What are the causes of leukopenia (low white blood cell count)?

From the Guidelines

Leukopenia is most commonly caused by viral infections, bacterial infections, certain medications, autoimmune disorders, bone marrow disorders, nutritional deficiencies, radiation exposure, and congenital disorders. The causes of leukopenia can be broadly categorized into several groups.

• Viral infections such as influenza, HIV, hepatitis, and COVID-19 can temporarily suppress bone marrow function, leading to leukopenia 1.
• Bacterial infections like typhoid fever and tuberculosis may also cause leukopenia.
• Certain medications, including chemotherapy drugs, antibiotics (chloramphenicol, sulfonamides), antipsychotics (clozapine), immunosuppressants (methotrexate, mycophenolate), and some anticonvulsants, frequently cause this condition.
• Autoimmune disorders like lupus and rheumatoid arthritis can attack white blood cells or their precursors, leading to leukopenia.
• Bone marrow disorders such as aplastic anemia, myelodysplastic syndromes, and leukemia can paradoxically cause leukopenia by disrupting normal blood cell production.
• Nutritional deficiencies, particularly vitamin B12, folate, and copper, can impair white blood cell production.
• Radiation exposure, whether therapeutic or accidental, damages bone marrow stem cells, leading to leukopenia.
• Congenital disorders like Kostmann syndrome and cyclic neutropenia represent rare genetic causes of leukopenia. Management of leukopenia depends on identifying and treating the underlying cause, which may involve discontinuing offending medications, treating infections, or addressing nutritional deficiencies 1. In patients with leukemia, management of cytopenias is crucial, and dose adjustments of tyrosine kinase inhibitors (TKIs) may be necessary to minimize hematopoietic toxicity 1. Overall, a comprehensive approach to diagnosing and managing leukopenia is essential to improve patient outcomes.

From the FDA Drug Label

To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis 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 Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased

Causes of leukopenia associated with clozapine use include:

• Unknown mechanism, not dose-dependent 2
• Clozapine use, with risk greatest during the first 18 weeks of treatment 2
• Possible concomitant use of other medications that may increase the risk of leukopenia, such as CYP1A2, CYP2D6, or CYP3A4 inhibitors 2 Note that the exact cause of leukopenia in patients taking clozapine is not fully understood and may involve multiple factors.

From the Research

Causes of Leukopenia

• Leukopenia is an abnormal reduction of circulating white blood cells, especially the granulocytes, and may result from reduced production of white blood cells or increased utilization and destruction, or both 3.
• Infection, drugs, malignancy, megaloblastosis, hypersplenism, and immunoneutropenia are responsible for most cases of neutropenia, a condition often used interchangeably with leukopenia 3.
• Extrinsic causes of chronic neutropenia can be varied, while intrinsic causes can include impaired proliferation and maturation of myeloid progenitor cells in the bone marrow 4.
• Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction, with drugs such as dipyrone, diclofenac, and ticlopidine commonly associated with neutropenia or agranulocytosis 5.
• Chemotherapy is also a common cause of leukopenia, with chemotherapy-induced leukopenia being a predictor of efficacy and associated with the survival of small-cell lung cancer patients 6.
• Anticonvulsant drugs, such as carbamazepine, phenytoin, and valproic acid, can also cause hematological disorders, including neutropenia, with careful hematological monitoring needed to prevent potentially fatal complications 7.

Types of Leukopenia

• Primary neutropenia is very rare and can be hereditary, especially in children, and may be associated with other developmental defects 3.
• Chronic neutropenia can be further described as extrinsic or intrinsic, with extrinsic causes being varied and intrinsic causes including impaired proliferation and maturation of myeloid progenitor cells in the bone marrow 4.
• Neutropenia can be classified as transient or chronic, with chronic neutropenia being a more serious condition that requires careful management and treatment 4.

Risk Factors

• Patients with neutropenia are at risk of developing life-threatening bacterial infections, with febrile neutropenia being a serious complication that requires systematic assessment and treatment with antibiotics 4.
• The risk of febrile neutropenia should be assessed systematically in neutropenic patients, with treatment aimed at managing the underlying cause of neutropenia 4.
• Severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs can range from approximately 1.6 to 15.4 cases per million population per year, with certain drugs being more commonly associated with neutropenia or agranulocytosis 5.