• Diamond-Blackfan anemia
  • Congenital pure red-cell aplasia (rare)
• Fanconi anemi
  • Constellation of varied cytopenias
  • Multiple congenital anomalies
  • Abnormal bone marrow chromosomal fragility
• Thalassemia syndromes
  • Defective globin synthesis
• Erythrocyte membrane defects
  • Hereditary spherocytosis
  • Elliptocytosis
  • Stomatocytosis
  • Pyropoikilocytosis
  • Infantile pyknocytosis
• Erythrocyte enzyme defects
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Pyruvate kinase deficiency
• Hemoglobinopathies
  • Sickle cell syndromes
  • Other unstable hemoglobins

• Septic shock
• Infection-related bone marrow suppression
  • Parvovirus B19 infection
• Infection-related hemolytic anemias
  • Epstein-Barr virus
  • Influenza
  • Coxsackievirus
  • Varicella
  • Cytomegalovirus
  • Escherichia coli
  • Pneumococcus
  • Streptococcus
  • Salmonella typhi
  • Mycoplasma

• Iron-deficiency anemia
  • Common cause of anemia in children, especially under the age of 3 years and in female adolescents
• Atropine ingestion
• Plumbism
  • Anemia usually due to coexisting iron deficiency. Very high lead levels associated with altered heme synthesis
• Vitamin B₁₂ and/or folate deficiency
  • Results in a megaloblastic anemia
• Medication-induced bone marrow suppression
  • Many chemotherapeutic agents for malignancy, antibiotics, especially trimethoprim-sulfamethoxazole
• Drug-related hemolytic anemia
  • Antibiotics
  • Antiepileptics
  • Azathioprine
  • Isoniazid
  • Non-steroidal anti-inflammatory drugs

• Acute blood loss
  • Chronic blood loss often presents as iron deficiency

• Malignancies include leukemia, a primary bone marrow malignancy as well as any malignancy that metastasizes to the bone marrow, displacing normal marrow cells
• Histiocytosis syndromes
  • Disseminated forms, marrow replacement
• Anemia of cancer even without bone marrow invasion

• Metabolic derangements
  • Severe electrolyte disturbance
  • pH disturbance
  • Inborn errors
• Schwachmann-Diamond syndrome
  • Marrow hypoplasia with associated pancreatic insufficiency and associated failure to thrive
• Systemic diseases
  • Anemia of chronic disease
  • Chronic renal disease
  • Uremia
• Hypothyroidism

• Anaphylaxis
• Disseminated intravascular coagulation

• Transient erythroblastopenia of childhood
  • Acquired pure red blood cell aplasia
• Aplastic anemia
  • Bone marrow failure syndrome with at least 2 of the 3 blood cell lines eventually affected
• Sideroblastic anemia
  • Defective iron utilization within the developing erythrocytes
• Autoimmune and isoimmune hemolytic anemias
• Microangiopathic hemolytic anemias
  • Thrombotic thrombocytopenic purpura (TTP)
  • Hemolytic uremic syndrome (HUS)
  • Disseminated intravascular coagulation (DIC)
• Mechanical destruction
  • Vascular malformation
  • Shunts
  • Abnormal valves
  • Prosthetic valves

Question: Rapid onset? (Hours to few days)
Significance: Suggests acute blood loss, autoimmune hemolytic anemia, and/or circulatory compromise.

Question: Weight loss, fever, night sweats, cough, and/or bone pain?
Significance: Suggest an underlying systemic illness, such as leukemia, infection, collagen vascular disease.

Question: Jaundice, dark urine?
Significance: Suggests hemolysis

Question: Age between 6 months and 3 years, or adolescent females?
Significance: Peak age ranges for iron deficiency.

Question: Age less than 6 months?
Significance: May represent a congenital anemia or isoimmunization.

Question: Male?
Signficance: Some red-cell enzyme X-linked defects, such as G6PD and phosphoglycerate kinase deficiencies are sex linked.

Question: African-American?
Significance: Hemoglobins S and C, alpha and beta-thalassemia trait, G6PD deficiency.

Question: Southeast Asian?
Significance: Hemoglobin E and a-thalassemia

Question: Mediterranean descent?
Significance: b-Thalassemia and G6PD deficiency

Question: Premature infant?
Significance: Increased risk of both iron and vitamin E deficiency. Exaggerated hyperbilirubinemia can be the presenting symptom of isoimmune hemolytic or other congenital hemolytic anemia.

Question: Pica?
Significance: Pica is often associated with both plumbism and iron and vitamin deficiency.

Question: Medications?
Significance: Can cause bone marrow suppression and/or hemolysis.

