BRS – Pediatrics: Hematology

Source: BRS Pediatrics, 2019

I. Anemia

A. General concepts
1. Definition. Anemia is a reduction in the red blood cell (RBC) number or in the hemoglobin (Hgb) concentration to a level more than 2 standard deviations below the mean.
2. Hgb and age

a. The Hgb is high at birth in most newborns and then declines, reaching the physiologic lowest point (nadir) between 2 and 3 months of age in the term infant and between 1 and 2 months of age in the preterm infant. Hgb values reach adult levels after puberty.
b. Fetal hemoglobin (Hgb F) is a major constituent of Hgb during fetal and early postnatal life. It declines and gradually disappears by 6–9 months of age.

3. Epidemiology. Anemia is one of the most common laboratory abnormalities during childhood. Approximately 20% of all children in the United States and 80% of children in developing nations have anemia at some time during childhood.

B. Classification
1. Classification is made on the basis of the mean corpuscular volume (MCV) and the morphologic appearance of the RBC (i.e., size, color, and shape). Terms used include the suffix -cytic, referring to size, and the suffix -chromic, referring to color. Primary classifications include the following:

a. Microcytic, hypochromic anemia (small, pale RBCs; low MCV)
b. Macrocytic anemia (large RBCs; high MCV)
c. Normocytic, normochromic anemia (normal RBCs in size, color, and shape; normal MCV)

2. Classification based on reticulocyte count is also helpful. The reticulocyte count reflects the number of immature RBCs in the circulation and, therefore, the activity of the bone marrow in producing RBCs. The usual percentage of RBCs that are reticulocytes is 1% (normal absolute count = 50,000 cells/mm3). In the steady state, when a patient has a normal Hgb level, the reticulocytes should constitute 1% of all RBCs. In most anemias, reticulocyte counts should rise. A low reticulocyte count indicates bone marrow failure or diminished hematopoiesis.
3. Figure 13-1 presents the differential diagnosis of anemia on the basis of the previously discussed classification schemes. Descriptions of the more common forms of anemia in childhood follow.
C. Clinical features of anemia (Table 13-1)
D. Microcytic, hypochromic anemias. The two most common types of microcytic, hypochromic anemia during childhood are iron-deficiency anemia and β-thalassemia minor.
1. Iron-deficiency anemia is the most common blood disease during infancy and childhood.

a. Etiology. The majority of cases are caused by inadequate iron intake.
1. Nutritional iron deficiency is most common in two age groups.

a. Nine to twenty-four months of age: owing to inadequate intake and inadequate iron stores (which are typically depleted by 4–6 months of age). Blood loss during birth may contribute to the anemia. The typical toddler’s diet consists of large quantities of iron-poor cow’s milk. Iron- rich foods (e.g., iron-fortified cereal, meats, legumes) or iron supplementation is therefore recommended beginning at 4–6 months of age to prevent anemia.
b. Adolescent girls: owing to poor diet, rapid growth, and loss of iron in
menstrual blood

2. Occult blood loss with resultant iron deficiency may be secondary to polyps, Meckel diverticulum, inflammatory bowel disease (IBD), peptic ulcer disease, celiac disease, and the early ingestion of whole cow’s milk before 1 year of age.

b. Clinical features. The signs and symptoms of anemia are listed in Table 13-1.
c. Laboratory findings

1. Because iron stores disappear first, an early finding of iron-deficiency anemia is low serum ferritin. Ferritin can be a useful assessment of iron stores; however, because ferritin is also an acute-phase reactant, it may be increased in infection, disease states, and stress, therefore appearing normal.
2. As serum iron decreases, iron-binding capacity increases, manifested as
increased transferrin and decreased transferrin saturation.
3. Increased free erythrocyte protoporphyrin may be noted.
4. Other findings include a normal or increased reticulocyte count.

d. Management
1. Elemental iron (4–6 mg/kg/day) is prescribed orally for mild to moderate anemia. Iron is given with vitamin C (e.g., orange juice) to enhance intestinal iron absorption.
2. Dietary counseling may be required to increase nutritional iron through iron- rich foods (e.g., meats, legumes, prunes, iron-fortified cereals).
3. RBC transfusion may be required for severe anemia associated with cardiovascular compromise. Not only will this improve oxygen-carrying capacity, but this will contribute to iron repletion.
4. Further evaluation to rule out other causes of anemia is necessary in patients with anemia unresponsive to iron.

2. α-Thalassemia and β-thalassemia syndromes
a. Definition. Thalassemia is a group of inherited anemias characterized by defective synthesis of one of the Hgb chains.
b. Pathophysiology

1. Normally, the major Hgb in RBCs is hemoglobin A1, a tetramer of two α- chains and two β-chains. HgbA2 and Hgb F may also be present in small amounts.
2. α-Thalassemia results from defective α-globin chain synthesis, and β- thalassemia results from defective β-globin chain synthesis.
3. Both types of thalassemia result in hemolysis that leads to increased bone marrow activity. As marrow activity increases, the marrow spaces enlarge, increasing the size of bones in the face, skull, and other bones if severe and untreated.

c. α-Thalassemia is the result of deletions of the α-globin chain and occurs predominantly in Southeast Asians. There are four states categorized on the basis of the number of α-globin genes deleted (normally there are four α-globin genes per diploid cell).

1. Silent carrier. One α-globin gene is deleted. Patients have no anemia and are
asymptomatic.
2. α-Thalassemia minor. Two α-globin genes are deleted. Patients have mild microcytic anemia.
3. Hgb H disease. Three α-globin genes are deleted. Patients have moderate to severe anemia at birth with an elevated Hgb Bart’s (which is a type of Hgb made up of four gamma-globins that bind oxygen very strongly and do not release it to tissue). Anemia is lifelong.
4. Fetal hydrops. Four α-globin genes are deleted. Only Hgb Bart’s are formed, and in utero, this causes profound anemia, congestive heart failure (CHF), and death if not identified early enough for intrauterine transfusion to occur.

d. β-Thalassemia is the result of mutations of the β-globin chain. Because there are only two β-globin genes in each cell, there are only two states:

1. β-Thalassemia major (Cooley anemia or homozygous β-thalassemia) may be caused by either total absence of the β-globin chains or deficient β-globin chain production.
a. Epidemiology. β-Thalassemia major occurs predominantly among patients of Mediterranean background.
b. Clinical features. Clinical findings include profound hemolytic anemia beginning in infancy, marked hepatosplenomegaly, and, if untreated, bone marrow hyperplasia in sites that result in a characteristic “thalassemia facies” appearance (frontal bossing, maxillary hyperplasia with prominent cheekbones, and skull deformities). Delayed growth and puberty may also be present.
c. Laboratory findings. Studies show severe hypochromia and microcytosis, elevated reticulocyte count, target cells and poikilocytes (abnormally shaped red blood cells) on the blood smear, and elevated unconjugated bilirubin, serum iron, and lactate dehydrogenase (LDH). Electrophoresis demonstrates low or absent Hgb A and elevated Hgb F.
d. Management. Treatment includes lifelong transfusions, chelation therapy to avoid iron overload and often splenectomy. Bone marrow transplant is curative and is the therapy of choice.
e. Complications. Hemochromatosis (iron accumulation within the heart, liver, lungs, pancreas, and skin) is a major complication and is caused by increased iron absorption from the intestine and from iron in transfused RBCs. Chelation of iron with the intravenous agent deferoxamine and/or the oral agent deferasirox promotes iron excretion and may help prevent or delay hemochromatosis.
2. β-Thalassemia minor (heterozygous β-thalassemia or β-thalassemia trait) causes a mild asymptomatic anemia with Hgb levels 2–3 g/dL below age- appropriate norms.
a. Laboratory findings include hypochromia and microcytosis with target cells and anisocytosis (excessive variation of size of RBCs) on smear.
b. No treatment is required.
c. It is important to note that patients with β-thalassemia minor may be very easily misdiagnosed as having iron-deficiency anemia and treated inappropriately with iron. However, the iron level in β-thalassemia minor is normal or elevated. Patients with thalassemia minor have normal to elevated RBC counts as opposed to iron deficiency in which the RBC count is low to normal.

3. Sideroblastic anemia is a group of anemias characterized by the presence of ring sideroblasts in the bone marrow. Ring sideroblasts result from the accumulation of iron in the mitochondria of RBC precursors. Sideroblastic anemia may be inherited or may be acquired as a result of drugs or toxins (e.g., isoniazid, alcohol, lead poisoning, chloramphenicol).
4. Lead poisoning (see Chapter 1, section IV.J) and chronic diseases, such as malignancy, infections, and kidney disease (termed anemia of inflammation), may present with a microcytic, hypochromic anemia.

