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

Causes of Leukopenia (Low White Blood Cell Count)

Primary Etiologic Categories

Chemotherapy and myelosuppressive drugs represent the most common iatrogenic cause of leukopenia through direct bone marrow suppression, affecting granulocyte production. 1

Medication-Induced Causes

• Cytotoxic chemotherapy agents cause transient cytopenias due to delayed recovery of normal hematopoiesis, with the depth of leukopenia correlating with drug dose and timing. 2, 1, 3
• Thiopurine therapy (azathioprine, 6-mercaptopurine) in inflammatory bowel disease patients precipitates leukopenia in 3.2% of cases, often compounded by concurrent nutritional deficiencies and related to 6-thioguanine accumulation in bone marrow tissue. 2, 3
• Methotrexate and other immunosuppressive therapies used in sarcoidosis and autoimmune conditions contribute to hematologic abnormalities. 2

Infection-Related Causes

• Bacterial infections, especially overwhelming sepsis, cause leukopenia through increased white blood cell utilization and destruction rather than decreased production. 1, 4
• Influenza A infection transiently suppresses bone marrow output, producing leukopenia (WBC <4.0 × 10³/µL) in 8–27% of cases with associated lymphopenia; severe disease shows markedly low counts and high mortality. 3
• The combination of fever plus leukopenia suggests severe bacterial infection with poor prognosis, particularly in community-acquired pneumonia where leukopenia is consistently associated with excess mortality. 3

Hematologic Malignancies

• Leukemias and lymphomas can present with paradoxical leukopenia despite being proliferative disorders, particularly when bone marrow is extensively infiltrated. 1
• Myelodysplastic syndromes cause ineffective hematopoiesis with stable cytopenia (≥6 months duration, or 2 months with specific karyotype abnormalities). 1

Autoimmune and Inflammatory Conditions

• Autoimmunity is detected as an important factor leading to isolated leukopenia, with 53.8% of cases having an autoimmune diagnosis or laboratory finding in recent studies. 5
• In sarcoidosis, compartmentalization of white blood cells to the site of organ involvement is a common cause of leukopenia and lymphopenia, even in the absence of splenomegaly. 2
• Autoimmune thyroid disease and other autoimmune/autoinflammatory diseases account for approximately 39% of nonneutropenic leukopenia cases. 5

Nutritional Deficiencies

• Vitamin B12 or folate deficiency impairs DNA synthesis and leads to ineffective white cell production with macrocytosis, identified by elevated mean corpuscular volume (MCV) on CBC. 2, 3, 5
• Iron deficiency anemia is the most frequent reason for isolated leukopenia in nonneutropenic patients (21.8%), and also contributes in neutropenic patients (10.2%). 5

Splenic Sequestration

• Splenomegaly with sequestration may be a more common cause of hematologic abnormalities than bone marrow involvement in conditions like sarcoidosis. 2
• Hypersplenism causes peripheral destruction and sequestration of white blood cells. 4, 5

Primary Immunodeficiency Disorders

• Wiskott-Aldrich syndrome presents with T-cell lymphopenia and neutropenia variants, while X-linked neutropenia from gain-of-function WAS mutations presents as isolated neutropenia. 1
• Severe combined immunodeficiency (SCID) can present with various patterns of leukopenia. 1

Other Causes

• Hepatic sarcoidosis contributes to hematologic abnormalities through multiple mechanisms. 2
• Radiotherapy sequelae account for 1.7–1.8% of leukopenia cases through bone marrow suppression. 5

Critical Diagnostic Approach

A complete blood count with differential is essential to characterize the specific white blood cell lineage affected and identify other cytopenias. 1, 6

Key Diagnostic Steps

• Obtain manual differential count immediately to calculate absolute neutrophil count (ANC) and assess for left shift, immature forms, or dysplasia. 3, 7
• Peripheral blood smear review is necessary to assess for dysplasia, blast cells, and abnormal cell morphology. 1, 7
• Assessment of all three major blood cell lines (WBC, hemoglobin, platelets) is essential—abnormalities in two or more suggest a primary bone marrow disorder and should prompt hematology consultation. 3, 7
• Medication history, focusing on chemotherapy, immunosuppressants, and other marrow-toxic drugs, is crucial in diagnosing leukopenia. 1
• Check previous blood counts to assess the dynamic development of leukopenia and determine if it is transient or chronic. 7, 8

When to Pursue Further Investigation

• Bone marrow aspiration and biopsy with cytogenetics may be required for persistent unexplained leukopenia, particularly when neutrophil count <1500/µL or when dysplasia is suspected. 1
• Infectious workup, including blood cultures, is necessary if fever or sepsis is suspected. 1

Clinical Significance and Risk Stratification

The major danger of neutropenia is overwhelming infection risk, which increases dramatically when neutrophil count falls below 100/µL. 1, 4

Risk Assessment Based on ANC

• ANC ≥1.5 × 10³/µL with normal differentials in an otherwise healthy adult is clinically insignificant and requires only repeat testing in 4–6 weeks to confirm stability. 3
• ANC <1.0 × 10³/µL indicates high infection risk and warrants closer monitoring. 3
• ANC <0.5 × 10³/µL is associated with severe neutropenia and substantial infection risk. 3

Red Flags Requiring Urgent Evaluation

• Febrile neutropenia (temperature >38.5°C with ANC <0.5 × 10⁹/L) requires immediate empiric broad-spectrum antibiotics before culture results. 1
• Progressive decline over serial measurements indicates evolving bone marrow disorder. 3
• Recurrent infections suggest functional immune deficiency despite cell counts. 3
• Splenomegaly or lymphadenopathy suggests hematologic malignancy. 3

Common Pitfalls to Avoid

Leukopenia and lymphocyte predominance suggest an alternative diagnosis to Kawasaki disease, where leukocytosis with granulocyte predominance is typical. 2

In patients with isolated leukopenia, physicians should not overlook autoimmune screening, as autoimmunity accounts for over half of cases when isolated antinuclear antibody positivity is included. 5

Do not assume benign etiology in elderly patients or those with persistent leukopenia—bone marrow evaluation is often necessary to exclude myelodysplastic syndrome or other hematologic disorders. 5, 8