Pancytopenia, Aplastic Anemia & Myelodysplastic Syndromes
Empty, invaded, or dysplastic marrow — or a spleen hoarding cells
Approach to pancytopenia
Two mechanisms. When all three lineages are low, either the marrow is not producing — failure (aplastic anemia), clonal disease (MDS), infiltration (leukemia, lymphoma, myeloma, metastatic carcinoma, granulomas, fibrosis), or megaloblastic arrest (B12 or folate deficiency) — or an active marrow's output is lost peripherally. A low reticulocyte count with a normal spleen points to production failure; splenomegaly or evidence of consumption points to peripheral loss.
- Sequestration: hypersplenism, most often from cirrhosis with portal hypertension.
- Immune destruction: SLE and other autoimmune disease.
- Consumption: DIC, sepsis, hemophagocytic lymphohistiocytosis (fever, splenomegaly, very high ferritin).
- Marrow-suppressing infections and toxins: HIV, viral hepatitis, miliary tuberculosis, visceral leishmaniasis; alcohol, chemotherapy, methotrexate, azathioprine.
| Smear finding | Suggests | Next step |
|---|---|---|
| Teardrop cells + leukoerythroblastosis (nucleated RBCs, myelocytes) | Myelophthisis (metastatic breast, prostate, lung cancer; granulomas) or myelofibrosis | Core biopsy — the aspirate is often a dry tap |
| Macro-ovalocytes + hypersegmented neutrophils (≥6 lobes) | B12 or folate deficiency | B12 and folate levels; replace |
| Hypogranular, bilobed (pseudo-Pelger–Huët) neutrophils | MDS | Marrow with cytogenetics |
| Circulating blasts | Acute leukemia or MDS with excess blasts | Marrow with flow cytometry and cytogenetics |
| Schistocytes | DIC or another microangiopathy | PT, aPTT, fibrinogen, D-dimer |
Copper deficiency. After bariatric surgery or with excess zinc (supplements, zinc-containing denture cream), copper deficiency causes anemia and neutropenia with ring sideroblasts that mimic MDS, plus a myeloneuropathy resembling B12 deficiency (sensory ataxia, spastic gait).
Exclude B12, folate, and copper deficiency, alcohol, HIV, and marrow-toxic drugs (methotrexate, azathioprine) before calling anything MDS — all produce macrocytosis and dysplastic-looking cells, and all are reversible.
- CBC, reticulocyte count, smearproduction failure or peripheral loss?
- Reversible causesB12, folate, copper; drug and alcohol history; HIV and hepatitis serologies
- Examine the spleensplenomegaly → hypersplenism or infiltration
- Bone marrow aspirate and core biopsyfor blasts, dysplasia, or unexplained pancytopenia: cellularity, infiltration, fibrosis
- Cytogenetics and flow cytometryMDS karyotype; PNH clone
Aplastic anemia
Definition. Pancytopenia with low reticulocytes and a hypocellular marrow in which fat replaces hematopoietic tissue, without infiltration, fibrosis, or dysplasia. Spleen, lymph nodes, and liver are normal, so splenomegaly argues against the diagnosis. Most cases are immune: cytotoxic T cells, acting partly through interferon-γ, destroy hematopoietic stem cells — which is why immunosuppression works.
Causes. Most cases are idiopathic. Recognized triggers:
- Idiosyncratic drugs: chloramphenicol, carbamazepine, methimazole/PTU, sulfonamides, felbamate. Chloramphenicol also causes a dose-related, reversible marrow suppression, distinct from its rare, dose-independent, often fatal aplasia.
- Benzene; radiation and cytotoxic chemotherapy (predictable and dose-dependent).
- Seronegative (non-A–E) hepatitis, typically in young men, weeks to months after the hepatitis.
- Inherited marrow failure: Fanconi anemia; telomere disorders such as dyskeratosis congenita (nail dystrophy, reticulated skin pigmentation, oral leukoplakia).
PNH overlap and clonal evolution. Flow cytometry for GPI-anchored proteins (CD55/CD59, FLAER) finds PNH clones in up to half of patients. A clone can expand into hemolytic PNH with hemoglobinuria and thrombosis, and aplastic anemia can also evolve into MDS or AML.
Fanconi anemia. An autosomal recessive defect in DNA interstrand crosslink repair. Clues: short stature, café-au-lait spots, absent thumbs or radii, renal anomalies, and marrow failure in childhood, with a high lifetime risk of AML and squamous cell cancers of the head and neck and anogenital region. Chromosome breakage after diepoxybutane or mitomycin C exposure confirms it. Test children and young adults before HSCT: these patients need reduced-intensity conditioning, and sibling donors must be screened.
Supportive care. Stop any suspect drug. Minimize transfusions in potential transplant candidates — alloimmunization raises the risk of graft rejection — and avoid blood from relatives. Give leukoreduced products (fewer HLA antibodies, CMV transmissions, and febrile reactions) that are also irradiated (prevents transfusion-associated GVHD). Transfuse platelets below 10,000/μL or for bleeding, and treat any fever as febrile neutropenia.
