Definition/General
Introduction:
Aplastic anemia is a bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow
Results from quantitative and qualitative defects in hematopoietic stem cells
Bone marrow shows <25% cellularity with increased fat spaces
Can be acquired (90%) or inherited (10%)
Immune-mediated destruction is the most common mechanism.
Origin:
Results from stem cell damage or immune-mediated destruction
Acquired causes: drugs, chemicals, infections, radiation
Autoimmune mechanisms: T-cell mediated stem cell destruction
Inherited forms: Fanconi anemia, dyskeratosis congenita
Idiopathic: 70% of cases have no identifiable cause
Viral infections: EBV, hepatitis, parvovirus B19.
Classification:
Severe aplastic anemia: bone marrow cellularity <25%, absolute neutrophil count <500/μL
Very severe: ANC <200/μL
Non-severe: cellularity <25% but higher blood counts
Acquired: idiopathic, drug-induced, viral, autoimmune
Inherited: Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome.
Epidemiology:
Incidence: 2-3 cases per million annually
Bimodal age distribution: peaks at 20-30 and >60 years
Asia: higher incidence (3-fold) than Western countries
Male predominance in young adults
Drug-induced: chloramphenicol most common historically
Mortality: 70% without treatment, <10% with appropriate therapy.
Clinical Features
Presentation:
Pancytopenia with symptoms of anemia, thrombocytopenia, neutropenia
Fatigue and weakness (anemia)
Bleeding and bruising (thrombocytopenia)
Recurrent infections (neutropenia)
No hepatosplenomegaly (distinguishes from other causes)
No lymphadenopathy.
Symptoms:
Progressive fatigue and weakness
Shortness of breath on exertion
Easy bruising and petechiae
Prolonged bleeding from minor cuts
Frequent infections (bacterial, fungal)
Pallor of skin and mucous membranes
Menorrhagia in women.
Risk Factors:
Drug exposure: chloramphenicol, phenylbutazone, gold salts
Chemical exposure: benzene, pesticides, solvents
Viral infections: hepatitis (non-A, non-B, non-C), EBV, parvovirus
Radiation exposure
Family history (inherited forms)
Autoimmune diseases
Asian ethnicity.
Screening:
Complete blood count: pancytopenia with low reticulocyte count
Peripheral blood smear: no immature cells, no dysplastic changes
Bone marrow biopsy: essential for diagnosis
Flow cytometry: exclude PNH, assess for CD34+ cells
Cytogenetics: normal karyotype
Viral studies: hepatitis panel, EBV, CMV.
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Gross Description
Appearance:
Bone marrow biopsy shows marked hypocellularity (<25% of normal)
Increased fat spaces replacing hematopoietic tissue
Scattered residual hematopoietic cells
Preserved bone trabeculae.
Characteristics:
Paucity of hematopoietic precursors in all lineages
Normal morphology of residual cells
Increased stromal elements: fat cells, reticulin fibers
Absence of abnormal cells or infiltrates.
Size Location:
Diffuse hypocellularity throughout bone marrow spaces
Patchy distribution of residual hematopoietic foci
Peritrabecular location of remaining cells
Increased marrow cavity size due to fat replacement.
Multifocality:
Generalized bone marrow involvement
No extramedullary hematopoiesis
Spleen and liver normal size (no organomegaly)
Lymph nodes not enlarged
Thymus may be involved in some inherited forms.
Microscopic Description
Histological Features:
Marked reduction in all hematopoietic lineages
Cellularity <25% of age-adjusted normal
Increased fat cells (>75% of marrow space)
Scattered lymphocytes and plasma cells
Preserved sinusoids and vascular architecture
Normal bone trabeculae.
Cellular Characteristics:
Residual hematopoietic cells show normal morphology
No dysplastic changes (excludes MDS)
Rare megakaryocytes present
Lymphocytes and plasma cells relatively preserved
Macrophages may contain hemosiderin
No blast cells or abnormal infiltrates.
Architectural Patterns:
Loss of normal hematopoietic architecture
Fat replacement of cellular areas
Preserved sinusoidal network
Minimal reticulin fibrosis
No paratrabecular aggregates
Absence of granulomas or tumor infiltration.
Grading Criteria:
Cellularity assessment: percentage of cellular vs
fat areas
Severe: <25% cellularity with severe peripheral cytopenias
Very severe: <25% cellularity with ANC <200/μL
Non-severe: <25% cellularity with less severe cytopenias
Age adjustment: normal cellularity decreases with age.
