What is the appropriate workup for a patient with leukopenia (low white blood cell count)?

Workup of Leukopenia

The appropriate workup for leukopenia should include a complete blood count with differential, peripheral blood smear examination, bone marrow aspiration and biopsy with cytogenetic analysis, flow cytometry, and targeted molecular testing based on clinical suspicion. 1, 2

Initial Evaluation

• Complete blood count (CBC) with differential is essential to determine the severity of leukopenia and identify which cell lines are affected 1
• Manual peripheral blood smear examination provides crucial information about cell morphology, dysplasia, and potential causes of leukopenia 2
• Review of medication history to identify potential drug-induced causes of leukopenia 3
• Evaluation of other blood cell lines (red blood cells, platelets) to determine if there is isolated leukopenia or pancytopenia, which suggests bone marrow involvement 2
• Assessment of the absolute neutrophil count (ANC) to classify the severity of neutropenia (if present) 1

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy are indicated for persistent unexplained leukopenia, especially when accompanied by other cytopenias 4
• Bone marrow samples should be processed for:
  • Morphologic evaluation of aspirate smears and core biopsy 4
  • Cytochemical studies to assist in diagnosis and classification 4
  • Conventional cytogenetic analysis (karyotype) 4
  • Flow cytometry immunophenotyping 4
  • Molecular genetic testing and/or FISH as appropriate 4

Specialized Testing

• Flow cytometry immunophenotyping should include markers sufficient to distinguish between various hematologic malignancies 4, 5
• Molecular genetic testing should be guided by clinical suspicion and initial findings 4
• Cytogenetic analysis to identify chromosomal abnormalities that may indicate specific hematologic disorders 4
• Consider testing for infectious causes of leukopenia, including viral studies (hepatitis B, hepatitis C, HIV) 5
• Coagulation studies including prothrombin time, partial thromboplastin time, and fibrinogen 5

Additional Considerations Based on Clinical Presentation

• For patients with fever and severe neutropenia (ANC <500/mcL), immediate blood cultures and broad-spectrum antibiotics are indicated 2
• If splenomegaly is present, consider imaging studies to evaluate for hypersplenism 3
• For episodic leukopenia, consider conditions such as Familial Mediterranean Fever 6
• In cases with suspected malignancy, additional tests such as serum lactate dehydrogenase (LDH) and uric acid levels should be obtained 5
• For patients with suspected autoimmune disorders, appropriate autoimmune serologies should be performed 7

Interpretation and Follow-up

• Classify leukopenia as transient or chronic based on duration 1
• For chronic leukopenia, further categorize as extrinsic (drug-induced, infectious, autoimmune) or intrinsic (bone marrow disorders) 1
• Serial monitoring of blood counts may be necessary to establish patterns and response to interventions 2
• The severity, duration, and clinical status of the patient should guide the urgency and extent of the workup 1

Common Pitfalls to Avoid

• Failing to check previous blood counts to establish the chronicity of leukopenia 2
• Not performing a manual differential count, which can miss important morphological abnormalities 2
• Overlooking medication-induced causes, which are among the most common etiologies of leukopenia 3
• Delaying treatment in febrile neutropenia, which can lead to increased mortality 2
• Not storing samples appropriately for potential future molecular or genetic studies 4