Pancytopenia from bone marrow failure with a hypocellular marrow — usually immune-mediated destruction of stem cells.
Also known as: aplastic anemia, AA, bone marrow failure
Overview
Bone marrow failure characterized by peripheral pancytopenia and a hypocellular bone marrow (<25% cellularity or 25-50% with <30% residual hematopoietic cells), in the absence of an abnormal infiltrate or marrow fibrosis. Acquired aplastic anemia is most often immune-mediated; inherited forms (Fanconi anemia, dyskeratosis congenita) are distinct.
Epidemiology
Rare (~2 cases per million per year in Western countries, 3-7x higher in Asia). Bimodal age distribution: peaks at 15-25 and >60 years. No sex predominance.
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T-cell mediated autoimmune destruction of CD34+ hematopoietic stem cells is the central mechanism in most acquired cases. Cytotoxic T cells secrete IFN-gamma and TNF-alpha, inducing stem cell apoptosis. The result is global cytopenia. Inherited forms involve defects in DNA repair (Fanconi) or telomere maintenance (dyskeratosis congenita).
Clinical presentation
Symptoms
Insidious onset of pancytopenia symptoms over weeks to months
Peripheral smear — normocytic or macrocytic; no blasts, no dysplastic cells, normal-appearing residual cells
Bone marrow biopsy (essential) — hypocellular (<25%) with fat replacement, residual hematopoiesis trilineage but reduced, no blasts, no fibrosis, no infiltrate
Flow cytometry on peripheral blood and marrow to exclude PNH (CD55/CD59 loss on RBCs/granulocytes) and leukemia
Cytogenetics and FISH (5q-, monosomy 7) to exclude MDS
Severity classification: Severe AA (Camitta criteria): marrow cellularity <25% + 2 of 3 — ANC <500, platelets <20K, reticulocytes <60K/μL. Very severe: ANC <200
Chromosomal breakage testing (mitomycin C, diepoxybutane) in patients <40 to exclude Fanconi anemia
Telomere length testing if dyskeratosis congenita suspected
Imaging
Not routinely required for diagnosis; chest CT if pulmonary infection suspected
Diagnostic algorithm
Severity
Marrow Cellularity
ANC
Platelets
Reticulocytes
Non-severe
<25%
>500
>20K
>60K
Severe (Camitta)
<25% (or 25-50% with <30% residual)
<500
<20K
<60K
Very severe
<25%
<200
<20K
<60K
Camitta criteria for aplastic anemia severity — requires marrow hypocellularity plus 2 of 3 peripheral cytopenia thresholds.
Treatment
First-line
Discontinue any suspected offending drug or toxin
Supportive care: RBC and platelet transfusion (irradiated, leukoreduced — avoid related donors if HSCT planned to prevent alloimmunization), prophylactic antimicrobials in severe cases
Allogeneic HSCT (matched sibling donor) — first-line for patients <40-50 with severe AA and matched sibling; 80% long-term survival
Immunosuppressive therapy (IST) — for older patients or those without matched sibling donor: horse antithymocyte globulin (ATG) + cyclosporine ± eltrombopag
Eltrombopag (TPO mimetic) — added to first-line IST per RACE trial; improves response rates
Second-line / adjunct
Repeat IST or alternative donor HSCT (matched unrelated donor, haploidentical) for refractory or relapsed disease
Eltrombopag monotherapy for refractory cases
Androgens (danazol, oxymetholone) — historical; some role in inherited bone marrow failure
Hematopoietic growth factors (G-CSF, EPO) — limited role; can be tried but rarely effective alone
Avoid live vaccines; aggressive infection management
Complications
Infection — leading cause of mortality (especially invasive fungal in prolonged neutropenia)
Hemorrhage — intracranial bleeding from severe thrombocytopenia
Iron overload from chronic transfusion
Clonal evolution to PNH (~10-15%), MDS, or AML
Graft-versus-host disease and graft failure following HSCT
ATG-related serum sickness, infusion reactions
Cyclosporine nephrotoxicity, hypertension
PANCE pearls
Severe aplastic anemia is a hematologic emergency — high mortality without prompt diagnosis and treatment.
Always exclude PNH (flow cytometry for CD55/CD59) and MDS (cytogenetics, careful morphology) before committing to AA diagnosis — therapy differs.
Matched sibling donor HSCT cures ~80% of young patients with severe AA — best initial therapy when available.
Horse ATG is superior to rabbit ATG for AA (Scheinberg et al., NEJM 2011); the opposite is true for solid organ transplant rejection.
Adding eltrombopag to ATG+cyclosporine (triple therapy) improves response rates and is now standard (RACE trial).
Fanconi anemia must be excluded in younger patients before HSCT conditioning — they cannot tolerate standard chemotherapy doses.
Pancytopenia + organomegaly or lymphadenopathy is NOT aplastic anemia — look for leukemia, lymphoma, or storage disease.
References
BSH 2016 — Guidelines for the diagnosis and management of adult aplastic anaemia (Killick et al., Br J Haematol)
RACE Trial — Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia (Peffault de Latour et al., NEJM 2022)
Scheinberg et al. — Horse versus Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia (NEJM 2011)
Young — Aplastic Anemia (Young, NEJM 2018)
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