Which laboratory tests should be ordered to evaluate a low white blood cell count (leukopenia)?

Laboratory Evaluation of Leukopenia

Order a complete blood count with differential, peripheral blood smear review, and comprehensive metabolic panel as the initial workup for low white blood cell count. 1, 2

Initial Essential Laboratory Tests

Core Testing Panel

• CBC with differential to quantify absolute neutrophil count, lymphocyte count, and other white cell subsets 1, 2
• Peripheral blood smear (manual review) to assess for dysplasia, abnormal cell morphology, and evaluate red blood cells and platelets 3
• Comprehensive metabolic panel including liver function tests, lactate dehydrogenase, and uric acid 1
• Reticulocyte count if anemia is present to assess bone marrow production 4

The peripheral blood smear is particularly critical because it provides information beyond cell counts—specifically dysplasia and morphologic abnormalities that suggest bone marrow dysfunction or hematologic malignancy. 3

Assess for Bi- or Pancytopenia

If hemoglobin or platelet counts are also reduced, this indicates bone marrow production failure and requires more urgent evaluation. 3 Check:

• Hemoglobin levels (anemia threshold <10 g/dL warrants hematology consultation) 4
• Platelet count (thrombocytopenia alongside leukopenia suggests marrow dysfunction) 5, 4

Etiology-Directed Testing Based on Clinical Context

If Neutropenia Present (ANC <1500/µL)

• Vitamin B12 and folate levels to evaluate for megaloblastic causes 6, 2
• Autoimmune serologies: antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA) 1, 2
• Thyroid function tests (TSH, free T4) as autoimmune thyroid disease is common 2
• Iron studies (serum ferritin, transferrin saturation) as iron deficiency is the most frequent cause in both neutropenic and non-neutropenic leukopenia 2

In one study of isolated leukopenia, autoimmune conditions (including thyroid disease and other autoimmune/autoinflammatory diseases) accounted for over 50% of cases when including isolated ANA positivity. 2

If Infection Suspected

• Viral serologies for HIV, hepatitis B and C, EBV, CMV 6
• Strongyloides and parasitic infection testing if travel history or eosinophilia present 1
• Blood cultures if febrile 1

Viral infections, particularly influenza, commonly cause leukopenia with normal differential proportions. 7

If Hematologic Malignancy Suspected

Bone marrow aspirate and biopsy with the following studies: 1

• Morphology assessment
• Immunohistochemistry (CD117, CD25, tryptase)
• Conventional cytogenetics
• FISH for specific abnormalities
• Flow cytometry to assess for aberrant immunophenotypes 1
• Reticulin/collagen stains for fibrosis 1

Indications for bone marrow examination include: 2, 3

• Progressive decline in WBC count over time
• Presence of dysplasia on peripheral smear
• Unexplained bi- or pancytopenia
• Circulating blasts
• Severe neutropenia (ANC <500/µL) without obvious cause

Additional Testing for Specific Scenarios

• Serum tryptase and vitamin B12 if myeloproliferative neoplasm suspected (elevated in PDGFRA fusion genes and systemic mastocytosis) 1
• Serum immunoglobulin levels including IgE if hypersplenism or lymphoid disorder suspected 1
• Medication review as drugs are responsible for 8.5-12.7% of leukopenia cases 2

Critical Action Points

When to Expedite Evaluation

Immediate hematology consultation is mandatory if: 4, 3

• Fever with severe neutropenia (ANC <500/µL)—this is agranulocytosis requiring immediate broad-spectrum antibiotics 3
• Hemoglobin <10 g/dL with leukopenia 4
• Thrombocytopenia with leukopenia 4
• Elevated LDH with decreased haptoglobin 4
• Presence of blasts on peripheral smear 1

Monitoring Strategy

• Repeat CBC in 2-4 weeks if initial leukopenia is mild and patient is asymptomatic 5
• Progressive decline over time is more concerning than stable low counts 7
• Development of recurrent infections, unexplained fever, or additional cytopenias warrants immediate further investigation 7

Common Pitfalls to Avoid

• Do not assume isolated leukopenia is benign without reviewing the peripheral smear 3
• Do not overlook iron deficiency as a cause—it was the most common etiology in both neutropenic (10.2%) and non-neutropenic (21.8%) patients with isolated leukopenia 2
• Do not delay bone marrow examination in patients with progressive leukopenia or additional cytopenias 3
• Do not forget to screen for autoimmune conditions, which collectively represent the most frequent cause of isolated leukopenia 2