Causes of Leukopenia
Leukopenia results from either decreased production of white blood cells in the bone marrow or increased destruction/utilization in the periphery, with the most common causes being medications (especially immunosuppressives), infections, autoimmune conditions, and hematologic malignancies.
Medication-Induced Leukopenia
Immunosuppressive medications are among the most frequent culprits:
Azathioprine and 6-mercaptopurine cause bone marrow toxicity manifesting as leukopenia in approximately 3.2% of patients, occurring when 6-thioguanine accumulates in bone marrow tissue 1.
The risk is highest in patients with thiopurine methyltransferase (TPMT) deficiency, particularly those homozygous for low-activity alleles (1 in 300 people), though TPMT genotype cannot explain the majority of leukopenia cases 1.
Mycophenolate mofetil is myelosuppressive and typically causes leukopenia associated with thrombocytopenia 1.
Sirolimus demonstrates dose-dependent association with anemia and may affect white cell production 1.
Antimicrobial agents including ganciclovir and trimethoprim-sulfamethoxazole commonly cause leukopenia 1.
Drug interactions can potentiate leukopenia: sulfasalazine, mesalamine, allopurinol, cotrimoxazole, or diuretics increase the TPMT-6-TG route activity 1.
Autoimmune and Inflammatory Conditions
Autoimmunity represents a major contributor to isolated leukopenia:
In a recent study of isolated leukopenia, 53.8% of cases had autoimmune diagnosis or laboratory findings when including isolated antinuclear antibody positivity 2.
Autoimmune thyroid disease accounted for 21.8% of nonneutropenic leukopenia cases 2.
Other autoimmune/autoinflammatory diseases represented 17.3% of nonneutropenic cases and 17% of neutropenic cases 2.
Autoimmune conditions can cause immune-mediated neutropenia, particularly in infancy and early childhood 3.
Hematologic Malignancies and Bone Marrow Disorders
Primary bone marrow pathology frequently presents with leukopenia:
Hematologic malignancies (chronic and acute leukemias, non-Hodgkin's lymphoma, myelodysplastic syndromes) cause leukopenia through marrow infiltration with malignant cells or dysfunctional marrow 1.
Hematopoietic disorders accounted for 11.9% of neutropenic leukopenia cases 2.
Refractory hematologic malignancies are associated with marrow failure from the underlying disease and multiple lines of prior cytotoxic therapy 1.
Infections
Viral infections are the most common infectious cause:
Viral infections cause transient leukopenia, particularly in children, and represent the most frequent cause of temporary white blood cell reduction 3.
Cytomegalovirus (CMV) infection can present with anemia and leukopenia in transplant recipients 1.
Infections accounted for 5.5% of nonneutropenic and 6.8% of neutropenic leukopenia cases in one series 2.
Nutritional Deficiencies
Megaloblastic causes contribute to leukopenia:
Iron deficiency anemia was the most common single etiology, accounting for 21.8% of nonneutropenic and 10.2% of neutropenic leukopenia cases 2.
Vitamin B12 deficiency causes megaloblastosis leading to leukopenia 4.
Hypersplenism and Sequestration
Splenic sequestration increases peripheral destruction:
Hypersplenism causes leukopenia through increased sequestration and destruction of white blood cells 1, 4.
Moderate leukopenia is common in cirrhosis, likely due to hypersplenism, accounting for 2.7% of nonneutropenic and 1.7% of neutropenic cases 1, 2.
Radiation Therapy
Prior radiation causes lasting marrow suppression:
- Radiotherapy sequelae accounted for 1.8% of nonneutropenic and 1.7% of neutropenic leukopenia cases 2.
Primary/Congenital Neutropenia
Rare hereditary conditions present in childhood:
Primary neutropenia is very rare and sometimes hereditary, potentially associated with other developmental defects 4.
Congenital myelopathy and syndromes represent rare causes of prolonged leukopenia in children 3.
Critical Diagnostic Considerations
When evaluating leukopenia, always assess:
Check for bi- or pancytopenia, which usually implies insufficient bone marrow production and requires different diagnostic approach 5.
Review previous blood counts to assess the dynamic development of leukopenia 5.
Perform manual peripheral blood smear to evaluate for dysplasia and obtain accurate differential counts 5.
Exclude concomitant infections and malignancies as potential causes or complications 1.
Common pitfall: Isolated lymphopenia with azathioprine therapy may be due to lymphocytotoxicity from imidazole derivatives and requires dose reduction if lymphocyte count falls below 0.5 × 10⁹/L 1.