What is aplastic anemia?

Aplastic Anemia

Aplastic anemia is a bone marrow failure syndrome characterized by pancytopenia and severely hypocellular bone marrow, where normal hematopoietic cells are replaced by fat cells, leading to inadequate production of all blood cell lines. 1

Pathophysiology

• Aplastic anemia results from the loss of hematopoietic "stem" cells in the bone marrow, which are replaced by fat cells, leading to pancytopenia 2
• Three main mechanisms cause bone marrow destruction in aplastic anemia:
  • Direct injury to bone marrow cells
  • Immune-mediated destruction (most common in acquired cases)
  • Inherited or clonal bone marrow failure disorders 3
• The pathophysiology is predominantly immune-mediated in most acquired cases, with activated type 1 cytotoxic T cells attacking hematopoietic stem cells 4

Clinical Presentation

• Universal symptoms include fatigue, exhaustion, and pallor due to anemia 2
• Hemorrhagic syndrome occurs in approximately 79% of patients due to thrombocytopenia 2
• Fever may be present in about 36% of patients, often related to neutropenia and subsequent infections 2
• The disease typically shows two age peaks: in younger patients under 30 years (48%) and in those over 60 years (27%) 2

Diagnostic Approach

Diagnosis requires a comprehensive evaluation to distinguish aplastic anemia from other hypocellular disorders like hypocellular myelodysplastic syndrome (H-MDS) and hypocellular acute myeloid leukemia (H-AML) 5:

• Peripheral blood evaluation:

  • Complete blood count showing pancytopenia
  • Examination of at least 100 cells to assess for dysplasia of granulocytes and presence of blasts 5

• Bone marrow assessment:

  • Bone marrow aspirate with 500-cell differential count when possible 5
  • Examination for dysplasia in erythroid precursors, granulocytes, and megakaryocytes 5
  • Iron stain to assess for ring sideroblasts (their presence excludes aplastic anemia) 5
  • Bone marrow biopsy (1-2 cm core) is critical and necessary for diagnosis, showing:
    • Severely reduced cellularity (<20% in severe cases), corrected for patient age 5
    • Absence of abnormal localization of immature precursors (ALIP) 5
    • Reticulin staining to assess fibrosis 5

• Additional testing:

  • Cytogenetic analysis and FISH to rule out clonal disorders 5
  • Flow cytometry to assess for abnormal cell populations 5
  • PNH screening by flow cytometry or molecular techniques 5
  • Molecular and genetic testing including next-generation sequencing to exclude inherited bone marrow failure syndromes 3, 1

Distinguishing Features from Related Disorders

• Aplastic anemia vs. H-MDS:

  • H-MDS may show mild dyserythropoiesis, which can also be seen in aplastic anemia 5
  • The presence of moderate to severe erythroid dysplasia (bi/trinucleated forms, numerous Howell-Jolly bodies, nuclear budding/bridging) or abnormal sideroblasts excludes aplastic anemia 5
  • H-MDS typically shows at least 5% blasts in bone marrow in the absence of significant dysplasia 5

• Aplastic anemia vs. H-AML:

  • H-AML shows clusters of immature precursors (ALIP) in a hypocellular setting 5
  • CD34 immunostaining reveals many positive blasts in H-AML versus rare positive cells in aplastic anemia 5
  • H-AML typically has ≥20% blasts on bone marrow aspirate 5

Treatment Approaches

• Hematopoietic stem cell transplantation (HSCT):

  • First-line treatment for patients younger than 50 years with an HLA-identical sibling donor 1
  • Offers the best chance for cure and long-term survival 2, 4

• Immunosuppressive therapy (IST):

  • First-line for patients without a suitable donor or those >50 years old 1
  • Current standard regimen includes equine antithymocyte globulin, cyclosporine A, and eltrombopag 1
  • Antilymphocyte/antithymocyte globulins have shown significant efficacy 2, 6

• Supportive care:

  • Blood product transfusions for symptomatic anemia and severe thrombocytopenia 6
  • Infection prevention and prompt treatment of infections 4

Prognosis

• Without treatment, mortality from severe aplastic anemia approaches 70% within 2 years 1
• Survival is significantly better for patients with disease duration longer than one year 2
• Bone marrow transplantation offers superior survival compared to other treatment methods 2
• Age and gender do not significantly impact survival, but treatment modality does 2

Clinical Pitfalls and Caveats

• Diagnosis can be challenging due to the paucicellularity of bone marrow aspirates; bone marrow biopsy is essential 5
• Age correction is necessary when assessing bone marrow cellularity to avoid misdiagnosis 5
• Careful exclusion of hypocellular variants of MDS and AML is critical, as treatment approaches differ significantly 5
• Evolution to clonal hematologic diseases remains problematic even after successful treatment 4
• Previous genotoxic exposure or therapy must be excluded as they can cause hypocellular marrows resembling aplastic anemia 5