TABLE 15-1. Normal Hemoglobin and Mean Corpuscular Volume (MCV) by Age
NORMAL HEMOGLOBIN BY AGE
Normal values of hemoglobin and red cell parameters vary with age (see Table 15-1).
ANEMIA
DEFINITION
Reduced circulating red blood cell (RBC) mass.
CLASSIFICATION
Size and hemoglobin content (mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC]) (see Table 15-2).
Mechanism—loss/sequestration, ↑ destruction, ↓ production.
PATHOPHYSIOLOGY
Less oxygen transport.
↓ blood volume.
↑ cardiac output.
SIGNS AND SYMPTOMS
Somnolence, light-headedness, headache.
Angina, dyspnea, palpitations, flow murmur.
Fatigue, claudication, edema.
Pallor—conjunctiva, palmar creases.
Hepatosplenomegaly in some cases.
Irritability.
Pica: Desire to eat unusual things (eg, clay).
DIAGNOSIS
Family history.
Exposure history.
Past medical history, including medications.
TABLE 15-2. Anemias
Physical exam.
Complete blood count (CBC): See Table 15.2.
Peripheral blood smear: See Table 15-3.
Platelet and white blood cell (WBC) size, morphology.
Possible bone marrow aspirate/biopsy—cellularity, morphology, stroma.
TABLE 15-3. Some Erythrocyte Morphology and Inclusion Bodies
Chemistry—liver function tests (LFTs), lactic dehydrogenase (LDH), creatinine (Cr), uric acid.
Imaging as appropriate.
Other special tests—serum ferritin, B12, folate, reticulocyte count, Coombs’ test, osmotic fragility, etc.
TREATMENT
Supplement or remove causative factor.
Support hemodynamics as appropriate.
Coombs test: Direct—detects auto-IgG bound RBCs (autoimmune hemolysis); indirect—detects unbound autoantibodies to RBCs (antenatal, pretransfusion testing).
Physiologic Anemia of Infancy
Normal newborns have higher hemoglobin until third week.
↓ to 9–11 g/dL at 8–12 weeks.
Decline in hemoglobin level is both more extreme and more rapid in premature infants: 7–9 g/dL by 3–6 weeks.
ETIOLOGY
Abrupt cessation of erythropoiesis with the onset of respiration.
↓ survival of fetal RBCs.
Expansion of blood volume in first 3 months.
No therapy needed.
Transient erythroblastopenia of childhood (TEC).
The most common acquired red cell aplasia in children.
Age 6 months to 3 years (most children > 12 months).
Schilling test:
Radiolabeled B12 used to investigate B12 deficiency
Normal newborn Hgb is 14–20 g/dL.
Transient Erythroblastopenia of Childhood
A previously healthy 1-year-old male infant had a cold 8 weeks ago. He now is pale and irritable and refuses to eat. A CBC shows Hgb 5.0, Hct 10%, MCV 80, reticulocyte count 0%, WBC 9, platelets 400K. Think: Transient erythroblastopenia of childhood (TEC).
TEC occurs in previously healthy children and is often preceded by a viral infection. Classic history is gradual onset of pallor between the ages of 1 and 4 years. Characteristic features include normocytic anemia, severe reticulocytopenia, transient neutropenia, and ↑ platelet counts. It is often confused with Diamond-Black-fan anemia. TEC is a self-limited condition and has an excellent prognosis.
Diamond-Blackfan should be differentiated from transient erythroblastopenia of childhood based on the features listed.
Age (average age of diagnosis = 3 months)
Macrocytic (↑ MCV)
Reticulocytopenia
DEFINITION
Transient failure of the bone marrow to produce RBCs usually at 18–26 months; may occur at < 6 months and up to 10 years.
ETIOLOGY
Possible link to parvovirus B19.
SIGNS AND SYMPTOMS
Gradual pallor and fatigue; appearance better than expected for Hgb level.
DIFFERENTIAL DIAGNOSIS
Diamond-Blackfan anemia.
Etiology: Genetic.
Age: During first year.
↑ MCV.
↑ Red cell adenosine deaminase (ADA).
↑ Hemoglobin F.
↑ i Antigen.
DIAGNOSIS
CBC: Hgb 5–7, clinically insignificant neutropenia.
Normochromic, normocytic anemia (MCV normal for age).
Reticulocyte count initially < 1%, ↑ with recovery (↑ MCV during recovery).
Any child with presumed TEC who requires more than one transfusion should be considered for alternate diagnoses.
TREATMENT
Supportive until RBC production returns; should occur spontaneously in 30–60 days.
If continues, different causes of the anemia must be investigated.
NUTRITIONAL ANEMIAS
Iron Deficiency Anemia
A 9-month-old child who has been fed whole milk from early infancy presents with the following lab values: Hgb 7.5 g, MCV 62, RBC 3.2. Think: Iron deficiency anemia.
Consumption of large amounts of cow’s milk is the most common dietary pattern in children with iron deficiency anemia. Cow’s milk has poor iron bioavailability, especially in infants < 12 months. In the first year, full-term infants need to absorb 1.2 mg of elemental iron. Since only up to 10% of dietary iron is absorbed, daily intake of iron should exceed 12 mg. Characteristic findings are microcytic, hypochromic anemia, low mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), ↑ red cell distribution width (RDW), and ↓ reticulocyte count. Depletion of iron stores is the earliest finding.
ETIOLOGY
Inadequate intake (whole cow’s milk has no iron).
Loss of iron.
Bleeding.
Rapid growth spurts (early infancy and adolescence).
Prematurity (↓ iron stores).
Chronic diseases (juvenile rheumatoid arthritis [JRA], cystic fibrosis [CF]).
EPIDEMIOLOGY
Most common anemia in children.
Especially 6 months to 3 years old.
Rare in infants under 6 months.
Mentzer Index
MCV/RBC
≥ 13 Iron deficiency
≤ 13 Thalassemia trait
SIGNS AND SYMPTOMS
Usual symptoms of anemia.
Cheilosis/angular stomatitis, glossitis.
Koilonychia (spoon nails).
Esophageal web.
