7.2 Macrocytic, Normocytic & Hemolytic Anemias

ABIM Internal Medicine Exam

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7.1 Approach to Anemia & the Microcytic Anemias 7.2 Macrocytic, Normocytic & Hemolytic Anemias 7.3 Hemoglobinopathies, Thalassemias & Paroxysmal Nocturnal Hemoglobinuria 7.4 Platelet Disorders, Thrombocytopenia & the Bleeding Patient 7.5 Coagulation Factor Disorders, Thrombophilia & Anticoagulant Reversal 7.6 Acute Leukemias, Chronic Leukemias & Myeloproliferative Neoplasms 7.7 Lymphomas & Plasma Cell Disorders 7.8 Myelodysplastic Syndrome, Myeloproliferative Neoplasms & Porphyria 7.9 Transfusion Medicine & Late Complications of Transplantation

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7.2 Macrocytic, Normocytic & Hemolytic Anemias

Key Takeaways Explain This Topic AI

Glucose-6-phosphate dehydrogenase deficiency, autoimmune hemolytic anemia and microangiopathic hemolytic anemia are the enumerated hemolytic anemia topics, and the direct antiglobulin test separates the immune from the non-immune causes.

Methylmalonic acid is elevated in vitamin B12 deficiency but normal in folate deficiency, which distinguishes the two when levels are borderline.

Correcting folate without correcting vitamin B12 can precipitate irreversible neurologic injury.

Warm autoimmune hemolysis is IgG-mediated and responds to corticosteroids, whereas cold agglutinin disease is complement-mediated and requires cold avoidance with rituximab rather than steroids.

A glucose-6-phosphate dehydrogenase assay can be falsely normal during an acute episode because the deficient older cells have already been destroyed, so it must be repeated about three months later.

Last updated: August 2026

1. Macrocytic Anemias (MCV > 100 fL)

Macrocytic anemias are categorized based on peripheral blood smear morphology into megaloblastic and non-megaloblastic etiologies.

Megaloblastic vs. Non-Megaloblastic Macrocytosis

Megaloblastic Anemias: Caused by impaired DNA synthesis with preserved RNA/protein synthesis (nuclear-cytoplasmic dyssynchrony). Peripheral blood smear shows hypersegmented neutrophils (≥ 1 neutrophil with ≥ 6 lobes, or ≥ 5% of neutrophils with ≥ 5 lobes) and large oval macrocytes (macro-ovalocytes).

Non-Megaloblastic Macrocytosis: Intact DNA synthesis; smear shows round macrocytes without neutrophil hypersegmentation. Etiologies include chronic alcohol consumption, chronic liver disease, marked reticulocytosis, hypothyroidism, and myelodysplastic syndrome (MDS).

Vitamin B12 (Cobalamin) vs. Folate Deficiency

Diagnostic Feature Vitamin B12 (Cobalamin) Deficiency Folate (Vitamin B9) Deficiency

Body Stores & Time to Depletion High hepatic stores; takes 3 to 5 years to deplete Minimal body stores; takes 3 to 4 months to deplete

Primary Etiologies Pernicious anemia (autoantibodies against Intrinsic Factor [anti-IF, 95% specific] or gastric parietal cells), ileal resection, Crohn disease involving terminal ileum, strict vegan diet, Metformin (interferes with calcium-dependent ileal uptake), chronic PPI / H2RA therapy, Diphyllobothrium latum Malnutrition (elderly, severe alcohol abuse), increased requirement (hemolysis, pregnancy), malabsorption (celiac disease), medications: Methotrexate, Trimethoprim, Pyrimethamine (dihydrofolate reductase inhibitors), Phenytoin, Sulfasalazine

• Serum Methylmalonic Acid (MMA) Elevated (> 0.40 mcmol/L) Normal
• Serum Total Homocysteine Elevated Elevated

Neurologic Manifestations Yes: Subacute Combined Degeneration (SCD) of the spinal cord (demyelination of dorsal columns [loss of vibration, fine touch, proprioception, sensory ataxia] and lateral corticospinal tracts [spasticity, hyperreflexia, extensor plantars]); peripheral neuropathy; cognitive decline ("megaloblastic madness") No: Purely hematologic manifestations; neurological deficits are absent

Repletion Rule Replete B12 (1000 mcg IM daily x 1 week, then weekly x 4 weeks, then monthly; or high-dose oral 1000–2000 mcg daily) MANDATORY: Always rule out or concurrently treat B12 deficiency before administering high-dose folate; folate corrects the anemia but permits irreversible progression of subacute combined degeneration

2. Normocytic & Hemolytic Anemias

Hemolysis represents premature destruction of circulating red blood cells (erythrocyte lifespan < 120 days).

