What causes neutropenia?

What Causes Neutropenia

Neutropenia results from three primary mechanisms: decreased neutrophil production in the bone marrow, increased peripheral destruction or utilization, and abnormal distribution or sequestration of neutrophils. 1, 2

Primary Etiologic Categories

Decreased Production (Most Common in Clinical Practice)

• Myelosuppressive chemotherapy is the single most common cause of clinically significant neutropenia, particularly leading to febrile episodes requiring urgent intervention 3, 4
• The severity depends on specific chemotherapy agents, with high-risk regimens (lenalidomide plus alkylating agents or doxorubicin) causing neutropenia rates exceeding 50% 5
• Bone marrow infiltration by malignancy directly impairs neutrophil production 4
• Congenital neutropenia syndromes result from genetic mutations affecting neutrophil development, including mutations in ELANE, HAX1, and SBDS genes 1
• Nutritional deficiencies can impair bone marrow production of neutrophils 1

Increased Destruction or Utilization

• Drug-induced neutropenia through immune-mediated mechanisms represents a significant cause, occurring as an idiosyncratic reaction to various medications 6, 2
• Autoimmune disorders cause antibody-mediated destruction of neutrophils 1, 2
• Infections themselves can cause neutropenia through rapid utilization and consumption of neutrophils, creating a vicious cycle where bacterial, viral, and fungal pathogens both cause and complicate neutropenia 4, 6
• Acute neutropenia evolves over days when neutrophil use is rapid and production cannot compensate 7

Abnormal Distribution

• Excessive splenic sequestration removes neutrophils from circulation 7
• Compartmental shifts of neutrophils away from circulating blood can create apparent neutropenia 5

Specific Infectious Agents That Cause Neutropenia

While infections are both a cause and consequence of neutropenia, certain pathogens directly suppress neutrophil production:

• Bacterial infections can directly cause neutropenia through bone marrow suppression 4
• Viral infections, including HSV, RSV, parainfluenza, influenza A and B, and VZV, can suppress neutrophil production 8
• Fungal infections may contribute to neutropenia, though they more commonly occur as a consequence rather than cause 4

Clinical Context and Risk Stratification

Duration matters critically: Prolonged neutropenia exceeding 10 days significantly amplifies infection risk and suggests an underlying production defect rather than transient consumption 3

• Baseline ANC <1000 cells/µL before treatment initiation identifies patients at higher risk for severe neutropenia 5
• Patient characteristics including disease stage and previous treatment history modify risk 5
• Chronic neutropenia lasting 3 months or longer indicates reduced production, increased destruction, or excessive sequestration requiring thorough investigation 7

Important Mechanistic Distinctions

• Acute-onset neutropenia (days) typically reflects infection, antibody-mediated destruction, or idiosyncratic drug reactions 2
• Chronic neutropenia (months) suggests intrinsic defects in myeloid progenitor cells, acquired disorders of bone marrow, or secondary causes from systemic disease 7
• Severe congenital neutropenia involves genetic defects affecting membrane structures, secretory vesicles, mitochondrial metabolism, ribosome biogenesis, transcriptional regulation, and cytoskeletal dynamics 7

Critical Pitfall to Avoid

Do not assume neutropenia is solely a consequence of treatment or infection—it may be the primary hematologic disorder requiring investigation, particularly when neutropenia persists beyond expected recovery periods or occurs without obvious precipitating factors 7. Patients with intrinsic neutrophil production defects carry increased risk for progression to myelodysplasia and acute myeloid leukemia 1, 7.