Causes of Aplastic Anemia
Aplastic anemia results from three primary mechanisms: immune-mediated destruction of hematopoietic stem cells (most common in acquired cases), direct bone marrow injury from toxins/drugs/radiation, and inherited bone marrow failure syndromes. 1, 2
Immune-Mediated Causes (Most Common in Acquired Cases)
The majority of acquired aplastic anemia cases are immune-mediated, where autoreactive cytotoxic T lymphocytes destroy hematopoietic stem cells. 2, 3 This aberrant immune response is triggered by:
- Environmental exposures (drugs, viruses, toxins) that initiate the autoimmune process, though most cases remain idiopathic despite thorough investigation 2
- Type 1 cytotoxic T cells that directly attack bone marrow progenitor cells through dysregulated activation pathways 3
Drug and Chemical Exposures
Numerous medications and chemicals can cause aplastic anemia through direct marrow toxicity: 4
- Benzene exposure (most common chemical cause, accounting for 23% of identifiable cases in one series) 4
- Chloramphenicol and thiamphenicol (antibiotic-induced marrow suppression) 4
- Antirheumatic drugs (NSAIDs and disease-modifying agents) 4
- Antituberculous medications 4
- Sulfonamides 4
- Insecticides and other environmental toxins 4
- Immune checkpoint inhibitors (rare but increasingly recognized cause) 5
Infectious Causes
Viral infections can trigger aplastic anemia through direct marrow suppression or immune activation: 5
- Parvovirus B19 (targets erythroid progenitor cells, causing transient aplastic crisis) 5
- Hepatitis viruses (non-A, non-B, non-C hepatitis associated with subsequent marrow failure) 2, 4
- Cytomegalovirus, toxoplasmosis, coxsackie virus (rare causes) 5
Inherited Bone Marrow Failure Syndromes
Genetic disorders cause aplastic anemia through intrinsic stem cell defects: 1, 2
- Telomere repair gene mutations (increasingly recognized through next-generation sequencing) 1, 3
- Fanconi anemia (DNA repair defect) 1
- Dyskeratosis congenita (telomerase deficiency) 1
- Other inherited marrow failure syndromes with variable penetrance 1
Radiation Exposure
Ionizing radiation causes direct DNA damage to rapidly dividing hematopoietic stem cells, leading to dose-dependent marrow aplasia. 6 This includes therapeutic radiation and accidental exposures.
Idiopathic Cases
Despite comprehensive evaluation, 50-70% of aplastic anemia cases remain idiopathic with no identifiable trigger. 2, 3 These likely represent immune-mediated disease where the inciting antigen or exposure cannot be determined.
Important Clinical Pitfall
The degree of bone marrow cellularity on biopsy does not always correlate with functional capacity - some patients have normocellular or even hypercellular marrows despite pancytopenia, requiring careful morphologic assessment and exclusion of myelodysplastic syndrome or hypocellular acute myeloid leukemia. 5, 4 A low reticulocyte index (<1.0-2.0) confirms decreased RBC production and helps distinguish aplastic anemia from hemolytic processes. 5