Master aplastic anemia, pure red cell aplasia, and bone marrow failure syndromes for ASCP hematology exam.

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Chapter 11 โ€” BONE MARROW FAILURE

ASCP Board Exam ยท Lab-Focused Study Guide
Aplastic Anemia (Acquired & Inherited) ยท Severity Criteria ยท Fanconi ยท Dyskeratosis Congenita ยท SBDS ยท PRCA ยท DBA vs TEC ยท CDA ยท Myelophthisic ยท CKD Anemia ยท Practice Questions

1 ยท Priority Table & Quick Foundation

Topic Priority Why It’s Tested
Aplastic anemia features: pancytopenia, reticulocytopenia, hypocellular marrow, stem cell depletion; no splenomegaly, no blasts, normal reticulin HIGH Core recognition โ€” and how to separate it from leukemia, MDS, hairy cell
Severity criteria (MAA, SAA, VSAA โ€” Table 22-1) HIGH Calculation-style classification questions
Acquired AA: idiopathic (70%) vs secondary; dose-dependent vs idiosyncratic; autoimmune CD8 T-cell mechanism HIGH Mechanism and etiology questions
Treatment: HSCT (<40 y with HLA-identical sibling) vs IST (ATG + cyclosporine) HIGH ‘Best success rate in young patients’ item
Fanconi anemia: DEB/MMC chromosome breakage test, physical anomalies, AR (FANCB X-linked), cancer risk HIGH Diagnostic test identification
Pancytopenia differential (Table 22-2): AA vs PNH vs MDS vs megaloblastic vs leukemia vs hairy cell HIGH Differential diagnosis tables
DBA vs TEC (Table 22-4): age, MCV, Hb F, erythrocyte ADA HIGH Pure red cell aplasia comparison
Anemia of CKD: โ†“ EPO; ESA therapy with iron targets HIGH Mechanism item
PNH clones in AA; flow for CD55/CD59 (RBC), CD24/CD14 (WBC) MEDIUM Overlap with Chapter 3
Dyskeratosis congenita triad and telomerase genes (DKC1, TERC, TERT) MEDIUM Telomere mechanism question
Shwachman-Bodian-Diamond: pancreatic insufficiency + neutropenia MEDIUM Recognition
CDA I/II/III features (bridges, binucleated forms, giant multinucleated; HEMPAS) MEDIUM ‘Binucleated precursors + hemosiderosis’ item
Myelophthisic anemia: leukoerythroblastosis, teardrops MEDIUM Film recognition
Incidence figures, gene lists, telomerase gene polymorphisms LOW Recall only
๐ŸŽฏ KEY POINT โ€” Where to spend your time

Focus: aplastic anemia features and severity grading, idiosyncratic autoimmune mechanism, HSCT vs IST, Fanconi DEB test, the pancytopenia differential, DBA vs TEC, CDA II binucleated cells, and โ†“ EPO in CKD. Skim: full gene lists (FANC Aโ€“P, RPS genes), incidence numbers, and polymorphism details.

Quick Foundation โ€” from zero

  • Bone marrow failure = the marrow makes too few blood cells in one or more lines.
  • When all three lines fall โ†’ pancytopenia: anemia (fatigue, pallor), neutropenia (infections), thrombocytopenia (bleeding).
  • Aplastic anemia is the classic failure: the hematopoietic stem cells are gone or defective, so the marrow is mostly fat (hypocellular) โ€” nothing abnormal has replaced it.
  • It is usually acquired โ€” most often an autoimmune T-cell attack on stem cells, sometimes triggered by drugs, chemicals or viruses โ€” or, less often, inherited (Fanconi anemia, dyskeratosis congenita, Shwachman-Bodian-Diamond).
  • Other failures hit only red cells (pure red cell aplasia), produce defective red cells (CDA), crowd out the marrow (myelophthisic anemia), or lack the EPO signal (kidney disease).
๐Ÿ’ก Analogy

The marrow is a farm. In aplastic anemia the seed bank (stem cells) has been burned โ€” the fields are empty (fat), even though fertilizer (growth factors) is piled high. In myelophthisic anemia weeds (tumor, fibrosis) take over the fields. In PRCA only one crop (red cells) fails. In CKD the farmer never gets the order to plant (no EPO).

๐Ÿฅ Why this matters clinically

Pancytopenia can mean aplastic anemia, leukemia, MDS, PNH or Bโ‚โ‚‚ deficiency โ€” each treated differently. Inherited forms matter too: a sibling who carries the same mutation must not be used as a stem cell donor.

Concept Plain-English Explanation
Pancytopenia Decrease in RBCs, WBCs and platelets
Reticulocytopenia Low reticulocyte count โ€” marrow isn’t responding
Hypocellular marrow Mostly fat, few blood-forming cells
Idiopathic Cause unknown
Idiosyncratic Unpredictable reaction, unrelated to dose
Telomere Protective cap on chromosome ends; short telomeres โ†’ cells age and die early
Leukoerythroblastosis Immature WBCs and nucleated RBCs in the blood โ€” sign of marrow infiltration
ESA Erythropoiesis-stimulating agent (recombinant EPO)

2 ยท Core Content Tables

2.1 Pathophysiology of Bone Marrow Failure

Feature Details
Six mechanisms โ‘  Destruction of HSCs (drugs, chemicals, radiation, viruses, autoimmunity) โ‘ก premature senescence/apoptosis of HSCs from genetic mutations โ‘ข ineffective hematopoiesis (stem cell mutations, Bโ‚โ‚‚/folate deficiency) โ‘ฃ disrupted marrow microenvironment โ‘ค โ†“ growth factors/hormones โ‘ฅ infiltration by abnormal cells
Aplastic anemia Mechanisms โ‘  and โ‘ก
Consequences Thrombocytopenia โ†’ bleeding, bruising ยท โ†“ RBC/Hb โ†’ fatigue, pallor, cardiovascular complications ยท neutropenia โ†’ life-threatening bacterial/fungal infections. Severe pancytopenia can be rapidly fatal

