduction of unmodified cow's milk before the age of 1 year
Excessive milk intake (>24 ounces per day)
Poor intake of iron-rich foods (meats or fortified infant cereal)
Travel history Travel to/from areas of endemic infection suggests infectious etiology such as malaria or tuberculosis
Developmental history Developmental delay is associated with iron deficiency, vitamin B12/folic acid deficiency, and Fanconi anemia
G6PD: glucose-6-phosphate dehydrogenase; CBC: complete blood count.
Normal values for hemoglobin, hematocrit, and mean corpuscular volume in children
Hemoglobin (g/dL) Hematocrit (%) MCV (fL)

Age
50 th percentile Lower limit* 50 th percentile Lower limit* 50 th percentile Lower limit* Upper limit*
1 year ¶ White 12.5 11 37 32 80 71 89
Black 12 11 36 31 77 63 88
2 to 3 years White 12.6 11 37 33 82 74 89
Black 12 11 36 32 80 64 89
4 to 6 years White 12.9 11.7 38 34 84 77 91
Black 12.5 11 37 33 83 67 91
7 to 10 years White 13.5 12 40 35 85 78 91
Black 12.7 11.2 38 34 84 72 92
11 to 14 years White Female 13.7 12.3 40 36 87 80 94
Male 14.3 12.6 42 36 87 80 94
Black Female 12.9 10.6 38 33 86 71 95
Male 13.6 11.8 40 35 86 73 95
15 to 18 years White Female 13.7 11.5 40 34 89 81 96
Male 15.4 13.7 46 40 89 81 96
Black Female 12.8 10.7 38 32 87 71 96
Male 14.9 12.9 44 38 87 75 96
MCV: mean corpuscular volume; fL: femtoliter.
* Lower limits are defined as the 2.5 th percentile for all values, except hemoglobin levels at 1 and 2 to 3 years, which are based upon recommendations from the American Academy of Pediatrics. Upper limits
are defined as the 97.5 th percentile for all values.
¶ Normal values for hemoglobin, hematocrit, and MCV change dramatically during the first year of life. Refer to UpToDate topic on the approach to the child with anemia for a discussion of normal values in
infants <1 year old.
References:
1. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and Oski's Hematology and Oncology of Infancy and Childhood, 8 th ed, Orkin SH, Fisher DE, Ginsburg D, et al (Eds), WB
Saunders, Philadelphia 2015. p.293.
2. Cembrowski GS, Chan J, Cheng C. NHANES 1999-2000 data used to create comprehensive health-associated race-, sex- and age-stratified pediatric reference intervals for the Coulter MAXM. Laboratory Hematol 2004;
10:245.
3. Baker RD, Greer FR, Committee on Nutrition American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics 2010;
126:1040.
Reticulocytes after supravital staining
Supravital stain of a peripheral blood smear shows blue-stained residual reticulin

