Classification and Management of Anemia

Definition

• Harrison's Principles of Internal Medicine 22E, p. 492

Classification of Anemia

A. Morphological Classification (by MCV)

1. Microcytic Hypochromic Anemia (MCV < 80 fL)

• Iron deficiency anemia - most common cause worldwide
• Thalassemia - defects of globin protein synthesis
• Anemia of chronic disease/inflammation - functional iron deficiency due to hepcidin
• Sideroblastic anemia - defects of heme synthesis

2. Macrocytic Anemia (MCV > 100 fL)

• Megaloblastic (oval macrocytes) - defects of DNA synthesis
  • Vitamin B12 deficiency
  • Folate deficiency
  • Drugs (methotrexate, chemotherapy, some anti-epileptics)
  • Myelodysplasia
• Non-megaloblastic (round macrocytes) - membrane defects
  • Liver disease, hypothyroidism, alcohol use, reticulocytosis, dysproteinemia, hypoxia

3. Normocytic Normochromic Anemia (MCV 80-100 fL)

• Aplastic anemia, pure red cell aplasia
• Anemia of renal disease (EPO deficiency)
• Endocrinopathies
• Marrow invasion (neoplasm, granulomas)
• Early iron deficiency, acute hemorrhage

B. Pathophysiological Classification (by Mechanism)

1. Blood Loss

• Acute: trauma, surgery
• Chronic: GI lesions (peptic ulcer, colon cancer), gynecologic causes - leads to iron deficiency

2. Increased Destruction (Hemolytic Anemias)

• Red cell membrane disorders: hereditary spherocytosis, elliptocytosis
• Enzyme deficiencies: G6PD deficiency (commonest), pyruvate kinase deficiency
• Hemoglobin abnormalities: sickle cell disease, thalassemia syndromes

• Immune-mediated: autoimmune hemolytic anemia (warm/cold), transfusion reactions, hemolytic disease of newborn
• Microangiopathic: HUS, DIC, TTP - schistocytes on smear
• Infections: malaria, babesiosis
• Paroxysmal nocturnal hemoglobinuria (PNH) - acquired loss of GPI-linked glycoproteins
• Cardiac traumatic hemolysis (defective valves)

3. Decreased Production (Hypoproliferative/Underproduction)

• Represents ≥75% of all cases of anemia
• Nutritional deficiency: Iron (most common), B12, folate, copper, Vitamin C
• Aplastic anemia - stem cell depletion; Fanconi anemia (inherited), immune-mediated (acquired)
• EPO deficiency: renal disease, anemia of inflammation/aging
• Marrow replacement (myelophthisis): leukemia, myeloma, myelofibrosis, metastatic cancer, granulomas
• Stem cell defects: myelodysplasia, leukemia

Management of Anemia

General Approach

1. Identify and treat the underlying cause
2. Correct hemoglobin and restore normal tissue oxygenation
3. Blood transfusion for severe/symptomatic anemia (Hb <7 g/dL or hemodynamically unstable)

1. Iron Deficiency Anemia (IDA)

• Ferrous sulfate 325 mg TDS (elemental iron ~65 mg/tablet) on empty stomach
• Vitamin C co-administration enhances absorption
• Continue for 3-6 months after Hb normalizes to replenish stores
• Side effects: nausea, constipation, black stools

• Iron sucrose, ferric carboxymaltose, iron dextran
• Indications: malabsorption, intolerance, severe IDA, perioperative

• Robbins & Kumar Basic Pathology, p. 393

2. Megaloblastic Anemia

• Pernicious anemia (lack of intrinsic factor): parenteral cyanocobalamin 1000 mcg IM daily x 7 days, then weekly x 4 weeks, then monthly for life
• Oral B12 1000-2000 mcg/day is now equally effective for dietary deficiency and many other causes
• Neurological manifestations (subacute combined degeneration) require B12, not folate alone

• Folic acid 5 mg/day orally for 4 months
• Never give folate alone without ruling out B12 deficiency - can mask hematologic signs while neurological damage progresses

• Both high MMA + high homocysteine = B12 deficiency
• Normal MMA + high homocysteine alone = folate deficiency
• Lippincott Illustrated Reviews Pharmacology, p. 1481

3. Anemia of Chronic Disease

• Treat the underlying inflammatory condition
• Erythropoiesis-stimulating agents (ESA: epoetin alfa, darbepoetin) for anemia of CKD
• ESAs should not be started until iron deficiency is treated; target Hb ≤11-12 g/dL (higher targets increase cardiovascular risk and thrombosis)
• IV iron supplementation as adjunct to ESA therapy

4. Hemolytic Anemia

• Warm type: corticosteroids (prednisolone 1 mg/kg/day) - first line; splenectomy if refractory; rituximab for refractory cases
• Cold type: avoid cold exposure; treat underlying cause; rituximab

• Avoid oxidant triggers (primaquine, dapsone, fava beans, nitrofurantoin)
• Blood transfusion for severe hemolytic crisis

• Splenectomy (curative for hemolysis); folate supplementation; pneumococcal vaccination prior to splenectomy

• Hydroxyurea increases fetal hemoglobin (HbF), reduces sickling
• Penicillin prophylaxis, vaccinations
• Blood transfusions for crises; bone marrow transplant (curative)

5. Aplastic Anemia

• Mild/moderate: immunosuppression with anti-thymocyte globulin (ATG) + cyclosporine + G-CSF
• Severe: allogeneic bone marrow/stem cell transplantation (definitive treatment, especially in young patients)
• Supportive: blood transfusions, platelet transfusions, treat infections

6. Anemia of Renal Disease

• Recombinant erythropoietin (epoetin alfa) or darbepoetin SC/IV
• Correct iron deficiency before starting ESA
• Target Hb: 10-11.5 g/dL (do not exceed 12 g/dL - risk of thrombosis, hypertension)

Summary Table: Morphological Classification

• Always classify anemia using BOTH morphological AND pathophysiological approaches
• Iron deficiency anemia is the most common cause worldwide; pernicious anemia is the most common cause of B12 deficiency
• Never give folate alone without excluding B12 deficiency
• Blood transfusion is indicated only for symptomatic anemia or Hb <7 g/dL (not as first-line treatment)
• The reticulocyte count is the key test to differentiate hyperproductive (hemolysis/bleeding) from hypoproductive anemia