Blue sclera.
Splenomegaly.
DIAGNOSIS
↓ serum ferritin (< 10 ng/mL).
↓ serum iron.
↑ iron-binding capacity.
Microcytic and hypochromic, ↑ RDW.
Low reticulocyte count.
↑ platelet count (> 600,000/mm3).
Hypercellular marrow with erythroid hyperplasia.
↓ stainable iron.
TREATMENT
Ferrous sulfate 3 mg/kg/day for at least 8 weeks after a normal Hgb level is obtained.
Retic response to oral iron within 4 days.
Remember: Ferritin is an acute phase reactant. A normal or high ferritin does not exclude iron deficiency during an acute infection.
Lead Poisoning
A 2½-year-old boy with hyperactivity lives in old apartment building with peeling paint on the walls. His gait has become ataxic and his speech has regressed. His Hgb is 8.5 g. Think: Lead poisoning.
Lead poisoning is usually caused by exposure to dust and paint chips from interior surfaces of homes. The initial signs and symptoms may be nonspecific. Laboratory screening should be considered for children at risk for lead poisoning and should be screened routinely starting at age 1 year. A blood lead level of ≥ 10 μg/dL is considered abnormal. To avoid contamination, a venous sample should be obtained for confirmation. Other features are anemia and basophilic stippling on peripheral smear and elevated free erythrocyte protoporphyrin level.
Chronic lead poisoning interferes with iron utilization and hemoglobin synthesis.
DEFINITION
Variant of iron deficiency anemia.
ETIOLOGY
Environmental (aerosolized and oral).
Lead-containing paint.
Screening for lead poisoning occurs at 10–14 months and at 2 years of age.
PATHOPHYSIOLOGY
Irreversible binding with sulfhydryl group of proteins.
Inhibits enzymes involved in heme production.
Impairs iron utilization.
SIGNS AND SYMPTOMS
Acute encephalopathy.
Lead lines—thick transverse radiodense lines in the metaphyses of growing bones on radiographs.
DIAGNOSIS
Microcytic hypochromic anemia, basophilic stippling.
↑ serum lead and free erythrocyte protoporphyrin (FEP) level. Lead level < 9 is considered acceptable.
↑ urine coproporphyrin.
TREATMENT
Environment control, education, level dependent.
70 μg/dL—medical emergency: Dimercaprol (BAL) followed by ethylenediaminetetraacetic acid (EDTA)—5 days’ treatment.
45–69 μg/dL: Both medical and environmental intervention including chelation (EDTA or DMSA).
20–45 μg/dL: Environmental evaluation + pharmacologic treatment such as EDTA provocative chelation test.
10–19 μg/dL: Education.
Prevention: Banning of lead-based paint in 1978.
Lead paint remains the most common cause of lead poisoning.
Folate Deficiency
DEFINITION
Megaloblastic anemia.
ETIOLOGY
Deficient intake or absorption.
Pregnancy (↑ requirement).
Very-low-birth-weight (VLBW) infants.
Drugs (phenytoin, methotrexate).
Vitamin C deficiency.
Goat’s milk is folate deficient.
EPIDEMIOLOGY
Peak age 4–7 months.
Green vegetables, fruits, liver, and kidneys contain folate.
SIGNS AND SYMPTOMS
Features of anemia.
Failure to gain weight.
Chronic diarrhea.
DIAGNOSIS
Macrocytic anemia, thrombocytopenia, neutropenia (hypersegmented PMNs).
Low reticulocyte count.
↑ LDH.
Bone marrow hypercellular and megaloblastic changes.
Serum and RBC folate levels.
TREATMENT
Parenteral folic acid only after confirmation.
Folic acid is contraindicated in vitamin B12 deficiency, because it will mask anemia, yet B12 deficiency neurologic symptoms will progress.
RBC folate is the best indicator of chronic deficiency.
Vitamin B12 Deficiency
DEFINITION
Megaloblastic anemia.
ETIOLOGY
Inadequate intake (strict vegetarians).
Pernicious anemia.
Surgery of stomach or terminal ileum.
PATHOPHYSIOLOGY
Deficiency of intrinsic factor due to autoimmunity or gastric mucosal atrophy prevents adequate B12 absorption.
Subacute combined systems disease in B12 deficiency—demyelination of dorsal and lateral columns of spinal cord:
↓ vibration sense
↓ proprioception
Gait apraxia
Spastic paraparesis
Paresthesias
Incontinence
Impotence
SIGNS AND SYMPTOMS
Juvenile pernicious anemia.
Red, beefy tongue.
Premature graying, blue eyes, vitiligo.
Myxedema, gastric atrophy.
Weakness, irritability, anorexia.
Neurologic (ataxia, paresthesias, hyporeflexia, Babinski response, clonus).
DIAGNOSIS
Macrocytic anemia, large hypersegmented neutrophils.
↑ LDH.
Methylmalonic acid in urine.
Anti-intrinsic factor antibody.
Schilling test.
TREATMENT
Vitamin B12 IM monthly.
Oral therapy is contraindicated.
Copper Deficiency
PATHOPHYSIOLOGY
Copper is essential for production of red blood cells, transferrin, and hemoglobin.
SIGNS AND SYMPTOMS
Refractory anemia, pancytopenia.
Osteoporosis.
Ataxia, spasticity.
Menke disease in newborns—X linked.
ETIOLOGY
Copper-deficient total parenteral nutrition (TPN).
Persistent infantile diarrhea.
Post gastric bypass surgery.
Zinc supplementation (↓ copper absorption).
DIAGNOSIS
Hypochromic anemia unresponsive to iron supplementation.
Neutropenia.
Impaired bone calcification.
Serum copper and ceruloplasmin levels.
Dietary copper is found in liver, oysters, meat, fish, whole grains, nuts, and legumes.
TREATMENT
Treat underlying cause.
Anemia of Chronic Disease
ETIOLOGY
JRA, systemic lupus erythematosus (SLE), ulcerative colitis.
Malignancies.
Renal disease.
DIAGNOSIS
Can be normochromic and normocytic or hypochromic and microcytic.
