What causes a drop in White Blood Cell (WBC) count?

Causes of Decreased White Blood Cell Count

A drop in WBC count results from either decreased production in the bone marrow, increased destruction/consumption of white blood cells, or sequestration in tissues—with medications (particularly chemotherapy and immunosuppressants), infections, autoimmune conditions, and primary bone marrow disorders being the most common culprits.

Medication-Induced Leukopenia

Chemotherapy and Immunosuppressive Agents

• Cytotoxic chemotherapy is the most common iatrogenic cause of leukopenia, with dose-dependent myelosuppression occurring predictably after treatment 1
• Azathioprine and cyclophosphamide should be stopped or reduced by 50% if WBC drops below 4,000/mm³ or platelets fall below 100,000/mm³, with weekly monitoring until recovery 1
• Clozapine carries significant risk of agranulocytosis and requires extensive monitoring protocols 1:
  • Baseline WBC must be ≥3,500/mm³ before initiating therapy
  • Weekly blood counts for first 6 months, then biweekly thereafter
  • Immediate discontinuation required if WBC drops below 2,000/mm³ or absolute neutrophil count (ANC) below 1,000/mm³
  • Stop medication if WBC 2,000-3,000/mm³ or ANC 1,000-1,500/mm³, with daily monitoring for infection

Other Medications

• Carbamazepine and other medications with bone marrow suppression potential should be avoided when using agents like clozapine 1
• Corticosteroids paradoxically can cause leukocytosis rather than leukopenia 2

Infectious Causes

Viral Infections

• Viral respiratory infections typically cause lower WBC and granulocyte counts compared to bacterial infections 3
• Certain viral infections can directly suppress bone marrow production or increase peripheral consumption of white blood cells 3

Bacterial Infections

• Overwhelming sepsis can paradoxically cause leukopenia through consumption, though most bacterial infections cause leukocytosis 2, 3
• Bacterial infections with high WBC and granulocyte counts (>15.0-20.0 × 10⁹/L) have 86-95% specificity for bacterial etiology 3

Hematologic Malignancies

Acute Leukemias

• Acute promyelocytic leukemia (APL) often presents with low WBC counts (≤10 × 10⁹/L) at diagnosis 1
• Patients with low WBC at presentation may delay chemotherapy until genetic confirmation, though ATRA should be started immediately upon suspicion 1
• Primary bone marrow disorders should be suspected with extremely elevated or depressed WBC counts, especially with concurrent red blood cell or platelet abnormalities 2

Bone Marrow Infiltration

• Weight loss, bleeding, bruising, hepatosplenomegaly, lymphadenopathy, and immunosuppression increase suspicion for marrow disorders 2

Autoimmune and Immune-Mediated Causes

• Autoimmune destruction of white blood cells can occur through antibody-mediated mechanisms
• Drug-induced immune reactions may cause selective destruction of leukocytes 1

Technical and Artifactual Causes

Laboratory Artifacts

• In vitro leukoagglutination can cause spuriously low WBC counts on automated analyzers 4
• This phenomenon may be temperature-dependent or anticoagulant-dependent 4
• Blood smear examination is mandatory when leukoneutropenia is detected to rule out aggregation artifact 4

Clinical Context and Risk Stratification

High-Risk Scenarios Requiring Immediate Action

• WBC <2,000/mm³ or ANC <1,000/mm³ requires immediate medication discontinuation and daily monitoring for infection 1
• Febrile neutropenia represents a medical emergency requiring blood cultures before antibiotics and infectious disease consultation 1, 5
• WBC >100,000/mm³ paradoxically represents emergency due to brain infarction and hemorrhage risk 2

Monitoring Recommendations

• Patients on chemotherapy or immunosuppressants require regular CBC monitoring, with frequency based on agent and risk profile 1
• Avoid invasive procedures (central lines, lumbar puncture, bronchoscopy) during active neutropenia due to hemorrhagic complications 1, 5

Common Pitfalls

• Do not assume all low WBC counts are real—always verify with blood smear to exclude leukoagglutination 4
• Do not continue myelosuppressive medications when WBC drops below critical thresholds without dose adjustment 1
• Do not delay ATRA in suspected APL while awaiting genetic confirmation if clinical suspicion is high 1
• Concurrent medications that lower blood counts should be identified and avoided when possible 1