Causes of Low White Cell Count and When to Refer to Hematology
Patients with unexplained cytopenias should be referred to hematology for evaluation. 1
Common Causes of Leukopenia
Primary Hematologic Disorders
- Myelodysplastic syndrome (MDS)
- Acute leukemia
- Aplastic anemia
- Large granular lymphocytic leukemia 2
- Bone marrow infiltration by malignant cells 1
Infections
- Viral infections (HIV, hepatitis, CMV, EBV)
- Bacterial infections (typhoid fever, tuberculosis)
- Rickettsial diseases 2
Medication-Induced
- Immunosuppressants (azathioprine)
- Antidepressants (clozapine)
- Mood stabilizers (carbamazepine) 2
- Chemotherapeutic agents
Autoimmune Causes
- Autoimmune neutropenia
- Systemic lupus erythematosus
- Rheumatoid arthritis
Other Causes
- Hypersplenism
- Nutritional deficiencies (B12, folate)
- Chronic inflammatory conditions
- Congenital disorders (rare) 3
Diagnostic Approach
Initial Evaluation
- Complete blood count (CBC) with differential
- Peripheral blood smear examination
- Reticulocyte count
- Comprehensive metabolic panel 2
Additional Testing Based on Clinical Suspicion
- Bone marrow aspiration and biopsy (if primary bone marrow disorder suspected)
- Viral studies (HIV, hepatitis, CMV, EBV)
- Autoimmune markers
- Vitamin B12 and folate levels
When to Refer to Hematology
Immediate Referral Needed
- Severe neutropenia (ANC < 500/μL) with fever
- Pancytopenia or bicytopenia
- Abnormalities in two or more cell lines 1
- Rapidly declining white cell counts
- Suspected acute leukemia or other primary bone marrow disorder
Routine Referral Recommended
- Persistent unexplained leukopenia despite discontinuation of potential causative medications
- Recurrent infections in the setting of leukopenia
- Leukopenia with associated splenomegaly or lymphadenopathy
- Leukopenia with abnormal cells on peripheral smear 2
Management Approach
General Principles
- Identify and treat underlying cause
- Discontinue suspected causative medications when possible
- Regular CBC monitoring every 2-4 weeks for patients with leukopenia 2
Specific Treatments
- For medication-induced leukopenia: discontinue offending agent and consider alternatives
- For infectious causes: appropriate antimicrobial therapy
- For severe neutropenia with fever: hospitalization and broad-spectrum antibiotics 2
- For autoimmune causes: corticosteroids (prednisone 1-2 mg/kg/day) may be considered 2
Specialized Treatments (After Hematology Referral)
- For MDS: erythropoiesis-stimulating agents, hypomethylating agents, or transfusion support
- For acute leukemia: induction chemotherapy
- For aplastic anemia: immunosuppressive therapy or stem cell transplantation 2
Clinical Pearls and Pitfalls
Pearls
- Always check previous blood counts to understand the chronicity and progression of leukopenia 4
- Examine all cell lines - concurrent abnormalities in red blood cells or platelets suggest bone marrow pathology
- Medication review is essential as drug-induced leukopenia is common and potentially reversible
Pitfalls
- Failing to recognize neutropenic fever as a medical emergency requiring immediate intervention
- Attributing leukopenia to medications without excluding other serious causes
- Overlooking chronic lymphocytic leukemia (CLL) as a cause of recurrent infections due to hypogammaglobulinemia despite normal or elevated white cell counts 1
By following this systematic approach to evaluating and managing leukopenia, clinicians can identify the underlying cause, determine appropriate timing for hematology referral, and initiate proper treatment to improve patient outcomes.