E. Macrocytic (megaloblastic) anemias. These anemias are characterized by large RBCs with MCV > 95. The two major causes in children are folic acid and vitamin B12 deficiencies. In addition, rare but important causes of macrocytic anemia include bone marrow failure syndromes [e.g., Fanconi anemia, see section II.B.1].
1. Folic acid deficiency

a. Etiology. Causes include decreased folic acid intake (i.e., from a diet lacking uncooked fresh fruits and vegetables or from exclusive feedings with goat’s milk as the sole source of milk protein) and decreased intestinal absorption of folic acid (i.e., from diseases affecting the small intestine, such as celiac disease, chronic infectious enteritis, Crohn disease, or medications, such as anticonvulsants and oral contraceptives).
b. Clinical features. In addition to the characteristic signs and symptoms of anemia, patients may have failure to thrive, chronic diarrhea, and irritability.
c. Diagnosis. Documentation of low serum folic acid is diagnostic.
d. Management. Treatment includes dietary folic acid and identification and treatment of the underlying cause.

2. Vitamin B12 deficiency

a. Normal physiology. To be absorbed, dietary vitamin B12 must first combine with a glycoprotein (intrinsic factor) secreted by the gastric parietal cells. Absorption then occurs in the terminal ileum.
b. Etiology. Causes include inadequate dietary intake (e.g., from a strict vegetarian [vegan] diet), an inherited inability to secrete intrinsic factor (juvenile pernicious anemia), or an inability to absorb vitamin B12 (e.g., Crohn disease, short gut syndrome).
c. Clinical features. In addition to the characteristic features of anemia, patients may also have anorexia, a smooth red tongue, and neurologic manifestations (such as ataxia, hyporeflexia, and positive Babinski responses).
d. Diagnosis. Documentation of low serum vitamin B12 level is diagnostic.
e. Management. Treatment is by monthly intramuscular vitamin B12 injections.

F. Normocytic, normochromic anemias. These anemias are characterized by normal size (normal MCV) and shape of the RBCs.
1. General concepts
a. Common causes include hemolytic anemias (premature destruction of RBCs), some RBC aplasias, and sickle cell (SS) anemia.
b. Reticulocyte count may be used to differentiate among the disorders [see Figure 13-1].

1. Low reticulocyte count reflects bone marrow suppression or failure and can be seen with RBC aplasias, viral suppression, medication effect, and pancytopenia associated with aplastic anemia.
2. High reticulocyte count reflects high bone marrow production of RBCs as seen in hemolytic anemias, recent acute hemorrhage, or any other condition associated with shortened RBC life span.

2. Hemolytic anemias
a. Intrinsic RBC defects that cause hemolysis include RBC membrane disorders and RBC enzyme disorders. Examples of RBC membrane disorders include hereditary spherocytosis and hereditary elliptocytosis, and examples of RBC enzyme disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase (PK) deficiency.

1. Hereditary spherocytosis is the most common inherited abnormality of the RBC membrane and occurs predominantly in persons of Northern European ancestry. There is a large spectrum of phenotypes, with some patients who are largely asymptomatic and others who are transfusion-dependent starting in infancy.
a. Etiology. There is a deficiency or abnormality of the structural RBC membrane protein spectrin, causing the RBC to assume its spherical shape. Inheritance is usually autosomal dominant.
b. Clinical features. Clinical findings are related to extravascular hemolysis. Infants may present with jaundice and anemia. By 2–3 years of age, patients develop pallor, weakness, and splenomegaly, as spherocytes are trapped in the spleen and destroyed. Other complications include aplastic crises, most commonly associated with parvovirus B19 infection, and pigmentary gallstones.
c. Laboratory findings. Studies show an elevated reticulocyte count, hyperbilirubinemia, spherocytes on blood smear, increased MCHC (mean corpuscular hemoglobin concentration), and abnormal RBC fragility with osmotic fragility studies.
d. Management. Treatment includes transfusions. Splenectomy cures the disorder, but to decrease the incidence of invasive disease caused by encapsulated bacteria, splenectomy is generally delayed until after 5 years of age.
2. Hereditary elliptocytosis is another autosomal dominant defect in the structure of spectrin that may or may not result in hemolysis. Clinical features are more variable than in hereditary spherocytosis. The majority of patients are asymptomatic, although 10% have jaundice at birth, and later may develop splenomegaly and gallstones. Elliptical RBCs are found on blood smear in older children. Treatment includes splenectomy for patients with severe chronic hemolysis. No treatment is needed for patients who have well- compensated hemolysis.
3. Glycolytic enzymatic defects of RBCs include glucose-6-phosphate dehydrogenase deficiency and PK deficiency.
a. Glucose-6-phosphate dehydrogenase deficiency (G6PD) is the most common RBC enzymatic defect. It may occur as an acute hemolytic disease, induced by infection or medications, or as a chronic hemolytic disease. The epidemiology, etiology, clinical findings, and treatment are described in Table 13-2.
b. PK deficiency is an autosomal recessive disorder that results in decreased production of PK isoenzyme leading to ATP (adenosine triphosphate) depletion and decreased RBC survival.
1. Clinical features include pallor, jaundice, and splenomegaly. Kernicterus has been reported in neonates.
2. Laboratory findings include varying degrees of anemia and a blood smear showing polychromatic RBCs.
3. Diagnosis is by finding decreased PK activity in the RBCs.
4. Management includes transfusions and splenectomy for severe disease.
b. Defects extrinsic to the RBC that cause hemolysis
1. Autoimmune hemolytic anemia (AIHA) occurs when antibodies are misdirected against the RBCs.
a. Etiology

1. Primary AIHA is generally idiopathic in which no underlying disease is identified. Viral infections and occasionally drugs may be causal in some patients.
2. Secondary AIHA is associated with an underlying disease process, such as lymphoma, systemic lupus erythematosus (SLE), or immunodeficiency.
b. Clinical features
1. Fulminant acute-type AIHA occurs in infants and young children and is preceded by a respiratory infection. Presenting features include the acute onset of pallor, jaundice, hemoglobinuria, and splenomegaly. A complete recovery is expected.
2. Prolonged-type AIHA is characterized by a protracted course and high mortality. Underlying disease is frequently present.
c. Laboratory findings. Studies show severe anemia, spherocytes on blood smear, prominent reticulocytosis, and leukocytosis. A direct Coombs test is positive (detects coating of antibodies on the surface of RBCs or complement).
d. Management. Treatment may include transfusions that unfortunately may provide only transient benefit. Corticosteroids are often used for severe anemia and are continued until hemolysis diminishes. The acute form responds well to steroids.
2. Alloimmune hemolytic anemia occurs when antibodies from someone else are directed at the patients’ RBCs and is most commonly caused by newborn Rh and ABO hemolytic diseases.
a. Rh hemolytic disease occurs when the mother, who has no Rh antigen (maternal Rh negative), produces antibodies to the Rh antigen on her fetus’s RBCs (fetal Rh positive). In subsequent pregnancies, antibodies pass from the mother to the fetus causing hemolysis that presents as severe jaundice (which can lead to kernicterus), anemia, hepatosplenomegaly, and hydrops fetalis. A direct Coombs test is strongly positive.
b. ABO hemolytic disease occurs when the mother is blood group O and her fetus is blood group A, B, or AB. The mother produces antibodies to either the A or B blood group antigen that then pass to the fetus, causing hemolysis with resultant jaundice. A direct Coombs test is weakly positive. Of note, ABO disease can occur in the first pregnancy, unlike Rh hemolytic disease.
c. Management. Treatment may include phototherapy for mild to moderate jaundice and exchange transfusion for severe jaundice.
3. Microangiopathic hemolytic anemia
a. Definition. This form of anemia results from mechanical damage to RBCs caused by passage through an injured vascular endothelium.
b. Etiology. Causes include severe hypertension, hemolytic uremic syndrome (HUS), artificial heart valves, a giant hemangioma, and disseminated intravascular coagulation (DIC).
c. Clinical features. Signs and symptoms are those characteristic of anemia and thrombocytopenia.
d. Laboratory findings. Studies show RBC fragmentation seen as “burr” cells, “target” cells, and irregularly shaped cells on the blood smear, along with thrombocytopenia.