Laboratory Hallmarks of Active Hemolysis

Increased RBC Turnover: Elevated Serum Lactate Dehydrogenase (LDH) and Elevated Indirect (Unconjugated) Bilirubin with normal liver enzymes.

Free Hemoglobin Binding: Decreased or undetectable Serum Haptoglobin (haptoglobin binds free hemoglobin dimers; complex is cleared by hepatic reticuloendothelial system).

Marrow Response: Reticulocytosis (Corrected RI ≥ 2.0%), polychromasia, and nucleated RBCs.

Intravascular-Specific Markers: Free hemoglobinemia, hemoglobinuria (dipstick positive for blood without intact RBCs on urinalysis), and urinary hemosiderinuria (positive Prussian blue stain on urine sediment 3–7 days post-hemolysis).

Autoimmune Hemolytic Anemias (AIHA)

Feature Warm Autoimmune Hemolytic Anemia (Warm AIHA) Cold Agglutinin Disease (CAD)

Antibody Class & Thermal Amplitude IgG autoantibodies; maximal binding at 37°C IgM autoantibodies; binds RBCs at 0°C to 4°C

Site & Mechanism of Hemolysis Extravascular: IgG-coated RBCs are recognized by splenic macrophage Fc receptors → partial phagocytosis creates Microspherocytes Intravascular / Extravascular: IgM binds RBCs in cold extremities → activates classic complement cascade → C3b opsonization leads to hepatic Kupffer cell clearance, or MAC complex (C5b-9) triggers intravascular lysis

Direct Antiglobulin Test (DAT / Coombs) Positive for IgG or IgG + C3d Positive for C3d ONLY (IgM dissociates at 37°C during laboratory washing)

Peripheral Smear Abundant microspherocytes , polychromasia RBC agglutination / clumping (grossly visible in tube, elevated spurious MCHC > 36 g/dL)

Associated Conditions Idiopathic (50%), Systemic Lupus Erythematosus (SLE), Chronic Lymphocytic Leukemia (CLL), Non-Hodgkin Lymphoma, Drugs (Cephalosporins, Penicillins, Methyldopa, Fludarabine) Mycoplasma pneumoniae infection, Epstein-Barr Virus (EBV / infectious mononucleosis), Waldenström Macroglobulinemia, marginal zone lymphoma

Clinical Triggers Unrelated to temperature Cold ambient temperature exposure: acrocyanosis, livedo reticularis, Raynaud phenomenon, painful dusky fingers/toes/nose/ears

First-Line Management High-dose Oral Prednisone (1.0–1.5 mg/kg/day) ; add Rituximab early for severe disease Strict cold avoidance / thermal protection ; First-line medical therapy is Rituximab (alone or + Bendamustine) or Sutimlimab (monoclonal C1s complement inhibitor)

Ineffective Therapies Transfusion (use least incompatible blood if life-threatening) Corticosteroids and Splenectomy are completely INEFFECTIVE (splenic clearance does not occur in IgM/C3b-mediated disease)

3. Enzymopathy, Fragmentation & Drug-Induced Hemolysis

The direct antiglobulin test splits the hemolytic anemias into two halves. A positive test means antibody-mediated destruction — the warm and cold syndromes above, plus drug-induced immune hemolysis. A negative test moves the differential to the non-immune causes: enzyme defects, membrane defects, hemoglobinopathies, and mechanical fragmentation. The three non-immune categories below account for most remaining board items.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common human enzyme defect, affecting roughly 400 million people worldwide. It is X-linked recessive , so it is fully expressed in males; heterozygous females have two red cell populations and hemolyze to a degree that depends on lyonization.

Mechanism: G6PD is the rate-limiting enzyme of the hexose monophosphate shunt, which is the mature red cell's only source of NADPH. Mature erythrocytes have no nucleus and no mitochondria, so they cannot regenerate the enzyme. Without NADPH, reduced glutathione cannot be regenerated, and oxidant stress denatures hemoglobin into precipitates called Heinz bodies — visible only with a supravital stain such as crystal violet, never on the routine Wright-Giemsa smear. Splenic macrophages pluck the rigid precipitates out of passing cells, leaving the "bite cells" (degmacytes) and blister cells that do appear on the ordinary smear.

