What is on the differential diagnosis for Aplastic Anemia?

Key differentials include Myelodysplastic syndrome (hypocellular MDS), Acute leukemia (aleukemic presentation), Paroxysmal nocturnal hemoglobinuria, Megaloblastic anemia (severe B12/folate), Marrow infiltration, Hypersplenism, Drug-induced cytopenias (non-aplastic).

What are the high-yield PANCE pearls for Aplastic Anemia?

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.

Hematology · PANCE / PANRE

Aplastic Anemia

Written & clinically reviewed by Ryan Busch, PA-C · Updated July 2026 · Report an error

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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Risk factors

Idiopathic in 70-80% — autoimmune destruction of hematopoietic stem cells presumed
Drugs: chloramphenicol, sulfonamides, NSAIDs, antiepileptics (carbamazepine, phenytoin), gold, propylthiouracil, methimazole
Toxins: benzene, pesticides, radiation
Viral: hepatitis (non-A, non-B, non-C 'seronegative hepatitis'), EBV, HIV, parvovirus B19 (transient, especially in immunocompromised)
Pregnancy (rare)
Paroxysmal nocturnal hemoglobinuria — frequent overlap
Inherited syndromes: Fanconi anemia (congenital anomalies, chromosomal breakage), dyskeratosis congenita (nail dysplasia, oral leukoplakia, skin pigmentation), Diamond-Blackfan (pure red cell aplasia), Shwachman-Diamond

Pathophysiology

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
Anemia: fatigue, dyspnea on exertion, pallor
Thrombocytopenia: easy bruising, petechiae, mucosal bleeding, epistaxis, menorrhagia
Neutropenia: fever, recurrent or unusual infections (bacterial, fungal)
No constitutional B symptoms (no weight loss, drenching sweats) suggests AA over lymphoma/leukemia

Signs / physical exam

Pallor, petechiae (lower extremities, dependent areas), ecchymoses
Mucosal bleeding, gingival bleeding, oral candidiasis
Fever from infection (often febrile neutropenia)
ABSENCE of hepatosplenomegaly or lymphadenopathy (their presence points to alternative diagnosis)

Classic findings

Pancytopenia with hypocellular marrow biopsy in a young adult or older patient without organomegaly or constitutional B symptoms.

Differential diagnosis

Myelodysplastic syndrome (hypocellular MDS) — Dysplasia, cytogenetic abnormalities (5q-, monosomy 7), increased blasts; can overlap
Acute leukemia (aleukemic presentation) — Marrow blasts >20%; flow cytometry diagnostic
Paroxysmal nocturnal hemoglobinuria — Intravascular hemolysis, hemoglobinuria, thrombosis; flow cytometry for CD55/CD59 (GPI-anchored proteins) loss; overlaps with AA
Megaloblastic anemia (severe B12/folate) — Macrocytic, hypersegmented PMNs, megaloblastic marrow with hypercellularity
Marrow infiltration — Metastatic cancer, lymphoma, miliary TB, fibrosis; biopsy reveals abnormal cells or fibrosis
Hypersplenism — Cytopenia from sequestration; marrow cellular and active; splenomegaly
Drug-induced cytopenias (non-aplastic) — Marrow cellular; resolves with drug discontinuation

Diagnostic workup

Diagnostic criteria

Pancytopenia + bone marrow hypocellularity <25% (or 25-50% with <30% residual hematopoietic cells) + exclusion of other causes (leukemia, MDS, PNH, congenital syndromes).

Labs

CBC — pancytopenia: Hb low, neutrophils low, platelets low; reticulocyte count low (corrected ARC <1%)
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
Hepatitis panel, HIV, B12/folate, ferritin, EBV, parvovirus PCR
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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