Question: Recent trauma and/or surgery?
Significance: Blood loss can result in iron deficiency.

Question: Recent infection?
Significance: Can be associated with hemolysis or bone marrow suppression.

Question: Familial history?
Significance: Some of the congenital hemolytic anemias are autosomal dominant. Familial history of splenectomy and/or early cholecystectomy can be a clue for a previously undiagnosed hemolytic anemia.

Finding: Rapid respiratory rate, decreased blood pressure, weak pulses, slow capillary refill
Significance: Vital signs indicate pallor due to acute severe blood loss, shock, or other emergencies.

Finding: Frontal bossing and prominence of the malar and maxillary bones
Significance: Thalassemia, due to extramedullary erythropoiesis

Finding: Glossitis
Significance: Vitamin B₁₂ deficiency

Finding: Retinopathy
Significance: Sometimes hemoglobin S or C disease

Finding: Icterus of sclerae and mucous membranes
Significance: May indicate hemolysis

Finding: Systolic flow murmur
Significance: Chronic anemia

Finding: Bruits
Significance: May indicate vascular malformations

Finding: Enlarged spleen
Significance: Hemolytic anemias, malignancy, infection

Finding: Petechiae and bruising
Significance: May indicate an associated thrombocytopenia, coagulopathy, or vasculitis

Finding: Dysmorphic features
Significance: Both Diamond-Blackfan and Fanconi anemias are associated with other congenital defects, including thumb abnormalities, short stature, congenital heart disease.

Test: Hemoglobin or hematocrit
Significance: Establishes the presence of anemia as the etiology for pallor

Test: Mean corpuscular volume (MCV)
Significance: Divides anemias into microcytic, normocytic, and macrocytic

Test: Reticulocyte count
Significance: Distinguishes between decreased production and increased destruction of red cells

Test: Coomb’s test and antibody screen
Significance: Identifies immune-mediated red-cell destruction

Test: Peripheral blood smear
Significance: Specific morphologic findings can be diagnostic

Test: Iron studies: iron-binding capacity, serum Fe, ferritin, transferrin
Significance: Diagnosis of iron deficiency anemia or anemia of chronic disease

Test: Hgb electrophoresis, quantitative Hgb A₂ or F
Significance: Diagnosis of hemoglobinopathy

Test: Lead studies: serum lead, free erythrocyte protoporphyrin
Significance: Diagnosis of plumbism

Test: Osmotic fragility
Significance: Diagnosis of red cell membrane defects

Test: Quantitative red-cell enzyme assays
Significance: Diagnosis of inherited RBC enzyme deficiencies

Test: Serum folate, RBC folate, and serum vitamin B₁₂ levels
Significance: Diagnosis of deficiency of these vitamins

Test: Bone marrow aspiration and biopsy
Significance: Diagnosis of malignancy or bone marrow failure syndrome

• Phase Hemodynamic compromise
• Severe anemia
• Anemias other than dietary iron deficiency or anemia of chronic disease
• All bone marrow failure or infiltrative processes

• Complete blood count, reticulocyte count, past blood counts if available

• If there is circulatory failure without anemia, treatment requires intensive monitoring and access to critical care in an emergency room or ICU. Fluid resuscitation and/or inotropic pressor support as needed.
• Acute blood loss: treat circulatory failure as described. Transfuse with packed red blood cells, platelets, and fresh frozen plasma as needed.
• Severe anemia of unclear etiology with hemodynamic instability: transfuse with packed red blood cells cautiously. In an autoimmune hemolytic process, the child is at significant risk of a hemolytic transfusion reaction. Obtain blood for diagnostic studies before transfusion.
• Malignancies: Emergency care should be directed toward treatment of circulatory failure and possible associated infection, and then to rapid diagnosis and treatment of the malignancy. Consultation with an oncologist should be sought as soon as possible.

• Parents often fail to notice pallor of gradual onset. Grandparents or others who see child less often may be the first to suspect pallor.
• Hematologic pallor: Often well-appearing pale child with anemia. Pallor is clinically apparent when the hemoglobin is less than 9 g/dL.
• Non-hematologic pallor: Generally ill-appearing child. Any condition with peripheral vasoconstriction that alters the distribution of blood flow away from the skin surface.

Graham EA. The changing face of anemia in infancy. Pediatr Rev 1995;15:175–183.

Monzon CM, Beaver D, Dillon TD. Evaluation of erythrocyte disorders with mean corpuscular volume (MCV) and red cell distribution width (RDW). Clin Pediatr 1987;26:632–638.

Sills RH. Indications for bone marrow examination. Pediatr Rev 1995;16:226–228.

Segal GB. Anemia. Pediatr Rev 1988;1O:77–98.