2.2 Aplastic Anemia โ€” Definition & Etiology (Boxes 22-1, 22-2)

Feature Details
History First described by Ehrlich (1888); named by Vaquez and Aubertin (1904)
Characteristic features Pancytopenia ยท reticulocytopenia ยท bone marrow hypocellularity ยท depletion of hematopoietic stem cells
Acquired (80โ€“85%) Idiopathic ~70% of all cases (cause unknown) ยท secondary 10โ€“15%
Secondary โ€” dose-dependent/predictable (~10% of secondary) Cytotoxic drugs, benzene, radiation โ€” marrow usually recovers after withdrawal
Secondary โ€” idiosyncratic (~70% of secondary) Drugs (Box 22-3: chloramphenicol, sulfonamides, gold, penicillamine, carbamazepine, hydantoins, NSAIDs, chloroquine, methimazole, acetazolamideโ€ฆ), chemicals (insecticides, cutting/lubricating oils) โ€” unpredictable, unrelated to dose, may occur monthsโ€“years after exposure
Secondary โ€” viruses EBV, hepatitis (non-A, non-B, non-C, non-G) โ€” 2โ€“10% have hepatitis 1โ€“3 months before pancytopenia; HIV; parvovirus B19
Secondary โ€” miscellaneous PNH, autoimmune diseases (~10%), pregnancy (<100 cases)
Inherited (15โ€“20%) Fanconi anemia, dyskeratosis congenita, Shwachman-Bodian-Diamond syndrome
Incidence ~1 in 500,000/year in North America/Europe; 2โ€“3ร— higher in Asia. Peaks 15โ€“25 y and >60 y; no gender predisposition
Susceptibility ~2ร— HLA-DR2/DR15; GST polymorphisms (GSTT1 null) โ€” may increase benzene sensitivity

2.3 Acquired Aplastic Anemia โ€” Pathophysiology

Feature Details
Primary lesion Quantitative and qualitative deficiency of HSCs; CD34โบ cells โ‰ค10% of normal; โ†‘ Fas and apoptosis genes; poor colony formation
Stroma Normal โ€” produces normal or โ†‘ growth factors; supports healthy donor CD34โบ cells
Growth factors Elevated EPO, TPO, G-CSF, GM-CSF; FLT3 ligand up to 200ร— โ€” yet ineffective
Direct damage DNA injury from cytotoxic drugs, chemicals, radiation, viruses
Immune damage (evidence) โ‘  โ†‘ cytotoxic CD8โบ T cells with oligoclonal expansion โ‘ก โ†‘ IFN-ฮณ and TNF-ฮฑ (inhibit hematopoiesis, induce apoptosis) โ‘ข โ†‘ T-bet โ‘ฃ โ†‘ TNF-ฮฑ receptors on CD34โบ โ‘ค improvement with IST. ~โ…” respond to IST
Loss of regulation โ†“ CD4โบCD25โบFOXP3โบ regulatory T cells; cytokine gene polymorphisms
Telomeres ~โ…“ have short telomeres in granulocytes; ~10% have TERC or TERT mutations; ~4% have SBDS mutations โ€” some ‘acquired’ cases may actually be DKC or SBDS
Donor caution Don’t use HLA-matched siblings who carry the same mutation

2.4 Aplastic Anemia โ€” Clinical & Laboratory Findings

Feature Details
Symptoms Insidious anemia (pallor, fatigue, weakness); bleeding (petechiae, bruising, epistaxis, mucosal bleeding, menorrhagia, retinal/intestinal/intracranial hemorrhage). Fever/infection unusual at presentation. Splenomegaly and hepatomegaly absent
CBC Pancytopenia (initially 1โ€“2 lines may be low); โ†“ ANC; lymphocytes N or โ†“; Hb usually <10 g/dL; MCV โ†‘ or N; โ†“ % and absolute retic
Film Macrocytic or normocytic RBCs; neutrophils, monocytes, platelets โ†“; toxic granulation possible; no blasts or immature cells; RBCs and platelets otherwise normal
Chemistry โ†‘ serum iron and % saturation (โ†“ iron use); liver tests abnormal in hepatitis-associated AA
PNH clones ~โ…” have small PNH clones (<25%); ~10% develop clinical PNH. Flow: CD59 on RBCs, CD24 and CD14 on granulocytes/monocytes (replaced Ham test)
Marrow Prominent fat with patchy cellularity; biopsy required for cellularity; erythroid, granulocytic and megakaryocytic cells โ†“; dyserythropoiesis possible, but no dysplasia of granulocytes or platelets; no blasts or infiltrates; reticulin normal
Cytogenetics Abnormal karyotype after IST: 14% at 5 y, 20% at 10 y; monosomy 7 and trisomy 8 most common; FISH more sensitive (hypocellular marrow gives few metaphases)
๐Ÿงช PRE-ANALYTICAL โ€” Marrow & flow in suspected aplastic anemia*
  • Core biopsy is essential โ€” aspirates are often dilute (‘dry’ or bloody) and misrepresent cellularity
  • Obtain samples for cytogenetics/FISH (heparin) and PNH flow (EDTA peripheral blood) at diagnosis
  • Transfuse judiciously and use leukoreduced/irradiated products to avoid alloimmunization before HSCT

2.5 Severity Criteria (Rodak Table 22-1)

Moderate (MAA) Severe (SAA) Very Severe (VSAA)
Bone marrow Hypocellular + at least 2 of the following Cellularity <25% (or 25โ€“50% with <30% residual hematopoietic cells) + at least 2 of the following Same as SAA
Neutrophils (ร— 10โน/L) 0.5โ€“1.5 0.2โ€“0.5 <0.2
Platelets (ร— 10โน/L) 20โ€“50 <20 Same as SAA
Other Hb โ‰ค10 g/dL plus retic <30 ร— 10โน/L Retic <20 ร— 10โน/L or <1% corrected for Hct Same as SAA

Tip: SAA and VSAA differ only by the neutrophil count (<0.2 ร— 10โน/L = very severe).

