Chapter 105: Hemolytic Anemias¶
Chapter 105 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Hemolytic anemias are classified into intracorpuscular (membrane, enzymatic, redox) and extracorpuscular (immune, mechanical) defects.
- Key diagnostic features include jaundice, splenomegaly, increased reticulocyte count, and elevated indirect bilirubin.
- Hereditary spherocytosis (HS) is the most common inherited hemolytic anemia, with prevalence 1:2000–1:5000 in European populations.
- G6PD deficiency is a common X-linked enzymopathy causing oxidative stress-induced hemolysis, prevalent in tropical regions.
- Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by CD59/CD55 deficiency and complement-mediated intravascular hemolysis.
1. DEFINITION & OVERVIEW¶
Hemolytic anemias result from increased red cell destruction (hemolysis) exceeding marrow compensatory capacity. Hemolysis may be intravascular (e.g., PNH) or extravascular (e.g., HS). Classification includes intracorpuscular defects (membrane, enzymatic, redox) and extracorpuscular factors (immune, mechanical).
Table 105-1: Classification of Hemolytic Anemias¶
| Category | Intracorpuscular Defects | Extracorpuscular Factors |
|---|---|---|
| Inherited | Hemoglobinopathies, Enzymopathies, Membrane Defects | Familial Hemolytic-Uremic Syndrome (aHUS) |
| Acquired | Paroxysmal Nocturnal Hemoglobinuria (PNH) | Autoimmune Hemolytic Anemia (AIHA), Mechanical Hemolysis |
Table 105-2: Common Features of Hemolytic Disorders¶
| General Examination | Laboratory Findings |
|---|---|
| Jaundice, Pallor | Increased reticulocytes, unconjugated bilirubin, LDH |
| Splenomegaly | Decreased haptoglobin, increased indirect bilirubin |
| Gallstones | Anemia (normocytic/macrocytic) |
1.1 Classification of Hemolytic Anemias¶
Intracorpuscular defects: Membrane (HS, hereditary elliptocytosis), enzymatic (G6PD deficiency, pyruvate kinase deficiency), redox (G6PD deficiency). Extracorpuscular factors: Immune (AIHA), mechanical (microangiopathic hemolysis), acquired (PNH).
1.2 Laboratory Features¶
Increased reticulocytes, unconjugated bilirubin, LDH, and decreased haptoglobin. Presence of Heinz bodies in G6PD deficiency. Splenomegaly and gallstones are common in chronic hemolysis.
2. EPIDEMIOLOGY¶
Hereditary spherocytosis (HS) has prevalence 1:2000–1:5000 in European populations. G6PD deficiency affects 10–15% of males in malaria-endemic regions. PNH has prevalence 5–10 per million globally, with higher rates in Southeast Asia. Autoimmune hemolytic anemia (AIHA) incidence 1–3 per 100,000/year.
2.1 Risk Factors¶
G6PD deficiency: Malaria, oxidative agents (primaquine, fava beans). HS: Family history. PNH: Bone marrow failure, complement dysregulation.
2.2 Demographics¶
HS: More common in males. G6PD deficiency: Prevalent in tropical/subtropical regions. PNH: Equal gender distribution, often presents in young adults.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Hemolysis results from membrane/cytoskeleton defects (HS), enzymatic deficiencies (G6PD, pyruvate kinase), or immune-mediated destruction (AIHA). Red cell metabolism (glycolysis, pentose shunt) and complement activation pathways are critical in pathogenesis.
Table 105-3: Inherited Red Cell Membrane-Cytoskeleton Disorders¶
| Gene | Protein | Disease | Inheritance |
|---|---|---|---|
| SPTA1 | a-Spectrin | Hereditary Spherocytosis | Autosomal Recessive |
| ANK1 | Ankyrin | Hereditary Spherocytosis | Autosomal Dominant |
| SLC4A1 | Band 3 | Hereditary Spherocytosis | Autosomal Dominant |
| PIEZO1 | Mechanosensitive Channel | Dehydrated Stomatocytosis | Autosomal Dominant |
Table 105-4: Red Cell Enzyme Abnormalities¶
| Enzyme | Gene | Inheritance | Clinical Features |
|---|---|---|---|
| G6PD | Xq28 | X-linked | Oxidative hemolysis, favism |
| PK | 1q22 | Autosomal Recessive | Chronic hemolysis, splenomegaly |
| PGK1 | Xq21.1 | X-linked | Neurological deficits, hemolysis |
| GPI | 11q23 | Autosomal Recessive | Neurological deficits, hemolysis |
3.1 Membrane-Cytoskeleton Defects¶
HS: Ankyrin/spectrin defects. Hereditary elliptocytosis: Band 3/PIEZO1 mutations. Stomatocytosis: ABCB6/GLUT1 mutations.
