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Anemia - Complete University Exam Guide

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1. Definition

• Men: < 13 g/dL
• Women: < 12 g/dL
• Pregnant women: < 11 g/dL

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2. Classification

A. By Red Cell Size (MCV-based) - Wintrobe Classification

Macrocytic anemias are further divided: oval macrocytes (megaloblastic - B12/folate/drugs) vs. round macrocytes (alcohol, liver disease, hypothyroidism, reticulocytosis).

B. By Mechanism (Reticulocyte-Based)

At least 75% of all anemias are hypoproliferative. The most common cause is mild-moderate iron deficiency or inflammation. - Harrison's 22e

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3. Diagnostic Approach - Flowchart

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4. Major Anemia Types

4.1 Iron Deficiency Anemia (IDA)

• Blood loss (most common in adults - GI bleeding, menstruation)
• Poor intake / malabsorption (celiac disease)
• Increased demand (pregnancy, growth)

• Iron required for heme synthesis (4 atoms per hemoglobin molecule, ~1 billion per RBC)
• Depletion stages: depleted stores → transport iron falls → hemoglobin synthesis impaired

Ferritin is an acute-phase reactant - it can be falsely normal/elevated in inflammation even with iron deficiency.

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4.2 Megaloblastic Anemia (B12 and Folate Deficiency)

• Causes: Pernicious anemia (lack of intrinsic factor - autoimmune), strict veganism, malabsorption, gastrectomy, Crohn's disease, metformin use
• Blood smear: Macrocytic RBCs, hypersegmented neutrophils (>5 lobes)
• Bone marrow: Hypercellular with large abnormal red cell precursors
• Neurological features: Subacute combined degeneration of spinal cord (posterior + lateral columns) - does NOT occur with folate deficiency

• Causes: Poor diet, alcohol use, pregnancy, malabsorption, drugs (methotrexate, phenytoin, trimethoprim)
• Identical hematologic picture to B12 deficiency
• No neurological complications

EXAM TRAP: Giving folate to a B12-deficient patient will correct the anemia but will NOT prevent neurological damage - and may actually mask B12 deficiency. Always check B12 before treating.

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4.3 Anemia of Chronic Disease / Inflammation (ACD)

• Chronic inflammation (infection, cancer, autoimmune disease, CKD) elevates cytokines (IL-6, TNF-α)
• IL-6 stimulates liver to produce hepcidin
• Hepcidin blocks ferroportin → traps iron inside macrophages → functional iron deficiency
• Reduced EPO production and EPO responsiveness
• Result: RBCs can't be made despite adequate iron stores

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4.4 Hemolytic Anemias

• High reticulocyte count
• Elevated LDH
• Elevated indirect (unconjugated) bilirubin
• Low haptoglobin
• Hemoglobinuria (in intravascular hemolysis)

Key Hemolytic Subtypes:

• Point mutation: glutamate → valine at position 6 of β-globin chain
• HbS polymerizes when deoxygenated → RBCs sickle
• Results in vaso-occlusion, hemolysis, chronic end-organ damage
• Complications: painful crises, stroke, acute chest syndrome, splenic sequestration, avascular necrosis
• Peripheral smear: sickle cells, target cells, Howell-Jolly bodies (functional asplenia)

• X-linked recessive enzyme defect
• RBCs vulnerable to oxidative stress
• Triggers: infections, fava beans, medications (primaquine, dapsone, nitrofurantoin)
• Peripheral smear: Heinz bodies (denatured Hb), bite cells

• Warm AIHA (IgG): most common; caused by autoantibodies at 37°C - spleen destroys coated RBCs
• Cold AIHA (IgM): triggered by cold; complement activation
• Diagnosis: Direct Antiglobulin Test (Coombs) = POSITIVE
• Treatment: steroids (warm AIHA), avoid cold exposure (cold AIHA), rituximab

• Autosomal dominant defect in spectrin/ankyrin/band 3 proteins → loss of RBC membrane → spherocytes
• Symptoms: hemolytic anemia + splenomegaly + jaundice + pigment gallstones
• Osmotic fragility test positive; treated by splenectomy in severe cases

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4.5 Aplastic Anemia

• Idiopathic (most common - immune-mediated T-cell destruction of stem cells)
• Drugs: chloramphenicol, NSAIDs, chemotherapy
• Viral infections: hepatitis (seronegative), EBV, CMV, parvovirus B19
• Radiation
• Inherited: Fanconi anemia, dyskeratosis congenita

• Pancytopenia with relative lymphocytosis on peripheral smear
• Bone marrow biopsy: hypocellular marrow replaced by fat (gold standard)
• Diagnosis of exclusion

• Severe: ≥2 of: neutrophils < 0.5×10⁹/L, platelets < 20×10⁹/L, reticulocytes < 20×10⁹/L

• Young patients: allogeneic bone marrow transplant (BMT) - potentially curative
• Older patients / no donor: anti-thymocyte globulin (ATG) + cyclosporine + eltrombopag

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4.6 Anemia of Renal Disease (CKD)

• Primary mechanism: decreased EPO production by peritubular cells
• Contributing factors: functional iron deficiency, chronic bleeding, shortened RBC survival, marrow suppression
• Usually normocytic, normochromic
• Treatment: recombinant EPO (epoetin alfa / darbepoetin) + iron supplementation

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5. Bone Marrow Examination

1. Circulating immature cells (blasts)
2. Severe pancytopenia
3. Very low reticulocyte counts (< 0.1%)
4. Circulating nucleated RBCs
5. Evidence of marrow infiltration (teardrop cells)
6. Unexplained severe anemia

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6. Key Lab Values - Quick Reference

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7. Exam High-Yield Summary Table

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8. Treatment Principles

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9. Common Exam Traps

1. Ferritin in inflammation: Can be high even in IDA - look at transferrin saturation + clinical context
2. Folate masking B12 deficiency: Folate corrects blood count but neurological damage continues - always check B12 first
3. Thalassemia trait vs IDA: Both are microcytic; thalassemia has normal ferritin, very low MCV (often < 70), high RBC count (Mentzer index: MCV/RBC < 13 = thalassemia, > 13 = IDA)
4. Aplastic anemia = normocytic: Not microcytic despite severe anemia - rule out by bone marrow biopsy
5. Reticulocyte count must be corrected: Correct for degree of anemia using: Corrected reticulocyte % = reticulocyte % × (patient Hct / 45)
6. PNH: Paroxysmal Nocturnal Hemoglobinuria - complement-mediated intravascular hemolysis; Coombs NEGATIVE; diagnosed by flow cytometry (GPI-anchor deficiency)

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