Pediatric Chronic Anemia Workup
- Author: Susumu Inoue, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
To evaluate anemia, obtain initial laboratory tests, including a complete blood count (CBC), a reticulocyte count, and a review of the peripheral smear. Imaging studies can play a role in the diagnosis of underlying disease, while bone marrow aspiration and biopsy can be used to identify the presence of tumor cells and determine cellular morphology.
Note different normal ranges for different ages. Some laboratories provide only a uniform reference range for the entire pediatric age group and not for specific age groups. Interpret this carefully to avoid misdiagnosis. Hemoglobin and hematocrit levels can be used interchangeably, depending on professional preference and familiarity. Essentially, the hematocrit level is 3 times the hemoglobin value.
Red cell indices are quite informative, particularly mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW).
Note that reference ranges for these parameters also vary with age. Because of this, the author suggests using the MCV cut-off point of 70 plus age in years for patients aged 7 years or younger (eg, MCV < 72 is abnormal for a patient aged 2 y).
A high RDW (eg, ≥19-20) with microcytic picture is most often indicative of iron deficiency anemia in the pediatric population. The RDW is also very high in anemia with reticulocytosis, including sickle cell disease.
Macrocytosis suggests folate/vitamin B-12 deficiency; however, nutritional deficiencies of these vitamins are rare. Diamond-Blackfan anemia, aplastic anemia, and myelodysplastic syndrome often present with macrocytic anemia. Patients with sickle cell anemia who have been on hydroxyurea also show macrocytosis.
Note that in newborns, MCV is physiologically in the range of 120-102. Beyond the immediate newborn period, MCV exceeding 98 is very uncommon in children; if the volume exceeds 98, it usually indicates a serious hematologic problem, such as myelodysplastic syndrome, leukemia, aplastic anemia, Diamond-Blackfan anemia, or metabolic disorder.
In most, but not all cases of HS, the MCHC exceeds the upper limit of the reference range.
Reticulocytes are immature, nonnucleated RBCs. An increase in the reticulocyte count (in particular, the absolute reticulocyte count) indicates active erythropoiesis.
The relative reticulocyte count is useful in determining whether anemia is caused by decreased production, increased destruction, or loss of RBCs. An elevated number of reticulocytes is (eventually) observed in individuals with anemia caused by hemolysis or blood loss; note that the absence of reticulocytosis may simply reflect a lag in the response to the acute onset of anemia.
The term reticulocyte count is often inaccurately used to refer to the percentage of reticulocytes, a value that must be interpreted in light of the degree of anemia. Thus, a finding of 2-3% reticulocytes (vs the reference value of approximately 1%) in a patient in whom the hemoglobin level is only one third to one half of reference range does not indicate a reticulocyte response.
Some clinicians prefer to use either the absolute number of reticulocytes/μL of blood or a reticulocyte percentage that is corrected for the degree of anemia. The corrected reticulocyte count equals (patient hematocrit)/(reference range hematocrit) multiplied by the percentage reticulocyte count.
Examination of the peripheral smear is particularly helpful in normocytic anemia. The red cell morphology itself is quite often diagnostic. The following are examples of abnormal cell morphology in normocytic picture:
Ghost, bite, blister, or helmet cells (G-6-PD), as depicted in the image below
Target cells (hemoglobin C, liver disease, thalassemia), as depicted in the image below
Stippled RBCs, basophilic stippling (in all conditions with increased reticulocyte count and in lead poisoning and 5' nucleotidase deficiency), as depicted in the image below
Increased polychromasia (reticulocytosis)
Normal RBC morphology does not exclude hemolysis.
Additional Laboratory Tests
Additional laboratory tests that may be indicated in the diagnosis and treatment of patients with acute anemia include the following:
Bilirubin level, lactate dehydrogenase (LDH) level (hemolytic anemia), and serum haptoglobulin level (decreased or none in chronic hemolytic anemia)
Direct antiglobulin or Coombs test (autoimmune hemolytic anemia)
Hemoglobin electrophoresis (hemoglobinopathies)
Hemoglobin A2 quantitation (β-thalassemia trait, increased above 3.5%)
Red cell enzyme studies (eg, G-6-PD, pyruvate kinase), osmotic fragility (spherocytosis) (G-6-PD-deficient red cells may show a normal G-6-PD screening result in the presence of reticulocytosis, and therefore, actual enzyme quantitation is strongly recommended; a normal enzyme level in the presence of reticulocytosis indicates a deficiency)
Iron, total iron-binding capacity, and ferritin levels (iron deficiency anemia); soluble (serum) transferrin receptor (differentiation of iron deficiency anemia [increased] from anemia of chronic disease [normal]); free erythrocyte protoporphyrin (FEP) or zinc erythrocyte protoporphyrin (for partially treated iron-deficiency anemia), increased in the presence of normal serum iron)
Stool for occult blood (examine at least 3 specimens; in the presence of demonstrated intestinal blood loss, any given stool specimen finding may be negative, which is why multiple specimens are required before one can conclude a negative finding.)