Definitive therapy. Matched-sibling allogeneic HSCT is first-line and curative for severe disease in younger patients (generally under 40–50), at the cost of GVHD and graft-failure risk. Older patients and those without a matched sibling receive horse ATG plus cyclosporine plus eltrombopag, a thrombopoietin-receptor agonist that also stimulates stem cells. Responses take 3–6 months, and relapse and clonal evolution (PNH, MDS, AML) remain long-term risks.
| Feature | Aplastic anemia | MDS | Infiltration / fibrosis |
|---|---|---|---|
| Marrow | Hypocellular, fatty | Usually hypercellular | Replaced by tumor, granulomas, or fibrosis; dry tap |
| Dysplasia | Absent | ≥10% of a lineage | Absent |
| Blasts | Not increased | <20% | Variable |
| Spleen | Normal | Usually normal | Often enlarged in myelofibrosis |
| Smear | Few reticulocytes, no abnormal cells | Macro-ovalocytes, pseudo-Pelger–Huët | Teardrops, leukoerythroblastosis |
| Karyotype | Usually normal | Often abnormal | Depends on cause |
Pure red cell aplasia
Findings. Isolated anemia with reticulocytes near zero and absent erythroid precursors in an otherwise normal marrow; white cells and platelets are preserved.
Causes. Thymoma (obtain a chest CT; thymectomy, adding cyclosporine if anemia persists), parvovirus B19, T-cell large granular lymphocyte leukemia, autoimmune disease, drugs, and anti-erythropoietin antibodies after ESA therapy. Diamond–Blackfan anemia is the congenital form in infants.
Parvovirus B19. The virus enters erythroid progenitors through the P antigen (globoside) and leaves giant pronormoblasts. In a healthy host it causes a brief, silent pause in erythropoiesis; with chronic hemolysis (sickle cell disease, hereditary spherocytosis) the pause becomes a transient aplastic crisis; in the immunocompromised (HIV, transplant, chemotherapy) infection persists as chronic PRCA. Diagnose with serum B19 PCR — serology misleads because these patients cannot make antibody — and treat with IVIG, reducing immunosuppression where possible.
Isolated neutropenia
Drug-induced agranulocytosis. An idiosyncratic ANC below 500/μL, usually within the first 3 months of therapy, presenting with fever and sore throat. Classic culprits: clozapine, thionamides (methimazole, PTU), sulfasalazine, TMP-SMX, dapsone, procainamide. Stop the drug permanently — methimazole and PTU cross-react, so never swap one for the other, and clozapine is not restarted. Treat fever as febrile neutropenia with blood cultures and an IV antipseudomonal β-lactam such as cefepime; G-CSF can hasten recovery, which usually comes within 1–3 weeks.
Duffy-null associated neutrophil count. Formerly benign ethnic neutropenia: a stable ANC, often 1,000–1,500/μL, in people of African or Middle Eastern ancestry whose red cells lack the Duffy antigen, Fy(a−b−). Infection risk is not increased and the marrow is normal, so reassure and avoid needless biopsies or withholding of indicated drugs. The Duffy antigen is the Plasmodium vivax receptor, which explains the selection of Duffy-null status in West Africa.
Other causes. Postviral suppression, autoimmune neutropenia (SLE; Felty syndrome with rheumatoid arthritis and splenomegaly), T-cell LGL leukemia, cyclic neutropenia (ELANE mutations, roughly 21-day cycles), and B12, folate, or copper deficiency.
Myelodysplastic syndromes
Who gets MDS. A clonal stem cell disorder of older adults (median age about 70) and of patients with prior chemotherapy, radiation, or benzene exposure. Therapy-related MDS after alkylating agents appears about 5–10 years later, often with chromosome 5 or 7 losses, and has a poor prognosis. Clonal hematopoiesis of indeterminate potential (CHIP: somatic mutations, normal counts) is a precursor state.
Ineffective hematopoiesis. The marrow is usually hypercellular, yet cells die before release, producing macrocytic anemia with or without neutropenia and thrombocytopenia — often found incidentally, or with fatigue, infection, or bleeding.
Diagnosis. The smear shows macro-ovalocytes and hypogranular, bilobed pseudo-Pelger–Huët neutrophils. The marrow shows dysplasia in at least 10% of a lineage, micromegakaryocytes, and ring sideroblasts — erythroid precursors whose iron-laden mitochondria encircle the nucleus on Prussian blue stain, associated with SF3B1 mutation. Blasts are below 20%; at 20% or more the disease is AML. Karyotype drives prognosis: isolated del(5q) is favorable, while monosomy 7, complex karyotype, and TP53 mutation are poor. IPSS-R and the molecular IPSS-M combine blasts, karyotype, mutations, and depth of cytopenias into lower- and higher-risk groups; higher-risk disease usually means excess blasts (5–19%), a poor karyotype, or TP53 mutation.
| Feature | Lower-risk MDS | Higher-risk MDS |
|---|---|---|
| Goal | Transfusion independence, quality of life | Delay AML, prolong survival, cure if possible |
| Core therapy | RBC transfusion (chelate if heavily transfused); ESA if serum EPO ≤500 mU/mL; luspatercept first line or after ESA failure, especially with ring sideroblasts/SF3B1 | Azacitidine or decitabine (DNA methyltransferase inhibitors); azacitidine prolongs survival |
| Special case | Del(5q): lenalidomide | Fit patient: allogeneic HSCT |
| Cure | Seldom pursued | Allogeneic HSCT is the only cure |
5q− syndrome. Typically an older woman with macrocytic anemia, normal or high platelets, and hypolobated megakaryocytes. Lenalidomide often produces transfusion independence; monitor for cytopenias and venous thromboembolism.
MDS can transform into AML, and infection, bleeding, and transfusional iron overload are the other major threats over time.