What causes a low white blood cell (WBC) count or leukopenia?

Causes of Low White Blood Cell Count (Leukopenia)

Leukopenia can be caused by numerous conditions affecting white blood cell production or destruction, with the most common causes being infections, medications, malignancies, autoimmune disorders, and bone marrow disorders. 1

Definition

• Leukopenia: Abnormal reduction of circulating white blood cells, especially granulocytes 2
• Neutropenia: Absolute neutrophil count (ANC) less than 1,500/mcL 3

Major Categories of Causes

1. Decreased Production of White Blood Cells

Bone Marrow Disorders:

• Myelodysplastic syndromes (MDS)
• Acute leukemias (AML, ALL)
• Aplastic anemia
• Bone marrow infiltration by malignancy

Nutritional Deficiencies:

• Vitamin B12 deficiency
• Folate deficiency
• Severe malnutrition

Medications and Toxins:

• Chemotherapeutic agents
• Immunosuppressants (azathioprine)
• Antipsychotics (clozapine)
• Antithyroid medications
• Antibiotics (trimethoprim-sulfamethoxazole, beta-lactams)
• Anticonvulsants
• Anti-inflammatory drugs
• Alcohol

2. Increased Destruction or Utilization

Infections:

• Viral infections (HIV, hepatitis, CMV, EBV)
• Bacterial infections (typhoid fever, tuberculosis)
• Overwhelming infections/sepsis
• Rickettsial diseases

Autoimmune Disorders:

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Autoimmune neutropenia
• Large granular lymphocytic leukemia

Hypersplenism:

• Splenic sequestration
• Portal hypertension
• Cirrhosis

3. Other Causes:

• Congenital disorders (cyclic neutropenia, Kostmann syndrome)
• Radiation exposure
• Idiopathic causes

Diagnostic Evaluation

Initial evaluation of leukopenia should include 1:

• Complete blood count (CBC) with differential
• Peripheral blood smear examination
• Reticulocyte count
• Comprehensive metabolic panel

Additional testing based on clinical suspicion:

• Bone marrow examination if pancytopenia or suspected hematologic malignancy
• Serum protein electrophoresis and immunofixation
• Flow cytometry
• Cytogenetic studies
• Imaging studies (chest X-ray, abdominal ultrasound) if infection or malignancy suspected

Management Considerations

Management depends on the underlying cause and severity:

1. For medication-induced leukopenia:

   • Discontinue suspected causative medications when possible 1

2. For infectious causes:

   • Appropriate antimicrobial therapy

3. For severe neutropenia (ANC <500/μL) or neutropenic fever:

   • Consider G-CSF (filgrastim) at 5 μg/kg/day subcutaneously 4, 1
   • Immediate broad-spectrum antibiotics for neutropenic fever

4. For underlying hematologic conditions:

   • Disease-specific therapy (e.g., hypomethylating agents for MDS)
   • Consider hematopoietic stem cell transplantation for eligible patients with severe conditions

5. Monitoring:

   • Regular CBC monitoring every 2-4 weeks in patients with leukopenia 1

Common Pitfalls in Management

• Failing to recognize neutropenic fever as a medical emergency
• Attributing leukopenia solely to medications without excluding other serious causes
• Overuse of growth factors in mild cases
• Ignoring other cytopenias that may indicate a more serious underlying condition

Remember that the risk of infection increases significantly when the ANC falls below 500/μL, and neutropenic fever should be treated as a medical emergency requiring immediate intervention with broad-spectrum antibiotics.