Hgb ranges 7–10 g/dL.
Low serum iron with normal or low total iron-binding capacity (TIBC).
Elevated serum ferritin.
TREATMENT
Treat underlying cause.
Iron if concomitant iron deficiency is present.
HEMOLYTIC ANEMIAS
See Figure 15-1.
SIGNS AND SYMPTOMS
Can vary from asymptomatic to generalized symptoms to severe pain crises.
Icterus, fever, splenomegaly.
↑ products of RBC destruction.
Compensatory ↑ in hematopoiesis-reticulocytosis.
See Table 15-4.
DIAGNOSIS
↑ direct bilirubin.
↓ haptoglobin (intravascular especially).
↑ hemoglobinuria/hemosiderinuria (intravascular).
↑ LDH.
FIGURE 15-1. Hemolytic anemias.
TABLE 15-4. Hemolysis
Hemolytic Disease of the Newborn
DEFINITION
Erythroblastosis fetalis.
ETIOLOGY
Maternal sensitization to Rh, ABO, or other blood system antigens (Kell, Duffy).
PATHOPHYSIOLOGY
Paternal heterozygosity allows an Rh-positive (or other alloantibody) infant to be carried by an Rh-negative mother.
Maternal blood comes into contact with fetal blood cells.
Maternal antibodies are produced against the Rh antigen.
During a subsequent pregnancy with an Rh-positive infant, maternal antibodies cross the placenta and bind to fetal RBCs, → hemolysis.
Destruction of RBCs causes ↑ unconjugated bilirubin, becoming clinically apparent only after delivery as the placenta effectively metabolizes it.
Severe anemia → ↑ extramedullary erythropoiesis, with potential replacement of hepatic parenchyma.
EPIDEMIOLOGY
Severe Rh disease is rare in the United States nowadays.
Rh sensitization occurs in 11 of 10,000 pregnancies.
< 1% of births are associated with significant hemolysis.
Approximately 50% of affected newborns do not require treatment, 25% are term but die or develop kernicterus, and 25% become hydropic in utero.
SIGNS AND SYMPTOMS
Hemolytic anemia.
Fetal hydrops:
Large placenta.
↑ unconjugated hyperbilirubinemia—rapidly progressive jaundice after birth, kernicterus.
Abdominal distention—hepatosplenomegaly, ascites, hepatic dysfunction.
Abduction of limbs, loss of flexion.
Scalp edema.
Purpura.
Cyanosis.
DIAGNOSIS
Positive direct Coombs’ test.
TREATMENT
Know blood types of both parents early in the pregnancy.
Prophylaxis (RhoGam) during and immediately after delivery for mothers at risk for alloimmunization
Exchange transfusion to infant of Rh-negative blood.
Mutation causing sickle cell disease: Glu-6-val.
Sickle Cell Disease (SCD)
A 16-month-old African-American boy is brought to the ED because of crying and refuses to stand. He has no fever, vomiting, or diarrhea. His parents denied trauma or fall. On examination, he is afebrile. He cries when his right leg is touched. X-ray of his right leg showed no fracture. Think: Sickle cell disease.
Acute sickle cell painful episode (painful crisis) is the most common presentation in children with SCD. Newborn screening has resulted in detection in early infancy. CBC shows chronic hemolytic anemia with low hematocrit and hemoglobin levels and a reticulocytosis. Peripheral smear may show sickled forms, target cells, and polychromasia suggestive of reticulocytosis.
DEFINITION
Chronic hemolytic anemia due to premature destruction of red cells.
ETIOLOGY
Defect in β-globin–hemoglobin S (HgbS)—substitution of glutamic acid at sixth position of β chain by valine.
As part of a routine genetic screening, a term African-American newborn has Hgb F, A, and S. Possible diagnoses on quantitative testing could be HgbAS trait or HgbS-thalassemia.
PATHOPHYSIOLOGY
Unusual solubility problem in the deoxygenated state.
HgbS is a low-affinity hemoglobin.
EPIDEMIOLOGY
Autosomal recessive.
One in 500 African-Americans.
Eight percent of African-Americans are carriers.
Four sickle cell crises:
Vaso-occlusive crisis
Aplastic crisis (parvovirus)
Sequestration crisis
Hemolytic crisis
SIGNS AND SYMPTOMS
Appears after 6 months of age (when HbF is ↓).
Anemia (due to hemolysis).
Vaso-occlusive: Leg ulcers, stroke, priapism, pain crises.
Hand-foot syndrome (swollen hands and feet).
Infection (encapsulated organisms):
Streptococcus pneumoniae (30%)
Haemophilus influenzae
Salmonella osteomyelitis
Splenomegaly.
Cardiac enlargement.
Short stature, delayed puberty.
Gallstones/jaundice.
The most common cause of fatal sepsis in patients with sickle cell disease is Streptococcus pneumoniae.
DIAGNOSIS
Newborn screening.
Hgb electrophoresis (definitive test).
HgbS 90%.
HgbF 2–10%.
No HgbA.
Hgb ranges 5–9 g/dL.
Peripheral smear—target cells and sickled cells.
↑ WBCs and platelets.
There now exists universal newborn screening for sickle cell disease.
TREATMENT
Pneumococcal vaccine (at 2 and 5 years).
Prophylactic penicillin by 4 months of age.
Painful crisis—hydration and analgesics.
Priapism—exchange transfusion.
Thalassemia
A 2-year-old boy has required transfusion since early infancy. Think: β-Thalassemia major.
Children with β-thalassemia usually become symptomatic in early infancy because of progressive hemolytic anemia and cardiac decompensation. Severe hypochromia and microcytosis is the characteristic of β-thalassemia. The hemoglobin level declines progressively in the first year and may be as low as 3–4 g/dL, requiring transfusion.
DEFINITION
Hereditary hemolytic anemia.
ETIOLOGY
Total or partial deletions of globin chain.
α-Thalassemia (gene deletion):
Hgb Bart’s (four-gene deletion).
HgbH (three-gene deletion).
α-Thalassemia minor (two-gene deletion).
Silent carrier (one-gene deletion).