(ribosomal RNA) in reticulocytes.
Courtesy of Stanley L Schrier, MD.
Physical findings as clues to the etiology of anemia in children
Finding Possible etiology
Skin
Hyperpigmentation Fanconi anemia
Petechiae, purpura Autoimmune hemolytic anemia with thrombocytopenia, hemolytic-uremic syndrome, bone marrow aplasia, bone marrow infiltration
Carotenemia Suspect iron deficiency in infants
Jaundice Hemolytic anemia, hepatitis, and aplastic anemia
Cavernous hemangioma Microangiopathic hemolytic anemia
Ulcers on lower extremities Sickle cell disease (S and C hemoglobinopathies), thalassemia
Facies
Frontal bossing, prominence of the malar and maxillary bones Congenital hemolytic anemias, thalassemia major, severe iron deficiency
Eyes
Microcornea Fanconi anemia
Tortuosity of the conjunctival and retinal vessels Sickle cell disease (S and C hemoglobinopathies)
Microaneurysms of retinal vessels Sickle cell disease (S and C hemoglobinopathies)
Cataracts Glucose-6-phosphate dehydrogenase deficiency, galactosemia with hemolytic anemia in newborn period
Vitreous hemorrhages S hemoglobinopathy
Retinal hemorrhages Chronic, severe anemia
Edema of the eyelids Infectious mononucleosis, exudative enteropathy with iron deficiency, renal failure
Blindness Osteopetrosis
Mouth
Glossitis Vitamin B12 deficiency, iron deficiency
Angular stomatitis
Chest
Unilateral absence of the pectoral muscles Poland syndrome (increased incidence of leukemia)
Shield chest Diamond-Blackfan syndrome
Hands
Triphalangeal thumbs Red cell aplasia
Hypoplasia of the thenar eminence Fanconi anemia
Spoon nails Iron deficiency
Spleen
Enlargement Congenital hemolytic anemia, leukemia, lymphoma acute infection, portal hypertension
Reproduced with permission from: Oski FA, Brugnara G, Nathan DG. A diagnostic approach to the anemia patient. In: Nathan and Oski's Hematology of Infancy and Childhood. WB Sauders, Philadelphia. 1998. p.378.
Diagnostic approach to isolated anemia in children: Morphologic classification
HGB: hemoglobin; MCV: mean corpuscular volume; TIBC: total iron-binding capacity; TEC: transient erythroblastopenia of childhood; G6PD: glucose-6-phosphate dehydrogenase; HUS: hemolytic uremic syndrome; TT
thrombotic thrombocytopenic purpura; DIC: disseminated intravascular coagulation; HU: hydroxyurea; PMNs: polymorphonuclear cells; LDH: lactate dehydrogenase; DAT: direct antiglobulin test; RDW: red cell distribu
* HGB levels vary considerably by age, race, and sex; when diagnosing anemia, HGB values should be compared with age-, race-, and sex-adjusted norms. Mild anemia occurring at 6 to 9 weeks of life is consistent wit
"physiologic anemia" and is not pathologic. Falsely elevated HGB values may occur when measured using capillary samples (eg, finger or heel "sticks"), particularly when using microhematocrit measurements. Spurio
may also occur with automated counters in the presence of lipemia, hemolysis, leukocytosis, or high immunoglobulin levels.
¶ The RDW can be helpful in differentiating thalassemia from iron deficiency. High RDW is typical of iron deficiency, whereas the RDW is usually normal in patients with thalassemia (though elevated RDW can occur).
Δ Anemia of chronic disease typically presents as a normocytic anemia but can have low MCV.
◊ Selected testing is based upon review of the patient's history and examination of the peripheral blood smear.
§ In children with mild microcytic anemia and dietary history that is suggestive of iron deficiency, serum iron studies (ie, ferritin, iron, and TIBC levels) are generally not necessary. In these children, a therapeutic trial o
be used to confirm the diagnosis.
¥ Evidence of hemolysis includes jaundice, indirect hyperbilirubinemia, elevated lactate dehydrogenase, and/or decreased haptoglobin.
‡ Findings on blood smear may suggest an underlying etiology of anemia, but they are generally not diagnostic. Further confirmatory testing should be carried out to confirm the diagnosis.
References:
1. Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Nathan and Oski's Hematology and Oncology of Infancy and Childhood, 8 th ed, Orkin SH, Fisher DE, Ginsburg D, et al (Eds), WB Saunders, P
2015. p.293.
2. Rapaport SI. Diagnosis of anemia. In: Introduction to hematology, JB Lippincott, Philadelphia 1987. p.15.
The diagnostic approach to pallor in children
* Initial hemoglobin and red blood cell indices may be normal despite severe hemorrhage.
¶ Examples of possible conditions are provided within appropriate categories.

Evaluation of Pallor in Children

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7/15/2021 Evaluation of pallor in children - UpToDate

Official reprint from UpToDate®

Evaluation of pallor in children

● Decreased erythrocyte production

Decreased RBC production

Increased RBC destruction

Other conditions that cause pallor

● Decreased red blood cell production

● Increased red blood cell destruction

● Reticulocyte count x HCT(pt)/HCT(nL)

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Topic 6447 Version 19.0

Differential diagnosis for pallor in children

Decreased erythrocyte or hemoglobin production

Vitamin B12 deficiency

Transient erythroblastopenia of childhood (TEC)

Anemia of chronic disease

Increased erythrocyte destruction

Pyruvate kinase deficiency

Sickle cell syndromes*

Autoimmune hemolytic anemia* ¶

Isoimmune hemolytic anemia*

Disseminated intravascular coagulation*

Hemolytic uremic syndrome*

Thrombotic thrombocytopenic Purpura*

Cavernous hemangioma (Kasabach Merritt syndrome)

Idiopathic pulmonary hemosiderosis

Fair skinned complexion

Graphic 65774 Version 3.0

Initial shock management in children in settings with access to ICU care

Graphic 129655 Version 1.0

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70611 Version 5.0

Peripheral smear in microangiopathic hemolytic anemia

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 70851 Version 8.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0

Helmet cells in microangiopathic hemolytic anemia

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 50715 Version 5.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0

Peripheral blood smear in iron deficiency anemia showing

Graphic 64267 Version 8.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 59683 Version 5.0

Elliptical red cells in hereditary elliptocytosis

Courtesy of Carola von Kapff, SH (ASCP).

Graphic 63129 Version 4.0

Normal peripheral blood smear

High-power view of a normal peripheral blood smear. Several platelets