2.6 Treatment & Prognosis of Acquired AA

Feature Details
First steps Stop the causative agent; judicious transfusions (avoid alloimmunization); platelets not transfused above 10,000/ยตL unless bleeding
HSCT Treatment of choice for SAA in patients <40 y with an HLA-identical sibling (only 20โ€“30% qualify). 10-year survival: 91% children, 74% adults (sibling); 75%/63% (matched unrelated)
IST Antithymocyte globulin (ATG) (โ†“ activated T cells) + cyclosporine (inhibits T-cell function) for >40 y or no sibling donor. ~โ…” respond; 30โ€“40% relapse. Second course: ~65% response after relapse, 30% if refractory. 10-year survival 75% children, 63% adults
Predictors of IST response PNH cells (CD55โปCD59โป) โ†’ ~2ร— more likely to respond; PNH cells + HLA-DR2 โ†’ 3.5ร—
Not recommended G-CSF, other growth factors, steroids โ€” don’t improve survival or response
Supportive Antibiotic and antifungal prophylaxis in prolonged neutropenia; mildโ€“moderate AA may just be monitored
Late risks after IST 10-year risk of hemolytic/thrombotic PNH; 10โ€“20% risk of MDS or leukemia; monosomy 7 predicts poor outcome

2.7 Inherited Bone Marrow Failure Syndromes (Rodak Table 22-3)

Feature Fanconi Anemia (FA) Dyskeratosis Congenita (DKC) Shwachman-Bodian-Diamond (SBDS)
Frequency Most common inherited AA; 1โ€“5 per million; carrier 1 in 300; 3ร— in Ashkenazi Jews, South African Afrikaners Rare; <600 cases ~8.5 per million live births
Inheritance Autosomal recessive (FANCB X-linked); 15 genes (FANCA most frequent) X-linked recessive (DKC1 โ€” dyskerin), AD (TERC, TERT, TINF2), AR; 8 genes Autosomal recessive; 90% biallelic SBDS mutations
Mechanism Defective DNA damage response (FA core complex โ†’ ID complex โ†’ effector repair proteins); chromosome fragility to cross-linking agents; oxidant hypersensitivity Very short telomeres โ€” defective telomerase complex Ribosome metabolism and mitotic spindle stability defects; short telomeres; abnormal stroma
Clinical Only โ…” have malformations: thumb/radial anomalies, microcephaly, cafรฉ-au-lait spots, short stature, eye/kidney/genital anomalies, low birth weight. Pancytopenia at 5โ€“10 y Triad: abnormal skin pigmentation, dystrophic nails, oral leukoplakia (usually <10 y); median diagnosis 15 y; pulmonary fibrosis, premature gray hair, liver disease Exocrine pancreatic insufficiency (malabsorption in infancy), neutropenia with infections, delayed bone maturation, failure to thrive, short stature
Blood Pancytopenia, โ†“ retic, MCV โ†‘ (macrocytosis often first); thrombocytopenia often precedes others; Hb F โ†‘; โ†‘ ฮฑ-fetoprotein Pancytopenia, macrocytic RBCs, Hb F โ†‘; 80โ€“90% marrow abnormalities by 30 y Nearly all neutropenia (<1.5 ร— 10โน/L); ยฝ anemia or thrombocytopenia; ยผ pancytopenia; โ…” โ†‘ Hb F; RBCs usually normocytic
Marrow Hypocellular Hypocellular Usually hypocellular (can be normal or hypercellular)
Diagnostic test Chromosome breakage of cultured lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC) โ€” breaks and ring chromosomes. 10โ€“15% false-negative from somatic mosaicism โ†’ test skin fibroblasts Mutation testing (~40โ€“75% identified); flow-FISH for very short telomeres in multiple WBC subsets 72-h fecal fat โ†‘; โ†“ serum trypsinogen and isoamylase for age; normal sweat chloride (vs cystic fibrosis); SBDS gene testing
Cancer risk >90% marrow failure by 40 y; โ…“ MDS/AML (median 14 y); ยผ solid tumors (median 26 y) โ€” head/neck, anogenital, vulvar (4300ร—), esophageal (2300ร—), AML (800ร—) 40% cancer by 50 y (AML, MDS, epithelial) AML/MDS 19% at 20 y, 36% at 30 y
Treatment Transfusions, G-CSF/GM-CSF; HSCT only cure (screen siblings; reduced-intensity conditioning); gene therapy unsuccessful Transplant limited by pulmonary fibrosis; androgens give transient response in 50โ€“70%; median survival 42 y G-CSF, transfusions, pancreatic enzyme replacement; transplant for severe disease/MDS/AML; 5-y survival 60โ€“65%
๐Ÿงช PRE-ANALYTICAL โ€” Chromosome breakage (DEB/MMC) test*
  • Sodium heparin peripheral blood, fresh, room temperature, shipped promptly to a cytogenetics lab (lymphocytes must be viable to culture)
  • Recent transfusion can dilute patient lymphocytes; mosaicism can give a false negative โ†’ skin fibroblast culture (Rodak)