β-Thalassemia:
Homozygous (β-thalassemia major).
Heterozygous (β-thalassemia minor).
β-thalassemia major is fatal without regular transfusion.
SIGNS AND SYMPTOMS
Severe hemolytic anemia.
Hepatosplenomegaly.
Extramedullary hematopoiesis (classic facies—maxillary overgrowth and skull bossing).
DIAGNOSIS
Hypochromic, microcytic anemia.
Hgb < 5 g/dL.
Reticulocytopenia.
Markedly ↑ LDH (ineffective erythropoiesis).
Hgb electrophoresis:
HgbA: ↓ or absent
↑ HgbA2
HgbF: Marked elevation
TREATMENT
Monthly transfusion of packed RBCs to maintain Hgb > 10 g/dL.
Splenectomy if requiring > 240 mL/kg of packed RBCs/year.
Hemosiderosis:
Cardiomyopathy
Cirrhosis
Diabetes
HEMOLYTIC ENZYMOPATHIES
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
A previously well 2-year-old African-American male child is treated with sulfonamide. Two days later, he develops fever, back pain, dark urine, and anemia. Blood smear shows fragmented erythrocytes. Think: G6PD deficiency.
The highest prevalence of G6PD deficiency is in Africans and people of Mediterranean descent. It is a recessive X-linked trait; therefore, males are at higher risk. Episodic hemolysis is the characteristic of G6PD deficiency. It is caused by exposures that cause oxidant stress such as infection or drugs. Sulfonamides and antimalarial drugs (primaquine and chloroquine) are the common agents.
A male child has sudden onset of dark urine, pallor, and jaundice after an exposure to an oxidant stress. Think: G6PD deficiency.
Most patients are asymptomatic unless exposed to an oxidant stress that results in a hemolytic crisis. Jaundice and splenomegaly may be present during an acute crisis. Heinz bodies, indicative of denatured hemoglobin, are typically present and can be detected by a methyl violet stain. G6PD levels can be deceptively normal during an acute crisis because of an elevated reticulocyte count. Therefore, G6PD levels should be obtained weeks to months later to obtain an actual baseline measurement.
DEFINITION
Enzyme defect of hexose monophosphate (HMP) pathway, resulting in hemolysis when exposed to stresses such as infection or certain drugs.
Develops 24–48 hours after the exposure of an oxidizing agent.
ETIOLOGY
Hereditary ↓ of G6PD that normally maintains adequate level of glutathione in a reduced state in RBCs.
Parents of a child with G6PD deficiency should be provided a list of drugs and foods to avoid.
PATHOPHYSIOLOGY
Oxidized glutathione complexes with Hgb, forming Heinz bodies.
RBC less deformable.
Splenic macrophages “bite out” RBCs.
EPIDEMIOLOGY
Most common hemolytic enzymopathy.
X-linked.
Higher incidence in African-American, Middle Eastern, and Mediterranean populations.
SIGNS AND SYMPTOMS
Episodic intravascular hemolysis secondary to oxidant stress (drugs, fava beans, etc.).
Spontaneous chronic nonspherocytic hemolytic anemia.
Jaundice, dark urine.
Splenomegaly.
Suspect G6PD deficiency when G6PD activity is within low normal range in the presence of high reticulocyte count.
DIAGNOSIS
Reduced G6PD activity in RBCs.
Anemia, Heinz bodies, and bite cells on peripheral smear.
Reticulocytosis.
Elevated serum bilirubin and LDH.
↓ serum haptoglobin.
Hemoglobinuria.
TREATMENT
Removal of oxidant stressor.
Oxygen.
Transfusion of packed RBC for Hgb < 6, hemodynamic instability, ongoing hemolysis.
G6PD deficiency protects against parasitism of erythrocytes (such as malaria).
Pyruvate Kinase (PK) Deficiency
DEFINITION
Congenital hemolytic anemia (↓ RBC PK).
PATHOPHYSIOLOGY
Pyruvate kinase catalyzes the final step in the glycolytic pathway.
Drugs causing hemolysis in G6PD deficiency:
Aspirin
Sulfonamides
Ciprofloxacin
Antimalarials
EPIDEMIOLOGY
Second most common hemolytic enzymopathy.
Autosomal recessive.
SIGNS AND SYMPTOMS
Chronic hemolytic anemia.
Hyperbilirubinemia/failure to thrive (FTT) in newborn.
↓ reticulocytes (selective destruction).
Ingestion of fava beans can cause hemolysis in patients with G6PD deficiency (“favism”).
DIAGNOSIS
↓ RBC PK activity.
TREATMENT
Avoid oxidant stresses.
Exchange transfusion (hyperbilirubinemia).
Transfusion of packed RBCs if severe anemia or aplastic crisis.
Splenectomy (after 5–6 years of age), if persistently severe anemia or frequent transfusion requirement, will ↑ reticulocyte count.
Folate supplementation.
HEMOLYTIC MEMBRANE DEFECTS
Hereditary Spherocytosis
A 4-year-old boy has pallor and a family history of gallstone surgery. His Hgb is 8 g, retics 11, bili 2. Think: Hereditary spherocytosis.
Hereditary spherocytosis is a common inherited hemolytic anemia that is transmitted as an autosomal dominant. The characteristic feature is spherocytic red cells that are intrinsically defective. Hemolysis results in reticulocytosis and indirect hyperbilirubinemia. Splenomegaly and gallstones are common. Spherocytes are present in the peripheral blood smear. Splenectomy is helpful in reducing the rate of hemolysis.
DEFINITION
Red cell membrane defect → abnormally shaped erythrocytes and hemolysis.
ETIOLOGY
Genetic defect in erythrocyte membrane proteins, such as ankyrin.
PATHOPHYSIOLOGY
Abnormal proteins cause destabilized RBC membrane—spherocytes.
Abnormal RBCs become sequestered in the spleen and hemolyze.
EPIDEMIOLOGY
Autosomal dominant.
SIGNS AND SYMPTOMS
Commonly asymptomatic.
Evidence of hemolysis.
Aplastic/hemolytic crisis.
Splenomegaly.