e. Management. Therapy includes supportive care and treatment of the underlying cause.
3. SS hemoglobinopathies
a. Epidemiology. SS disease occurs in 1 in 800 black newborns in the United States. Eight percent have S trait. Compound heterozygotic disease can occur with Hgb C or β-thalassemia, leading to Hgb SC or sickle β-thalassemia disease, respectively.
b. Etiology and pathophysiology
1. SS disease is caused by a single amino acid substitution of valine for glutamic acid on the number 6 position of the β-globin chain of Hgb.
2. The mutation results in polymerization of Hgb within the RBC membrane when the RBC is exposed to low oxygen or acidosis.
3. Polymerization of Hgb results in a distorted RBC shape (sickled) that leads to decreased RBC life span (hemolysis) and occlusion of small vessels, resulting in distal ischemia, infarction, and organ dysfunction.
4. SS disease is the result of having two genes for Hgb S (homozygous).
5. S trait is defined as having only one gene for Hgb S (heterozygous). Persons with S trait have Hgb A (50–60%), Hgb S (35–45%), and a small percentage of Hgb F. Patients are asymptomatic without anemia unless exposed to severe hypoxemia. Some patients have an inability to concentrate the urine or may present with hematuria (5%) during adolescence.
c. Diagnosis. Diagnosis of SS disease is now usually made at birth through state newborn screening programs. Hgb electrophoresis is a highly sensitive and specific test that demonstrates Hgb S and Hgb F (fetal hemoglobin) in the newborn with SS disease.
d. Clinical features. Clinical characteristics are not generally present until protective Hgb F declines (by 6 months of age). Clinical episodes are often termed crises because they occur suddenly. Table 13-3 describes the clinical features and management of the common SS disease crises.
e. Laboratory findings (Table 13-4)
f. Management Historically, infection was the leading cause of death due to impaired splenic function.
1.
a. Patients are at risk for infection with encapsulated bacteria (i.e., Haemophilus influenzae type b, Streptococcus pneumoniae, Salmonella, Neisseria meningitidis).
b. Fever in any patient with SS disease is managed with urgent assessment and appropriate cultures (blood and urine), chest radiograph to rule out pneumonia, and parenteral antibiotics until bacterial infection can be safely excluded.
c. Osteomyelitis may occur and may mimic a painful bone crisis. Infection is most commonly caused by Salmonella species acquired through the gastrointestinal (GI) tract, although Staphylococcus aureus may also cause osteomyelitis. Clinical features include fever and pain, induration, tenderness, warmth, and erythema of the involved area. Treatment includes appropriate intravenous antibiotics.
g. Preventive care
1. Hydroxyurea, a chemotherapeutic agent that increases Hgb F, has been shown to decrease the incidence of vaso-occlusive crises.
2. Daily oral penicillin prophylaxis is started in the first few months of life to decrease the risk of S. pneumoniae infection.

3. Daily folic acid is given to prevent folic acid deficiency.
4. Routine immunizations and also yearly influenza vaccination, 23-valent polysaccharide pneumococcal vaccine at 2 years of age, and meningococcal vaccine should all be given.
5. Serial transcranial Doppler ultrasound or magnetic resonance angiography is recommended beginning at 2 years of age to identify patients at increased risk for stroke.
6. Bone marrow transplant is curative and is considered for children with severe manifestations.
h. Prognosis
1. Median life expectancy is in the 50s.
2. Long-term complications include delayed growth and puberty, cardiomegaly, hemochromatosis, cor pulmonale, pulmonary hypertension, renal insufficiency, gallstones, poor wound healing, avascular necrosis of the femoral and humeral heads, osteopenia, retinopathy, and diminished cognitive and school performance.
i. Other SS diseases include sickle cell–thalassemia disease (with clinical features similar to SS disease) and sickle cell–hemoglobin C disease (Hgb SC disease) caused by the inheritance of both Hgb S and Hgb C genes. Clinical features of Hgb SC disease are less severe than SS disease.
4. RBC aplasias are a group of congenital or acquired blood disorders characterized by anemia, reticulocytopenia, and a paucity of RBC precursors in the bone marrow. The clinical features of the three most common disorders occurring in childhood, congenital hypoplastic anemia (Diamond–Blackfan anemia), transient erythroblastopenia of childhood, and parvovirus B19–associated RBC aplasia, are presented in Table 13-5.

FIGURE 13.1 Classification and differential diagnosis of anemia. DIC = disseminated intravascular coagulation; HUS = hemolytic uremic syndrome; TEC = transient erythroblastopenia of childhood; G6PD = glucose-6-phosphate dehydrogenase; RBC = red blood cell.

Table 13-1
Clinical Features of Anemia

Mild

Pallor (noted especially on skin and on mucous membranes) Diminished attention
Moderate

Weakness and fatigue

Decreased exercise tolerance

Irritability

Tachycardia

Tachypnea

Anorexia

Systolic heart murmur
Severe

Congestive heart failure

Cardiac dilation

Shortness of breath

Hepatosplenomegaly Spoon-shaped nails
Table 13-2
Features of Glucose-6-Phospate Dehydrogenase (G6PD) Deficiency

Epidemiology
Mediterranean, Arabic, Asian, and African ethnic groups
Pathophysiology
G6PD enzyme is critical for protecting the RBC from oxidative stress; deficiency results in RBC damage when the RBC is exposed to oxidants
Triggers of hemolysis
Infection Fava beans
Drugs (e.g., sulfa, salicylates, antimalarials)
Clinical features
Symptoms occur 24–48 hours after exposure to oxidant
Hemolysis occurs, resulting in abdominal pain, V/D, fever, and hemoglobinuria followed by jaundice; HSM may be present
Laboratory findings
Hemoglobinuria
Elevated reticulocyte count

Smear shows “bite” cells, “hemighosts” and Heinz bodies
Diagnosis
Low levels of G6PD in RBCs
Treatment
Transfusions as needed; splenectomy is not beneficial
V/D = vomiting, diarrhea; RBC = red blood cell; HSM = hepatosplenomegaly.

Table 13-3
Clinical Features and Management of Crises Occurring in Sickle Cell Disease

Crisis Clinical Features Management
Vaso-occlusive crisis
Painful bone crisis
Most common crisis Ischemia/infarction of bone or marrow
Deep, gnawing, or throbbing pain lasting 3–7 days Subtype: acute dactylitis—painful swelling of digits of the hands and feet
Pain control
Intravenous fluids at 1–1.5 × maintenance
Incentive spirometry to decrease the risk of acute chest syndrome
Severe, unremitting pain may respond to partial exchange transfusion. (Simple transfusion of RBCs is not indicated. It increases viscosity of blood and may worsen crisis.)
Acute abdominal crisis
Abdominal pain and distension
Often caused by sickling within mesenteric artery
Low threshold for imaging the abdomen
Same management as for painful bone crisis
Stroke
Dysarthria and hemiplegia, but may be asymptomatic Occurs in up to 11% of patients (subclinical stroke occurs in up to 20% of patients)
Same management as for painful bone crisis
Urgent exchange transfusion Patient should be started on chronic transfusion program to prevent recurrence, which occurs in 60–90%
Priapism
Painful, sustained erection
Always consider SS disease in any patient presenting with priapism
Same management as for painful bone crisis
Acute chest syndrome (ACS)

New pulmonary infiltrate associated with respiratory symptoms (e.g., cough, shortness of breath, chest pain) Hypoxemia
May be severe and may cause up to 25% of deaths in patients with SS disease
Causes include infection (e.g., viral, Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pneumoniae), sickling, atelectasis, fat embolism, painful bone crisis involving the ribs, and pulmonary edema from fluid overload
Careful hydration and pain management
Oxygen
Appropriate antibiotics (usually cefuroxime and azithromycin) Incentive spirometry
Early use of partial exchange transfusion in a patient who does not improve rapidly
Sequestration crisis
Rapid accumulation of blood in spleen (or less commonly, liver)
Occurs in patients <6 years of age
Abdominal distension, abdominal pain, shortness of breath, tachycardia, pallor, fatigue, and shock; mortality can be high
Lab findings: low Hgb; elevated reticulocytes
Supportive care Transfusion of RBCs
Splenectomy recommended by some practitioners because recurrence occurs in up to 50%

Aplastic crisis Temporary cessation of RBC production often caused by parvovirus B19 or other infectious agent
Pallor, fatigue, tachycardia
Lab findings: low Hgb; low reticulocytes Supportive care Transfusion of RBCs
Hyperhemolytic crisis
Rapid hemolysis; often occurs in patients with other hemolytic diseases (e.g., G6PD deficiency)
Pallor, fatigue, tachycardia, jaundice
Lab findings: low Hgb; elevated reticulocytes; elevated bilirubin
Supportive care Transfusion of RBCs
RBCs = red blood cells; SS = sickle cell; G6PD = glucose-6-phosphate dehydrogenase; Hgb = hemoglobin.

