What causes a low white blood cell (WBC) count, or leukopenia?

Low White Blood Cell Count (Leukopenia): Causes

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

Primary Mechanisms

The fundamental causes can be organized into two pathophysiologic categories:

• Decreased bone marrow production: Impaired proliferation and maturation of myeloid progenitor cells leads to insufficient white blood cell generation 2
• Increased peripheral destruction or utilization: Accelerated consumption or destruction of circulating white blood cells exceeds production capacity 1

Major Etiologic Categories

Medications and Drug-Induced Causes

Medications represent one of the most common reversible causes of leukopenia in clinical practice:

• Thiopurines (azathioprine, 6-mercaptopurine): Cause bone marrow toxicity including leukopenia, pancytopenia, and thrombocytopenia, occurring in approximately 3.2% of patients with inflammatory bowel disease 3
• Chemotherapy agents: Cytarabine and other myelosuppressive chemotherapy drugs predictably cause neutropenia as a dose-limiting toxicity 3
• Immunosuppressive agents: Various immunosuppressive medications can suppress bone marrow function 3

Infections

• Acute and chronic infections: Both bacterial and viral infections commonly cause transient leukopenia through increased utilization and bone marrow suppression 1, 4
• HIV infection: Causes progressive lymphopenia, particularly affecting CD4+ T-cells, with chemotherapy potentially causing sustained drops in CD4+ counts 3
• Severe infections: Community-acquired pneumonia with leukopenia (WBC <4,000 cells/mm³) is associated with excess mortality and increased risk of complications including ARDS 3

Malignancies and Bone Marrow Disorders

Primary bone marrow disorders should be suspected when leukopenia occurs with:

• Acute leukemias: Present with bone marrow infiltration causing pancytopenia, with patients often appearing acutely ill 3
• Chronic leukemias: Often diagnosed incidentally with abnormal blood counts in otherwise asymptomatic patients 5
• Myelodysplastic syndromes: Cause ineffective hematopoiesis with cytopenias 3
• Bone marrow infiltration: From metastatic malignancies or lymphomas 3

Autoimmune and Immune-Mediated Causes

• Immunoneutropenia: Antibody-mediated destruction of neutrophils 1
• Autoimmune disorders: Including Adult-Onset Still's Disease, which paradoxically can present with either leukocytosis or leukopenia depending on disease phase 3
• Inflammatory bowel disease: Associated with anemia of chronic disease and potential medication-related leukopenia 3

Nutritional Deficiencies

• Megaloblastosis: Vitamin B12 and folate deficiency impair DNA synthesis, causing ineffective hematopoiesis with macrocytosis and cytopenias 3
• Severe malnutrition: Impairs bone marrow production capacity 3

Hypersplenism

• Splenic sequestration: Enlarged spleen sequesters and destroys white blood cells, causing peripheral leukopenia despite normal or increased bone marrow production 1

Hereditary and Congenital Causes

• Primary neutropenia syndromes: Rare hereditary conditions, sometimes associated with other developmental defects, particularly in children 1
• Immuno-osseous dysplasias: Including Schimke syndrome and cartilage-hair hypoplasia, presenting with T-cell lymphopenia, growth retardation, and skeletal abnormalities 3

Critical Clinical Pitfalls

When evaluating leukopenia, always check for bi- or pancytopenia, as this usually indicates insufficient bone marrow production rather than isolated peripheral destruction. 6 A manual peripheral blood smear is essential and provides critical information about cell morphology, dysplasia, and potential causes 6.

Leukopenia with fever represents a medical emergency, particularly when absolute neutrophil count is <500 cells/mm³ (agranulocytosis). 6 These patients require immediate hospital admission and broad-spectrum antibiotics to reduce mortality 6.

In patients with inflammatory conditions, leukopenia carries particularly poor prognostic significance—in community-acquired pneumonia, WBC <4,000 cells/mm³ is consistently associated with excess mortality, ARDS, and septic shock 3. Similarly, in Adult-Onset Still's Disease, pancytopenia should prompt immediate evaluation for hemophagocytic syndrome requiring urgent immunosuppressive treatment 3.