Causes of Low White Blood Cell Count (Leukopenia)
Low WBC counts result primarily from chemotherapy-induced bone marrow suppression, overwhelming infections causing increased WBC destruction, hematologic malignancies, or primary bone marrow disorders. 1
Primary Mechanisms and Etiologies
Leukopenia develops through two fundamental pathways: decreased production or increased destruction/utilization of white blood cells 2. Understanding which mechanism predominates guides diagnostic and therapeutic decisions.
Decreased Production Causes
Chemotherapy and myelosuppressive drugs represent the most frequent iatrogenic cause through direct bone marrow suppression affecting granulocyte production 1. This includes:
- Cytotoxic chemotherapy agents causing transient cytopenias due to delayed recovery of normal hematopoiesis 3
- Anti-tuberculosis drugs (rifampicin and isoniazid) with incidence rates of 1.2% in men and 5.9% in women 4
- Other marrow-toxic medications including immunosuppressants 1
Bone marrow disorders causing ineffective hematopoiesis include:
- Myelodysplastic syndromes presenting with stable cytopenia lasting ≥6 months (or 2 months with specific karyotype abnormalities) 1
- Leukemias and lymphomas paradoxically presenting with leukopenia despite being proliferative disorders 1
- Aplastic anemia causing pancytopenia 3
Nutritional deficiencies affecting production:
- Vitamin B12 or folate deficiency causing megaloblastic changes with macrocytic anemia and leukopenia 3
Increased Destruction/Utilization Causes
Bacterial infections, especially overwhelming sepsis, cause leukopenia through increased WBC utilization and destruction rather than decreased production 1. This represents a critical diagnostic consideration as it requires immediate intervention.
Hypersplenism causes sequestration and destruction of circulating white blood cells 2.
Immunoneutropenia from autoimmune destruction of neutrophils 2.
Primary Immunodeficiency Disorders
Primary immunodeficiency syndromes present with various patterns of leukopenia 3:
- Wiskott-Aldrich syndrome with T-cell lymphopenia and neutropenia variants 1
- X-linked neutropenia from gain-of-function WAS mutations presenting as isolated neutropenia 1
- Severe combined immunodeficiency (SCID) with profound lymphopenia 3
Critical Diagnostic Approach
A complete blood count with differential is essential to characterize which specific WBC lineage is affected and identify other cytopenias 1. This distinguishes isolated neutropenia from pancytopenia, fundamentally altering the differential diagnosis.
Peripheral blood smear review is necessary to assess for dysplasia, blast cells, and abnormal cell morphology 1. Manual differential counting provides information on potential causes including dysplasia 5.
Medication history focusing on chemotherapy, immunosuppressants, and marrow-toxic drugs is crucial 1. Review all medications including recent additions.
Check previous blood counts to assess the dynamic development of leukopenia—acute versus chronic onset dramatically changes the differential 5.
Infectious workup including blood cultures is necessary if fever or sepsis is suspected 1. This takes priority in febrile patients.
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.
Management Priorities
Febrile neutropenia (temperature >38.5°C with absolute neutrophil count <0.5 × 10⁹/L) requires immediate empiric broad-spectrum antibiotics before culture results 1. This represents a medical emergency with significant mortality risk if untreated 5.
The major danger of neutropenia is overwhelming infection risk, which increases dramatically when neutrophil count falls below 100/µL 1, 2. Mortality increases substantially without prompt antimicrobial therapy 2.
Granulocyte colony-stimulating factor (G-CSF) should be considered in patients with fever and neutropenia who have high-risk features including 3:
- Expected prolonged (≥10 days) and profound (≤0.1 × 10⁹/L) neutropenia
- Age >65 years
- Pneumonia, hypotension, multiorgan dysfunction
- Invasive fungal infection
However, G-CSF is contraindicated during chest radiotherapy 1.
Prophylactic antimicrobials should be considered for prolonged neutropenia based on institutional protocols 1.
For drug-induced leukopenia, chemotherapy may continue in most cases as WBC counts often recover spontaneously or stabilize during treatment 4. However, progressive decline mandates drug discontinuation 4.
Dose adjustments of chemotherapy may be necessary in patients with prolonged or severe treatment-induced neutropenia 1.
Common Pitfalls
Do not routinely use CSFs for afebrile neutropenic patients 3. Reserve for high-risk situations only.
Bi- or pancytopenia usually implies insufficient bone marrow production rather than isolated peripheral destruction, requiring bone marrow evaluation 5.
Patients with pre-treatment WBC counts between 3,000-4,000/mm³ are at higher risk for developing significant leukopenia during chemotherapy 4.