Table 13-4
Usual Laboratory Findings in Sickle Cell Anemia

Red blood cell life span 10–50 days
Hemoglobin 6–9 g/dL
Hematocrit 18–27%
Reticulocyte count 5–15%
White blood cell count 12,000–20,000 cells/mm3
Platelet count Increased, often > 500,000 platelets/µL
Bilirubin Increased
Blood smear Sickled cells, target cells, Howell–Jolly bodies
Bone marrow Erythroid hyperplasia
Table 13-5
Characteristics of the Red Blood Cell Aplasias

Aplasia Etiology Clinical Features Laboratory Findings Treatment
Congenital hypoplastic anemia (Diamond–
Blackfan
Unknown Autosomal recessive or autosomal
Anemia within the first year of life
Rapid onset
One-fourth to one-third have
↓Hgb
↓Reticulocytes
↑Hgb F
↓or normal
RBC transfusion Corticosteroids (up to 70% respond)
anemia) dominant
inheritance physical findings:
craniofacial, renal, cardiac platelet count
Marrow: Bone marrow
transplant if no
anomalies; short stature; ↓RBC response to
triphalangeal thumbs precursors; corticosteroids
Signs and symptoms of other marrow
anemia elements
normal
TEC
Unknown
Anemia begins >1 year of age
↓Hgb
Spontaneous
Possible Slow in onset ↓Reticulocytes recovery within
postviral Signs and symptoms of Normal several weeks
autoimmune anemia platelet count No treatment
reaction Marrow: required
↓RBC
precursors
Parvovirus B19– associated pure RBC aplasia*
Parvovirus B19
infection
Anemia generally not symptomatic
May have associated URI
↓Hgb
↓Reticulocytes Normal
Spontaneous recovery within 2 weeks
symptoms and facial rash platelet count RBC transfusions
(“slapped cheeks”) of fifth may be required
disease for patients with
Aplastic crisis in patients aplastic crisis
with SS disease associated with
SS disease
*Note that Epstein–Barr virus, cytomegalovirus, human immunodeficiency virus (HIV), and drugs (e.g., chloramphenicol) may cause an acquired RBC aplasia similar to parvovirus B19.

TEC = transient erythroblastopenia of childhood; SS = sickle cell; URI = upper respiratory infection; Hgb = hemoglobin; RBCs = red blood cells.

II. Pancytopenia and Aplastic Anemia
A. Definition. Pancytopenia is defined as low white blood cells (WBCs), RBCs, and platelets and implies bone marrow failure.
B. Pancytopenia may be congenital or acquired.
1. Congenital aplastic anemia is also known as Fanconi anemia.
a. Etiology. Inheritance is autosomal recessive.
b. Clinical features
1. Onset of bone marrow failure occurs at a mean age of 7 years. Typical presentation is with ecchymosis and petechiae.
2. Skeletal abnormalities, which include short stature in almost all patients, and
absence or hypoplasia of the thumb and radius
3. Skin hyperpigmentation
4. Renal abnormalities, including renal tubular acidosis
c. Laboratory findings. Studies show pancytopenia, RBC macrocytosis, low reticulocyte count, elevated Hgb F, and bone marrow hypocellularity.
d. Management. Treatment includes transfusions of RBCs and platelets as needed, and bone marrow transplant from an HLA-compatible donor, if available. Immunosuppressive therapy (e.g., corticosteroids, cyclosporin) may also help.
2. Acquired aplastic anemia
a. Etiology. Causes include drugs (e.g., sulfonamides, anticonvulsants, chloramphenicol), infections (e.g., human immunodeficiency virus [HIV], Epstein– Barr virus [EBV], cytomegalovirus [CMV], hepatitis), chemicals, and radiation. These all may damage bone marrow stem cells directly or may induce autoimmune destruction. Acquired aplastic anemia is most often idiopathic.
b. Clinical features. Signs and symptoms include bruising, petechiae, pallor, and fatigue, or serious infection as a result of neutropenia.
c. Laboratory findings. Studies show pancytopenia, low reticulocyte count, and hypocellular bone marrow.
d. Management. Treatment includes identifying and stopping the causative agent, transfusions as needed, bone marrow transplant, and immunosuppressive therapy.

III. Polycythemias
A. Definition. Polycythemia is defined as an increase in RBCs relative to total blood volume. It may also be defined as a hematocrit (Hct) > 60% or as an Hgb or Hct more than 2 standard deviations above normal values for age.
B. Primary polycythemia (polycythemia vera) is an extremely rare cause of polycythemia during childhood. This is a myeloproliferative disorder seen typically in older adults.
C. Secondary polycythemia is caused by increased erythropoietin production. Production may be appropriate or inappropriate.
1. Appropriate polycythemia may be caused by chronic hypoxemia as a result of cyanotic congenital heart disease (the most common cause of polycythemia in childhood), pulmonary disease, or living at high altitudes.
2. Inappropriate polycythemia may be caused by benign and malignant tumors of the kidney, cerebellum, ovary, liver, and adrenal gland; excess hormone production (e.g., corticosteroids, growth hormone, androgens), and kidney disease.
3. Clinical features include a ruddy facial complexion with a normal-sized liver and spleen.
4. Laboratory findings reveal elevated Hgb and Hct but normal platelet and WBC counts. Erythropoietin levels are high.
5. Management is directed toward identifying and treating the underlying cause. Phlebotomy is also used to keep the Hct < 60%.
D. Relative polycythemia refers to an apparent increase in RBC mass caused by a decrease in plasma volume. The most common cause is dehydration, and this should be considered in every patient with a high Hgb or Hct. Appropriate fluid management normalizes the Hct.
E. Complications of polycythemia include thrombosis (vaso-occlusive crisis, stroke, myocardial infarction) and bleeding.

IV. Disorders of Hemostasis
A. General concepts
1. Hemostasis requires normal function of three important elements: blood vessels, platelets, and soluble clotting factors. Hemorrhage may result from deficiency or dysfunction of any of these elements. Thrombosis may also occur but is rare during childhood.
2. The clotting cascade is depicted in Figure 13-2.
3. Clinical features suggesting abnormal hemostasis include the following:
a. Cutaneous bleeding (e.g., ecchymoses, petechiae)
b. Spontaneous epistaxis that is severe and recurrent without an obvious cause
c. Prolonged bleeding after simple surgical procedures, circumcision, trauma, or dental extraction
d. Recurrent hemarthroses
e. Deep venous thrombosis, pulmonary embolism, or stroke
4. Diagnostic studies. Evaluation for clotting abnormality typically includes these screening tests:
a. Complete blood count (CBC)
b. Platelet count
c. Blood smear to evaluate platelet morphology
d. Activated partial thromboplastin time (aPTT)
e. Prothrombin time (PT)
f. Platelet function assay
g. The laboratory and clinical findings of coagulation disorders are summarized in
Table 13-6.
5. The differential diagnosis of disorders of hemostasis is summarized in Figure 13-3.
B. Congenital clotting factor disorders. These disorders include deficiency of factor VIII and von Willebrand disease (both of which are factor VIII–related disorders) and deficiency of factor IX.
1. General considerations. Factor VIII disorders include two inherited disorders, hemophilia A and von Willebrand disease, which are described in more detail below. These two diseases involve different regions and different functions of the factor VIII molecule.
a. Hemophilia A represents a defect in factor VIII procoagulant activity (antihemophilic factor; factor VIII protein). Platelet function is normal.
b. In von Willebrand disease, factor VIII procoagulant activity is variable, but platelet function is defective because of a decrease or defect in von Willebrand factor, a protein required for platelet adhesion to blood vessel wall. It also functions as a carrier protein for factor VIII.
2. Factor VIII deficiency—hemophilia A
a. Inheritance is X-linked and occurs in 1 in 5000–10,000 male births. More than 200 different mutations or deletions have been identified in the factor VIII gene.
b. Clinical features
1. Hemarthroses (involving the knees, elbows, and ankles most commonly) and deep soft tissue bleeding are the hallmarks. Bleeding into the iliopsoas muscle may be especially severe as a result of delayed recognition of the bleeding and the potential for significant blood accumulation. Risk of serious and life-threatening hemorrhage is lifelong.
2. Severe, moderate, and mild forms exist based on the activity level of factor