2.8 Differentiating Causes of Pancytopenia (Rodak Table 22-2)

Condition Peripheral Blood Bone Marrow Lab Tests Clinical
Aplastic anemia No immature WBCs/RBCs; โ†“ retic; MCV โ†‘/N Hypocellular; no blasts/abnormal cells; reticulin N; RBC dyspoiesis possible; no WBC/PLT dyspoiesis PNH cells may be present; chromosome abnormalities possible No splenomegaly
PNH Retic โ†‘; MCV N/โ†‘; nRBCs ยฑ Erythroid hyperplasia; may be hypocellular PNH cells (CD59โป RBCs; CD24, CD16, CD14โป WBCs); hemoglobinuria ยฑ No splenomegaly; thrombosis possible
MDS Variable pancytopenia; โ†“ retic; MCV N/โ†‘; blasts and abnormal cells Hypercellular (20% hypocellular); dyspoiesis in โ‰ฅ1 line; blasts; reticulin โ†‘ Chromosome abnormalities usual Splenomegaly uncommon
Megaloblastic MCV โ†‘; oval macrocytes; hypersegs Hypercellular, megaloblastic โ†“ Bโ‚โ‚‚ and/or folate No splenomegaly
Acute leukemia Blasts Hypercellular; blasts โ†‘; reticulin โ†‘ Chromosome abnormalities possible Splenomegaly possible
Hairy cell leukemia Hairy cells; monocytes โ†“ Hairy cells + fibrosis; reticulin โ†‘ Flow CD19, CD20, CD22, CD11c, CD25, CD103, FMC7; TRAP + Splenomegaly 60โ€“70%

Other mimics: lymphoma, myelofibrosis, mycobacterial infections; anorexia nervosa (hypocellular marrow with โ†“ fat cells โ€” reverses with correction).

2.9 Pure Red Cell Aplasia (PRCA)

Feature Details
Definition Selective, severe โ†“ of erythroid precursors in an otherwise normal marrow โ†’ severe (usually normocytic) anemia, reticulocytopenia, normal WBC and platelets
Acquired โ€” primary Idiopathic or autoimmune
Acquired โ€” secondary Thymoma, hematologic malignancy, solid tumors, infection, chronic hemolytic anemia, collagen vascular disease, drugs/chemicals
Acquired โ€” treatment Treat underlying cause; immunosuppression โ€” cyclosporine (65โ€“87% response) better than corticosteroids (30โ€“62%)
TEC (transient erythroblastopenia of childhood) Acquired PRCA in young children; viral history in ~ยฝ โ†’ immune suppression of red cell production; normocytic, Hb F and erythrocyte ADA usually normal; transfusion if symptomatic; recovers in weeks
DBA (Diamond-Blackfan anemia) Congenital erythroid hypoplasia of infancy; 7โ€“10 per million; >90% in first year (median 8 weeks). Ribosomal protein genes โ€” RPS19 (~25%), RPS7/10/17/24/26, RPL5/11/35A; ~50% autosomal dominant. ~ยฝ have craniofacial anomalies, short stature, thumb malformations. Severe macrocytic anemia with reticulocytopenia; WBC N/โ†“, PLT N/โ†‘; normal karyotype
DBA treatment RBC transfusions, corticosteroids (50โ€“75% respond; side effects); overall survival 75% at 40 y; transplant >90% survival <10 y with matched-related donor

DBA vs TEC (Rodak Table 22-4)

Test Result (% of patients) DBA TEC
Erythrocyte ADA โ†‘ at diagnosis 85% 5%
MCV โ†‘ at diagnosis 80% 5%
MCV โ†‘ in remission 80% 0%
Hb F โ†‘ at diagnosis 50โ€“85% 1โ€“2%
Hb F โ†‘ in remission 50โ€“85% 0%

2.10 Congenital Dyserythropoietic Anemias (CDA)

Feature CDA I CDA II (HEMPAS) CDA III
Inheritance / gene AR ยท CDAN1 (codanin-1, chr 15) AR ยท SEC23B (chr 20; COPII vesicle transport) โ€” most common AD (familial, Swedish family) ยท KIF23 (cytokinesis) โ€” least common
Hb 6.5โ€“11.5 (mean 9.5) g/dL 9โ€“12 (mean 11) g/dL 8โ€“14 (mean 12) g/dL โ€” mild
Blood Macrocytic; poikilocytosis, basophilic stippling, Cabot rings Normocytic; aniso/poikilocytosis, basophilic stippling Macrocytic; poikilocytosis, basophilic stippling
Marrow Megaloblastoid; internuclear chromatin bridges; <5% binucleated; spongy ‘Swiss cheese‘ heterochromatin (EM) Normoblastic; 10โ€“35% binucleated, rare multinucleated; pseudo-Gaucher cells Megaloblastoid; giant multinucleated erythroblasts (up to 12 nuclei)
Special test EM Positive Ham acidified-serum test (not sucrose hemolysis); anti-i agglutination; abnormal band 3 migration on SDS-PAGE โ€”
Clinical Malformations of fingers/toes, pigmentation, neurologic; iron overload; splenomegaly, hepatomegaly Iron overload, jaundice, gallstones, splenomegaly Rarely needs transfusion; no iron overload
Treatment Interferon-ฮฑ, iron chelation Splenectomy, iron chelation Usually none

All CDAs: refractory anemia, reticulocytopenia, hypercellular marrow with ineffective erythropoiesis and distinctive dysplasia; megaloblastoid changes not due to Bโ‚โ‚‚/folate; granulopoiesis and thrombopoiesis normal; secondary hemosiderosis even without transfusion (hemolysis + โ†‘ iron absorption); jaundice, gallstones, splenomegaly; do not progress to aplastic anemia or malignancy. Types IVโ€“VII are rare/controversial.

