What initial laboratory tests should be ordered to evaluate leukopenia?

Initial Laboratory Workup for Leukopenia

Start with a complete blood count (CBC) with manual differential and peripheral blood smear review to confirm leukopenia, assess absolute neutrophil count, and identify dysplastic changes or circulating blasts. 1, 2

Essential First-Line Tests

Core Laboratory Studies

• CBC with manual differential count is mandatory to determine the absolute neutrophil count, evaluate for bi- or pancytopenia, and enumerate blast cells 1, 2
• Peripheral blood smear review must be performed by a trained professional to assess white blood cell morphology, identify dysplasia, and detect abnormal cells that automated counters may miss 1, 2, 3
• Comprehensive metabolic panel including lactate dehydrogenase, uric acid, potassium, calcium, and phosphorus to monitor for tumor lysis syndrome and assess systemic conditions 1, 2
• Liver function tests to evaluate hepatic involvement as a potential cause 2

Nutritional and Metabolic Assessment

• Vitamin B12 and folate levels should be checked to exclude megaloblastic processes as a cause of leukopenia 1, 2
• Reticulocyte count to assess bone marrow activity 1
• Serum iron, ferritin, and transferrin saturation to identify iron deficiency, which frequently coexists with leukopenia 1

Additional Screening Tests

• LDH, bilirubin, and uric acid as general markers of cellular turnover and possible hemolysis 1
• Direct antiglobulin test (DAT) to rule out autoimmune hemolysis 1
• Serologic testing for hepatitis B, hepatitis C, CMV, and HIV before initiating any immunosuppressive therapy 1

When to Escalate to Bone Marrow Examination

Absolute Indications

• Dysplastic changes on peripheral blood smear warrant immediate bone marrow evaluation 1, 2
• Persistent or worsening cytopenia lasting >2-4 weeks despite repeat CBCs requires bone marrow aspiration and biopsy 1, 4
• Pancytopenia or bicytopenia mandates bone marrow examination, as this implies insufficient bone marrow production 2, 4
• Circulating blasts or other morphologic abnormalities on smear require immediate bone marrow workup 2, 4

Required Bone Marrow Studies When Indicated

• Bone marrow aspirate with iron (Prussian blue) staining for detailed morphological assessment 1, 4
• Bone marrow core biopsy to evaluate overall cellularity and marrow architecture 1, 4
• Multicolor flow cytometry (8-10 colors) to exclude paroxysmal nocturnal hemoglobinuria and large-granular-lymphocyte disorders 1, 4
• Conventional cytogenetic analysis (karyotyping) to detect clonal abnormalities such as del 17p, del 11q, or monosomy 7 1, 4
• FISH studies when specific chromosomal abnormalities are suspected 1, 4
• Molecular genetic testing (PCR, RT-PCR, or next-generation sequencing) tailored to suspected disease subtype 1, 4

Context-Specific Additional Testing

For Suspected Autoimmune Etiology

• Antinuclear antibodies and antineutrophil cytoplasmic antibodies for non-neutropenic leukopenia 2, 4
• Quantitative serum immunoglobulin levels including IgE 2, 4
• Erythrocyte sedimentation rate and C-reactive protein to evaluate inflammation 2, 4

For Suspected Infectious Causes

• Serology for Strongyloides and other parasitic infections 2
• Stool ova and parasites test 2
• Gastrointestinal PCR panel if indicated 2

For Rare but Treatable Causes

• Copper deficiency assessment in unexplained cases, as this is an uncommon yet reversible cause 1
• Serum erythropoietin before transfusion when myelodysplastic syndrome is suspected 1

Critical Clinical Pitfalls

Do not delay bone marrow examination when dysplasia is present on smear—this finding suggests underlying marrow failure or pre-leukemic conditions and requires immediate comprehensive evaluation. 1, 2

Medication review is essential, as drugs are the most common cause of acquired neutropenia; a detailed medication history must be obtained before extensive workup. 4, 5

Repeat the CBC within 2-4 weeks if initial leukopenia is mild and isolated, as transient causes (viral infections, medications) may resolve spontaneously. 1, 4, 6