Folate and vitamin B-12 levels (macrocytic/megaloblastic anemia)
Blood typing and cross matching to assess possible isoimmune anemia in a neonate and to prepare for transfusion
Viral antibody titers and viral DNA by PCR assay (eg, Epstein-Barr virus, cytomegalovirus, parvovirus B19, HIV)
Urinalysis and blood urea nitrogen (BUN)/creatinine levels to assess renal function
Thyroxine (T 4)/thyroid-stimulating hormone (TSH) levels to exclude hypothyroidism
Radiography and Echocardiography
Chest radiography and echocardiography are indicated for suspected congestive heart failure.
Skull films and films of the hands and wrists may show expanded marrow space. Spine radiography may reveal a paraspinal (vertebral) pseudotumor due to marked expansion of the bone marrow (usually in thalassemia major).
Ultrasonography and CT Scanning
In cases of suspected hypersplenism, using ultrasonography or computed tomography (CT) scanning to detect a large spleen is not recommended. If a thorough physical examination does not detect a palpable spleen, hypersplenism is not a likely diagnosis.
Ultrasonography of the gallbladder for the presence of gallstones in patients with chronic hemolytic anemia may be valuable if the patient has recurrent abdominal pain. Abdominal pain due to gallstones in children is not always in the right upper quadrant. The author has received reports of left upper quadrant pain in children with gallstones that subsided after cholecystectomy.
Other imaging studies are indicated to detect underlying pathology, including the following:
Magnetic resonance imaging (MRI) of bones for suspected osteomyelitis
Positron emission tomography (PET) scanning for suspected lymphoma (Hodgkin lymphoma and non-Hodgkin lymphoma)
Endoscopy for GI ulcers, inflammatory bowel disease, celiac disease
Exclude impending high-output congestive heart failure using electrocardiography (ECG).
Specimens from bone marrow aspiration and biopsy are often essential in helping to characterize overall cellularity, the presence or absence of tumor cells, the morphology and maturation of red cell precursors, and the presence or absence of stainable iron.
Bone marrow aspiration and biopsy can be used to rule out leukemia, aplastic anemia, tumor cells in the marrow (such as neuroblastoma), megaloblastosis, marrow dysplasia, and hemophagocytosis. It can also be employed in detection of the absence of 1 cell line due to pure red cell aplasia or parvovirus infection.
Dowling MM, Quinn CT, Plumb P, Rogers ZR, Rollins NK, Koral K. Acute silent cerebral ischemia and infarction during acute anemia in children with and without sickle cell disease. Blood. 2012 Nov 8. 120(19):3891-7. [Medline].
Baker C, Grant AM, George MG, Grosse SD, Adamkiewicz TV. Contribution of Sickle Cell Disease to the Pediatric Stroke Burden Among Hospital Discharges of African-Americans-United States, 1997-2012. Pediatr Blood Cancer. 2015 Dec. 62 (12):2076-81. [Medline].
Skeppner G, Kreuger A, Elinder G. Transient erythroblastopenia of childhood: prospective study of 10 patients with special reference to viral infections. J Pediatr Hematol Oncol. 2002 May. 24(4):294-8. [Medline].
Penchansky L, Jordan JA. Transient erythroblastopenia of childhood associated with human herpesvirus type 6, variant B. Am J Clin Pathol. 1997 Aug. 108(2):127-32. [Medline].
Prassouli A, Papadakis V, Tsakris A, Stefanaki K, Garoufi A, Haidas S. Classic transient erythroblastopenia of childhood with human parvovirus B19 genome detection in the blood and bone marrow. J Pediatr Hematol Oncol. 2005 Jun. 27(6):333-6. [Medline].
Iolascon A, Camaschella C, Pospisilova D, Piscopo C, Tchernia G, Beaumont C. Natural history of recessive inheritance of DMT1 mutations. J Pediatr. 2008 Jan. 152(1):136-9. [Medline].
Global Burden of Disease Pediatrics Collaboration, Kyu HH, Pinho C, et al. Global and National Burden of Diseases and Injuries Among Children and Adolescents Between 1990 and 2013: Findings From the Global Burden of Disease 2013 Study. JAMA Pediatr. 2016 Mar 1. 170 (3):267-87. [Medline].
Henderson S, Timbs A, McCarthy J, Gallienne A, Van Mourik M, Masters G. Incidence of haemoglobinopathies in various populations - the impact of immigration. Clin Biochem. 2009 Dec. 42(18):1745-56. [Medline].
Williams TN, Weatherall DJ. World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb Perspect Med. 2012 Sep. 2(9):a011692. [Medline].
Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3. 115(22):4331-6. [Medline].
Baker RD, Greer FR. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics. 2010 Nov. 126(5):1040-50. [Medline].
Wiseman DH, May A, Jolles S, et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood. 2013 Jul 4. 122 (1):112-23. [Medline]. [Full Text].
Iolascon A, De Falco L. Mutations in the gene encoding DMT1: clinical presentation and treatment. Semin Hematol. 2009 Oct. 46(4):358-70. [Medline].
Finberg KE. Iron-refractory iron deficiency anemia. Semin Hematol. 2009 Oct. 46(4):378-86. [Medline].