Gallstones.
Leg ulcers.
Positive family history.
DIAGNOSIS
↑ osmotic fragility.
Spherocytes on peripheral film.
Reticulocytosis.
Hyperbilirubinemia.
Hereditary spherocytosis has the following characteristics: ↑ osmotic fragility, ↑ reticulocyte count, positive family history, and splenomegaly. Coombs’ test is not positive.
TREATMENT
Splenectomy (avoid or at least delay until > 5 years old).
Pneumococcal, meningococcal, and Haemophilus influenzae (Hib) vaccines before splenectomy.
Treatment does not fix underlying RBC defect.
Paroxysmal Nocturnal Hemoglobinuria
DEFINITION
Complement-induced hemolytic anemia caused by acquired defect in RBC membrane.
Red urine (intravascular hemolysis worse with relative hypoxia at night vs. more concentrated urine at night).
Thrombosis.
SIGNS AND SYMPTOMS
Hemolysis worse during sleep → morning hemoglobinuria.
Marrow failure.
Intermittent or chronic hemolytic anemia.
Leukopenia, thrombocytopenia.
Complications can include thromboembolic phenomenon and acute myelogenous leukemia.
Splenectomy predisposes patients to overwhelming postsplenectomy infections (OPSIs) caused by encapsulated organisms:
Streptococcus pneumoniae
Neisseria meningitidis
Haemophilus influenzae
DIAGNOSIS
↑ LDG, ↓ haptoglobin, direct Coombs’ is negative since hemolysis is not antibody directed.
Sucrose lysis test, Ham’s acid hemolysis test.
Flow cytometry.
TREATMENT
Prednisone.
Bone marrow transplantation for severe disease.
Splenectomy is not indicated.
Eculizumab (humanized antibody which inhibits the activation of terminal complement components).
Iron supplementation unless frequently transfused.
Folic acid supplementation.
Onset of paroxysmal nocturnal hemoglobinuria is in late childhood.
APLASTIC ANEMIA
DEFINITION
Rare group of closely related disorders → ↓ numbers of blood cells in each of the lines—RBCs, WBCs, and platelets.
ETIOLOGY
Exact cause is unknown.
Chemical exposure.
Viral infection.
Genetic causes (eg, Fanconi’s anemia).
SIGNS AND SYMPTOMS
Fatigue (fewer RBCs).
Infections (fewer WBCs).
Bleeding (fewer platelets).
↑ risk of leukemia.
DIAGNOSIS
CBC—suspicious if at least two of the three cell lines are ↓.
Bone marrow biopsy is definitive.
TREATMENT
Platelet and RBC transfusions.
Immunosuppressive drugs—antilymphocyte globulin (ALG), antithymocyte globulin (ATG), cyclosporine.
Growth factors—erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF).
Stem cell transplantation is definitive cure but requires chemotherapy and/or radiation in preparation.
THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)
DEFINITION
Hemolytic anemia that results from deposition of abnormal VWF multimers into microvasculature.
Diagnostic pentad for TTP:
FAT RN
Fever
Anemia
Thrombocytopenia
Renal dysfunction
Neurologic abnormality
SIGNS AND SYMPTOMS
Fever.
Microangiopathic hemolytic anemia.
Thrombocytopenia.
Abnormal renal function.
Neurologic signs.
DIAGNOSIS
Normal prothrombin time (PT) and activated partial thromboplastin time (aPTT).
Microangiopathic hemolytic anemia.
Abnormal red cell morphology with schistocytes, spherocytes, helmet cells.
↑ reticulocyte count.
Thrombocytopenia.
TREATMENT
Plasmapheresis
Corticosteroids
Splenectomy
HEMOLYTIC-UREMIC SYNDROME (HUS)
Ten days after an episode of viral diarrhea, a 2-year-old boy has pallor and icterus and petechiae of the skin and mucous membranes. His mother reports that he has not urinated for 24 hours. Characteristic lab findings include fragmented erythrocytes on smear, ↑ blood urea nitrogen (BUN), ↑ reticulocyte count, indirect hyperbilirubinemia, and normal platelet count. Think: HUS.
HUS is a common cause of renal failure in children. Triad: microangiopathic hemolytic anemia, thrombocytopenia, and uremia. Onset is usually preceded by gastroenteritis. It may be epidemic during summer months. Platelet count is usually low, but may be normal early in the course of illness.
ETIOLOGY
Acute gastroenteritis caused by Escherichia coli O157:H7 (produces a shiga-like toxin).
SIGNS AND SYMPTOMS
Hemolytic anemia
Thrombocytopenia
Acute renal failure (ARF)
DIAGNOSIS
History of bloody diarrhea.
Abnormal red cell morphology.
Thrombocytopenia with normal megakaryocytes in marrow.
Urine—protein, RBCs, and casts.
TREATMENT
Fluid management.
Dialysis.
Plasmapheresis (for neurologic complications).
Antibiotics not indicated.
Immune Thrombocytopenic Purpura (ITP)
A 4-year-old previously healthy girl with purple skin lesions had a visit to the ED with an upper respiratory infection (URI) a month ago. CBC is normal except for low platelets. Think: ITP.
Typical presentation: Sudden onset of generalized petechiae and purpura in a previously healthy child. Often, there is a history of a viral infection weeks before the onset. Physical examination is usually normal except petechiae and purpura. Complete remission occurs in most children.
ITP is the most common thrombocytopenia of childhood.
DEFINITION
Acquired hemorrhagic disorder that results from excessive destruction of platelets—typically benign.
Acute (remission within 6 months).
Chronic (> 6 months).
Also called autoimmune thrombocytopenic purpura.
ETIOLOGY
Unknown.
Associated with antecedent viral illnesses (varicella, rubella, mumps, infectious mononucleosis) in 50–65% of cases.
Purpuric lesions do not blanch.
PATHOPHYSIOLOGY
Immune mechanism—autoantibodies.
Sensitization.
Primary ITP is a diagnosis of exclusion.
DIAGNOSIS
Diagnosis of exclusion.
WBC and Hgb levels normal.
Normal peripheral smear except thrombocytopenia.
