What causes leucopenia?

Causes of Leucopenia

Leucopenia results from either decreased production of white blood cells in the bone marrow, increased destruction or utilization, or both, with medications (especially chemotherapy and immunosuppressants), infections, hematologic malignancies, and autoimmune processes being the primary culprits. 1, 2

Medication-Related Causes

Chemotherapy and Immunosuppressive Agents

• Chemotherapy agents are the most common cause of leucopenia through direct bone marrow suppression. 2
• Azathioprine and 6-mercaptopurine cause bone marrow toxicity with leucopenia occurring in approximately 3.2% of patients overall, with severe leucopenia (WBC <2,500 cells/mm³) in 5.3% of rheumatoid arthritis patients and 16% of renal transplant recipients. 1
• Patients with thiopurine methyltransferase (TPMT) deficiency or NUDT15 deficiency face dramatically increased risk for severe, life-threatening myelosuppression because 6-thioguanine accumulates in bone marrow tissue. 1

Critical Caveat About TPMT Testing

• Normal TPMT testing does NOT exclude risk of leucopenia—only 27% of leucopenia cases are explained by common TPMT variants, meaning the majority of cases occur despite normal enzyme activity. 1
• TPMT enzyme activity measurement becomes unreliable after blood transfusions and with certain drug interactions. 1
• Profound leucopenia can develop suddenly and unpredictably between blood tests, occurring in around 3% of patients on thiopurines. 3

Other Medications

• Penicillin and cephalosporin antibiotics cause leucopenia in 76% of cases when doses exceed 150 mg/kg/day, particularly when administered for two or more weeks. 4
• Immune checkpoint inhibitors can induce hematologic immune-related adverse events including leucopenia. 1

Malignancy-Related Causes

Hematologic Malignancies

• Chronic lymphocytic leukemia (CLL), acute leukemias, and non-Hodgkin's lymphoma cause leucopenia through bone marrow infiltration or immune-mediated mechanisms. 1, 2
• In CLL, autoimmune mechanisms can cause cytopenias, with autoimmune granulocytopenia being less common than hemolytic anemia or thrombocytopenia. 1
• Myelodysplastic syndromes impair normal blood cell production in the bone marrow. 1
• Aplastic anemia causes pancytopenia including leucopenia. 1

Infection-Related Causes

• Viral infections, particularly HIV and HCV, commonly cause leucopenia. 1
• Cytomegalovirus infection can lead to cytopenias including leucopenia. 1
• Bacterial infections, especially severe sepsis, can cause leucopenia. 2
• Leucopenia from community-acquired pneumonia (WBC <4,000 cells/mm³) is consistently associated with excess mortality and increased risk of acute respiratory distress syndrome. 1

Other Important Causes

Autoimmune and Immune-Mediated

• Autoimmune disorders can cause leucopenia through immune-mediated destruction of white blood cells. 1
• Post-transplant immunosuppression can cause leucopenia. 1
• Graft failure after allogeneic transplantation results in severe leucopenia with mortality up to 80%. 1

Bone Marrow Disorders

• Bone marrow diseases including fibrosis and other malignancies can cause leucopenia. 1
• Megaloblastosis and hypersplenism are responsible for some cases. 5

Environmental and Toxic Exposures

• Various prescription and non-prescription drugs, as well as environmental toxins, can cause leucopenia. 1

Clinical Significance and Risk Stratification

The risk of infection increases dramatically when neutrophil counts fall below 500/mcL, with the highest risk (10-20%) occurring at counts below 100/mcL. 1, 2

• Approximately 50-60% of patients who become febrile during neutropenia have an established or occult infection. 2
• Leucopenia occurring in bacteremic pneumococcal disease and gram-negative community-acquired pneumonia carries particularly high mortality risk. 1
• In patients with alcohol abuse history, adverse manifestations of septic shock and ARDS may be delayed or masked when leucopenia is present, requiring ICU monitoring. 1

Diagnostic Approach

Examine the peripheral blood smear to determine which white blood cell lines are affected and look for morphological abnormalities such as dysplasia. 1, 6

• Check previous blood counts to assess the dynamic development of leucopenia. 6
• Evaluate red blood cell count and platelet count—bi- or pancytopenia usually implies insufficient bone marrow production. 6
• Consider bone marrow examination in patients with unexplained persistent leucopenia, especially in older adults. 1
• Exclude EDTA-dependent platelet agglutination, which can cause pseudo-thrombocytopenia. 1