What are the causes of leukopenia?

Causes of Leukopenia

Leukopenia is primarily caused by bone marrow suppression, medication effects, infections, and malignancies, with the most serious consequence being increased infection risk, particularly when neutrophil counts fall below 500/mcL. 1

Definition and Clinical Significance

• Leukopenia refers to an abnormal reduction of circulating white blood cells, especially granulocytes, and is often used interchangeably with neutropenia 2
• The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with highest risk (10-20%) at counts below 100/mcL 3, 4
• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 3

Medication-Related Causes

• Chemotherapy agents are the most common cause of leukopenia through bone marrow suppression 1, 4
• Immunosuppressive medications used in autoimmune disorders, including azathioprine and 6-mercaptopurine, can cause bone marrow toxicity leading to leukopenia 3, 1
• Antibiotics, particularly sulfonamides like trimethoprim-sulfamethoxazole, can cause agranulocytosis, aplastic anemia, and leukopenia as adverse effects 5
• Anti-tuberculous drugs including rifampicin and isoniazid can cause leukopenia, with higher incidence in women (5.9%) than men (1.2%) 6
• Penicillins and cephalosporins at high doses (≥150 mg/kg/day) for extended periods (≥2 weeks) can cause leukopenia 7
• Thiopurines (azathioprine, 6-mercaptopurine) can cause severe bone marrow toxicity, especially in patients with thiopurine methyltransferase (TPMT) deficiency 3

Disease-Related Causes

• Hematologic malignancies including acute leukemia, chronic leukemia, and lymphomas can cause leukopenia through bone marrow infiltration 1
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 1
• Aplastic anemia causes pancytopenia including leukopenia 1
• Viral infections, particularly HIV, HCV, and cytomegalovirus, can cause leukopenia 1
• Bacterial infections can cause leukopenia, especially in severe sepsis 3
• Autoimmune disorders can cause leukopenia through immune-mediated mechanisms 1
• Hypersplenism can cause leukopenia due to increased sequestration and destruction of white blood cells 2

Other Causes

• Radiation exposure can cause bone marrow suppression leading to leukopenia 1
• Nutritional deficiencies, particularly vitamin B12 and folate deficiency causing megaloblastic anemia 2
• Congenital disorders including cyclic neutropenia and severe congenital neutropenia 8
• Immune neutropenia including primary autoimmune neutropenia 2

Clinical Evaluation of Leukopenia

• Examine peripheral blood smear to determine which white blood cell lines are affected and to look for morphological abnormalities 1
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially in older adults 1
• Check previous blood counts to understand the dynamic development of leukopenia 9
• Evaluate red blood cell and platelet counts; bi- or pancytopenia usually implies insufficient bone marrow production 9

Management Considerations

• For medication-induced leukopenia, consider dose reduction or discontinuation of the offending agent 1
• For patients with febrile neutropenia, prompt empiric antimicrobial therapy with an anti-pseudomonas β-lactam agent is essential 3, 4
• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients 1
• For autoimmune-mediated leukopenia, corticosteroids are often the first-line treatment 1
• Monitoring frequency should be based on the severity of leukopenia and underlying condition 1

Common Pitfalls and Caveats

• Signs and symptoms of inflammation and infection are often diminished or absent in patients with neutropenia 4
• In patients with leukopenia and fever, immediate broad-spectrum antibiotic therapy must be initiated to prevent serious complications 1
• EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and should be excluded when evaluating cytopenias 1
• Patients with TPMT deficiency are at high risk for severe myelosuppression with thiopurine therapy and should have TPMT testing before treatment initiation 3