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

Causes of Low White Blood Cell Count (Leukopenia)

A low white blood cell count (leukopenia) can be caused by a wide range of conditions including medications, infections, bone marrow disorders, autoimmune diseases, and congenital disorders. The most common causes vary depending on clinical context and patient demographics.

Medication-Related Causes

• Chemotherapy agents are among the most common causes of leukopenia due to bone marrow suppression 1
• Immunosuppressive medications used for autoimmune disorders frequently cause leukopenia 1
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 1
• Azathioprine and 6-mercaptopurine used in inflammatory bowel disease can cause bone marrow toxicity 1
• Various prescription and non-prescription drugs can cause leukopenia through different mechanisms 1, 2

Disease-Related Causes

Hematologic Disorders

• Chronic lymphocytic leukemia (CLL) can cause cytopenias through bone marrow infiltration or immune-mediated mechanisms 1, 3
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 1
• Aplastic anemia causes pancytopenia including leukopenia 1
• Hematologic malignancies including acute leukemias and non-Hodgkin's lymphoma can cause leukopenia 1

Infectious Causes

• Viral infections, particularly HIV and HCV, can cause leukopenia 1
• Cytomegalovirus infection can lead to cytopenias, including leukopenia 1
• Tickborne rickettsial diseases often present with leukopenia 3
• Bacterial infections can sometimes cause leukopenia rather than leukocytosis 2

Immune-Mediated Causes

• Primary immunodeficiency disorders can present with leukopenia 3
• Autoimmune disorders can cause leukopenia through antibody-mediated destruction 4
• Familial Mediterranean fever can cause episodic leukopenia through autophagy and apoptosis 5

Other Causes

• Hypersplenism can lead to increased destruction of white blood cells 2
• Nutritional deficiencies, particularly vitamin B12 and folate deficiency (megaloblastosis) 2
• Environmental toxin exposure 1
• Post-transplant immunosuppression 1
• Congenital disorders (rare) 2

Diagnostic Approach

• Examine peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities 1
• Review medication history to identify potential drug-induced causes 4
• Check previous blood counts to understand the pattern and duration of leukopenia 6
• Evaluate for associated cytopenias (anemia, thrombocytopenia) which may suggest bone marrow dysfunction 6
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially in older adults 1

Clinical Significance and Risk Assessment

• The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with high risk (10-20%) at counts below 100/mcL 1
• Patients with cancer and leukopenia are at particularly high risk for infectious complications 1
• In patients with HIV, leukopenia may increase the risk of opportunistic infections 1
• Patients with autoimmune disorders may have increased susceptibility to infections when leukopenic 1

Management Considerations

• For medication-induced leukopenia, consider dose reduction or discontinuation of the offending agent 1
• For autoimmune-mediated leukopenia, corticosteroids are often the first-line treatment 1
• In patients with febrile neutropenia, prompt empiric antimicrobial therapy with an anti-pseudomonas β-lactam agent, carbapenem, or piperacillin-tazobactam is recommended 1, 4
• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1
• Monitoring frequency should be based on the severity of leukopenia and underlying condition 1

Common Pitfalls and Caveats

• EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and should be excluded when evaluating cytopenias 1
• In patients with leukopenia and fever, immediate broad-spectrum antibiotic therapy must be initiated to prevent serious complications 1
• Chronic lymphocytic leukemia can affect laboratory measurements like HbA1c, which should be considered when managing comorbidities 7
• Neutropenia in children may be hereditary and associated with other developmental defects 2