What are the causes of neutropenia (low neutrophil count)?

From the Guidelines

Neutropenia is primarily caused by a combination of congenital and acquired factors, including genetic disorders, medication-induced neutropenia, infections, autoimmune disorders, nutritional deficiencies, and bone marrow disorders, as highlighted in recent studies 1. The causes of neutropenia can be categorized into several groups, with congenital causes including genetic disorders such as severe congenital neutropenia, cyclic neutropenia, and Kostmann syndrome. Acquired causes are more common and include medication-induced neutropenia from drugs like chemotherapy agents, antibiotics (particularly beta-lactams, sulfonamides), antipsychotics, and anticonvulsants. Some key points to consider include:

• Infections can also cause neutropenia, particularly viral infections like HIV, hepatitis, influenza, and bacterial infections causing overwhelming sepsis.
• Autoimmune disorders such as lupus, rheumatoid arthritis, and Felty syndrome may lead to neutropenia through immune-mediated destruction of neutrophils.
• Nutritional deficiencies, particularly vitamin B12 and folate deficiency, can impair neutrophil production.
• Bone marrow disorders including leukemia, myelodysplastic syndromes, and aplastic anemia often present with neutropenia due to disrupted blood cell production.
• Splenic sequestration in conditions with enlarged spleens can trap neutrophils, reducing their circulation. According to a recent study published in 2024 1, severe congenital neutropenia (SCN) is a rare disorder that usually presents in infancy with absolute neutrophil counts <0.5 × 10^9/L, accompanied by recurrent life-threatening infections, and has an increased risk of MDS/AML. Management of neutropenia depends on identifying and treating the underlying cause while preventing infections through proper hygiene and sometimes prophylactic antibiotics or granulocyte colony-stimulating factors in severe cases, as recommended by recent guidelines 1.

From the FDA Drug Label

Clozapine can cause neutropenia (a low absolute neutrophil count (ANC)), defined as a reduction below pre-treatment normal levels of blood neutrophils. Severe neutropenia, ANC less than (<) 500/μL, occurs in a small percentage of patients taking clozapine and is associated with an increase in the risk of serious and potentially fatal infections. The mechanism by which clozapine causes neutropenia is unknown and is not dose-dependent

• Causes of neutropenia associated with clozapine use include:
  • Unknown mechanisms
  • Reduction below pre-treatment normal levels of blood neutrophils
• Risk factors for neutropenia:
  • Greatest during the first 18 weeks on treatment
  • Patients with baseline neutropenia
• Monitoring and management:
  • Obtain a CBC, including the ANC value, prior to initiating treatment with clozapine
  • Weekly ANC monitoring is required for all patients during the first 6 months of treatment
  • Reduce monitoring frequency based on ANC levels and treatment duration 2, 2, 2

From the Research

Causes of Neutropenia

• Neutropenia can be categorized into two types: congenital and acquired 3, 4
• Congenital severe chronic neutropenia (SCN) arises from mutations in various genes, with different inheritance patterns, including autosomal recessive, autosomal dominant, and X-linked forms 3
• The most common genetic cause of congenital neutropenia is alterations in the ELANE gene, which encodes neutrophil elastase 3, 5, 6
• Other genetic causes of congenital neutropenia include mutations in the HAX1 gene, which contributes to the activation of the granulocyte colony-stimulating factor (G-CSF) signalling pathway 6
• Acquired neutropenia can be caused by various factors, including viral infections, autoimmune disorders, and certain medications 4, 7

Types of Congenital Neutropenia

• Severe congenital neutropenia (SCN) is a rare hematological disorder characterized by severe neutropenia and recurrent infections 3, 5, 6
• Cyclic neutropenia (CyN) is a rare disorder characterized by periodic episodes of neutropenia and recurrent infections 3
• Other forms of congenital neutropenia include Shwachman-Diamond syndrome, glycogen storage disease type Ib, and WHIM syndrome 3, 4

Risk Factors and Complications

• Neutropenia can lead to life-threatening infections, particularly in patients with severe neutropenia 3, 4, 7
• Patients with congenital neutropenia are at increased risk of developing acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) 3, 5, 6
• Long-term treatment with G-CSF may increase the risk of leukemia in patients with congenital neutropenia 3, 4, 5