Causes of Chronically Low White Blood Cell Count (Leukopenia)
Chronically low WBC count results from either decreased production in the bone marrow, increased destruction/utilization of white cells, or sequestration, with the most common causes being medications, autoimmune disorders, infections (particularly viral), nutritional deficiencies, bone marrow disorders, and hypersplenism. 1
Primary Mechanisms and Major Categories
Leukopenia typically reflects neutropenia since neutrophils comprise 50-70% of circulating leukocytes, with neutropenia defined as an absolute neutrophil count (ANC) <1,500/mcL. 2 The underlying pathophysiology involves:
Decreased Production:
- Bone marrow disorders: Myelodysplastic syndromes, leukemias, aplastic anemia, megaloblastic anemia (B12/folate deficiency), and bone marrow fibrosis 3, 1
- Medications: Chemotherapy agents, immunosuppressive drugs, and various other medications that suppress bone marrow function 1, 2
- Nutritional deficiencies: Megaloblastosis from vitamin B12 or folate deficiency 1
- Impaired proliferation and maturation of myeloid progenitor cells in the bone marrow 2
Increased Destruction/Utilization:
- Autoimmune disorders: Systemic lupus erythematosus (SLE) with leukopenia prevalence of 22-41.8%, lymphopenia in 15-82%, and neutropenia in 20-40% of patients 4
- Infections: Particularly viral infections (HIV, HCV, CMV) and other chronic infections 3, 1
- Hypersplenism: Sequestration and destruction of white cells in an enlarged spleen 1
- Immunoneutropenia: Antibody-mediated destruction 1
Malignancy-Related:
- Lymphoproliferative disorders: Chronic lymphocytic leukemia (CLL) can paradoxically present with cytopenias due to marrow infiltration or autoimmune destruction 3
- Other hematologic malignancies with bone marrow involvement 3, 1
Critical Diagnostic Considerations
Always check previous blood counts to assess the dynamic development and chronicity of leukopenia, as this distinguishes acute from chronic processes. 5
Evaluate for bi- or pancytopenia, which usually implies insufficient bone marrow production and necessitates bone marrow examination. 5 A manual peripheral blood smear is essential and provides information on:
- Cell counts of individual leukocyte subgroups 5
- Dysplastic features suggesting myelodysplasia 5
- Abnormal cell morphology (schistocytes, inclusion bodies) 3
Specific Clinical Contexts
Autoimmune Cytopenias:
In CLL and other lymphoproliferative disorders, autoimmune hemolytic anemia (AIHA) or immune thrombocytopenic purpura (ITP) can cause cytopenias independent of marrow infiltration. 3 The Binet and Rai staging systems do not distinguish between autoimmune versus marrow infiltration as the cause of cytopenias. 3
Drug-Induced:
NSAIDs and other medications can contribute to cytopenias, particularly in patients with underlying conditions like Adult-Onset Still's Disease (AOSD). 3 Always obtain a comprehensive medication history including prescription, non-prescription drugs, and environmental toxin exposure. 3
Infection Risk:
The major danger of neutropenia is infection risk. 1 In SLE patients, while overall leukopenia may not significantly increase infection risk, low lymphocyte and neutrophil counts show strong association with major infections. 4 Patients with ANC <500/mcL are at highest risk for life-threatening bacterial infections. 2
Common Pitfalls
- Missing hereditary causes: Primary neutropenia, though rare, can be hereditary and associated with developmental defects, particularly in children 1
- Overlooking secondary causes: Always exclude infections, liver disease, alcoholism, recent transfusions, and recent vaccinations 3
- Ignoring constitutional symptoms: Fever, weight loss, hepatomegaly, or lymphadenopathy suggest underlying systemic disease (HIV, SLE, lymphoproliferative disorders) rather than isolated leukopenia 3
- Failing to assess splenomegaly: Moderate to massive splenomegaly suggests alternative diagnoses beyond simple leukopenia 3
Management Priorities
Febrile neutropenia (fever with ANC <500/mcL) is a medical emergency requiring immediate hospital admission and broad-spectrum antibiotics to reduce mortality. 5, 2 For chronic stable leukopenia, management focuses on identifying and treating the underlying cause rather than the leukopenia itself. 1, 2