What labs should be ordered for a patient with leukopenia (low white blood cell count)?

Laboratory Workup for Leukopenia

For patients with isolated leukopenia, obtain a CBC with manual differential and peripheral blood smear review as the essential first step, followed by a comprehensive metabolic panel; if pancytopenia or persistent/worsening leukopenia is present, proceed immediately to bone marrow aspiration and biopsy with flow cytometry, cytogenetics, and molecular studies. 1

Initial Essential Laboratory Tests

First-Line Testing (All Patients)

• CBC with manual differential count and peripheral blood smear review to assess absolute neutrophil count (ANC), evaluate for dysplasia, enumerate blast cells, and identify bi- or pancytopenia 2, 1, 3
• Comprehensive metabolic panel including lactate dehydrogenase, uric acid, potassium, calcium, and phosphorus to monitor for tumor lysis syndrome and assess systemic conditions 2, 1
• Liver function tests to evaluate hepatic involvement and potential causes 2

Critical Clinical Context

The peripheral blood smear is essential because it provides information beyond cell counts, including morphologic abnormalities and dysplasia that guide further workup 3. Review previous blood counts when available to assess the dynamic development and chronicity of leukopenia 3.

Risk Stratification Based on Neutrophil Count

Severe Neutropenia (ANC <1,500/mm³)

If neutropenia is present, particularly with ANC <1,000/mm³, the risk of life-threatening bacterial infections increases substantially 4, 3. Patients with fever and agranulocytosis require immediate hospital admission and broad-spectrum antibiotics 3.

Non-Neutropenic Leukopenia (ANC ≥1,500/mm³)

This represents a diagnostically challenging group where autoimmune conditions, iron deficiency anemia, and thyroid disease are the most common etiologies 5.

Advanced Testing: When to Proceed to Bone Marrow Evaluation

Indications for Bone Marrow Aspiration and Biopsy

Perform bone marrow examination when:

• Pancytopenia or bicytopenia is present 1
• Leukopenia is persistent or worsening on repeat CBC within 2-4 weeks 2
• Peripheral blood smear shows dysplasia, circulating blasts, or other abnormalities 2
• Clinical suspicion for hematologic malignancy or bone marrow failure syndrome 2, 1

Comprehensive Bone Marrow Workup Components

When bone marrow examination is indicated, obtain:

Morphologic Studies:

• Bone marrow aspirate, touch imprint, cell clots, and core biopsy for morphologic examination 2, 6
• If aspirate results in dry tap, perform cell count and morphology review on touch imprint preparation 6

Immunophenotyping:

• Multicolor comprehensive flow cytometry on bone marrow aspirate (or peripheral blood if bone marrow unavailable) to determine lineage and identify aberrant populations 2, 6, 1

Cytogenetic Analysis:

• Conventional karyotyping (must be performed on bone marrow) for diagnosis and subclassification 2, 6, 1
• FISH studies according to suspected diagnosis (e.g., BCR-ABL1, KMT2A rearrangements for acute leukemia) 2, 6

Molecular Studies:

• PCR, RT-PCR, or next-generation sequencing selective based on suspected subtype for prognosis and targeted therapy 2, 6, 1
• For suspected myeloid neoplasms: FLT3-ITD, IDH1, IDH2, TET2, WT1, DNMT3A, TP53, CEBPA, RUNX1 2

Additional Targeted Testing Based on Clinical Context

Autoimmune Workup (Most Common in Non-Neutropenic Leukopenia)

• Antinuclear antibodies and antineutrophil cytoplasmic antibodies 2
• Thyroid function tests (autoimmune thyroid disease found in 21.8% of non-neutropenic cases) 5
• Quantitative serum immunoglobulin levels including IgE 2
• Erythrocyte sedimentation rate and C-reactive protein 2

Infection Evaluation

• Serology testing for Strongyloides and other parasitic infections 2
• Stool ova and parasites test and gastrointestinal PCR 2
• HIV testing and viral serologies as clinically indicated 7

Nutritional Deficiencies

• Vitamin B12 and folate levels (megaloblastosis can cause leukopenia) 2, 7, 5
• Iron studies (iron deficiency anemia found in 21.8% of non-neutropenic and 10.2% of neutropenic cases) 5

Hypersplenism Evaluation

• Serum tryptase and vitamin B12 levels (elevated in myeloproliferative variants) 2
• Imaging to assess spleen size if clinically indicated 7

Monitoring Strategy for Severe Chronic Neutropenia

If severe chronic neutropenia is diagnosed, confirm diagnosis by evaluating serial CBCs with differential and platelet counts, and evaluating bone marrow morphology and karyotype before initiating treatment 8.

During initial treatment:

• Monitor CBCs with differential and platelet counts during the initial 4 weeks of therapy and during 2 weeks following any dosage adjustment 8
• Once clinically stable, monitor monthly during the first year 8
• After first year, less frequent routine monitoring if patient remains stable 8

Critical Pitfalls to Avoid

• Do not delay bone marrow examination in patients with persistent cytopenia, as this may impair diagnostic efforts and delay treatment of underlying conditions 8
• Do not overlook medication history as drugs are responsible for 12.7% of non-neutropenic and 8.5% of neutropenic leukopenia cases 5
• Do not assume isolated leukopenia is benign - 53.8% of cases have autoimmune diagnosis or laboratory findings 5
• Recognize that bi- or pancytopenia usually implies insufficient bone marrow production and requires more aggressive workup 3
• For patients with fever and severe neutropenia (ANC <500/mm³), immediate empiric broad-spectrum antibiotics are mandatory before completing diagnostic workup 3