Pancytopenia & Anemia classification
Always ask whether one process unifies all three lines or whether two independent cytopenias coexist.
The pancytopenia question
Pancytopenia is not a diagnosis. It is three lines failing at once — or appearing to. Before you name a marrow disease, ask whether one process unifies all three lines or whether two independent cytopenias are sharing a CBC ().
Infection
Viral: HIV, HBV/HCV, CMV/EBV, parvovirus. Bacterial: brucella, TB. Fungal: histo. Parasitic: leishmania, malaria, schisto. Marrow suppression from infection is reversible; do not miss the treatable one.
Marrow infiltration
Malignant: leukemia, MPN, MDS, myeloma, metastasis. Non-malignant: myelofibrosis, TB, histo, storage disease. Blasts, a leukoerythroblastic smear, or B symptoms push you here.
Marrow failure
Nutrition: ↓ B12, folate, copper, zinc; EtOH; anorexia. Immune destruction or suppression: aplastic anemia, PNH, drugs, LGLL, SLE/RA, sepsis, HLH. Ineffective hematopoiesis: MDS.
Destruction / sequestration
Consumption: autoimmune cytopenias, DIC/TMA. Splenomegaly: portal hypertension/cirrhosis, infection, SLE/RA, and the usual infiltrative suspects.
Congenital
Wiskott–Aldrich, Fanconi anemia, Shwachman–Diamond, dyskeratosis congenita, GATA2 deficiency, familial HLH. Age is a hint, not a rule-out — some present in young adults.
Always consider two independent cytopenias plus a unifying diagnosis. Both can be true.
Workup before you guess
History is the cheapest marrow biopsy: time course, prior treatments and transfusions, autoimmune or oncologic history, social and occupational exposures, travel, infection, and constitutional symptoms.
- Initial labs: CBC with differential, reticulocyte count, special slide (smear), type and screen, LFTs, TSH, iron studies, B12, folate, ESR/CRP, INR/PTT/fibrinogen.
- Add when the story asks: copper, zinc, vitamin E, LDH, haptoglobin, SPEP/SFLC, DAT, uric acid, ANA, HIV, HBV/HCV, CMV, EBV, parvovirus.
- Review meds on purpose: NSAIDs, PPIs, sulfas, antihistamines, chemo, anticonvulsants, antiprotozoals, heavy metals — and anything that arrived in the last month.
Now
Do not wait
Cytopenia plus blasts/'Others', B symptoms, splenomegaly, or a concomitant elevation in another line (for example, platelets falling while WBC is exploding).
Soon
Workup first, then biopsy
If the anemia/cytopenia labs above do not yield a diagnosis, bone-marrow biopsy is the next move — not another week of 'watchful waiting' on a falling ANC.
Anemia at the bedside
Symptoms of anemia are downstream of ↓ oxygen delivery: fatigue, lightheadedness, dyspnea on exertion, pallor, angina if there is CAD, claudication, cramps, abdominal pain, nausea. Compensation is ↑ RR, ↑ cardiac output (tachycardia, palpitations, a flow murmur, later high-output heart failure), and ↑ erythropoiesis that can hurt in the bones ().
- Hemolysis: dark urine, jaundice.
- Nutrient deficiency: glossitis (folate/B12/iron); motor or sensory deficits (B12); pica, koilonychia, angular cheilitis, restless legs (iron).
- Splenomegaly: cirrhosis, infection, thalassemia, malignancy, chronic hemolysis.
- Myeloma clues: constipation, bone pain. GI or menstrual blood loss. Unusual thromboses (PNH). Petechiae and purpura (coagulopathy or pancytopenia). Family history (thalassemia, sickle syndromes).
- 1
Calculate RI
RI = [% retic × (Hct / normal Hct)] / maturation factor. The formula corrects for anemia and for early release of young retics. Normal Hct is ~45%.
- 2
Is the marrow answering?
RI <2% is underproduction. RI >2% is loss or hemolysis. RI <0.1% is aplastic anemia or pure red-cell aplasia until proven otherwise.
- 3
Pick the lab panel
RI <2%: iron/TIBC/ferritin, folate/B12 (if not in the last 6 months), BMP, LFTs, TSH, CRP, and a look at prior CBCs. RI >2%: LDH, bilirubin, haptoglobin, DAT, coags, UA — and ask about recent bleeding.
If underproduction labs are unrevealing: ± SPEP/SFLC, hemoglobin electrophoresis, AM testosterone, EPO, bone-marrow biopsy.
