What are the causes of leukocytopenia?

Causes of Leukocytopenia

Leukocytopenia is most commonly caused by bone marrow disorders, medication effects, infections, autoimmune conditions, and peripheral destruction or sequestration mechanisms. 1, 2

Major Categories of Leukocytopenia Causes

Medication-Related Causes

• Chemotherapy agents are among the most common causes of bone marrow suppression leading to leukocytopenia 1
• Immunosuppressive medications used in autoimmune disorders, including azathioprine and 6-mercaptopurine, can cause leukocytopenia 1
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 1
• Various prescription and non-prescription drugs can cause bone marrow toxicity resulting in leukopenia 1

Malignancy-Related Causes

• Hematologic malignancies, including chronic lymphocytic leukemia (CLL), can cause cytopenias through bone marrow infiltration or immune-mediated mechanisms 3, 1
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow, leading to leukopenia 1
• Acute leukemias can cause leukopenia through bone marrow failure 1, 4
• Non-Hodgkin's lymphoma can cause leukopenia through bone marrow infiltration 1

Infection-Related Causes

• Viral infections, particularly HIV and HCV, can cause leukopenia 1
• Cytomegalovirus infection can lead to cytopenias, including leukopenia 1
• Severe bacterial infections can cause leukopenia, especially in later stages 4
• Overwhelming sepsis may lead to leukopenia after an initial leukocytosis 5

Bone Marrow Disorders

• Aplastic anemia causes pancytopenia including leukopenia 1, 2
• Myelofibrosis can lead to decreased production of white blood cells 2
• Megaloblastic anemia due to vitamin B12 or folate deficiency can cause leukopenia 2, 6
• Hemophagocytic syndrome can present with pancytopenia including leukopenia 2

Autoimmune Mechanisms

• Autoimmune neutropenia can occur in isolation or as part of systemic autoimmune disorders 1, 6
• In CLL, autoimmune mechanisms can cause cytopenias, with autoimmune hemolytic anemia and immune thrombocytopenia being more common than autoimmune granulocytopenia 3
• Systemic lupus erythematosus and other connective tissue diseases can cause leukopenia 2

Other Causes

• Hypersplenism can cause sequestration and destruction of white blood cells 6
• Radiation exposure can cause acute radiation syndrome with hematopoietic failure 2
• Post-transplant immunosuppression can cause leukopenia 1
• Physical and emotional stress can affect white blood cell counts 7
• Hereditary neutropenia syndromes (rare, especially in children) 6

Clinical Significance

• 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, especially if also on immunosuppressive therapy 1

Diagnostic Approach

• Complete blood count with differential is essential to confirm leukopenia and assess severity 2
• Peripheral blood smear examination is critical to identify morphological abnormalities and exclude pseudo-cytopenias 1, 2
• Review of medication history to identify potential drug-induced causes 4
• Bone marrow examination is indicated in most cases of unexplained persistent leukopenia, especially in older adults 1
• HIV and HCV testing is recommended in patients with unexplained leukopenia 2

Common Pitfalls and Caveats

• EDTA-dependent agglutination can cause pseudo-cytopenias and should be excluded when evaluating blood counts 1
• In patients with leukopenia and fever, immediate broad-spectrum antibiotic therapy must be initiated to prevent serious complications 1, 4
• Autoimmune cytopenias in CLL may have a better prognosis than cytopenias due to bone marrow infiltration 3
• The first treatment option for patients with autoimmune cytopenia with warm antibodies is corticosteroids 3
• Autoimmune cytopenias not responding to conventional autoimmune-oriented therapy are indications for CLL treatment 3