2.11 Myelophthisic Anemia

Feature Details
Definition Infiltration of marrow by abnormal cells that destroy/replace normal hematopoiesis
Infiltrates Metastatic tumors (lung, breast, prostate), leukemia, fibroblasts, inflammatory cells (miliary TB, fungal infection)
Mechanisms Cytokines/growth factors suppress hematopoiesis; disrupted architecture releases immature cells; stem cells move to spleen and liver (extramedullary hematopoiesis), which also release immature cells
Blood Mildโ€“moderate normocytic anemia, reticulocytopenia; teardrop cells, nucleated RBCs, immature myeloid cells (leukoerythroblastic picture), megakaryocyte fragments, giant platelets
Diagnosis Infiltrating cells seen on marrow aspirate or biopsy

2.12 Anemia of Chronic Kidney Disease

Feature Details
Primary cause Inadequate renal EPO production
Contributors Uremia (inhibits erythropoiesis, โ†‘ RBC fragility); blood loss and iron deficiency from hemodialysis and blood draws; inflammation; restricted diet
Blood Normocytic, normochromic, reticulocytopenia; burr cells common with uremia
Monitoring (KDOQI) Annual Hb in CKD; evaluate anemia if Hb <13.5 g/dL (men) or <12 g/dL (women)
Treatment Recombinant EPO or other ESAs; target Hb 11โ€“12 g/dL; >13 g/dL not recommended (cardiovascular/thromboembolic risk)
Iron targets % sat >20%; ferritin >100 ng/mL (non-dialysis) or >200 ng/mL (hemodialysis); iron not routinely given if ferritin >500 ng/mL
Functional iron deficiency (FID) Marrow can’t release iron fast enough for ESA-driven erythropoiesis: % sat <20% with normal/โ†‘ ferritin; responds to IV iron. Proposed criteria: โ†“ CHr, โ†‘ sTfR, >10% hypochromic RBCs
Other ESA hyporesponsiveness Chronic inflammation, infection, malignancy, aplastic anemia, antibody-mediated PRCA, thalassemia, myeloma, Hb H or Hb S
๐Ÿงช PRE-ANALYTICAL โ€” CKD anemia monitoring*
  • Draw pre-dialysis samples for Hb and iron studies (dialysis shifts fluid and iron values)
  • Check iron studies before IV iron doses (IV iron falsely raises serum iron for days)
  • Ferritin is also an acute phase reactant โ€” interpret with inflammation

*From general laboratory practice, not stated in Rodak Ch. 22.

3 ยท Visual Memory Hooks

๐Ÿง  Aplastic anemia features
โ€œPancytopenia, Retic-penia, Fat marrow, No stem cells โ€” and NO spleen, NO blasts, NO fibrosisโ€.
๐Ÿง  Etiology split
โ€œ70-15-15โ€ โ†’ ~70% idiopathic, 10โ€“15% secondary (acquired), 15โ€“20% inherited.
๐Ÿง  Dose-dependent vs idiosyncratic
โ€œChemo, Benzene, Radiation = Predictable; Chloramphenicol & friends = Surpriseโ€.
๐Ÿง  Mechanism
โ€œCD8 T cells + IFN-ฮณ/TNF-ฮฑ Torch the Tree (stem cells)โ€.
๐Ÿง  Severity
โ€œSAA: <25% cells, <0.5 PMN, <20 PLT, <20 retic โ€” VSAA if PMN <0.2โ€.
๐Ÿง  Treatment
โ€œUnder 40 with a Sibling โ†’ Stem cells; otherwise ATG + Cyclosporineโ€.
๐Ÿง  Fanconi
โ€œFanconi Fractures chromosomes with DEBโ€ โ†’ thumbs, short stature, cafรฉ-au-lait, cancer.
๐Ÿง  DKC triad
โ€œSkin, Nails, Mouth โ€” telomeres too Shortโ€ โ†’ pigmentation, dystrophic nails, leukoplakia.
๐Ÿง  SBDS
โ€œShwachman = Stool fat + Sick neutrophils; Sweat test normalโ€.
๐Ÿง  DBA vs TEC
โ€œDBA = Big cells, Babies, ADA โ†‘, Hb F โ†‘; TEC = Temporary, Toddlers, Totally normal indicesโ€.
๐Ÿง  CDA
โ€œI = bridges (Internuclear), II = Two nuclei + Ham positive (HEMPAS), III = gIant (up to 12 nuclei)โ€.
๐Ÿง  Myelophthisic
โ€œTeardrops + nRBCs + young granulocytes = something’s Invading the marrowโ€.
๐Ÿง  CKD
โ€œKidneys Kill EPO โ†’ normocytic + burr cellsโ€; target Hb 11โ€“12.
๐Ÿง  Hairy cell vs AA
โ€œHairy = big spleen, low monos, TRAP +; Aplastic = no spleenโ€.

Pattern Triggers

If you seeโ€ฆ Thinkโ€ฆ Becauseโ€ฆ
Pancytopenia, โ†“ retic, MCV โ†‘/N, hypocellular marrow, no blasts, no spleen Aplastic anemia Stem cell depletion
Pancytopenia weeks after non-A, non-B, non-C hepatitis Hepatitis-associated aplastic anemia Immune-mediated (IFN-ฮณ, cytokines)
Pancytopenia after chloramphenicol, sulfonamides, gold, carbamazepine Idiosyncratic drug-induced AA Unpredictable, dose-independent
Aplastic anemia + small CD59-negative RBC population PNH clone in AA ~โ…” have small clones; predicts IST response
Child with thumb anomalies, short stature, cafรฉ-au-lait, macrocytosis, โ†‘ Hb F Fanconi anemia โ†’ DEB/MMC test Chromosome fragility
Nail dystrophy, oral leukoplakia, reticulated pigmentation, pancytopenia Dyskeratosis congenita Telomerase defect
Infant with steatorrhea, neutropenia, normal sweat chloride Shwachman-Bodian-Diamond syndrome Pancreatic insufficiency + marrow failure
Infant <1 y with macrocytic anemia, โ†‘ Hb F, โ†‘ erythrocyte ADA, thumb anomaly Diamond-Blackfan anemia RPS gene mutation
Toddler after viral illness, normocytic anemia, โ†“ retic, normal Hb F/ADA Transient erythroblastopenia of childhood Transient immune suppression
Adult with isolated severe anemia, โ†“ retic, normal WBC/PLT, anterior mediastinal mass Acquired PRCA with thymoma Secondary PRCA
Refractory anemia, โ†“ retic, hemosiderosis, binucleated erythroid precursors CDA II (HEMPAS) Positive Ham test
Teardrops, nRBCs, myelocytes, history of breast cancer Myelophthisic anemia Metastatic infiltration
Normocytic anemia, burr cells, โ†‘ creatinine, โ†“ retic Anemia of CKD EPO deficiency + uremia
CKD on ESA not responding, % sat 15%, ferritin 400 Functional iron deficiency Iron can’t be released fast enough โ†’ IV iron
Pancytopenia, splenomegaly, โ†“ monocytes, TRAP + Hairy cell leukemia Marrow infiltration with fibrosis