Underproduction (RI <2%)
Once the marrow is quiet, MCV sorts the neighborhood (; ; JACC: Heart Failure;2019;7:36; ).
| MCV | First entities | What the labs add |
|---|---|---|
| Microcytic (<80) | IDA, thalassemia, sideroblastic | Iron studies first, then Mentzer and electrophoresis, then smear/marrow for rings |
| Normocytic (80–99) | AOCD, mixed IDA + B12/folate, organ-specific (kidney, endocrine, marrow) | Ferritin/TIBC, SPEP/SFLC, EPO, TSH, testosterone; marrow if still unexplained |
| Macrocytic (≥100) | Megaloblastic (B12, folate, copper, early MPN) vs non-megaloblastic (cirrhosis, EtOH, retics, hypoT, MDS/MM, meds) | Smear for hypersegmented neutrophils and oval macrocytes; MMA and homocysteine; meds review |
IDA
- ↓ iron, ↑ TIBC, ↓ ferritin (<30 is highly specific; <15 means no stainable iron in the marrow)
- Transferrin saturation (Fe/TIBC) <16%, or <20% when inflammation is present
- ↑ RDW — the cells are not all the same size yet
AOCD / inflammation
- ↓ iron, ↓ or normal TIBC, ↑ ferritin (often >100)
- Saturation ↓ or normal, usually <20%
- Mixed IDA + AOCD is common — ferritin can be 'normal' and still hide iron deficiency
| Microcytic cousin | Pattern | Next test |
|---|---|---|
| Thalassemia | Iron studies normal, MCV often <70, many small cells | Mentzer index (MCV/RBC) <13 is specific; hemoglobin electrophoresis |
| Sideroblastic | ↑ ferritin, saturation normal or high | Smear: basophilic stippling if lead. Marrow: ringed sideroblasts |
Normocytic organ-specific
- Kidney (CKD/ESRD): EPO should rise ~10-fold for every 10% drop in Hct. If it does not, that is the diagnosis.
- Endocrine: thyroid, pituitary, adrenal, parathyroid, testosterone. Lower metabolic rate → lower O2 demand → less EPO.
- Marrow: pure red-cell aplasia, aplastic anemia, MDS, myelofibrosis, myelophthisis, PNH, myeloma — SPEP, serum free light chains, biopsy.
- Dimorphic mixed deficiency (IDA plus ↓ folate/B12): a 'normal' MCV with a high RDW.
Macrocytic — megaloblastic vs not
Megaloblastic (hyperseg PMNs, oval macrocytes)
- Folate: ↑ homocysteine, normal MMA
- B12: ↑ homocysteine and ↑ MMA. Anti-IF antibody and ↑ gastrin if pernicious anemia. B12 level can be falsely normal
- Copper deficiency mimics B12, including the neuropathy
- Early myeloproliferative disease
Non-megaloblastic (MCV usually <110)
- Cirrhosis, alcohol
- Reticulocytosis from hemolysis or bleed (retics are large)
- Hypothyroidism
- MDS (refractory anemia) and myeloma
- Meds: antifolates, purine/pyrimidine analogs, AEDs, HAART, cytarabine, hydroxyurea
Destruction and loss (RI >2%)
A busy marrow means the cells are leaving the bloodstream — bled, lysed, or both. Split first by whether the red cell itself is broken, then by DAT and smear.
Extrinsic to the RBC
- MAHA: DAT-negative, schistocytes (≥2/HPF). Platelets often ~25k. ↑ LDH, ↑ indirect bili, ↓ haptoglobin. Go to the thrombocytopenia page (TTP/HUS/DIC/mechanical).
- Immune: DAT-positive, spherocytes. Warm (CLL, HIV, lymphoma, SLE): DAT IgG ± C3. Cold (EBV, lymphoid malignancy, mycoplasma): DAT C3 only.
- Drugs (penicillin, cephalosporins) and alloimmune (hemolytic transfusion reaction).
- Non-immune, DAT-negative: babesia, malaria, Carrion disease, C. perfringens, H. influenzae type B; lead, copper (Wilson), envenomation, hypotonic infusion; hypersplenism; vitamin E deficiency; mechanical valves and aortic stenosis.
Intrinsic to the RBC
- Hemoglobin disease (SS, HbC, thalassemia): electrophoresis.
- Enzyme: G6PD, pyruvate kinase. G6PD levels are often normal during an acute attack — recheck at 4 weeks and again at 3 months if still negative.
- Membrane: hereditary spherocytosis, elliptocytosis.
- Acquired: PNH — flow cytometry ± FLAER for the GPI anchor, smear is normal, urine hemoglobin/hemosiderin, intra-abdominal or cerebral thrombosis.
- Acute blood loss: GI bleed, large hematoma. This is still RI >2% once the marrow has had time to answer.
Intravascular hemolysis
- ↑↑ LDH, ↓↓ (often undetectable) haptoglobin
- Hemoglobinemia and hemoglobinuria
- PNH, MAHA, ABO mismatch, C. perfringens, severe G6PD
Extravascular hemolysis
- ↑ indirect bilirubin ± mild ↑ LDH ± mild ↓ haptoglobin (if free Hb escapes the spleen)
- Spleen and liver do the work
- Warm AIHA, hypersplenism, membrane defects