What is the appropriate workup and treatment for an adult patient with newly diagnosed leukopenia (decrease in white blood cells) and no significant past medical history?

Workup for Leukopenia in Adults

Begin with a complete blood count with differential and peripheral blood smear examination to determine the absolute neutrophil count (ANC) and identify whether this is isolated leukopenia or part of a bi- or pancytopenia, as the latter suggests bone marrow production failure requiring more urgent evaluation. 1, 2

Initial Assessment and Risk Stratification

Determine Severity and Urgency

• Calculate the absolute neutrophil count (ANC) immediately, as neutropenia is defined as ANC <1,500/mcL and represents the most clinically significant form of leukopenia 1
• Assess for fever (temperature >38.2°C), as febrile neutropenia is a medical emergency requiring immediate broad-spectrum antibiotics to reduce mortality 3, 2
• Review previous blood counts to determine if this is acute versus chronic leukopenia, which fundamentally changes the differential diagnosis 2

Critical Initial Laboratory Studies

• Complete blood count with differential to assess all three cell lines (red cells, white cells, platelets) 3, 1
• Peripheral blood smear with manual differential is essential and cannot be skipped—this identifies dysplasia, abnormal cell morphology, blast cells, and provides accurate cell counts 3, 2
• Reticulocyte count to assess bone marrow response 4

Diagnostic Algorithm Based on Cell Line Involvement

If Isolated Leukopenia/Neutropenia (Normal RBC and Platelets)

This suggests either increased destruction/utilization or selective production defect:

Medication and exposure history:

• Review all medications, as drugs are among the most common causes of neutropenia 5, 1
• Assess for recent infections, particularly viral infections which commonly cause transient leukopenia 5, 1
• Evaluate for autoimmune conditions and obtain antinuclear antibody (ANA) if clinically indicated 1

Additional testing for isolated neutropenia:

• HIV testing if risk factors present, as HIV can cause leukopenia 4
• Consider familial Mediterranean fever (FMF) evaluation if leukopenia is episodic in nature 6
• Vitamin B12 and folate levels if macrocytosis is present 4

If Bi-cytopenia or Pancytopenia (Multiple Cell Lines Affected)

This strongly suggests bone marrow production failure and requires more aggressive workup:

Immediate additional studies:

• Lactate dehydrogenase (LDH) and indirect bilirubin to assess for hemolysis or ineffective hematopoiesis 4
• Vitamin B12, serum/RBC folate, methylmalonic acid (MMA), and homocysteine to evaluate for megaloblastic anemia 4
• Iron studies (serum iron, total iron binding capacity, ferritin) to exclude concurrent iron deficiency 4
• Liver function tests and comprehensive metabolic panel 3

Bone marrow examination is indicated when:

• Diagnosis remains uncertain after initial laboratory testing 4
• Pancytopenia or bi-cytopenia is present 4, 2
• Peripheral smear shows dysplasia or abnormal cells 2
• Blasts are identified on peripheral smear 7, 8

Bone Marrow Evaluation (When Indicated)

Essential components of bone marrow workup:

• Bone marrow aspirate with smear preparation for morphological evaluation 8
• Bone marrow biopsy evaluated jointly with the aspirate 8
• Conventional cytogenetic analysis (cannot be replaced by FISH or molecular tests alone) to exclude clonal disorders 4, 7, 8
• Flow cytometry immunophenotyping if hematologic malignancy is suspected 4, 7
• Iron stain to detect ring sideroblasts (≥15% suggests myelodysplastic syndrome rather than pure megaloblastic anemia) 4

Special Considerations for Acute Myeloid Leukemia (AML)

If blasts are identified on peripheral smear or bone marrow shows ≥20% blasts, complete AML diagnostic workup before starting treatment:

Mandatory pre-treatment studies:

• Morphological examination of peripheral blood and bone marrow 7, 8
• Immunophenotyping by flow cytometry with panel sufficient to distinguish AML from other acute leukemias 7
• Conventional cytogenetic analysis (karyotyping) 7, 8
• Molecular genetic testing including FLT3-ITD, NPM1, CEBPA, and RUNX1 mutation analysis 7
• Coagulation screening particularly if morphology suggests acute promyelocytic leukemia 7, 8
• HLA typing of patient and family members for potential allogeneic stem cell transplantation 3, 7

Management of Febrile Neutropenia

If patient presents with fever and profound neutropenia (ANC <500/mcL):

• Admit immediately and initiate empirical broad-spectrum antimicrobial therapy without delay 3, 2
• Prophylactic fluoroquinolones may be appropriate for patients with expected prolonged profound granulocytopenia (<100/mm³ for two weeks) 3
• Serial surveillance cultures may be helpful to detect resistant organisms 3
• Platelet transfusions for counts ≤10 × 10⁹/L; between 10-20 × 10⁹/L if fever/infection present 3

Common Pitfalls to Avoid

• Do not start chemotherapy before obtaining satisfactory material for all diagnostic tests if malignancy is suspected 7
• Do not rely solely on automated differential counts—manual peripheral smear examination is mandatory 2
• Do not assume isolated leukopenia is benign—always calculate the ANC and assess infection risk 1
• Do not delay antibiotics in febrile neutropenic patients while awaiting culture results 3, 2
• Do not perform bone marrow biopsy in stable patients with obvious reversible causes (recent viral infection, medication effect) until observing for recovery 1