Commonly Confused Pairs

Feature A B
Aplastic anemia vs MDS Hypocellular, no dysplasia of WBC/PLT, no blasts, reticulin N Usually hypercellular, dyspoiesis, blasts, reticulin โ†‘
Aplastic anemia vs acute leukemia No blasts, no splenomegaly Blasts, splenomegaly possible
Idiopathic vs idiosyncratic Unknown cause Unpredictable reaction to a known agent
Dose-dependent vs idiosyncratic secondary AA Predictable; recovers after withdrawal Unpredictable; monthsโ€“years later
HSCT vs IST <40 y + HLA-identical sibling ATG + cyclosporine for others
SAA vs VSAA ANC 0.2โ€“0.5 ร— 10โน/L ANC <0.2 ร— 10โน/L
FA vs DKC DEB/MMC chromosome breakage; thumbs Short telomeres; nails/skin/leukoplakia
DBA vs TEC Infant; macrocytic; โ†‘ Hb F and ADA; congenital Young child; normocytic; normal Hb F/ADA; transient
CDA I vs II vs III Chromatin bridges Binucleated + Ham + (III) giant multinucleated
Myelophthisic vs aplastic Leukoerythroblastosis, teardrops No immature cells in blood
PRCA vs aplastic anemia Only erythroid โ†“; WBC/PLT normal All three lines โ†“
Anorexia nervosa vs AA marrow Hypocellular with โ†“ fat cells; reversible Hypocellular with โ†‘ fat

Timeline Table

Event / Group Onset Peak / Median Outcome Best Exam Use
Acquired aplastic anemia Any age Peaks 15โ€“25 y and >60 y โ€” Bimodal age
Hepatitis-associated AA 1โ€“3 months after hepatitis โ€” โ€” Timing clue
Idiosyncratic drug AA Monthsโ€“years after exposure โ€” Hard to prove cause Why history matters
Clonal evolution after IST โ€” 14% abnormal karyotype at 5 y, 20% at 10 y 10โ€“20% MDS/leukemia Monosomy 7, trisomy 8
Fanconi anemia Pancytopenia at 5โ€“10 y MDS/AML median 14 y; solid tumors median 26 y >90% marrow failure by 40 y Age of presentation
Dyskeratosis congenita Skin/nail findings <10 y Median diagnosis 15 y Median survival 42 y Triad first
SBDS Infancy (malabsorption) AML/MDS 19% at 20 y, 36% at 30 y 5-y survival 60โ€“65% Early GI symptoms
DBA >90% in first year Median 8 weeks 75% survival at 40 y Infant anemia
TEC Young children after viral illness โ€” Recovers within weeks Transient
CDA Childhood/adolescence (may be adulthood) โ€” Does not progress to AA/malignancy Chronic course

4 ยท Diagnostic Flowcharts

Flowchart 1 โ€” Pancytopenia: which cause? (Table 22-2)

Pancytopenia โ†’ Film + retic + Bโ‚โ‚‚/folate + marrow biopsy
Blasts in blood/marrow โ†’ Acute leukemia
Hairy cells, โ†“ monocytes, splenomegaly, TRAP + โ†’ Hairy cell leukemia
Oval macrocytes, hypersegs, โ†“ Bโ‚โ‚‚/folate โ†’ Megaloblastic anemia
Dyspoiesis โ‰ฅ1 line, cytogenetic abnormality, usually hypercellular โ†’ MDS
โ†‘ retic, CD59โป RBCs, hemoglobinuria/thrombosis โ†’ PNH
Hypocellular marrow, no blasts/dysplasia, reticulin N, no spleen โ†’ Aplastic anemia โ†’ grade severity, check PNH clone, rule out inherited forms
โš ๏ธ Common mistake: calling a hypocellular MDS ‘aplastic anemia’ โ€” about 20% of MDS cases are hypocellular; look for dysplasia and cytogenetic abnormalities.

Flowchart 2 โ€” Grade aplastic anemia (Table 22-1)

Hypocellular marrow โ†’ Count criteria: ANC, platelets, retic/Hb
Cellularity <25% + โ‰ฅ2 of: ANC <0.5, PLT <20, retic <20 ร— 10โน/L โ†’ Severe (SAA)
SAA criteria + ANC <0.2 ร— 10โน/L โ†’ Very severe (VSAA)
Hypocellular + โ‰ฅ2 of: ANC 0.5โ€“1.5, PLT 20โ€“50, Hb โ‰ค10 with retic <30 ร— 10โน/L โ†’ Moderate (MAA)
Severity guides treatment โ†’ SAA/VSAA โ†’ HSCT or IST ยท MAA โ†’ monitor
โš ๏ธ Common mistake: forgetting that SAA and VSAA share every criterion except the neutrophil count.

Flowchart 3 โ€” Treatment selection in severe acquired AA

SAA confirmed; stop causative agent; transfuse judiciously โ†’ Age and donor?
<40 y with HLA-identical sibling (and sibling not carrying a mutation) โ†’ HSCT
>40 y or no sibling donor โ†’ IST: ATG + cyclosporine (~โ…” respond)
Relapse or refractory โ†’ Second IST course or matched unrelated HSCT
Growth factors or steroids? โ†’ Not recommended โ€” no survival benefit
โš ๏ธ Common mistake: starting G-CSF as primary therapy. It doesn’t improve response or survival.