VIII protein.
a. Severe: spontaneous bleeding (<1% factor VIII protein activity)
b. Moderate: bleeding only with trauma (1–5% factor VIII protein activity)
c. Mild: bleeding only after surgery or major trauma (>5% factor VIII protein activity)
3. Central nervous system (CNS) bleeding is the most dreaded complication and is usually the result of head trauma.
c. Laboratory findings
1. Prolonged aPTT (in mild form, aPTT may be normal)
2. Normal PT, platelet count, and platelet function assay
3. Low factor VIII protein activity in the presence of normal von Willebrand factor assay
d. Management. Treatment includes prevention of trauma and replacement of factor
VIII. Desmopressin acetate (DDAVP) causes the release of stored factor VIII from the patient’s own cells and may be useful in mild hemophilia A.
3. von Willebrand disease. This group of disorders involves defects or deficiency in the von Willebrand factor (vWf) portion of the factor VIII complex and is the most common hereditary bleeding disorder.
a. Etiology. Inheritance is most commonly autosomal dominant.
b. Categories
1. Type I (classic type): mild quantitative deficiencies of vWf and factor VIII protein. It is the most common form.
2. Type II: qualitative abnormality in vWf
3. Type III: absence of vWf; the most severe type
c. Clinical features
1. Most patients have mild to moderate bleeding, usually involving mucocutaneous surfaces. More profound bleeding occurs in type III disease.
2. Common signs and symptoms include epistaxis, menorrhagia, bruising, and bleeding after dental extraction or tonsillectomy. Excessive bleeding after trauma may occur.
3. Hemarthroses are unusual.
d. Laboratory findings
1. Prolonged bleeding time and prolonged aPTT may be present, but not always (but they are always present in type III disease).
2. Quantitative assay for vWf antigen and activity (ristocetin cofactor assay) are diagnostic.
e. Management. DDAVP induces vWf release from endothelial cells and is used for mild to moderate bleeding and for prophylaxis before surgery. DDAVP is most useful in type I disease and is sometimes effective in type II disease. Cryoprecipitate, which contains intact vWf, may be used for serious bleeding, for extensive surgeries, or for type III disease.
4. Factor IX deficiency—hemophilia B (Christmas disease). This X-linked disorder has clinical features similar to those of hemophilia A and occurs in 1 in 50,000 males. aPTT is prolonged and low factor IX activity is found. PT and platelet count are normal. Management includes factor IX replacement.
C. Acquired clotting factor disorders
1. Vitamin K deficiency
a. Vitamin K, a fat-soluble vitamin, is essential for the synthesis of both procoagulant and anticoagulant factors, such as factors II, VII, IX, and X and proteins C and S.
b. Etiology

1. Dietary deficiency is unusual, except during early infancy.
2. Pancreatic insufficiency, biliary obstruction, and prolonged diarrhea may result in diminished ability to absorb vitamin K.
3. Medications may interfere with vitamin K metabolism (e.g., cephalosporins, rifampin, isoniazid, warfarin).
4. Hemorrhagic disease of the newborn is the result of vitamin K deficiency. It may occur early (within 24 hours after birth), within the first week of life (classic form), or late (1–3 months after birth).
c. Clinical features. Clinical manifestations include bruising, oozing from skin puncture wounds (e.g., previous blood draw sites), and bleeding into organs. Hemorrhagic disease of the newborn is characterized by serious bleeding in the early and late forms, but classic disease generally presents only with cutaneous bleeding, hematemesis, and bleeding from the circumcision site or umbilical cord. CNS bleeding may occur occasionally.
d. Laboratory findings include prolonged aPTT and PT.
e. Management. Treatment includes administration of vitamin K. Intramuscular administration of vitamin K after birth prevents hemorrhagic disease of the newborn. In severe disease, fresh-frozen plasma (FFP) may be needed.
2. Liver disease
a. The liver is the major site of production of most coagulation factors. Therefore, with liver disease, synthesis of clotting factors is often diminished, with the vitamin K– dependent factors most severely affected [see section IV.C.1.a]. Consumption of clotting factors and platelets may also occur with liver disease.
b. Laboratory findings. Laboratory results are the same as those seen in DIC [see section IV.C.3], including prolonged PT and aPTT, increased fibrin degradation products, and thrombocytopenia.
c. Management. Treatment includes vitamin K, FFP, and platelets as needed.
3. DIC
a. Definition. DIC refers to a group of laboratory and clinical features indicative of both accelerated fibrinogenesis and fibrinolysis. The initiating event is clotting that leads to consumption of procoagulant factors and resultant hemorrhage.
b. Etiology. DIC is a secondary phenomenon that occurs in response to local factors (e.g., large hemangiomas as seen in Kasabach–Merritt syndrome) and systemic factors (e.g., sepsis, hypothermia, malignancy, heat stroke, snakebite, burns).
c. Clinical features. Signs include cutaneous and internal organ bleeding.
d. Laboratory findings. Studies show thrombocytopenia, prolongation of PT and aPTT, reduction in clotting factors (especially fibrinogen and factors II, V, and VIII), elevated fibrin degradation products (positive D-dimer assay), and fragmented and helmet-shaped RBCs on blood smear.
e. Management. Therapy includes treatment of the underlying cause and transfusions of fibrinogen, FFP, and platelets as needed. Heparin may be useful if the underlying defect cannot be corrected.
D. Disorders of blood vessels. These diseases affect the integrity of blood vessels and may present with bleeding.
1. Henoch–Schönlein purpura, an IgA-mediated vasculitis, presents with palpable purpura on the lower extremities and buttocks, renal insufficiency, arthritis, and abdominal pain. Platelet count is normal. (See also Chapter 16, section I.)
2. Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by locally dilated and tortuous veins and capillaries of the skin and mucous membranes.

3. Scurvy is vitamin C deficiency and causes impaired collagen synthesis that results in weakened blood vessels.
4. Inherited disorders of collagen synthesis (e.g., Ehlers–Danlos syndrome) may result in capillary fragility.
5. Malnutrition and corticosteroids may weaken the collagen supporting vessels.
E. Platelet abnormalities
1. General concepts
a. Platelet abnormalities may be quantitative (i.e., decreased or increased in number) or qualitative (i.e., intrinsic abnormality in function).
b. Thrombocytopenia is defined as a decreased number of platelets, generally
<100,000/µL. It is the most common cause of bleeding.
2. Quantitative disorders may be secondary to diminished platelet production or to increased platelet destruction or sequestration (within the spleen). They may also be congenital or acquired.
a. Decreased platelet production
1. Congenital disorders
a. Wiskott–Aldrich syndrome is an X-linked disorder characterized by thrombocytopenia with unusually small platelets, eczema, and defects in T- and B-cell immunity.
b. Thrombocytopenia–absent radius (TAR) syndrome is an autosomal recessive disorder characterized by thrombocytopenia and limb abnormalities, especially absence of the radius (note that the thumb is present, in contrast to Fanconi anemia, in which the thumb is absent; see section II.B.1). Cardiac and renal disease may be present. Thrombocytopenia improves in the second or third year of life.
2. Acquired disorders are generally those that cause pancytopenia, including infiltration of the bone marrow, infections, drugs, and aplastic anemia [see section II.B.2].
b. Increased platelet destruction
1. Immune-mediated thrombocytopenias
a. Immune thrombocytopenic purpura (ITP) is the most common acquired platelet abnormality in childhood.
1. Etiology. ITP may be viral, drug-induced, or idiopathic.
2. Pathophysiology. Because ITP often follows a viral infection, it is thought that the virus triggers antibodies that cross-react with platelets, causing their destruction and removal by the spleen.
3. Clinical features. Illness typically occurs 1–4 weeks after a viral infection. It begins abruptly with cutaneous bleeding (e.g., petechiae, bruising) or mucous membrane bleeding (e.g., epistaxis, gum bleeding). Internal bleeding into the brain (occurs in <1%), kidneys, or GI tract may occur but are rare.
4. Laboratory findings. Studies reveal thrombocytopenia and a blood smear showing few large “sticky” platelets.
5. Management. Treatment includes supportive care. Very low platelet counts (<10,000/µL) or active bleeding warrants treatment with intravenous immunoglobulin (IVIG) or corticosteroids. Anti-D immunoglobulin is a second-line agent that may also be effective. This immunoglobulin binds to erythrocyte D antigen (Rh) on RBCs (patients must be Rh-positive). These antibody-coated RBCs are cleared by the spleen, preferentially allowing platelets to escape

