What causes leukopenia (low white blood cell count)?

What Causes a Low White Blood Cell Count (Leukopenia)

Leukopenia most commonly results from medications (especially chemotherapy and immunosuppressives), infections (particularly viral), bone marrow disorders (including malignancies and myelodysplastic syndromes), nutritional deficiencies, and autoimmune destruction of white blood cells.

Medication-Induced Causes

Medications are the most frequent culprit in clinical practice:

• Chemotherapy agents cause predictable dose-dependent bone marrow suppression, with neutropenia occurring in 70-100% of patients receiving intensive myelosuppressive regimens 1
• Immunosuppressive drugs including azathioprine and 6-mercaptopurine cause leukopenia in approximately 3.2% of inflammatory bowel disease patients through accumulation of toxic metabolites in bone marrow 1
• Patients with thiopurine methyltransferase (TPMT) deficiency are at particularly high risk for severe myelosuppression and should undergo testing before initiating thiopurine therapy 2
• Other common medications include corticosteroids (paradoxically can cause leukocytosis initially), antibiotics, allopurinol, sulfasalazine, mesalamine, and diuretics 1
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 3

Infection-Related Causes

Both viral and severe bacterial infections commonly cause leukopenia:

• Viral infections, particularly HIV and hepatitis C, are major causes, with HIV causing progressive CD4+ T-cell lymphopenia 3, 1
• Cytomegalovirus infection can lead to cytopenias including leukopenia 3
• Severe bacterial infections can cause leukopenia through both increased white cell utilization and bone marrow suppression 1
• Leukopenia in community-acquired pneumonia (WBC <4,000 cells/mm³) is a minor criterion for severe CAP and consistently associated with excess mortality 3

Bone Marrow Disorders

Primary bone marrow pathology should be suspected when multiple cell lines are affected:

• Hematologic malignancies including acute leukemia, chronic lymphocytic leukemia, and lymphomas cause leukopenia through bone marrow infiltration 3, 2, 1
• Myelodysplastic syndromes impair normal blood cell production, with dysplastic changes visible on peripheral smear 3, 1
• Aplastic anemia causes pancytopenia including leukopenia 3
• Abnormalities in two or more cell lines (red cells, white cells, platelets) strongly suggest primary bone marrow pathology and warrant hematology consultation 1

Autoimmune and Immune-Mediated Causes

Autoimmune destruction represents an important reversible cause:

• Autoimmune cytopenias can occur in chronic lymphocytic leukemia through immune-mediated mechanisms, though autoimmune granulocytopenia is less common than autoimmune hemolytic anemia or immune thrombocytopenia 3
• Corticosteroids are the first-line treatment for autoimmune-mediated leukopenia with warm antibodies 3, 2
• Post-transplant immunosuppression can cause leukopenia, with graft failure resulting in severe leukopenia and mortality up to 80% 3

Nutritional Deficiencies

Deficiencies affecting DNA synthesis impair white cell production:

• Vitamin B12 or folate deficiency causes megaloblastic anemia that impairs DNA synthesis in all rapidly dividing cells, including white blood cells 1
• Copper deficiency can mimic myelodysplastic syndrome findings and cause leukopenia with anemia, particularly in patients with prior gastrointestinal surgery or vitamin B12 deficiency history 4, 1

Other Causes

• Hypersplenism leads to increased sequestration and destruction of white blood cells 5
• Environmental toxins and various prescription and non-prescription drugs can cause leukopenia 3

Critical Clinical Pitfall

The most dangerous scenario is febrile neutropenia (fever with absolute neutrophil count <500/mcL or <1,000/mcL with expected decline), which is a medical emergency requiring immediate broad-spectrum antibiotics 2, 1. The risk of infection increases dramatically when neutrophil counts fall below 500/mcL, with the highest risk (10-20%) at counts below 100/mcL 3, 2. Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection 2.

Essential Diagnostic Approach

The minimum evaluation must include:

• Complete blood count with differential to assess all cell lines 1
• Manual peripheral blood smear examination to determine which white blood cell lines are affected and identify morphological abnormalities such as dysplasia 3, 1
• Review of previous blood counts to assess the dynamic development of leukopenia 6
• Bone marrow examination should be considered in patients with unexplained persistent leukopenia, especially older adults, or when bi- or pancytopenia suggests insufficient bone marrow production 3, 1