Flowchart 4 โ€” Child with marrow failure: acquired or inherited?

Child/young adult with cytopenias โ†’ Examine for physical anomalies; family history
Thumb/radial anomalies, short stature, cafรฉ-au-lait โ†’ DEB/MMC chromosome breakage โ†’ Fanconi anemia (fibroblasts if mosaic)
Nail dystrophy, leukoplakia, pigmentation โ†’ Telomere length (flow-FISH), DKC genes
Steatorrhea, neutropenia, normal sweat test โ†’ Fecal fat, trypsinogen, SBDS gene
Isolated macrocytic anemia in infant โ†’ DBA (ADA, Hb F, RPS genes)
None of the above โ†’ Acquired AA workup (still consider cryptic inherited forms)
โš ๏ธ Common mistake: treating inherited AA with IST (much less effective) or transplanting from a sibling with the same mutation.

Flowchart 5 โ€” Isolated anemia with low retic: PRCA, CDA or CKD?

Anemia + โ†“ retic, WBC and PLT normal โ†’ Marrow + creatinine
โ†‘ creatinine, normocytic, burr cells โ†’ Anemia of CKD โ†’ ESA + iron targets
Absent/near-absent erythroid precursors โ†’ PRCA โ†’ infant: DBA ยท child after virus: TEC ยท adult: check thymoma, drugs, tumors
Hypercellular erythroid marrow with bizarre dysplasia, hemosiderosis โ†’ CDA (I bridges ยท II binucleated/Ham + ยท III giant)
Teardrops, nRBCs, immature granulocytes โ†’ Myelophthisic โ†’ find infiltrate on biopsy
โš ๏ธ Common mistake: confusing CDA (hypercellular, ineffective) with PRCA (absent erythroid precursors).

5 ยท 25 High-Yield Facts

# Fact
1 Aplastic anemia shows pancytopenia, reticulocytopenia, marrow hypocellularity and depletion of hematopoietic stem cells.
2 About 80โ€“85% of aplastic anemia is acquired and 15โ€“20% inherited.
3 About 70% of aplastic anemia cases are idiopathic.
4 Cytotoxic drugs, benzene and radiation cause dose-dependent marrow suppression.
5 Idiosyncratic aplastic anemia is unpredictable and unrelated to dose; chloramphenicol is a classic example.
6 Hepatitis (non-A, non-B, non-C) may precede aplastic anemia by 1โ€“3 months.
7 Acquired aplastic anemia is mainly caused by autoimmune cytotoxic CD8โบ T cells releasing IFN-ฮณ and TNF-ฮฑ.
8 Stromal cells and growth factor levels are normal or increased in aplastic anemia.
9 About one-third of acquired aplastic anemia patients have shortened telomeres; about 10% have TERC or TERT mutations.
10 Splenomegaly and hepatomegaly are absent in aplastic anemia.
11 In aplastic anemia, RBCs are macrocytic or normocytic, and blasts are absent.
12 The marrow biopsy shows hypocellularity with normal reticulin and no infiltrates.
13 About two-thirds of aplastic anemia patients have small PNH clones.
14 Severe aplastic anemia requires <25% cellularity plus two of: ANC <0.5, platelets <20, retic <20 ร— 10โน/L.
15 Very severe aplastic anemia is defined by an ANC below 0.2 ร— 10โน/L.
16 HSCT is the treatment of choice for severe aplastic anemia in patients under 40 with an HLA-identical sibling.
17 Immunosuppressive therapy uses antithymocyte globulin plus cyclosporine; about two-thirds respond.
18 Fanconi anemia is the most common inherited aplastic anemia and is diagnosed by DEB or MMC chromosome breakage.
19 Fanconi anemia is autosomal recessive, except FANCB, which is X-linked.
20 Dyskeratosis congenita presents with abnormal skin pigmentation, dystrophic nails and oral leukoplakia due to short telomeres.
21 Shwachman-Bodian-Diamond syndrome combines exocrine pancreatic insufficiency with neutropenia.
22 Diamond-Blackfan anemia is congenital erythroid hypoplasia with macrocytosis and increased Hb F and erythrocyte ADA.
23 Transient erythroblastopenia of childhood follows viral illness and has normal MCV, Hb F and ADA.
24 CDA II (HEMPAS) shows binucleated erythroblasts and a positive Ham acidified-serum test.
25 Anemia of chronic kidney disease is caused mainly by inadequate renal erythropoietin production.
โญ EXAM TIP โ€” The single most testable pattern

Aplastic anemia = empty marrow, empty blood, no spleen, no blasts. Grade it (SAA: <25% cells + 2 of ANC <0.5 / PLT <20 / retic <20; VSAA if ANC <0.2). Treat with HSCT if <40 with a sibling, otherwise ATG + cyclosporine. In a child with anomalies, order DEB for Fanconi.

Quick Interpretation Table

Lab Finding Clinical Interpretation
16-y-old: WBC 2.0, Hb 7.9, MCV 104, PLT 15, retic 16 ร— 10โน/L, ANC 0.5; marrow 15% cellular, no blasts, normal karyotype, PNH negative Severe acquired aplastic anemia (hepatitis-associated) โ†’ HSCT if HLA-identical sibling
Marrow 10%, Hb 7, ANC 0.1, PLT 10 ร— 10โน/L Very severe aplastic anemia
Increased chromosome breaks with DEB Fanconi anemia
Infant, Hb 6, MCV 105, โ†‘ Hb F, โ†‘ erythrocyte ADA Diamond-Blackfan anemia
Refractory anemia, binucleated normoblasts, positive Ham test CDA II (HEMPAS)
Leukoerythroblastic film with teardrops Myelophthisic anemia
CKD patient on ESA, % sat 15%, ferritin 450 ng/mL Functional iron deficiency โ†’ IV iron

๐ŸŽด Flashcards โ€” Active Recall Practice

How it works: tap the card to flip it. Then mark it โœ“ Knew It or โœ— Review Again (buttons unlock after flipping). Use ๐Ÿ”€ Shuffle to randomize and ๐Ÿ Finish anytime โ€” your summary appears at the end, and you can drill only the cards you missed.