destruction. Platelet transfusions are generally avoided because transfused platelets are rapidly destroyed.
6. Prognosis. Most cases (70–80%) resolve spontaneously within months. Chronic ITP, which occurs in 10–20%, is diagnosed if ITP lasts >6 months. Chronic ITP results in long-lasting or relapsing thrombocytopenia and is more common in adults and in children older than 10 years. Splenectomy results in a normal platelet count in 75% of patients with chronic ITP, but because of the risk of infection after spleen removal, there is a reluctance to perform a splenectomy on children.
b. Neonatal immune-mediated thrombocytopenia
1. Passive autoimmune thrombocytopenia occurs when the mother has ITP, and antibodies against her own platelets cross the placenta and destroy the fetus’s platelets. The mother has thrombocytopenia.
2. Isoimmune thrombocytopenia occurs when the mother produces antibodies against her fetus’s platelets as a result of sensitization to an antigen that her own platelets lack. The mother’s platelet count is normal.
2. Drugs, DIC, and an enlarged spleen may all cause platelet destruction.
3. HUS is characterized by thrombocytopenia, in association with acute renal failure and hemolytic anemia (see Chapter 11, section VII).
4. Large hemangiomas may sequester and destroy platelets (e.g., Kasabach– Merritt syndrome characterized by an enlarging hemangioma, microangiopathic hemolytic anemia, thrombocytopenia, and consumptive coagulopathy).
3. Qualitative platelet disorders (i.e., defect in platelet function despite normal number) may be congenital or acquired.
a. Congenital disorders
1. Glanzmann thrombasthenia is an autosomal recessive disorder characterized by diminished ability of platelets to aggregate and form a clot as a result of deficient adhesive glycoprotein IIb/IIIa (receptor for fibrinogen) on the platelet cell membrane.
2. Bernard–Soulier syndrome is an autosomal recessive disorder characterized by decreased platelet adhesion as a result of absence of platelet membrane glycoprotein Ib (receptor for collagen). Severe hemorrhage may occur, and large unusual platelets are seen on blood smear.
b. Acquired disorders are usually caused by drugs (e.g., aspirin, valproic acid) that impair platelet function. Uremia and severe liver disease may also decrease platelet function.
F. Hypercoagulability
1. Inherited coagulation abnormalities leading to hypercoagulability most commonly include deficiencies of proteins C and S or antithrombin III, or mutations in factor V (factor V Leiden) and prothrombin.
a. Protein C deficiency
1. Protein C is a vitamin K–dependent factor that is the most potent anticoagulant protein known. Homozygous and heterozygous deficiency states have been described, and inheritance may be either autosomal recessive or dominant.
2. Clinical features

a. Homozygotes usually have no protein C activity and are detected soon after birth. Purpura fulminans, a nonthrombocytopenic purpura, is often the initial presentation. It is characterized by fever, shock, and rapidly spreading skin bleeding and intravascular thrombosis.
b. Heterozygotes often present later with deep venous or CNS thrombosis.
3. Diagnosis is by careful family history and specific testing for protein C.
4. Management. Treatment may include heparin, FFP, and warfarin. Purified concentrates of protein C have been used.
b. Protein S and antithrombin III deficiencies, and factor V Leiden and prothrombin mutations present similarly to protein C deficiency. Specific testing for levels and function of each factor is diagnostic.
2. Disease states associated with thrombosis include SS disease, malignancy, inflammatory disease (e.g., ulcerative colitis), liver disease, kidney disease (e.g., nephrotic syndrome), dehydration, vasculitis (e.g., Kawasaki disease), diabetes mellitus, and homocystinuria. Pregnancy and contraceptive use may also be associated with thrombosis.

FIGURE 13.2 Coagulation cascade. Activated partial thromboplastin time measures the function of the intrinsic pathway and the extrinsic pathway, except for factor VII; the prothrombin time measures the function of the extrinsic pathway (factors VII, X, and V), fibrinogen, and prothrombin (factor II). Factors in bold type are vitamin K–dependent coagulation factors.

Table 13-6
Laboratory and Clinical Findings in Coagulation Disorders

Disorder aPTT PT Platelet Function Assay Platelet Count Petechiae Hemarthroses
Factor VIII, IX deficiency Prolonged Normal Normal Normal No Yes
von Willebrand Prolonged Normal Abnormal Normal No Rare
Thrombocytopenia Normal Normal *
Low Yes No
Platelet function defect Normal Normal Abnormal Normal Yes No
Vitamin K deficiency Prolonged Prolonged Normal Normal Yes Yes
DIC Prolonged Prolonged Abnormal Low Yes Sometimes
*Platelet function assays may be unreliable with thrombocytopenia and therefore are typically not indicated.
aPTT = activated partial thromboplastin time; PT = prothrombin time; DIC = disseminated intravascular coagulation.

FIGURE 13.3 Overview of the differential diagnosis of disorders of hemostasis. DIC = disseminated intravascular coagulation; HUS = hemolytic uremic syndrome; HSP = Henoch–Schönlein purpura; TAR = thrombocytopenia–absent radius syndrome; ITP = immune thrombocytopenic purpura.

V. Neutropenia
A. General concepts
1. Definition. Neutropenia is a low absolute number of neutrophils and is often expressed as the absolute neutrophil count (ANC; percentage of WBCs that are neutrophils, bands, and immature myeloid cells).
2. Risk of infection is directly related to the ANC.
a. Mild neutropenia is an ANC of 1000–1500 cells/mm3.
b. Moderate neutropenia is an ANC of 500–1000 cells/mm3. Infection generally involves the mucous membranes and skin (e.g., stomatitis, cellulitis, gingivitis).
c. Severe neutropenia is an ANC of <500 cells/mm3. Severe infections may result, such as pneumonia, sepsis, and meningitis. S. aureus and Gram-negative bacteria (e.g., Klebsiella, Serratia, Escherichia coli, and Pseudomonas) are typical organisms.
B. Neutropenia caused by decreased production
1. Infections are the most common cause of neutropenia during childhood. Viruses (e.g., HIV, EBV, CMV, hepatitis A and B, influenza A, parvovirus B19), bacteria (e.g., typhus, Rocky Mountain spotted fever), and protozoans (e.g., malaria) may all suppress the bone marrow, marginate neutrophils, or exhaust marrow reserves, resulting in neutropenia.
2. Chronic benign neutropenia (CBN) of childhood, a common cause of neutropenia in children younger than 4 years, refers to a group of acquired and inherited disorders with noncyclic neutropenia as the only abnormality. Its etiology is presumed to be autoimmune.
a. Clinical features. CBN has a variable course, with most children having an increased incidence of mild infections, such as otitis media, sinusitis, pharyngitis, and cellulitis. Severe infections may occur but are uncommon. Children are otherwise healthy, with normal appearance and growth.
b. Laboratory findings. Studies show a low ANC with a normal or slightly low WBC. Bone marrow demonstrates immature neutrophil precursors (development of mature neutrophils is arrested).
c. Prognosis. In most children, CBN resolves spontaneously within months to years.
3. Severe congenital agranulocytosis (Kostmann syndrome) is an autosomal recessive disorder with frequent and life-threatening pyogenic bacterial infections beginning in infancy. ANC is usually <300 cells/mm3. These patients must be supported with granulocyte colony-stimulating factor or undergo bone marrow transplant for cure.
4. Cyclic neutropenia
a. Clinical features. Cyclic alterations in neutrophil counts result in regular episodes of neutropenia with resultant infections. Fever, oral ulcers, and stomatitis may occur during the neutropenia. Cycles last an average of 21 days in 70% of patients. Some cases are inherited in an autosomal dominant pattern.
b. Diagnosis is made by documenting the cyclic nature of the neutropenia by obtaining serial neutrophil counts during a 2- to 3-month period.
c. Treatment is with granulocyte colony–stimulating factor during periods of neutropenia, although some patients spontaneously remit during adolescence.
5. Genetic syndromes associated with neutropenia
a. Chédiak–Higashi syndrome is an autosomal recessive disorder characterized by oculocutaneous albinism, large blue-gray granules in the cytoplasm of neutrophils, neutropenia, and blond or brown hair with silver streaks. Patients are at high risk for serious infection.
b. Cartilage–hair hypoplasia syndrome is an autosomal recessive disorder

characterized by short stature, immunodeficiency, fine hair, and neutropenia.
6. Shwachman–Diamond syndrome is characterized by exocrine pancreatic insufficiency with malabsorption, short stature caused by metaphyseal chondrodysplasia, and neutropenia. Failure to thrive and recurrent infections (especially otitis media) are common.
7. Drugs (e.g., antibiotics, anticonvulsants, aspirin), environmental toxins, radiation, and chemotherapy may all cause neutropenia.
8. Metabolic diseases, such as hyperglycinemia, methylmalonic acidemia, and Gaucher disease, may result in neutropenia.
C. Neutropenia caused by increased destruction
1. Infections (especially viral)
2. Drugs
3. Hypersplenism
4. Autoimmune neutropenia describes a disorder in which antineutrophil antibodies are produced in response to infection (e.g., EBV), drugs, SLE, and juvenile rheumatoid arthritis (JRA), or for unknown reasons.
5. Isoimmune neutropenia describes the passive transfer of antineutrophil antibodies from the mother to her fetus after maternal sensitization by antigens on the fetal neutrophils. Infants are initially susceptible to infection, but neutropenia resolves by 8 weeks of life.

