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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Question 1HematologyMedium
A 22-year-old woman presents with 6 weeks of progressive fatigue, easy bruising, and gum bleeding when she brushes her teeth. She has no weight loss, night sweats, or bone pain. On exam she is pale with scattered petechiae over her shins and a few oral mucosal bleeds; there is no hepatosplenomegaly or lymphadenopathy. Labs show hemoglobin 7.2 g/dL, absolute neutrophil count 400/μL, platelets 18,000/μL, and a corrected reticulocyte count of 0.4%. The peripheral smear shows normocytic red cells with no blasts and no dysplastic forms. A bone marrow biopsy reveals a markedly hypocellular marrow (<25% cellularity) with fatty replacement and no fibrosis or abnormal infiltrate. Which of the following is the most likely diagnosis?
AAcquired aplastic anemia
BParoxysmal nocturnal hemoglobinuria
CFanconi anemia
DAcute myelogenous leukemia
Reveal answer & full explanation
Correct answer: A — Acquired aplastic anemia
AAcquired aplastic anemia✓
BParoxysmal nocturnal hemoglobinuria
CFanconi anemia
DAcute myelogenous leukemia
Why Acquired aplastic anemia is correct
The hallmark is pancytopenia (anemia, neutropenia, thrombocytopenia) with a low corrected reticulocyte count, indicating marrow underproduction rather than peripheral destruction or sequestration.
The bone marrow biopsy is diagnostic: markedly hypocellular (<25% cellularity) with fatty replacement and no fibrosis, blasts, dysplasia, or infiltrate.
The clinical picture fits classic acquired aplastic anemia — a young adult (bimodal peaks at 15-25 and >60) with insidious cytopenia symptoms, absence of constitutional B symptoms, and absence of hepatosplenomegaly or lymphadenopathy.
By Camitta criteria this is severe aplastic anemia (cellularity <25% plus 2 of 3: ANC <500, platelets <20K, reticulocytes <60K/μL) — a hematologic emergency requiring matched-sibling HSCT (first-line in patients <40-50) or immunosuppression with horse ATG, cyclosporine, and eltrombopag.
Why the others are wrong
Fanconi anemia — an inherited marrow-failure syndrome that also produces pancytopenia with a hypocellular, fatty marrow, but it usually declares itself in childhood (median age about 7) with short stature, thumb or radial anomalies, and café-au-lait macules, and it is confirmed by chromosomal breakage testing with diepoxybutane or mitomycin C; a 22-year-old with only 6 weeks of symptoms and no congenital anomalies noted on exam fits acquired disease, although breakage testing is still sent in young patients before HSCT to exclude it.
Acute myelogenous leukemia — an aleukemic presentation can cause pancytopenia, but the diagnosis requires >20% marrow blasts on biopsy/flow cytometry; this marrow is hypocellular with no blasts.
Paroxysmal nocturnal hemoglobinuria — overlaps with aplastic anemia but is defined by intravascular hemolysis with hemoglobinuria and thrombosis and loss of GPI-anchored CD55/CD59 on flow cytometry; this patient has a low reticulocyte count and no hemolysis, making PNH unlikely.
Question 2HematologyMedium
A 23-year-old man presents with 6 weeks of progressive fatigue, easy bruising, and gum bleeding. He takes no medications and has no fevers, weight loss, or night sweats. Exam shows pallor and scattered petechiae on the lower legs but no hepatosplenomegaly or lymphadenopathy. CBC shows hemoglobin 7.8 g/dL, ANC 400/μL, and platelets 18,000/μL, with a corrected reticulocyte count of 0.4%. Peripheral smear reveals reduced but morphologically normal cells with no blasts or dysplasia. Bone marrow biopsy is markedly hypocellular with fatty replacement and no fibrosis or infiltrate. Which of the following is most appropriate to confirm the diagnosis and exclude a key overlapping disorder?
ASerum erythropoietin concentration
BDirect antiglobulin (Coombs) test
CFlow cytometry for CD55 and CD59
DSerum vitamin B12 and folate levels
Reveal answer & full explanation
Correct answer: C — Flow cytometry for CD55 and CD59
ASerum erythropoietin concentration
BDirect antiglobulin (Coombs) test
CFlow cytometry for CD55 and CD59✓
DSerum vitamin B12 and folate levels
Why Flow cytometry for CD55 and CD59 is correct
The picture (pancytopenia, low reticulocyte count, markedly hypocellular marrow without blasts, dysplasia, fibrosis, or organomegaly, and no B symptoms) is classic acquired aplastic anemia.
Before committing to an aplastic anemia diagnosis you must exclude paroxysmal nocturnal hemoglobinuria (PNH), which frequently overlaps with AA and changes management.
PNH is caused by loss of GPI-anchored proteins; flow cytometry on RBCs and granulocytes showing loss of CD55 and CD59 establishes a PNH clone. Cytogenetics and morphology likewise exclude MDS, but among the listed options flow cytometry is the discriminating confirmatory test.
Why the others are wrong
Serum erythropoietin concentration — expectedly high in any severe anemia and is not diagnostic; it does not distinguish AA from its mimics.
Direct antiglobulin (Coombs) test — detects antibody-mediated (warm/cold) hemolysis; PNH hemolysis is complement-mediated and Coombs-negative, so this would not identify the overlapping disorder.
Serum vitamin B12 and folate levels — megaloblastic deficiency can produce pancytopenia, but it causes macrocytosis, hypersegmented neutrophils, and a hypercellular marrow with megaloblastic dysplasia; this patient's morphologically normal cells and fatty, hypocellular marrow argue against it, and the test neither confirms aplastic anemia nor screens for the PNH clone.
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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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