Bone marrow (not always indicated).
Normal erythrocytic and granulocytic series.
Normal or ↑ megakaryocytes.
Don’t give prednisone in ITP without a marrow examination.
TREATMENT
Treatment based on severity of bleeding.
Admit if platelet count is < 20.
> 80% recover within several months without treatment.
Intravenous immune globulin (IVIG) or anti-Rho antibodies.
Intravenous methylprednisolone.
Splenectomy.
Older children (> 4 years).
Severe ITP.
Chronic ITP (> 1 year).
Platelet transfusion generally not helpful.
DISSEMINATED INTRAVASCULAR COAGULATION (DIC)
DEFINITION
↑ fibrinogenesis and fibrinolysis.
ETIOLOGY
Sepsis.
Incompatible transfusion.
Rickettsial infection.
Snake bite.
Acute promyelocytic leukemia.
PATHOPHYSIOLOGY
Hypoxia
Acidosis
Tissue necrosis
Shock
Endothelial damage
DIC is frequently associated with purpura fulminans and acute promyelocytic leukemia.
SIGNS AND SYMPTOMS
Bleeding
Petechiae and ecchymoses
Hemolysis
DIAGNOSIS
↑ PT and aPTT.
↓ fibrinogen and platelets.
↑ fibrin degradation products and D-dimer.
TREATMENT
Treat underlying cause.
Replacement therapy:
Platelets (thrombocytopenia).
Cryoprecipitate (hypofibrinogenemia).
Fresh frozen plasma (FFP) (replacement of coagulation factors).
Heparin prevents consumption of coagulation factors.
COAGULATION DISORDERS
Bleeding due to platelet problems usually occurs immediately and is mucocutaneous.
Bleeding due to factor deficiencies is often “deeper” bleeding (intraarticular, intramuscular).
See Table 15-5.
von Willebrand Disease
A child presents with epistaxis, prolonged bleeding time, and a normal platelet count. Think: von Willebrand disease.
von Willebrand disease is the most common inherited bleeding disorder. A family history of an established bleeding disorder should be sought. Typical presentation: Mucocutaneous bleeding (excessive bruising, epistaxis, and menorrhagia). The evaluation involves qualitative and quantitative measurements of von Willebrand factor (vWF).
DEFINITION
Most common hereditary bleeding disorder, seen in up to 1% of population, resulting from deficiency of vWF (qualitative or quantitative).
TABLE 15-5. Coagulation Tests
ETIOLOGY
Autosomal dominant—chromosome 12.
Deficiency of factor VIII-R.
PATHOPHYSIOLOGY
Defective platelet function due to ↓ in level or function of von Willebrand cofactor.
SIGNS AND SYMPTOMS
Easy bruising.
Heavy or prolonged menstruation.
Frequent or prolonged epistaxis.
Prolonged bleeding after injury, surgery (circumcision), or invasive dental procedures.
DIAGNOSIS
↑ aPTT and bleeding time.
Abnormal factor VIII clotting activity.
Quantitative assay for vWF antigen.
Reduced ristocetin cofactor activity.
Abnormal platelet aggregation tests.
Normal platelet count.
TREATMENT
Usually no therapy necessary.
Avoid unnecessary trauma.
Desmopressin (DDAVP), factor VIII for surgery if needed.
Cryoprecipitate recommended only in life-threatening emergencies due to the risk of human immunodeficiency virus (HIV) and hepatitis infection.
Avoid aspirin and nonsteroidal anti-inflammatory drug (NSAID) use in patients with von Willebrand disease.
FACTOR VIII REPLACEMENT
Hemophilia
DEFINITION
Inherited coagulation defects.
Hemophilia A: Factor VIII deficiency.
Hemophilia B: Factor IX deficiency.
Patients with hemophilia may lose large amounts of blood into an iliopsoas hematoma.
PATHOPHYSIOLOGY
Slowed rate of clot formation.
SIGNS AND SYMPTOMS
Easy bruising.
Intramuscular hematomas.
Hemarthroses (ankles, then knees and elbows) → joint destruction if untreated.
Spontaneous hemorrhaging if levels < 5%.
DIAGNOSIS
Family history.
aPTT 2–3 times upper limit of normal.
Specific factor assays.
Only 30% of male infants with hemophilia bleed at circumcision.
TREATMENT
Early diagnosis.
Prevent trauma.
Recombinant factors.
Cryoprecipitate.
Beware of transfusion complications, including disease transmission.
1 unit of VIII/kg—↑2%
1 unit of IX/kg—↑1%
HYPERCOAGULABLE STATES
DEFINITION
Predisposition to thrombosis.
PATHOPHYSIOLOGY
Primary (inherited) or secondary (acquired) disturbances in the three areas of Virchow’s triad:
Endothelial damage (eg, inflammation, trauma, burns, infection, surgery, central lines, artificial heart valves).
Change in blood flow (eg, immobilization, local pressure, congestive heart failure [CHF], hypovolemia, hyperviscosity, pregnancy).
Hypercoagulability (eg, factor release secondary to surgery, trauma, malignancy); antiphospholipid antibodies, lupus, oral contraceptive use; genetic predispositions such as deficiencies of protein S, protein C, antithrombin III, or factor V Leiden; nephrotic syndrome, polycythemia vera, sickle cell anemia, homocystinemia, fibrinogenemia.
SIGNS AND SYMPTOMS
Deep vein thrombosis (DVT)
Pulmonary embolism (PE)
Myocardial infarction (MI)
Stroke
Recurrent pregnancy loss
DIAGNOSIS
Family history.
Patient history of recurrent, early, unusual, or idiopathic thromboses.
Appropriate screening.
Risk factor assessment.
TREATMENT
Reduce risk factors—mobilize patients, encourage to quit smoking and alcohol, hydrate.
Aspirin, heparin, warfarin, etc., as appropriate.
MALARIA
An 8-year-old American-born boy of Somali parents presents with fever for 1 week after returning from his vacation. On examination he has splenomegaly. Think: Malaria.