๐Ÿ“ Practice Quiz โ€” Test Your Knowledge

How it works: tap an answer for each case. You’ll get instant feedback with the full explanation and the examiner’s trap. Your final score appears once all 10 are answered.

๐Ÿชค Trap Questions โ€” Beat the Examiner

Harder on purpose. Each question targets a real misconception. After answering you’ll see the correct reasoning, the trap explained, why the examiner wrote it, and the wrong answer most students choose.

8 ยท Rapid Revision Sheet

๐Ÿ“– READ THIS 2 HOURS BEFORE YOUR EXAM

AA Numbers

  • Acquired 80โ€“85% ยท inherited 15โ€“20%
  • Idiopathic ~70% ยท secondary 10โ€“15%
  • 1 in 500,000/y (2โ€“3ร— Asia)
  • Peaks 15โ€“25 y and >60 y
  • CD34โบ โ‰ค10% of normal

AA Findings

  • Pancytopenia, โ†“ retic, MCV โ†‘/N
  • Hb usually <10 g/dL
  • No blasts ยท no spleen ยท reticulin N
  • โ†‘ serum iron, โ†‘ % sat
  • โ…” small PNH clones (CD59, CD24, CD14)

Severity

  • SAA: <25% cells + 2 of:
  • ANC <0.5 ยท PLT <20 ยท retic <20 ร— 10โน/L
  • VSAA: ANC <0.2
  • MAA: ANC 0.5โ€“1.5 ยท PLT 20โ€“50 ยท Hb โ‰ค10 + retic <30

AA Treatment

  • HSCT: <40 y + HLA-identical sibling
  • IST: ATG + cyclosporine (โ…” respond)
  • 30โ€“40% relapse
  • No G-CSF/steroids as therapy
  • PLT transfuse <10,000 unless bleeding
  • Monosomy 7 = poor prognosis

Fanconi

  • Most common inherited ยท AR (FANCB XLR)
  • Thumbs, cafรฉ-au-lait, short stature
  • MCV โ†‘ ยท Hb F โ†‘ ยท AFP โ†‘
  • DEB/MMC breakage (fibroblasts if mosaic)
  • >90% BMF by 40 ยท MDS/AML median 14 y

DKC & SBDS

  • DKC: skin, nails, leukoplakia ยท short telomeres
  • DKC1 (dyskerin, XLR), TERC, TERT
  • DKC: flow-FISH ยท median survival 42 y
  • SBDS: pancreatic insufficiency + neutropenia
  • SBDS: โ†“ trypsinogen, normal sweat Clโป

PRCA

  • Only erythroid โ†“ ยท WBC/PLT normal
  • Acquired: thymoma, tumors, drugs ยท cyclosporine
  • TEC: child, post-viral, normocytic, recovers
  • DBA: infant, macrocytic, RPS19, โ†‘ ADA, โ†‘ Hb F
  • DBA: steroids (50โ€“75%)

CDA

  • All: hypercellular, ineffective, hemosiderosis
  • I: AR, CDAN1, bridges, Swiss cheese
  • II: AR, SEC23B, HEMPAS, 10โ€“35% binucleated, Ham +
  • III: AD, KIF23, giant multinucleated (โ‰ค12)
  • Don’t progress to AA or malignancy

Myelophthisic & CKD

  • Myelophthisic: teardrops, nRBCs, immature WBCs
  • Lung, breast, prostate mets; TB, fungi
  • CKD: โ†“ EPO, normocytic, burr cells
  • ESA target Hb 11โ€“12 (not >13)
  • Iron: % sat >20%, ferritin >100 (>200 HD)

Pancytopenia Differential

  • AA: hypocellular, no spleen
  • MDS: dyspoiesis, blasts, โ†‘ reticulin
  • Megaloblastic: hypersegs, โ†“ Bโ‚โ‚‚/folate
  • Leukemia: blasts ยท hairy cell: TRAP +, spleen, โ†“ monos
  • PNH: โ†‘ retic, CD59โป, thrombosis

9 ยท Final Memory Map

  • ๐Ÿฆด BONE MARROW FAILURE
    • Pathophysiology
      • Stem cell destruction ยท premature senescence ยท ineffective ยท microenvironment ยท โ†“ growth factors ยท infiltration
      • Pancytopenia โ†’ fatigue, infection, bleeding
    • Acquired Aplastic Anemia
      • Idiopathic 70% ยท secondary (dose-dependent, idiosyncratic, viral, PNH, autoimmune, pregnancy)
      • CD8 T cells, IFN-ฮณ, TNF-ฮฑ ยท telomeres
      • Hypocellular ยท no blasts ยท no spleen
      • Severity: MAA / SAA / VSAA
      • HSCT vs ATG + cyclosporine
    • Inherited Aplastic Anemia
      • Fanconi (DEB/MMC)
      • Dyskeratosis congenita (telomeres)
      • Shwachman-Bodian-Diamond (pancreas)
    • Differential
      • PNH ยท MDS ยท megaloblastic ยท leukemia ยท hairy cell
      • Anorexia nervosa, lymphoma, myelofibrosis, TB
    • Pure Red Cell Aplasia
      • Acquired (thymoma, drugs) ยท TEC
      • DBA (RPS genes, โ†‘ ADA, โ†‘ Hb F)
    • CDA
      • I bridges ยท II binucleated/Ham + ยท III giant multinucleated
    • Other
      • Myelophthisic: leukoerythroblastosis, teardrops
      • CKD: โ†“ EPO, burr cells, ESA + iron



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