What is aplastic anemia?

Aplastic Anemia: Definition and Diagnostic Approach

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

Pathophysiology

Aplastic anemia results from the destruction of hematopoietic stem cells leading to bone marrow failure through three main mechanisms:

• Immune-mediated destruction: Most common mechanism, involving cytotoxic T-cell mediated attack on hematopoietic stem cells 2
• Direct injury: Can be caused by toxins, radiation, or certain medications
• Inherited or clonal disorders: Genetic abnormalities affecting bone marrow function 3

Diagnostic Criteria

The diagnosis of aplastic anemia requires:

1. Peripheral blood findings:

   • Pancytopenia (decreased red cells, white cells, and platelets)
   • Absence of circulating blasts
   • Count at least 100 cells to assess for dysplasia or blasts 4

2. Bone marrow evaluation:

   • Bone marrow biopsy: Critical for diagnosis, showing hypocellularity (<20%) 4, 1
   • Age-adjusted cellularity assessment: Essential as normal cellularity decreases with age 4
   • Bone marrow aspirate: 500 cell differential when possible 4, 1
   • Absence of significant dysplasia in all cell lines 4
   • Absence of abnormal localization of immature precursors (ALIP) 4

3. Additional essential studies:

   • Iron stain: To rule out ring sideroblasts (>5 granules around nuclear membrane excludes aplastic anemia) 4, 1
   • Reticulin stain: To assess for fibrosis 4
   • Cytogenetics/FISH: To rule out clonal disorders 4
   • Flow cytometry: For immunophenotyping 4
   • PNH screening: Using sensitive flow cytometry 4

Diagnostic Accuracy

• Single bone marrow aspirate plus peripheral blood has a diagnostic accuracy of only ~54%
• Adding bone marrow biopsy increases diagnostic accuracy to ~95% 1

Differential Diagnosis

Critical differential diagnoses to consider:

• Hypocellular Myelodysplastic Syndrome (H-MDS):

  • Distinguished by presence of dysplasia
  • May have abnormal sideroblasts
  • May show clusters of immature precursors 4

• Hypocellular Acute Myeloid Leukemia (H-AML):

  • Distinguished by ≥20% blasts in aspirate
  • Shows numerous clusters of immature precursors (ALIP)
  • Positive CD34 immunostaining revealing many blasts 4

Common Pitfalls in Diagnosis

1. Inadequate sampling: Bone marrow biopsy is essential as aspirates may be paucicellular 4

2. Insufficient cell count: A 500-cell differential is recommended for accurate blast percentage assessment 4

3. Failure to perform age-adjusted cellularity assessment: Normal cellularity decreases with age 4

4. Overlooking mild dysplasia: Some mild dyserythropoiesis can be seen in aplastic anemia and should not be confused with MDS 4

5. Missing clonal disorders: Comprehensive cytogenetic and molecular testing is essential 5

Treatment Approaches

Treatment options include:

• Immunosuppressive therapy (IST): Using antithymocyte globulin and cyclosporine A 6, 5

• Hematopoietic cell transplantation (HCT): Potentially curative, especially with HLA-matched related donors 6

• Supportive care: Including transfusions and infection prevention 5

The choice between these approaches depends on disease severity, patient age, donor availability, and other patient factors 5.