Review Test
1. You are evaluating a 2-month-old healthy full-term male infant at a routine health care maintenance visit. His mother is concerned because he seems pale. Although your examination is normal, you draw a hemoglobin (Hgb) level to reassure the parents. Which of the following statements is correct regarding the expected Hgb concentration?
A. Evidence of nutritional iron-deficiency anemia is likely.
B. The Hgb level is likely at its physiologic lowest point.
C. Fetal Hgb has disappeared by now, and the Hgb level will be slightly lower than that at birth.
D. The Hgb level was likely low at birth and is now increasing.
E. Evidence of macrocytic anemia is likely.
2. A 2-year-old boy is brought to your office with a history of multiple bacterial infections, including six episodes of otitis media, three episodes of sinusitis, and one episode of periorbital cellulitis. He is normal-appearing with normal growth and development. Biweekly laboratory assessments for the past 3 months have revealed consistently low white blood cell counts at 2000–2500 cells/mm3, with an absolute neutrophil count of 500–1000 cells/mm3. Which one of the following is the most likely diagnosis?
A. Chédiak–Higashi syndrome
B. Shwachman–Diamond syndrome
C. Chronic benign neutropenia of childhood
D. Cyclic neutropenia
E. Kostmann syndrome
3. A 3-year-old girl is brought to the office with petechiae and bruising on the face, chest, back, and lower extremities, which her mother noticed early this morning. The mother states that her daughter has been healthy except for a viral upper respiratory illness 2 weeks ago. Laboratory assessment reveals a platelet count of 25,000/µL. Which of the following statements regarding the likely diagnosis is correct?
A. Hemarthroses commonly occur in this disorder.
B. Spontaneous recovery within several weeks to months is expected.
C. Platelet transfusion should be urgently performed.
D. Prothrombin time and activated partial thromboplastin time are prolonged.
E. Considering the girl’s young age, this disorder will likely become chronic.
4. A 15-month-old girl has a hypochromic, microcytic anemia (hemoglobin of 10.6 g/dL) on a routine anemia screen performed in the office. History reveals a diet consisting of six 8-oz glasses of whole cow’s milk per day since the age of 9 months. Which of the following statements regarding the likely diagnosis is correct?
A. The anemia is caused by a benign disorder, and there are no physical or intellectual effects.
B. Low serum ferritin is a late finding.
C. The reticulocyte count is low, considering the impact of this disorder on the bone marrow.
D. Transferrin saturation is low.
E. Free erythrocyte protoporphyrin is low.
5. You are evaluating a term newborn female infant during a routine health maintenance evaluation at 2 weeks of age. You receive the results of a routine newborn screen performed on the second day of life. The results of the newborn screen are normal, with the exception of the sickle cell screen, which reveals that the infant has hemoglobin (Hgb) A, Hgb S, and Hgb F. Which of the following is correct regarding the diagnosis?

A. Mild anemia is expected.
B. A vaso-occlusive crisis involving the hands and feet is likely by 6 months of age.
C. Splenic function is expected to decrease by 3 years of age.
D. Penicillin prophylaxis should be started immediately.
E. Hematuria may be the only manifestation of this disorder.
6. An 8-year-old boy with sickle cell anemia presents with severe right arm pain that began today. His pain has been unresponsive to oral acetaminophen. His mother states that he has been afebrile, and she denies any trauma. On examination, his right arm is mildly tender and is minimally warm along the humerus. Range of motion of the upper extremity is normal. There is no fever. Which of the following is the appropriate initial management?
A. Obtaining a blood culture
B. Transfusion of red blood cells with a goal of an Hgb level of 14 g/dL
C. Bolus with 40 mL/kg of normal saline
D. Administration of ibuprofen and a narcotic
E. Magnetic resonance imaging (MRI) to rule out osteomyelitis
7. A 17-year-old girl presents with concerns about her menstrual periods. Menarche occurred at 13 years of age, and for the past 2 years, her menstrual cycles have been regular but characterized by extremely heavy bleeding lasting 7–8 days. She also has a history of frequent nosebleeds since early childhood. She denies bleeding into her joints and has been otherwise healthy. She also denies medications, including aspirin. Based on her history, which of the following is the most likely diagnosis?
A. Hemophilia A
B. Hemophilia B
C. Vitamin K deficiency
D. Immune thrombocytopenic purpura (ITP)
E. von Willebrand disease
8. A 7-year-old girl comes to your office for the first time. Her parents bring her to see you because she has had widespread bruising for 3 days. They also believe that she is abnormally pale. On examination, you note that she is pale and has multiple areas of ecchymosis on her arms, legs, and trunk. Her medical history is remarkable for being born with absence of her right thumb and right radius. Laboratory studies reveal a hemoglobin level of 7 g/dL, platelet count of 30,000/µL, and white blood cell count of 800 cells/mm3. Which of the following statements regarding the likely diagnosis is correct?
A. The reticulocyte count is elevated.
B. Spontaneous recovery from this disorder is likely.
C. The growth chart likely reveals short stature.
D. Intravenous immunoglobulin should be administered for immune thrombocytopenic purpura (ITP).
E. Causes of the disorder include drugs, radiation, or chemical exposure.
9. A 10-year-old Italian boy has had chronic anemia since infancy that is characterized by severe hypochromia and microcytosis. Examination reveals a short child, an enlarged liver and spleen, and prominent facial bones, especially the maxilla, forehead, and cheekbones. Which of the following statements regarding the likely diagnosis is correct?
A. Management should include supplemental iron.
B. Hemochromatosis is a likely future complication.
C. His hemoglobin (Hgb) electrophoresis will reveal Hgb S and Hgb F.
D. The cause of his disorder is deletion of the α-globin chain.
E. His blood smear will show spherocytes.
10. A 2-year-old girl has anemia with a hemoglobin level of 9.8 g/dL on routine laboratory screening. History reveals a diet consisting of large amounts of goat’s milk. Which of the

following statements regarding the anemia is correct?
A. The cause of the anemia is diminished intake of vitamin B12.
B. Spoon-shaped nails may be seen on examination.
C. Smooth red tongue may be seen on examination.
D. The anemia is normochromic and normocytic.
E. Management includes administration of folic acid.

The response items for questions 11–13 are the same. You will be required to select one answer for each item in the set.

A. Thrombocytopenia–absent radius (TAR) syndrome
B. Fanconi anemia
C. Wiskott–Aldrich syndrome
D. Immune thrombocytopenic purpura
E. Hemolytic uremic syndrome
F. Kasabach–Merritt syndrome
G. Glanzmann thrombasthenia
H. Bernard–Soulier syndrome

For each patient, select the likely diagnosis.

1. A 2-year-old boy with thrombocytopenia and a large hepatic hemangioma.
2. A 5-year-old boy with thrombocytopenia, moderate eczema, and both humoral and cell- mediated immunodeficiency.
3. A newborn girl with thrombocytopenia, ventricular septal defect, and absence of a radius. The girl’s thumb is present.

The response items for questions 14 and 15 are the same. You will be required to select one answer for each question in the set.

A. Transient erythroblastopenia of childhood
B. Diamond–Blackfan anemia
C. Parvovirus B19 red blood cell aplasia

For each clinical description, select the likely diagnosis.

1. A 6-month-old male infant presents with rapid onset of anemia. He has triphalangeal thumbs on examination. Corticosteroids improve his anemia.
2. A 2-year-old girl develops the gradual onset of significant anemia 2 weeks after a viral upper respiratory infection. Her anemia improves spontaneously.

The response items for questions 16–19 are the same. You will be required to select one answer for each item in the set.

A. Hemophilia B
B. Platelet function defect
C. Vitamin K deficiency
D. Disseminated intravascular coagulation (DIC)
E. von Willebrand disease
F. Immune thrombocytopenic purpura

For each patient, select the most likely diagnosis.

1. A 6-year-old boy with prolonged diarrhea lasting 2 weeks develops a hemarthrosis involving the knee. He has a prolonged prothrombin time and prolonged activated partial thromboplastin time with a normal platelet activation function assay.
2. A 2-year-old boy with newly diagnosed acute lymphocytic leukemia presents with fever, petechiae, and ecchymoses. He has thrombocytopenia, prolonged prothrombin time, prolonged activated partial thromboplastin time, and a prolonged platelet functional assay.
3. A 5-year-old boy presents with a hemarthrosis involving the knee. He has a normal prothrombin time, prolonged activated partial thromboplastin time, and normal platelet function assay.
4. An 8-year-old boy develops severe bleeding following tonsillectomy. He has a normal prothrombin time, prolonged activated partial thromboplastin time, and abnormal platelet function assay.

