Definition of Agranulocytosis
Agranulocytosis is defined as a severe decrease in granulocytes (neutrophils) in peripheral blood, specifically with an absolute neutrophil count (ANC) below 0.5 × 10⁹/L. 1, 2
Key Diagnostic Thresholds
- Granulocytopenia: Decrease of peripheral blood granulocytes below the lower limit of normal range 2
- Agranulocytosis: The severe form, characterized by granulocyte count < 0.5 × 10⁹/L 2
- Febrile neutropenia: When agranulocytosis (ANC <0.5×10⁹/L) occurs with fever ≥38.3°C (101°F) or sustained temperature ≥38.0°C (100.4°F) over one hour 1
Clinical Significance
Agranulocytosis represents a potentially life-threatening condition that occurs in approximately 0.2% to 0.5% of patients exposed to certain medications, particularly propylthiouracil 3. The disorder carries significant mortality risk, with approximately 5-10% of cases being fatal despite appropriate management 4. Patients with severe agranulocytosis (< 0.5 × 10⁹/L) are at high risk for severe infections and sepsis 1, 2.
Pathophysiology
The condition results from two primary mechanisms 5:
- Direct toxicity to the myeloid cell line
- Immune-mediated destruction of granulocytes, with drug-related antibodies responsible for neutropenia in the "immune type" of agranulocytosis 6
Common Causative Agents
Medications most frequently associated with agranulocytosis include 5, 4:
- Clozapine (approximately 1% incidence) 7
- Propylthiouracil (0.2-0.5% incidence) 3
- Methimazole 7
- Trimethoprim-sulfamethoxazole 5
- Antibacterials, antiplatelet agents, antithyroid drugs, antipsychotics, antiepileptics, and NSAIDs 4
Clinical Presentation
Patients may be completely asymptomatic at the time of discovery or present with severe sepsis. 4 The severity of neutropenia typically correlates with infection risk—patients with > 0.5 × 10⁹/L granulocytes usually remain asymptomatic unless they have concomitant immunodeficiency 2. Warning signs requiring immediate intervention include fever, sore throat, hypotension (systolic BP <90 mmHg), respiratory distress, and hypoxemia 1, 3.
Critical Timing
Agranulocytosis typically occurs within the first 3 months of therapy with offending medications 3. For clozapine specifically, weekly white blood cell count monitoring is required during the first 6 months, then every 2 weeks thereafter 7.