What are the main causes of leukopenia (low white blood cell count)?

Main Causes of Low White Blood Cell Count (Leukopenia)

The most common causes of leukopenia are chemotherapy-induced bone marrow suppression, bacterial infections (particularly overwhelming sepsis), autoimmune/autoinflammatory diseases, and drug-induced marrow toxicity. 1

Primary Etiologic Categories

Medication-Related Causes

• Chemotherapy agents represent the most frequent iatrogenic cause through direct bone marrow suppression, affecting granulocyte production 2, 1
• Other drugs account for 8.5-12.7% of leukopenia cases, requiring careful medication review 3

Infectious Causes

• Bacterial infections, especially overwhelming sepsis, cause leukopenia through increased white blood cell utilization and destruction rather than decreased production 1, 4
• Viral infections can suppress bone marrow function temporarily 4

Autoimmune/Autoinflammatory Disorders

• Autoimmune diseases are remarkably common, representing 17-17.3% of leukopenia cases across neutropenic and non-neutropenic patients 3
• Autoimmune thyroid disease accounts for 5.1-21.8% of cases depending on neutrophil count 3
• When including isolated antinuclear antibody positivity, autoimmunity accounts for 53.8% of all isolated leukopenia cases, making it the single most important diagnostic consideration 3

Hematologic Malignancies and Bone Marrow Disorders

• Leukemias and lymphomas can present with paradoxical leukopenia despite being proliferative disorders 1
• Myelodysplastic syndromes cause ineffective hematopoiesis with stable cytopenia (≥6 months duration, or 2 months with specific karyotype abnormalities) 2, 1
• Primary immunodeficiency disorders including Wiskott-Aldrich syndrome present with T-cell lymphopenia (20-30% of WAS patients) and neutropenia variants 2, 1

Nutritional Deficiencies

• Megaloblastosis from B12 or folate deficiency causes ineffective hematopoiesis, accounting for 1.7-1.8% of cases 4, 3
• Iron deficiency anemia paradoxically contributes to leukopenia in 10.2-21.8% of cases, more commonly in non-neutropenic patients 3

Hypersplenism

• Splenic sequestration causes peripheral leukopenia through increased white blood cell pooling and destruction, accounting for 1.7-2.7% of cases 4, 3

Rare Hereditary Causes

• Primary congenital neutropenia is very rare and may be hereditary with associated developmental defects, particularly in children 4
• X-linked neutropenia from gain-of-function WAS mutations presents as isolated neutropenia without other manifestations 2

Critical Diagnostic Approach

Essential Initial Workup

• Complete blood count with differential to characterize the specific white blood cell lineage affected and identify other cytopenias 1
• Peripheral blood smear review to assess for dysplasia, blast cells, and abnormal cell morphology 2
• Medication history focusing on chemotherapy, immunosuppressants, and other marrow-toxic drugs 1, 3

Secondary Investigations Based on Clinical Context

• Autoimmune screening (ANA, rheumatoid factor, thyroid antibodies) given the 53.8% prevalence of autoimmune associations 3
• Infectious workup including blood cultures if fever or sepsis is suspected 1
• Bone marrow aspiration and biopsy with cytogenetics for persistent unexplained leukopenia, particularly when neutrophil count <1500/µL or when dysplasia is suspected 2, 3
• Vitamin B12, folate, and iron studies to exclude nutritional causes 2, 3

Management Priorities

Immediate Interventions for High-Risk Situations

• Febrile neutropenia (temperature >38.5°C with absolute neutrophil count <0.5 × 10⁹/L) requires immediate empiric broad-spectrum antibiotics before culture results 1
• The major danger of neutropenia is overwhelming infection risk, which increases dramatically when neutrophil count falls below 100/µL 2, 4

Supportive Measures

• Granulocyte colony-stimulating factor (G-CSF) may be considered in severe neutropenia or high-risk situations, but is contraindicated during chest radiotherapy 1
• Prophylactic antimicrobials should be considered for prolonged neutropenia based on institutional protocols 1
• Dose adjustments of chemotherapy may be necessary in patients with prolonged or severe treatment-induced neutropenia 1

Common Diagnostic Pitfalls

• Spurious leukopenia can occur from EDTA-induced white blood cell agglutination, requiring blood smear confirmation 5
• Mean cell hemoglobin concentration (MCHC) abnormalities serve as important flags for spurious automated counts 5
• In 44-25 patients (depending on neutrophil count), no etiology is identified despite thorough workup, suggesting benign ethnic neutropenia or other unrecognized causes 3
• Physicians order bone marrow examination more frequently in neutropenic patients, but autoimmune screening should be prioritized first given the high prevalence 3