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

Causes of Leukopenia

Leukopenia is primarily caused by bone marrow suppression, infections, medications, malignancies, and autoimmune disorders, with the risk of infection significantly increasing when neutrophil counts fall below 500/mcL. 1

Common Causes of Leukopenia

Medication-Related Causes

• Chemotherapy agents commonly cause bone marrow suppression leading to leukopenia 1
• Immunosuppressive medications used in autoimmune disorders can cause leukopenia 1
• Azathioprine and 6-mercaptopurine used in inflammatory bowel disease can cause bone marrow toxicity including leukopenia 2
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 1
• Various prescription and non-prescription drugs, including exposure to environmental toxins 2

Malignancy-Related Causes

• Hematologic malignancies (chronic and acute leukemias, non-Hodgkin's lymphoma) can cause leukopenia through bone marrow infiltration 2
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 1
• Bone marrow diseases including leukemias, fibrosis, and other malignancies 2

Infection-Related Causes

• Viral infections, particularly HIV and HCV, can cause leukopenia 2
• Cytomegalovirus infection can lead to cytopenias including leukopenia 2
• Bacterial infections can cause transient leukopenia due to increased utilization and destruction of white blood cells 3

Autoimmune-Related Causes

• Systemic lupus erythematosus (SLE) and other autoimmune disorders can cause leukopenia through immune-mediated mechanisms 2, 4
• Autoimmune neutropenia occurs when autoantibodies are directed against a patient's own neutrophils 5
• Primary autoimmune neutropenia is more common in children and is typically self-limited 5
• Secondary autoimmune neutropenia often occurs in adults with concurrent autoimmune diseases 5

Other Causes

• Aplastic anemia causes pancytopenia including leukopenia 1
• Post-transplant immunosuppression can cause leukopenia 1
• Hypersplenism can lead to increased destruction of white blood cells 3
• Liver disease including alcoholic liver cirrhosis 2
• Megaloblastic anemia due to vitamin B12 or folate deficiency 2, 3
• Inherited disorders such as congenital neutropenias and Wiskott-Aldrich syndrome 2

Clinical Significance and Risk Assessment

• The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with a 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 chronic lymphocytic leukemia (CLL), those who receive multiple chemotherapeutic regimens are at significantly increased risk for developing severe infections 2
• Patients with HIV and leukopenia may have increased susceptibility to opportunistic infections 1
• Patients with autoimmune disorders may have increased susceptibility to infections when leukopenic, especially if also on immunosuppressive therapy 1

Diagnostic Approach

• Evaluate previous blood counts to understand the dynamic development of the leukopenia 6
• Check red blood cell and platelet counts; bi- or pancytopenia usually implies insufficient production in the bone marrow 6
• Examine peripheral blood smear to determine which white blood cell lines are affected and to look for morphological abnormalities 2
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially in older adults 2
• Assess for underlying conditions such as infections, autoimmune disorders, malignancies, and medication exposure 2, 7

Management Considerations

• Treatment should target the underlying cause of leukopenia 7
• For medication-induced leukopenia, consider dose reduction or discontinuation of the offending agent 2
• For autoimmune-mediated leukopenia, corticosteroids are often the first-line treatment 1
• In patients with febrile neutropenia, prompt antibiotic therapy is essential 1
• Granulocyte colony-stimulating factor remains the first-line therapy for severe neutropenia 5
• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1
• For patients with febrile neutropenia, empiric antimicrobial therapy with an anti-pseudomonas β-lactam agent, carbapenem, or piperacillin-tazobactam is recommended 2

Common Pitfalls and Caveats

• Leukopenia is often used interchangeably with neutropenia, but it can also involve lymphopenia or other white cell deficiencies 3
• EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and should be excluded when evaluating cytopenias 2
• Leukopenia may be transient and resolve without specific treatment, particularly when caused by viral infections 7
• In patients with leukopenia and fever, immediate broad-spectrum antibiotic therapy must be initiated to prevent serious complications 2
• Monitoring frequency should be based on the severity of leukopenia and underlying condition 1