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

Causes of Low WBC (Leukopenia)

Primary Etiologic Categories

Leukopenia results from either decreased production of white blood cells in the bone marrow, increased destruction/utilization in peripheral tissues, or both mechanisms simultaneously. 1

Medication-Induced Causes

• Chemotherapy agents are the most common cause of leukopenia through direct bone marrow suppression, affecting myeloid progenitor cell proliferation and maturation. 2
• Immunosuppressive medications including azathioprine and 6-mercaptopurine cause bone marrow toxicity, with leukopenia occurring in approximately 3.2% of patients overall, and severe leukopenia (WBC <2,500 cells/mm³) in 5.3% of rheumatoid arthritis patients and 16% of renal transplant recipients. 3
• Patients with thiopurine methyltransferase (TPMT) deficiency or NUDT15 deficiency face dramatically increased risk for severe, life-threatening myelosuppression from azathioprine, as 6-thioguanine accumulates in bone marrow tissue. 3
• Profound leukopenia can develop suddenly and unpredictably between blood tests in approximately 3% of patients on thiopurines. 3
• Critical pitfall: Normal TPMT testing does not exclude risk—only 27% of leukopenia cases are explained by common TPMT variants, and TPMT enzyme activity measurement is unreliable after blood transfusions or with certain drug interactions. 3
• Various prescription and non-prescription drugs, including environmental toxins, can cause leukopenia. 3

Hematologic Malignancies

• Chronic lymphocytic leukemia (CLL) causes cytopenias through bone marrow infiltration or immune-mediated mechanisms, with autoimmune mechanisms causing hemolytic anemia and thrombocytopenia more commonly than autoimmune granulocytopenia. 3
• Acute leukemias, non-Hodgkin's lymphoma, and other hematologic malignancies cause leukopenia through direct bone marrow infiltration and replacement of normal hematopoietic tissue. 3, 2
• Myelodysplastic syndromes impair normal blood cell production; in hypoplastic MDS with low bone marrow cellularity, immunomodulatory treatment similar to aplastic anemia may be offered. 3

Bone Marrow Failure Syndromes

• Aplastic anemia causes pancytopenia including leukopenia through immune-mediated destruction of hematopoietic stem cells. 3
• Graft failure after allogeneic transplantation results in severe leukopenia with mortality up to 80%. 3

Infection-Related Causes

• Viral infections, particularly HIV and HCV, cause leukopenia through direct viral effects on bone marrow progenitor cells. 3
• Cytomegalovirus infection leads to cytopenias including leukopenia. 3
• Bacterial infections, especially severe sepsis, can cause leukopenia through increased peripheral consumption and bone marrow suppression. 2
• Leukopenia (WBC count <4,000 cells/mm³) from community-acquired pneumonia is a minor criterion for severe CAP, consistently associated with excess mortality and increased risk of acute respiratory distress syndrome. 3

Autoimmune and Immune-Mediated Causes

• Autoimmune disorders cause leukopenia through antibody-mediated destruction of white blood cells or their precursors. 3
• In CLL patients, autoimmune cytopenias not responding to conventional autoimmune-oriented therapy are indications for CLL treatment. 3
• Post-transplant immunosuppression causes leukopenia through therapeutic suppression of bone marrow function. 3

Hypersplenism and Sequestration

• Hypersplenism causes leukopenia through increased sequestration and destruction of white blood cells in an enlarged spleen. 1

Nutritional and Metabolic Causes

• Megaloblastosis (vitamin B12 or folate deficiency) causes leukopenia through impaired DNA synthesis affecting rapidly dividing bone marrow cells. 1

Diagnostic Approach

Examine the peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities such as dysplasia. 3, 4

• Check previous blood counts to assess the dynamic development and chronicity of leukopenia. 4
• Evaluate for bi- or pancytopenia, which usually implies insufficient production in the bone marrow rather than isolated peripheral destruction. 4
• Consider bone marrow examination in patients with unexplained persistent leukopenia, especially in older adults. 3
• Exclude EDTA-dependent platelet agglutination, which can cause pseudo-thrombocytopenia and confound cytopenia evaluation. 3

Clinical Risk Stratification

The risk of infection increases significantly when neutrophil counts fall below 500/mcL, with the highest risk (10-20%) at counts below 100/mcL. 2

• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection. 2
• Patients with cancer and leukopenia are at particularly high risk for infectious complications. 3
• In patients with alcohol abuse history and leukopenia, adverse manifestations of septic shock and ARDS may be delayed or masked, benefiting from ICU monitoring. 3

Management Principles

For patients with febrile neutropenia, immediate broad-spectrum antibiotic therapy must be initiated to prevent serious complications—empiric antimicrobial therapy with an anti-pseudomonas β-lactam agent, carbapenem, or piperacillin-tazobactam is essential. 3, 2

• Antimicrobial prophylaxis may be indicated in severe neutropenia, especially in cancer patients. 2
• For autoimmune-mediated leukopenia, corticosteroids are often the first-line treatment. 3, 2
• For medication-induced leukopenia, consider dose reduction or discontinuation of the offending agent. 3
• CLL-related cytopenias are often efficiently corrected by appropriate antileukemic therapy rather than supportive measures alone. 5
• Growth factors such as G-CSF should be given according to ASCO guidelines during myelosuppressive chemotherapy, and may benefit patients with prolonged cytopenias after alemtuzumab treatment. 5

Critical Clinical Pitfalls

• Agranulocytosis with fever is life-threatening and requires immediate hospital admission with broad-spectrum antibiotics to reduce mortality. 4
• Do not assume that remission in hematologic malignancies equals immune recovery—absence of detectable disease does not restore normal immune function, particularly in CLL and multiple myeloma. 6
• Patients with severe lymphocytopenia require Pneumocystis jirovecii prophylaxis with trimethoprim-sulfamethoxazole regardless of remission status. 6