Immunohistochemistry
Positive Markers:
CD34: markedly reduced (<1% of nucleated cells)
Glycophorin A: rare erythroid precursors
Myeloperoxidase: rare granulocytic cells
CD61: rare megakaryocytes
CD3/CD20: preserved lymphocytes.
Negative Markers:
CD117: minimal or absent
TdT: negative (excludes ALL)
CD68: few macrophages
Reticulin stain: minimal increase
Trichrome: no significant fibrosis.
Diagnostic Utility:
CD34 enumeration: <1% supports aplastic anemia diagnosis
Flow cytometry: assess for PNH clone (CD55/CD59)
Exclude other disorders: leukemia, MDS, fibrosis
Assess stromal elements
Quantify lymphoid infiltrate.
Molecular Subtypes:
Idiopathic aplastic anemia: no identifiable cause
Drug-induced: history of causative medication
Post-infectious: viral triggers identified
Constitutional: genetic testing positive
Secondary: associated with other conditions.
Molecular/Genetic
Genetic Mutations:
FANC genes: Fanconi anemia (16 complementation groups)
TERC/TERT mutations: dyskeratosis congenita, telomere disorders
SBDS mutations: Shwachman-Diamond syndrome
GATA2 mutations: MonoMAC syndrome
RUNX1 mutations: familial platelet disorder
Somatic mutations: rare in acquired forms.
Molecular Markers:
Telomere length: shortened in many cases
Chromosome fragility: increased in Fanconi anemia
HLA typing: certain alleles associated with drug-induced AA
T-cell repertoire: oligoclonal expansion
Cytokine levels: elevated interferon-γ, TNF-α.
Prognostic Significance:
Severity classification: determines treatment urgency
Age: younger patients better candidates for BMT
Response to immunosuppression: 60-70% respond to ATG/cyclosporine
Secondary clonal evolution: PNH (15%), MDS (10%), AML (rare)
Inherited forms: require different management approach.
Therapeutic Targets:
Immunosuppressive therapy: antithymocyte globulin, cyclosporine
Hematopoietic stem cell transplantation: curative for young patients with matched donor
Supportive care: blood products, antibiotics, growth factors
Eltrombopag: thrombopoietin receptor agonist
Androgens: for selected cases.
Differential Diagnosis
Similar Entities:
Hypocellular MDS (dysplastic changes, cytogenetic abnormalities)
Acute leukemia (blast cells present)
Hairy cell leukemia (hairy cells, splenomegaly)
Primary myelofibrosis (increased reticulin, tear-drop cells)
Metastatic cancer (tumor cells present)
Anorexia nervosa (gelatinous transformation).
Distinguishing Features:
Aplastic anemia: normal morphology, no dysplasia, <25% cellularity
Hypocellular MDS: dysplastic changes, cytogenetic abnormalities
Acute leukemia: >20% blasts, immunophenotyping
Hairy cell leukemia: characteristic cells, splenomegaly
Myelofibrosis: increased reticulin, leukoerythroblastosis
Metastases: tumor cells identified.
Diagnostic Challenges:
Hypocellular MDS: may require cytogenetics and flow cytometry
Early aplastic anemia: may have >25% cellularity initially
Post-chemotherapy: bone marrow recovery vs
persistent aplasia
Inherited vs
acquired: family history and genetic testing
PNH association: requires flow cytometry screening.
Rare Variants:
Pure red cell aplasia: selective erythroid aplasia
Amegakaryocytic thrombocytopenia: isolated megakaryocyte aplasia
Severe chronic neutropenia: isolated granulocytic aplasia
Paroxysmal cold hemoglobinuria: transient aplastic crisis
Pregnancy-associated: rare, usually reversible.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow biopsy from [site], adequate for evaluation with [length] cm core
Cellularity
Markedly hypocellular bone marrow ([percentage]%, age-adjusted normal: [range]%)
Morphological Features
Marked reduction in all hematopoietic lineages with normal morphology of residual cells
Lineage Analysis
Erythroid: markedly reduced, Myeloid: markedly reduced, Megakaryocytes: rare
CD34+ Cells
CD34+ cells: <1% of nucleated cells (markedly reduced)
Special Studies
Flow cytometry: negative for PNH clone. Cytogenetics: normal karyotype
Final Diagnosis
Hypocellular bone marrow consistent with aplastic anemia ([severity])
Recommendations
Clinical correlation with peripheral blood counts. Consider immunosuppressive therapy or HSCT evaluation