Answers and Explanations
1. The answer is B [I.A.2]. The hemoglobin of a healthy full-term infant is high at birth and decreases during the next several months, reaching its nadir, or physiologic lowest point, by 2–3 months of age. The hemoglobin of a preterm infant is at its physiologic low point at 1–
2 months of age. Iron-deficiency anemia does not generally appear until 9–24 months of age, as a result of inadequate iron intake and depletion of iron stores acquired during fetal life.
Fetal hemoglobin, a major constituent of red blood cells during early postnatal life, gradually declines and disappears by 6–9 months of age. Macrocytic anemia, caused most commonly by folic acid or vitamin B12 deficiency, would not normally occur at 2 months of age.
2. The answer is C [V.B.2]. This patient’s clinical presentation and age are most consistent with chronic benign neutropenia (CBN) of childhood. This noncyclic neutropenia is most common in children younger than 4 years of age. CBN is characterized by normal appearance and growth and a history of mild infections, such as sinusitis, cellulitis, and otitis media. Absolute neutrophil count (ANC) and white blood cell counts are low. Chédiak–Higashi and Kostmann syndromes are characterized by more severe infections, and Chédiak–Higashi syndrome is also notable for the presence of oculocutaneous albinism. Kostmann syndrome (severe congenital agranulocytosis) is an autosomal recessive disorder with frequent severe infections and a very low ANC. Shwachman–Diamond syndrome is characterized by poor growth, pancreatic insufficiency, and metaphyseal chondrodysplasia. Cyclic neutropenia, as its name suggests, is characterized by regular cycles of neutropenia occurring on average every 21 days.
3. The answer is B [IV.E.2.b.(1) and Table 13-6]. The most likely diagnosis is immune thrombocytopenic purpura (ITP) based on the acuteness of the presentation and the classic history of signs and symptoms after a viral infection. Spontaneous recovery is the rule, occurring in 70–80% of patients. Clinical features of ITP most commonly include cutaneous or mucous membrane bleeding, rather than bleeding into joints (hemarthroses). Platelet transfusions are generally not recommended because transfused platelets will be destroyed by the patient’s antibodies. Patients with ITP have low platelet counts but normal activated partial thromboplastin time and prothrombin time. Treatment includes supportive care, intravenous immune globulin, or corticosteroids, and sometimes anti-D immunoglobulin. Chronic ITP occurs more commonly in patients older than 10 years.
4. The answer is D [I.D.1]. The history of excessive intake of iron-poor cow’s milk and the presence of a microcytic, hypochromic anemia at 15 months of age are both consistent with iron-deficiency anemia. In iron-deficiency anemia, findings include increased free erythrocyte protoporphyrin, increased transferrin, and decreased transferrin saturation. Significant physical and intellectual effects may occur in iron-deficiency anemia and include poor weight gain, diminished attention, and diminished abilities to learn. One of the earliest laboratory findings is a low serum ferritin. Reticulocyte count is often elevated, reflecting increased bone marrow activity.
5. The answer is E [I.F.3.d]. The presence of both hemoglobin (Hgb) A and Hgb S indicates that this patient has sickle cell trait (all children also have Hgb F at birth). The presence of Hgb A excludes sickle cell disease; affected patients with sickle cell disease have only Hgb S and Hgb
F. Patients with sickle cell trait are generally asymptomatic, although during adolescence they may have an inability to concentrate the urine or hematuria. Patients do not have anemia; they are generally free of crises, unless they have severe hypoxemia, and they have normal splenic function. Prophylactic penicillin is unnecessary given the normal splenic function.
6. The answer is D [Table 13-3]. Extremity pain in patients with sickle cell disease may be caused by trauma, osteomyelitis, or a vaso-occlusive crisis. Because there is no trauma or fever, a painful bone crisis (a type of vaso-occlusive crisis) is most likely. Appropriate management

includes pain control with a narcotic and a nonsteroidal anti-inflammatory agent. There is no need to obtain a blood culture because the child has no fever. Red blood cell transfusion to a hemoglobin level of 14 g/dL is inappropriate because it will lead to increased blood viscosity that may result in increased vaso-occlusion. If the pain is not well controlled with analgesia and improved hydration, a partial exchange transfusion might be indicated. Because osteomyelitis is less likely given the acute onset of the pain and the absence of fever, magnetic resonance imaging would not be an appropriate initial management step.
7. The answer is E [IV.B.3]. von Willebrand disease is characterized by mild to moderate bleeding in most patients. Common signs and symptoms include bruising, epistaxis, menorrhagia (i.e., prolonged or excessive uterine bleeding occurring at regular intervals), and bleeding after surgical procedures or dental extraction. Hemarthroses are unusual and are more typical in hemophilia A and B, in which deep soft tissue bleeding occurs. In addition, these bleeding disorders occur in males; they have X-linked inheritance. Vitamin K deficiency in an adolescent would likely be caused by medications or disorders that cause diminished vitamin K absorption, such as pancreatic insufficiency, biliary obstruction, or prolonged diarrhea. Symptoms would also likely be more severe. Immune thrombocytopenic purpura may present with petechiae, bruising, or nosebleeds. However, the onset of symptoms is generally acute.
8. The answer is C [II.B.1]. The patient most likely has Fanconi anemia, or congenital aplastic anemia, on the basis of pancytopenia, her age at presentation, and her history of absence (hypoplasia may also occur) of the thumb and radius. Fanconi anemia is an inherited lifelong disorder that results in bone marrow failure. Almost all patients have short stature, and many also have skin hyperpigmentation and kidney anomalies. Management includes transfusions and bone marrow transplant. Because Fanconi anemia is characterized by bone marrow failure, the reticulocyte count would be expected to be very low. Because the hemoglobin and white blood cell count are also low, this girl does not have immune thrombocytopenic purpura.
9. The answer is B [I.D.2.d]. This patient’s anemia and physical features suggest β-thalassemia. β-Thalassemia occurs most commonly in patients of Mediterranean background and is caused by deletion of the β-globin chain. If untreated, β-thalassemia results in bone marrow hyperplasia (often noted within the facial bones), delays in growth and puberty, and hepatosplenomegaly. Many children suffer from hemochromatosis (iron overload) as a complication, and therefore iron is contraindicated in these patients. The presence of both hemoglobin S and hemoglobin F is not consistent with β-thalassemia and would instead suggest sickle cell anemia. Spherocytes are not present on blood smear.
10. The answer is E [I.E.1]. Feedings exclusively with goat’s milk as a sole source of milk protein can lead to folic acid deficiency and a macrocytic anemia. Dietary folic acid is the treatment. Spoon-shaped nails are seen in iron-deficiency anemia, and a smooth red tongue is seen in vitamin B12 deficiency.
11. The answers are F, C, and A, respectively [IV.E.2.b.(4), IV.E.2.a.(1).(a), and IV.E.2.a.(1).(b)]. The 2-year-old boy has a large hemangioma that sequesters and destroys platelets, which is termed Kasabach–Merritt syndrome. The 5-year-old boy has Wiskott–Aldrich syndrome, which is characterized by eczema, defects in T- and B-cell immunity, and low platelet counts. The newborn girl has thrombocytopenia–absent radius (TAR) syndrome, which is characterized by thrombocytopenia, at times cardiac and renal disease, and absence of the radius. The thumb is present in TAR syndrome, in contrast to Fanconi anemia (pancytopenia with hypoplasia or absence of the radius and thumb).
12. The answers are B and A, respectively [Table 13-5]. The 6-month-old infant has Diamond– Blackfan anemia, which is characterized by rapid onset of anemia within the first year of life and physical abnormalities, including triphalangeal thumbs, short stature, and cardiac and

renal anomalies, in one-fourth to one-third of patients. Treatment includes transfusions and corticosteroids. The 2-year-old girl has transient erythroblastopenia of childhood, which is characterized by the slow onset of anemia after the first year of life. The cause is likely a postviral autoimmune reaction, and no treatment is generally required. Parvovirus B19 red blood cell aplasia generally results in no symptoms of anemia in healthy children. Associated features may include a “slapped cheek” red facial rash and upper respiratory symptoms.
13. The answers are C, D, A, and E, respectively [Table 13-6]. The clinical characteristics and laboratory abnormalities can differentiate the causes of bleeding in pediatric patients. The 6- year-old boy has vitamin K deficiency, which can occur with pancreatic insufficiency, biliary obstruction, and prolonged diarrhea. Vitamin K deficiency affects the vitamin K–dependent coagulation factors (II, VII, IX, and X) and therefore results in hemarthroses, a prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), and normal bleeding times. The 2-year-old boy has disseminated intravascular coagulation (DIC), which may be caused by malignancy, sepsis, snakebite, heat stroke, and burns. DIC is characterized by abnormalities in all coagulation constituents, including low platelet counts and prolonged aPTT, PT, and bleeding time. Both petechiae and hemarthroses may be present. The 5-year-old boy has hemophilia B, or factor IX deficiency. Hemophilia B is characterized by hemarthroses and prolonged aPTT, but normal PT and bleeding time. The 8-year-old boy has von Willebrand disease, which can present with epistaxis, menorrhagia, and bleeding after tonsillectomy or dental surgery. von Willebrand disease is characterized by prolonged aPTT and prolonged bleeding time, but normal PT. Hemarthroses may sometimes occur.