What causes leukopenia (low white blood cell count)?

Causes of Low White Blood Count (Leukopenia)

Leukopenia (low white blood cell count) is most commonly caused by medications, infections, autoimmune disorders, bone marrow disorders, and cancer-related conditions. Understanding the specific cause is essential for proper management and preventing complications related to immunosuppression.

Primary Causes of Leukopenia

1. Medication-Induced Leukopenia

• Chemotherapeutic agents - cause myelosuppression by design 1
• Immunosuppressants - particularly azathioprine which can cause bone marrow depression 1
• Antibiotics - especially trimethoprim/sulfamethoxazole which can cause blood dyscrasias 2
• Antiepileptic drugs - can cause folate deficiency leading to hematologic abnormalities 2

2. Infectious Causes

• Viral infections:

  • HIV infection 1
  • Hepatitis B and C 1
  • Cytomegalovirus (CMV)
  • Influenza

• Bacterial infections:

  • Overwhelming bacterial infections (sepsis)
  • Tuberculosis
  • Typhoid fever

3. Hematologic/Bone Marrow Disorders

• Primary bone marrow disorders:

  • Myelodysplastic syndromes 1
  • Aplastic anemia
  • Leukemias (paradoxically can present with leukopenia) 1
  • Myelofibrosis

• Nutritional deficiencies:

  • Vitamin B12 deficiency (megaloblastic anemia) 1
  • Folate deficiency 2
  • Copper deficiency

4. Autoimmune Disorders

• Systemic lupus erythematosus (SLE) - leukopenia reported in 22-41.8% of cases 3
• Rheumatoid arthritis
• Adult-onset Still's disease - common hematological abnormality 1
• Autoimmune neutropenia - immune-mediated destruction of neutrophils

5. Cancer-Related Causes

• Bone marrow infiltration by malignant cells 1
• Hematologic malignancies:
  • Leukemias (acute and chronic)
  • Lymphomas
  • Multiple myeloma 1
• Metastatic solid tumors to bone marrow

6. Other Causes

• Hypersplenism - excessive sequestration and destruction of white blood cells 4
• Congenital disorders - rare hereditary neutropenias 4
• Radiation exposure
• Alcoholism - direct toxic effect on bone marrow 2

Risk Stratification and Clinical Significance

The severity and clinical significance of leukopenia depends on:

1. Degree of leukopenia:

   • Mild: 3,000-4,000/μL
   • Moderate: 1,000-3,000/μL
   • Severe: <1,000/μL

2. Neutrophil count - risk of infection increases significantly when absolute neutrophil count falls below 500/μL 1

3. Duration - chronic leukopenia carries different implications than acute

4. Underlying cause - some etiologies have worse prognosis than others

Diagnostic Approach

When evaluating leukopenia, consider:

1. Complete blood count with differential - essential to determine which white cell lines are affected 1

2. Peripheral blood smear - may show abnormalities suggesting specific diagnoses 1

3. Medication review - identify potential drug-induced causes

4. Bone marrow examination - indicated in patients with:

   • Unexplained persistent leukopenia
   • Concurrent abnormalities in other blood cell lines
   • Suspected hematologic malignancy 1

5. Additional testing based on clinical suspicion:

   • Viral studies (HIV, hepatitis, CMV)
   • Autoimmune markers
   • Vitamin B12 and folate levels

Clinical Pearls and Pitfalls

• Neutropenia with fever represents a medical emergency requiring immediate broad-spectrum antibiotics 5

• Pancytopenia (reduction in all cell lines) suggests a bone marrow problem rather than isolated leukopenia 5

• Thiopurine methyltransferase (TPMT) testing should be considered before starting azathioprine to identify patients at high risk for severe myelosuppression 1

• Chronic lymphocytic leukemia (CLL) patients frequently have hypogammaglobulinemia leading to increased susceptibility to encapsulated bacteria 1

• Patients with advanced malignancy are at greater risk for infectious complications due to leukopenia from both the disease and treatments 1

By systematically evaluating these potential causes, clinicians can identify the underlying etiology of leukopenia and implement appropriate management strategies to prevent complications.