Malaria should be considered in any child who presents with fever and has traveled or resided in a malaria-endemic area. It is characterized by fever, chills, sweats, fatigue, anemia, and splenomegaly. The diagnosis is established by identification of organisms on peripheral smear.
DEFINITION
Blood-borne parasite infection.
ETIOLOGY
Transmitted by female Anopheles mosquito.
Four species of Plasmodium:
P falciparum
P malariae
P ovale
P vivax
HgbS confers resistance against Plasmodium falciparum.
EPIDEMIOLOGY
Most frequent cause of hemolysis worldwide.
SIGNS AND SYMPTOMS
Fever
Chills
Jaundice
Splenomegaly
Sweats
DIAGNOSIS
Traditional method: Identification of organisms on thick and thin peripheral blood smears obtained when patient is acutely febrile.
Newer methods include polymerase chain reaction (PCR) and immunoassays.
TREATMENT
See CDC Web site for specific guidelines—usually dependent on resistance in geographic location.
Chloroquine is used for P ovale, P vivax, P malariae, and chloroquine-sensitive P falciparum.
Significant areas of chloroquine-resistant P falciparum exist. In these places, mefloquine or atovaquone-proguanil should be used.
TRANSFUSION REACTIONS
EPIDEMIOLOGY
Approximately 4% of transfusions are associated with some form of adverse reaction.
Most are febrile nonhemolytic or urticarial.
See Table 15-6.
INDICATIONS FOR TRANSFUSION OF BLOOD PRODUCTS
Packed RBCs: Hgb < 8 or 8–10 if symptomatic.
Platelets: < 10,000/μL; 10,000–50,000 if bleeding; < 75,000 in preparation for surgery.
FFP: Treatment of bleeding from vitamin K deficiency, ↑ International Normalized Ratio (INR), liver disease, or during plasma exchange for TTP.
TABLE 15-6. Transfusion Reactions
Cryoprecipitate: Hypofibrinogenemia, hemophilia A, vWF deficiency, factor XIII deficiency.
Children rarely have febrile reactions to initial transfusion unless they are immunoglobulin A (IgA) deficient.
COMPLICATIONS
Hemolytic, febrile, and allergic reactions.
Transfusion-related acute lung injury (TRALI).
Disease transmission (eg, HIV, hepatitis B virus [HBV], hepatitis C virus [HCV], human T-lymphotropic virus [HTLV], cytomegalovirus [CMV], parvovirus).
Iron overload, electrolyte disturbances.
Fluid overload, hypothermia.
METHEMOGLOBINEMIA
ETIOLOGY
Inherited:
Deficiency of cytochrome b5 reductase.
Hgb M disease—inability to convert methemoglobin back to hemoglobin.
Acquired—↑ production of methemoglobin: Nitrites (contaminated water), xylocaine/benzocaine (teething gel), sulfonamides, benzene, aniline dyes, potassium chlorate.
Life-threatening transfusion reactions are nearly always due to clerical errors (wrong ABO blood type).
PATHOPHYSIOLOGY
Hgb iron in ferrous form.
Methemoglobin iron is in ferric form (< 2%) and is unable to transport oxygen.
Suspect methemoglobinemia if:
Oxygen-unresponsive cyanosis
Chocolate brown blood
SIGNS AND SYMPTOMS
Depends on the concentration:
10–30%: Cyanosis.
30–50%: Dyspnea, tachycardia, dizziness.
50–70%: Lethargy, stupor.
> 70%: Death.
DIAGNOSIS
Methemoglobin level—co-oximetry studies.
TREATMENT
Concentration dependent.
< 30%: Treatment not needed.
30–70%: IV methylene blue.
Hyperbaric O2.
Oral ascorbic acid (200–500 mg).
PORPHYRIA
DEFINITION AND ETIOLOGY
Porphyria refers to a group of disorders (inherited and acquired) characterized by an inherited deficiency of the heme biosynthetic pathway.
SIGNS AND SYMPTOMS
Acute (hepatic) porphyria: Abdominal pain, vomiting, neuropathy, mental disturbances, seizures, autonomic nervous system dysfunction, cardiac arrythmias, tachycardia; ↑ risk of hepatocellular carcinoma over lifetime.
Cutaneous (erythropoietic) porphyria: Edema, blister formation, ↑ hair growth, photosensitivity, red urine.
Precipitated by drugs, infection.
DIAGNOSIS
Spectroscopy: Blood, urine, stool.
Hyponatremia/syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Renal insufficiency.
Serum/urine porphyrin levels.
TREATMENT
For acute attacks: Analgesia, hydration, maintain electrolytes, IV hematin especially if low serum sodium or status epilepticus, high-carbohydrate diet, glucose 10% infusion.
Long-term management:
Avoid alcohol and all drugs that can precipitate an attack.
Sunscreen.
DISORDERS OF WHITE BLOOD CELLS
Neutropenia
DEFINITION
Absolute neutrophil count (ANC) < 1500/mm3:
Mild: 1000–1500
Moderate: 500–1000
Severe: < 500
ANC = Total WBC × (Segs + Bands).
ETIOLOGY
Congenital.
Kostmann syndrome.
Schwachman syndrome.
Fanconi syndrome.
Acquired.
Infection.
Immune.
Hypersplenism.
Drugs.
Aplastic anemia.
Vitamin B12, folate, or copper deficiency.
SIGNS AND SYMPTOMS
↑ susceptibility to bacterial infection.
Stomatitis, gingivitis, recurrent otitis media, cellulitis, pneumonia, and septicemia.
LEUKEMIA
A 3-year-old girl has had fever, anorexia, and fatigue for the past month. She has lost 5 kg. She has pallor, cervical adenopathy, splenomegaly, skin ecchymoses, and petechiae. Think: Acute leukemia.
Typical presentation: Pancytopenia—anemia (pallor and fatigue), thrombocytopenia (epistaxis, ecchymoses, and petechiae) and white cell may be low (sepsis) or high. Initial presentation may be nonspecific and subtle and develop over weeks to months. Final diagnosis depends on the results of bone marrow aspirate and biopsy.
EPIDEMIOLOGY
Leukemia is the most common malignancy, followed by brain tumors.
