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

Causes of Low White Blood Cell Count (Leukopenia)

Low white blood cell count (leukopenia) results from either decreased production in the bone marrow, increased destruction/utilization of white cells, or both, with the most common causes being medications (especially chemotherapy and immunosuppressives), infections, autoimmune conditions, bone marrow disorders, nutritional deficiencies, and hypersplenism. 1

Primary Mechanisms

Leukopenia occurs through two fundamental pathways 1:

• Reduced production: Bone marrow suppression from drugs, malignancy infiltration, or nutritional deficiencies prevents adequate white cell generation 1, 2
• Increased destruction/utilization: Accelerated consumption occurs with severe infections, autoimmune destruction, or hypersplenism 1, 3

Major Etiologic Categories

Medication-Induced (Most Common)

Drugs are the leading cause of leukopenia in clinical practice 1, 2:

• Chemotherapy agents: Cause predictable dose-dependent bone marrow suppression, with neutropenia occurring in 70-100% of patients receiving intensive myelosuppressive chemotherapy 4
• Immunosuppressives: Azathioprine and 6-mercaptopurine cause leukopenia in 3.2% of inflammatory bowel disease patients through accumulation of 6-thioguanine in bone marrow 4
• Anti-tuberculosis drugs: Rifampicin and isoniazid cause leukopenia in 1.2% of men and 5.9% of women, with higher rates in patients aged 20-79 years 5
• Other medications: Antibiotics (cotrimoxazole), allopurinol, sulfasalazine, mesalamine, and diuretics can trigger leukopenia 4

Infections

• Viral infections: Common cause of transient leukopenia 1
• Severe bacterial infections: Can cause both increased utilization and bone marrow suppression 1, 3
• HIV infection: Causes progressive CD4+ T-cell lymphopenia, with increased risk when CD4 counts fall below critical thresholds 4

Bone Marrow Disorders

Abnormalities in two or more cell lines (red cells, white cells, platelets) strongly suggest primary bone marrow pathology and warrant hematology consultation 4:

• Malignancy: Leukemia, lymphoma, or metastatic disease infiltrating marrow 1
• Myelodysplastic syndromes: Cause dysplastic changes visible on peripheral smear 4
• Aplastic anemia: Results in pancytopenia 1

Nutritional Deficiencies

• Megaloblastic anemia: Vitamin B12 or folate deficiency impairs DNA synthesis, affecting all rapidly dividing cells including white cells 4
• Copper deficiency: Can cause leukopenia with anemia 4

Autoimmune and Immunologic Conditions

• Autoimmune neutropenia: Antibody-mediated destruction of neutrophils 1, 2
• Primary immunodeficiencies: Idiopathic CD4+ lymphopenia, Schimke syndrome, and cartilage-hair hypoplasia cause T-cell lymphopenia 4
• Systemic lupus erythematosus and rheumatoid arthritis: Associated with leukopenia 1

Hypersplenism

Splenic sequestration and destruction of white cells causes leukopenia, typically with concurrent thrombocytopenia 1

Clinical Assessment Priorities

Severity Classification

Neutropenia severity determines infection risk 2:

• Mild: ANC 1,000-1,500/mcL
• Moderate: ANC 500-1,000/mcL
• Severe: ANC <500/mcL
• Life-threatening: ANC <100/mcL carries 10-20% risk of severe bloodstream infection 4

Critical Red Flags Requiring Immediate Action

Febrile neutropenia (fever with ANC <500/mcL or <1,000/mcL with expected decline) is a medical emergency requiring immediate broad-spectrum antibiotics 4:

• Fever defined as core temperature >38.3°C 4
• Mortality risk increases dramatically without prompt antibiotic therapy 6, 2
• Admission is mandatory for agranulocytosis with fever 6

Essential Diagnostic Workup

The minimum evaluation must include 4:

• Complete blood count with differential: Assess all three cell lines (WBC, hemoglobin, platelets) to distinguish isolated leukopenia from bi-cytopenia or pancytopenia 4
• Manual peripheral blood smear: Essential to identify dysplasia, immature cells, or morphologic abnormalities that suggest specific diagnoses 6
• Reticulocyte count: Low reticulocytes with pancytopenia indicate bone marrow production failure 4

Extended workup when cause unclear 4:

• Vitamin B12, folate levels
• HIV testing
• Antinuclear antibodies for autoimmune screening
• Bone marrow examination if pancytopenia or unexplained persistent leukopenia 4

Important Pitfalls

• Review previous blood counts: Essential to determine if leukopenia is acute or chronic, as this fundamentally changes the differential diagnosis 6
• Check medication history thoroughly: Including over-the-counter drugs and recent antibiotic courses 4, 5
• Don't miss bi-cytopenia or pancytopenia: Involvement of multiple cell lines indicates bone marrow pathology rather than isolated peripheral destruction 4
• Inflammatory markers can mask deficiencies: CRP elevation may falsely normalize ferritin in iron deficiency; inflammation affects interpretation of all nutritional markers 4

Special Populations

Cancer and Transplant Patients

Chemotherapy-induced neutropenia requires risk stratification using validated tools to identify low-risk patients who may be candidates for outpatient management versus high-risk patients requiring hospitalization 4

Inflammatory Bowel Disease

Thiopurine-induced leukopenia occurs in 3.2% of patients, with only 27% of cases explained by TPMT variants; requires monitoring but often allows continuation of therapy with spontaneous recovery 4