Causes of Low White Blood Cell Count (Leukopenia)
Leukopenia can be caused by reduced production of white blood cells, increased destruction, or both, with the most common causes being medications, infections, primary bone marrow disorders, and immune-mediated conditions. 1
Primary Causes of Leukopenia
1. Medication-Induced Leukopenia
- Chemotherapeutic agents
- Immunosuppressants (e.g., azathioprine, 6-mercaptopurine) 2
- Antibiotics (particularly sulfonamides, trimethoprim)
- Antipsychotics (especially clozapine)
- Antithyroid medications
2. Infections
- Viral infections (particularly HIV, hepatitis, CMV, EBV, parvovirus) 3
- Overwhelming bacterial infections (sepsis can cause initial leukocytosis followed by leukopenia)
- Typhoid fever
- Tuberculosis
- Parasitic infections
3. Primary Bone Marrow Disorders
- Leukemias (particularly when advanced)
- Myelodysplastic syndromes
- Aplastic anemia
- Myelofibrosis
- Bone marrow infiltration by cancer or granulomatous disease
4. Immune-Mediated Causes
- Autoimmune neutropenia
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Felty's syndrome
5. Nutritional Deficiencies
- Vitamin B12 deficiency 3
- Folate deficiency
- Copper deficiency
- Severe malnutrition
6. Genetic/Congenital Disorders
- Primary immunodeficiency disorders 3, 2
- Congenital neutropenias (e.g., Kostmann syndrome)
- Cyclic neutropenia
- Dyskeratosis congenita 2
7. Other Causes
- Hypersplenism (increased sequestration of white blood cells) 1
- Alcohol abuse (direct toxic effect on bone marrow)
- Radiation exposure
- Inflammatory bowel disease 2
Diagnostic Approach
When evaluating leukopenia, the following steps should be taken:
- Review medication history to identify potential causative agents
- Obtain complete blood count with differential to determine which white cell lines are affected
- Examine peripheral blood smear to assess cell morphology and maturity 4
- Check for associated cytopenias (anemia, thrombocytopenia) which may suggest bone marrow failure 4
- Evaluate for signs of infection or systemic illness
- Consider bone marrow examination if the cause remains unclear or primary bone marrow disorder is suspected
Severity Classification
The World Health Organization classifies leukopenia by severity 3:
- Mild: 3,000-4,000/mm³
- Moderate: 2,000-3,000/mm³
- Severe: <2,000/mm³
Clinical Implications
The major danger of leukopenia, particularly neutropenia, is the increased risk of infection 1. Patients with severe neutropenia (absolute neutrophil count <500/mm³) are at highest risk for life-threatening infections and may require:
- Prompt antimicrobial therapy for febrile episodes
- Prophylactic antibiotics in some cases
- Granulocyte colony-stimulating factors for severe cases
- Isolation precautions to prevent exposure to pathogens
Special Considerations
- Primary immunodeficiency disorders often present with recurrent infections and may have associated abnormalities in other organ systems 2, 3
- Medication-induced leukopenia typically resolves after discontinuation of the offending agent
- Autoimmune leukopenia may respond to immunosuppressive therapy
- Nutritional deficiencies require appropriate supplementation
Common Pitfalls
- Failing to check previous complete blood counts to determine if leukopenia is acute or chronic
- Not considering drug-induced causes, which are among the most common and potentially reversible
- Missing associated cytopenias that may indicate a more serious bone marrow disorder
- Overlooking mild leukopenia in patients with chronic inflammatory conditions
- Not recognizing that stress, including physical and emotional stress, can temporarily affect white blood cell counts 5