RISK FACTORS
Trisomy 21
Fanconi’s anemia
Bloom syndrome
Immune deficiency
Wiskott-Aldrich syndrome
Agammaglobulinemia
Ataxia–telangiectasia
SIGNS AND SYMPTOMS
Fever
Pallor
Bleeding
Bone pain
Abdominal pain
Lymphadenopathy
Hepatosplenomegaly
Acute Lymphoblastic Leukemia (ALL)
DEFINITION
Malignant disorder of lymphoblasts.
EPIDEMIOLOGY
Most common malignancy in children.
Eighty percent of leukemia in children.
SIGNS AND SYMPTOMS
Fatigue, anorexia, lethargy, pallor.
Bone pain.
Fever.
Bleeding, bruising, petechiae.
Lymphadenopathy.
Hepatosplenomegaly.
Bone tenderness.
Testicular swelling.
Septicemia.
DIAGNOSIS
CBC: Anemia, abnormal white count, low platelet count.
Electrolytes, calcium, phosphorus, uric acid, lactic dehydrogenase (LDH).
Chest x-ray (mediastinal mass).
Bone marrow—hypercellular, ↑ lymphoblasts.
Cerebrospinal fluid (CSF)—blasts.
Marrow exam is essential to confirm the diagnosis of ALL.
TREATMENT
Four phases:
Remission induction: Cytoxan, vincristine, prednisone, L-asparaginase, and/or doxorubicin.
Consolidation: May add 6MP, 6TG, or cytosine arabinoside.
Maintenance therapy: 2 years—methotrexate and 6MP, may add vincristine and prednisone.
CNS prophylaxis: Methotrexate to CSF, may have radiation to the head.
Infection prevention—antibiotics, isolation if necessary
Acute Myelogenous Leukemia (AML)
DEFINITION
Malignant proliferation of immature granular leukocytes.
EPIDEMIOLOGY
Fifteen to twenty percent of leukemia cases.
Occurs primarily in children < 1 year old.
One in 10,000 people.
ETIOLOGY
Predisposing factors:
Trisomy 21
Diamond–Blackfan syndrome
Fanconi’s anemia
Bloom syndrome
Kostmann syndrome
Toxins such as benzene
Immunosuppression
Polycythemia vera
SIGNS AND SYMPTOMS
Manifestations of anemia, thrombocytopenia, or neutropenia, including fatigue, bleeding, and infection.
Chloroma—localized mass of leukemic cells.
Bone/joint pain.
Hepatosplenomegaly.
Lymphadenopathy.
DIAGNOSIS
> 25% myeloblasts in the bone marrow, hypercellular.
Abnormal white count, platelet count, and anemia.
Bone destruction and periosteal elevation on x-ray.
TREATMENT
Two phases:
Remission induction: 1 week—anthracycline (daunorubicin) and cytosine arabinoside (cytarabine).
Postremission therapy: Several more courses of high-dose cytarabine chemotherapy, allogenic stem cell transplant, or autologous stem cell transplant.
Infection prevention—isolation, antibiotics.
RBC transfusions for anemia.
Platelet transfusions for bleeding.
Complete remission in 70–80%.
Chronic Myelogenous Leukemia (CML)
DEFINITION
Clonal disorder of the hematopoietic stem cell with Philadelphia chromosome translocation—t(9;22)(q34;q11).
EPIDEMIOLOGY
Tends to occur in middle-aged people.
CML often gets diagnosed when CBC shows elevated WBCs.
SIGNS AND SYMPTOMS
Insidious onset.
Splenomegaly (massive).
Fever, bone pain, sweating.
TREATMENT
Hydroxyurea
α-Interferon
Bone marrow transplant
Radiation
Juvenile Chronic Myelogenous Leukemia (JCML)
DEFINITION
Clonal condition involving pluripotent stem cell.
< 2 years.
Neurofibromatosis is associated with an ↑ incidence of JCML and leukemia.
EPIDEMIOLOGY
Ninety-five percent diagnosed before age 4.
SIGNS AND SYMPTOMS
Skin lesions (eczema, xanthoma, café au lait spots).
Lymphadenopathy.
Hepatosplenomegaly.
DIAGNOSIS
Monocytosis.
↑ marrow monocyte precursors.
Philadelphia chromosome absent.
Blast count.
< 5% (peripheral blood).
< 30% (marrow).
TREATMENT
Complete remissions have occurred with stem cell transplant.
Majority relapse, with overall survival of 25%.
Congenital Leukemia
DEFINITION
Serious neonatal malignancy.
EPIDEMIOLOGY
Rare.
AML more common, unlike the predominance of ALL in later childhood.
Lymphoma
DEFINITION
Lymphoid malignancy arising in a single lymph node or lymphoid region (liver, spleen, bone marrow).
Hodgkin’s.
Nodular sclerosing (46%—most common).
Mixed cellularity (31%).
Lymphocyte predominance (16%).
Lymphocyte depletion (7%).
Non-Hodgkin’s (10% of all pediatric tumors).
Lymphoblastic.
Burkitt’s (39%).
Large cell or histiocytic.
Reed-Sternberg cells are characteristic of Hodgkin’s lymphoma.
SIGNS AND SYMPTOMS
Fever, night sweats.
Weight loss, loss of appetite.
Cough, dysphagia, dyspnea.
Lymphadenopathy—lower cervical, supraclavicular.
Hepatosplenomegaly.
Suspicious lymph nodes are:
Painless, firm, and rubbery
In the posterior triangle
DIAGNOSIS
CBC, erythrocyte sedimentation rate (ESR).
Serum electrolytes, uric acid, LDH.
Chest x-ray.
Computed tomography (CT) of chest, abdomen, and pelvis.
Lymph node or bone marrow biopsy.
STAGING
Stage I: One lymph node involved.
Stage II: Two lymph nodes on same side of diaphragm.
Stage III: Lymph node involvement on both sides of diaphragm.
Stage IV: Bone marrow or liver involvement.
TREATMENT
Radiation for stage I or II disease.
Chemotherapy for stage III or IV.
