What is agranulocytosis?

What is Agranulocytosis

Agranulocytosis is a severe, life-threatening hematologic condition defined by an absolute neutrophil count below 0.5 × 10⁹/L (500 cells/μL), leaving patients critically vulnerable to overwhelming bacterial and fungal infections that can rapidly progress to sepsis and death. 1, 2

Definition and Clinical Significance

• Agranulocytosis represents the most severe form of neutropenia, specifically characterized by profound depletion of granulocytes (primarily neutrophils) in the peripheral blood 2, 3
• The condition carries a mortality rate of approximately 5% even with modern management, primarily due to severe infections including deep tissue infections, septicemia, and septic shock 3, 4
• Drugs account for 20-40% of all instances of cytopenias, making drug-induced agranulocytosis a critical adverse effect to recognize 3

Pathophysiology

Mechanisms of Development

• Idiosyncratic (Type B) reactions are the most common mechanism, characterized by unpredictable, "bizarre" hypersensitivity reactions unrelated to dose 2, 5
• Direct toxic effects on myeloid precursor cells in the bone marrow, causing suppression of neutrophil production 2, 4
• Immune-mediated destruction where chemically reactive drugs or their metabolites bind to proteins and trigger antibody formation against neutrophils and their precursors 2, 4
• Genetic factors play an important role, with recent identification of major susceptibility loci that may enable genomic-era diagnosis 6

Important Distinction

Unlike predictable agranulocytosis from cytotoxic chemotherapy agents, idiosyncratic drug-induced agranulocytosis is characterized by poor predictability and generally low incidence, making it particularly dangerous in routine clinical practice 2

Clinical Presentation

Cardinal Warning Signs

• Fever and sore throat are the hallmark early warning signs that should trigger immediate evaluation 1, 6
• Flu-like symptoms including generalized weakness and malaise are common initial manifestations 1
• Patients may present with signs of active infection or sepsis at diagnosis 3, 6
• Some patients are completely asymptomatic at the time neutropenia is discovered on routine laboratory testing 4

Common Causative Medications

• Methimazole and propylthiouracil (antithyroid drugs) are among the most frequently implicated agents 1, 4, 6
• Clozapine (antipsychotic) has well-established association requiring routine monitoring 4
• Trimethoprim-sulfamethoxazole (antibiotic) is commonly associated with agranulocytosis 4
• Several hundred drugs, toxins, and herbs have been reported to cause this condition 3

Diagnostic Approach

Laboratory Confirmation

• Absolute neutrophil count (ANC) below 0.5 × 10⁹/L establishes the diagnosis in the presence of a potentially causative drug 1, 6
• Complete blood count should be obtained immediately when warning symptoms develop 1
• Thrombocytopenia may coexist with agranulocytosis in some drug reactions 1

Critical Pitfall

Clinical suspicion must be high because the condition can progress rapidly to life-threatening sepsis within hours, particularly with gram-negative bacterial infections 7

Management Principles

Immediate Actions

• Discontinue the offending medication immediately to prevent further myeloid damage—this is the single most critical intervention 4, 6
• Initiate broad-spectrum antibiotics empirically for any febrile patient, even before culture results, as gram-negative bacteremia can be rapidly fatal 7, 3
• Consider isolation precautions during severe neutropenia to reduce infection exposure 5

Adjunctive Therapy

• Granulocyte colony-stimulating factor (G-CSF) should be considered in high-risk patients, though its role is not definitively established and must be individualized 3, 4
• Granulocyte transfusions have uncertain benefit and are not routinely recommended, but may be considered in refractory cases 5

Expected Course

• Agranulocytosis is usually self-limiting once the toxic drug is withdrawn, with complete resolution typically occurring within two weeks 5
• However, mortality during the acute phase remains high (approximately 5%), making aggressive supportive care mandatory 3, 4

Definitive Management

For conditions like hyperthyroidism where agranulocytosis occurred during antithyroid drug therapy, patients will require alternative definitive treatment such as radioactive iodine ablation or thyroidectomy once recovered 6

Prevention Strategy

Patient education is the most effective way to reduce mortality from drug-induced agranulocytosis, emphasizing the need to immediately report fever, sore throat, or other signs of infection during treatment with high-risk medications 6