What is aplastic anemia?

Aplastic Anemia: Diagnosis and Clinical Features

Aplastic anemia is a rare, life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and a hypocellular bone marrow (<20% cellularity) in the absence of significant dysplasia or abnormal cell clusters. 1

Pathophysiology

Aplastic anemia results from immune-mediated destruction of early hematopoietic cells by cytotoxic T lymphocytes. This leads to:

• Severe reduction in hematopoietic stem cells
• Failure of blood cell production across all lineages
• Replacement of bone marrow with fat cells
• Peripheral blood pancytopenia

Diagnostic Criteria

Diagnosis requires a comprehensive evaluation with specific findings:

Peripheral Blood Evaluation

• Pancytopenia (reduction in all blood cell lines)
• Absence of blasts
• Minimal or absent dysplasia in granulocytes
• Low reticulocyte count
• Count at least 100 cells on peripheral blood film 1

Bone Marrow Assessment

• Bone marrow biopsy is critical and necessary for diagnosis 1
• Hypocellular marrow (<20% cellularity, age-adjusted)
• Absence of abnormal localization of immature precursors (ALIP)
• Absence of significant dysplasia in any cell lineage
• Blast percentage <5%
• Perform a 500 cell differential when possible 1

Additional Essential Testing

• Standard cytogenetics/interphase FISH to rule out abnormal cytogenetics (which would suggest MDS or leukemia)
• Flow cytometry to assess for abnormal cell populations
• PNH screening by sensitive flow cytometry (PNH clones are found in up to 50% of aplastic anemia patients)
• Iron stain to rule out ring sideroblasts (>5 granules around nuclear membrane excludes aplastic anemia) 1

Diagnostic Accuracy and Challenges

• Single bone marrow aspirate plus peripheral blood has a diagnostic accuracy of only ~54%
• Adding bone marrow biopsy increases diagnostic accuracy to ~95% 1
• Cases with diagnostic uncertainty should be reviewed by at least two experienced observers 2

Common Diagnostic Pitfalls

1. Inadequate bone marrow sampling
2. Misinterpreting focal granulocytic hyperplasia
3. Failure to perform age-adjusted cellularity assessment
4. Missing subtle dysplasia
5. Relying solely on bone marrow aspirate 1

Differential Diagnosis

Aplastic anemia must be distinguished from:

• Hypocellular myelodysplastic syndromes (H-MDS)
• Hypocellular acute myeloid leukemia (H-AML)
• Other bone marrow failure syndromes

The distinction from H-MDS is clinically relevant because the risk of progression to acute leukemia is much greater in H-MDS than in aplastic anemia 2.

Treatment Approaches

Treatment options depend on disease severity, patient age, and donor availability:

1. Hematopoietic Cell Transplantation (HCT):

   • Potentially curative option
   • First-line for pediatric patients and younger adults with matched sibling donors
   • Recent advances have improved outcomes with alternative donors 3

2. Immunosuppressive Therapy (IST):

   • Standard approach for older adults and patients without matched donors
   • Typically includes antithymocyte globulin and cyclosporine A
   • Recent addition of eltrombopag has shown promising results 4

Prognosis

Without treatment, severe aplastic anemia has high mortality. With modern treatments:

• HCT offers potential cure with long-term survival
• IST can achieve remission in 60-70% of cases but has limited durability and risk of long-term complications including secondary malignancies 3

Early diagnosis and prompt initiation of appropriate therapy are critical for improving outcomes in patients with aplastic anemia.