Two variants with different severity:

Variant Population Enzyme Kinetics Clinical Severity

G6PD A- African ancestry; about 10-15% of Black males in the United States Enzyme is unstable, so only older red cells are deficient Self-limited, mild-to-moderate hemolysis; the young cells released in response survive, so the hemoglobin recovers even if exposure continues

G6PD Mediterranean Mediterranean, Middle Eastern, and South Asian ancestry Enzyme is deficient in cells of all ages Severe hemolysis that may require transfusion; favism — brisk hemolysis after eating fava beans — occurs in this variant

Triggers: infection is the single most common precipitant ; then oxidant drugs — dapsone, primaquine and tafenoquine, rasburicase, nitrofurantoin, sulfamethoxazole, methylene blue, phenazopyridine , and high-dose intravenous vitamin C — and fava beans . Diabetic ketoacidosis can also precipitate an episode.

Presentation: abrupt intravascular hemolysis beginning 24-72 hours after exposure, with jaundice, dark cola-colored urine, back or abdominal pain, a falling hemoglobin, a high LDH, an elevated indirect bilirubin, and an absent haptoglobin. The direct antiglobulin test is negative .

The diagnostic trap tested most often: a quantitative G6PD assay drawn during the acute episode can be falsely normal , because the deficient older cells have already been destroyed and the surviving reticulocytes released in response are enzyme-replete. Confirm by repeating the assay roughly 3 months after the episode has resolved, once the red cell population has re-aged.

Management: withdraw the oxidant, support with hydration, and transfuse only for severe or symptomatic anemia; most episodes are self-limited. Screen for G6PD deficiency before prescribing dapsone or rasburicase — rasburicase is contraindicated because it generates hydrogen peroxide and causes both severe hemolysis and methemoglobinemia. Note that methylene blue, the usual antidote for methemoglobinemia, is itself contraindicated in G6PD deficiency because its reduction requires NADPH; use ascorbic acid or exchange transfusion instead.

Microangiopathic Hemolytic Anemia (MAHA)

MAHA is mechanical fragmentation of red cells forced through fibrin strands or damaged endothelium. It is defined by schistocytes (helmet cells and fragments) on the smear together with a high LDH, an absent haptoglobin, and an elevated indirect bilirubin — and, critically, a negative direct antiglobulin test , which is what separates fragmentation hemolysis from autoimmune hemolysis at the bedside.

• Cause Distinguishing Feature
• Thrombotic thrombocytopenic purpura (TTP) ADAMTS13 activity < 10%; normal PT/aPTT and normal fibrinogen
• Shiga toxin-mediated HUS Preceding bloody diarrhea, prominent acute kidney injury, usually in children

Complement-mediated (atypical) HUS Dysregulated alternative complement pathway; treated with eculizumab or ravulizumab

Disseminated intravascular coagulation The one MAHA with a prolonged PT/aPTT, a low fibrinogen, and high D-dimer

Malignant hypertension / scleroderma renal crisis Extreme blood pressure with retinopathy; the hematologic picture resolves with blood pressure control

• Preeclampsia with severe features / HELLP Pregnancy after 20 weeks; transaminitis and thrombocytopenia
• Disseminated malignancy Often with a leukoerythroblastic smear and marrow infiltration
• Mechanical shear Prosthetic valve dysfunction, paravalvular leak, or a ventricular assist device

Drug-induced Quinine (classically abrupt after a single exposure), gemcitabine, tacrolimus and cyclosporine, VEGF inhibitors

The urgent decision is TTP versus everything else : unexplained MAHA plus thrombocytopenia is TTP until proven otherwise and warrants emergent plasma exchange without waiting for the ADAMTS13 result. Platelet transfusion is avoided in suspected TTP unless there is life-threatening bleeding. Detailed management is developed with the platelet disorders in the following material.

Drug-Induced Immune Hemolytic Anemia

Distinct from the oxidant hemolysis of G6PD deficiency, these are antibody-mediated and therefore direct antiglobulin test positive .

Hapten / drug-adsorption type: high-dose penicillins and cephalosporins coat the red cell membrane; antibody binds the drug-membrane complex, producing gradual extravascular hemolysis. The test is positive for IgG.

Immune-complex / neoantigen type: classically ceftriaxone and cefotetan , and also piperacillin. Antibody binds a drug-membrane neoantigen and fixes complement, causing abrupt, severe intravascular hemolysis that can be fatal within hours of a repeat dose. The test is positive for C3.

True autoantibody induction: methyldopa, fludarabine, and immune checkpoint inhibitors induce an antibody indistinguishable from idiopathic warm autoimmune hemolysis; it may persist for months after the drug is stopped.

Management in every subtype begins with stopping the offending drug and avoiding future exposure to it and to closely related agents. Corticosteroids are added for severe or persisting hemolysis, particularly in the autoantibody type.