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

Causes of Leukopenia

Leukopenia results from either decreased production of white blood cells in the bone marrow, increased destruction/utilization, or both, with the most common causes being medications (especially chemotherapy and immunosuppressants), infections, hematologic malignancies, autoimmune disorders, and bone marrow failure syndromes. 1, 2

Medication-Related Causes

Chemotherapy agents are the most frequent cause of leukopenia through direct bone marrow suppression 2. This represents the leading iatrogenic cause in clinical practice.

Immunosuppressive medications commonly implicated include:

• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with leukopenia occurring in approximately 3.2% of patients overall, with severe leukopenia (WBC <2500 cells/mm³) in 5.3% of rheumatoid arthritis patients and 16% of renal transplant recipients 1
• Thiopurine-related leukopenia is particularly dangerous in patients with thiopurine methyltransferase (TPMT) deficiency or NUDT15 deficiency, who face dramatically increased risk for severe, life-threatening myelosuppression 1
• Critical caveat: TPMT genotype and enzyme activity explain only 27% of leukopenia cases, so normal TPMT testing does NOT exclude risk 1
• Profound leukopenia can develop suddenly and unpredictably between blood tests in around 3% of patients on thiopurines 1

Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leukopenia 1

Other medications include corticosteroids (paradoxically can cause leukocytosis or leukopenia depending on context), lithium, and various prescription/non-prescription drugs 1

Hematologic Malignancy-Related Causes

Bone marrow infiltration from hematologic malignancies is a major cause:

• Acute and chronic leukemias (including chronic lymphocytic leukemia) cause leukopenia through bone marrow infiltration or immune-mediated mechanisms 1, 2
• Lymphomas (particularly non-Hodgkin's lymphoma) can infiltrate marrow 1
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow 1

Autoimmune cytopenias in CLL can occur through autoimmune mechanisms, with autoimmune hemolytic anemia and immune thrombocytopenia being more common than autoimmune granulocytopenia 1. Importantly, autoimmune cytopenias in CLL may have a better prognosis than cytopenias due to bone marrow infiltration 1.

Infection-Related Causes

Viral infections are important causes:

• HIV infection is the primary viral cause of persistent CD4+ lymphopenia 3
• Hepatitis C virus (HCV) can cause leukopenia 1
• Cytomegalovirus can lead to cytopenias including leukopenia 1, 3

Bacterial infections, especially severe sepsis, can cause leukopenia 2. This is particularly concerning as leukopenia (WBC count <4,000 cells/mm³) from community-acquired pneumonia is a minor criterion for severe CAP and is consistently associated with excess mortality 1.

Autoimmune and Immune-Mediated Causes

Autoimmunity is a critical and often underrecognized cause: In one study of isolated leukopenia, 53.8% of cases had an autoimmune diagnosis or laboratory finding 4. The most frequent autoimmune associations include:

• Autoimmune thyroid disease (21.8% in nonneutropenic patients) 4
• Other autoimmune/autoinflammatory diseases (17.3% in nonneutropenic patients) 4
• Autoimmune laboratory abnormalities even without established disease 4

Aplastic anemia causes pancytopenia including leukopenia through immune-mediated bone marrow failure 1

Bone Marrow Failure and Production Defects

Myelodysplastic syndromes impair normal blood cell production 1. In hypoplastic MDS with low bone marrow cellularity, immunomodulatory treatment similar to aplastic anemia may be offered 5.

Bone marrow fibrosis and other infiltrative processes can cause leukopenia 1

Radiation exposure causes predictable lymphocyte depletion, with a 50% decline in absolute lymphocyte count within 24 hours indicating potentially lethal exposure 3

Other Important Causes

Hypersplenism leads to sequestration and destruction of white blood cells 1, 4

Nutritional deficiencies:

• Vitamin B12 deficiency can cause megaloblastic changes affecting white blood cell production 4
• Iron deficiency anemia was found in 21.8% of nonneutropenic leukopenic patients in one study 4

Post-transplant complications: Graft failure after allogeneic transplantation results in severe leukopenia with mortality up to 80% 1

Diagnostic Approach

Examine the peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities 1. This is essential and provides information on potential causes such as dysplasia 6.

Check previous blood counts to assess the dynamic development of leukopenia 6. Evaluate whether this represents isolated leukopenia or is part of bi- or pancytopenia, as the latter usually implies insufficient bone marrow production 6.

Consider bone marrow examination in patients with unexplained persistent leukopenia, especially in older adults 1, 3. Physicians order bone marrow examination more frequently in patients with neutropenia 4.

Measure lymphocyte subsets (CD4+, CD8+, B cells) to characterize specific deficiencies when lymphopenia is present 3

Critical Clinical Pitfalls

EDTA-dependent platelet agglutination can cause pseudo-thrombocytopenia and should be excluded when evaluating cytopenias 1

Normal TPMT testing does not exclude risk of thiopurine-induced leukopenia, as it explains only 27% of cases 1

TPMT enzyme activity measurement is influenced by blood transfusions and drug interactions, making interpretation unreliable in certain clinical contexts 1

In patients with alcohol abuse history, adverse manifestations of septic shock and ARDS may be delayed or masked when leukopenia is present, benefiting from ICU monitoring 1