3.2 Enzymatic Deficiencies¶
G6PD deficiency: Oxidative stress. Pyruvate kinase deficiency: Glycolytic pathway failure. P5N deficiency: Basophilic stippling.
3.3 Redox Metabolism¶
G6PD deficiency impairs NADPH production, leading to oxidative damage. Defects in glutathione metabolism exacerbate hemolysis.
4. CLINICAL FEATURES¶
Symptoms include jaundice, pallor, splenomegaly, and dark urine. Acute hemolysis may present with hemoglobinuria, while chronic cases show normocytic anemia with reticulocytosis. Complications include gallstones, iron overload, and thrombosis.
Table 105-5: WHO Classification of G6PD Variants¶
| Variant Class | Median Activity (%) | Clinical Manifestations |
|---|---|---|
| A | <20% | Chronic hemolytic anemia |
| B | <45% | Neonatal jaundice, acute hemolytic anemia |
| C | >60% | None reported |
| D | Any | Uncertain significance |
Table 105-6: Drugs Causing Hemolysis in G6PD Deficiency¶
| Drug Class | High Risk | Medium/Low Risk |
|---|---|---|
| Antimalarials | Primaquine, Tafenoquine | Chloroquine, Hydroxychloroquine |
| Sulphonamides | Dapsone, Sulfadimidine | Sulfamethoxazole, Sulfasalazine |
| Antibiotics | Ciprofloxacin, Cotrimoxazole | Nalidixic Acid, Nitrofurantoin |
| Analgesics | Acetylsalicylic Acid (>3g/d) | Acetaminophen, Phenacetin |
4.1 Acute vs. Chronic Presentation¶
Acute: Hemoglobinuria, severe anemia, renal failure. Chronic: Normocytic anemia, splenomegaly, gallstones.
4.2 Laboratory Findings¶
Increased reticulocytes, unconjugated bilirubin, LDH, and decreased haptoglobin. Presence of Heinz bodies in G6PD deficiency.
5. DIFFERENTIAL DIAGNOSIS¶
Differentiate from other anemias (e.g., iron deficiency, B12 deficiency) and non-hemolytic causes of jaundice. Consider autoimmune hemolytic anemia (AIHA), PNH, and mechanical hemolysis.
Table 105-7: Intravascular Hemolysis Causes¶
| Condition | Mechanism | Diagnostic Test |
|---|---|---|
| PNH | Complement-mediated | Flow cytometry (CD59/CD55) |
| Condition | Mechanism | Diagnostic Test |
|---|---|---|
| Paroxysmal Cold Hemoglobinuria | Donath-Landsteiner antibody | Coombs test |
| Microangiopathic Hemolysis | Shear stress | Peripheral smear (schistocytes) |
| Favism | G6PD deficiency | G6PD assay |
5.1 Acquired Hemolytic Anemias¶
AIHA (warm/cold antibodies), PNH, drug-induced hemolysis, mechanical hemolysis (e.g., prosthetic valves).
5.2 Inherited Hemolytic Anemias¶
HS, hereditary elliptocytosis, G6PD deficiency, pyruvate kinase deficiency.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic workup includes CBC, reticulocyte count, peripheral smear, LDH, bilirubin, haptoglobin, and specific tests (e.g., Coombs test, Ham test, flow cytometry). Genetic testing for inherited disorders is critical.
Table 105-8: Acquired Immune Hemolytic Anemias¶
| Clinical Setting | Antibody Type | Temperature | Treatment |
|---|---|---|---|
| Warm AIHA | IgG | 37°C | Corticosteroids, rituximab |
| Cold AIHA (CAD) | IgM | 4–30°C | Avoid cold exposure, splenectomy |
| Paroxysmal Cold Hemoglobinuria | IgM | 4°C | Corticosteroids, plasma exchange |
6.1 Laboratory Tests¶
CBC, reticulocyte count, peripheral smear, LDH, indirect bilirubin, haptoglobin, Coombs test, Ham test, flow cytometry (CD59/CD55).
6.2 Imaging¶
Abdominal ultrasound for splenomegaly, gallstones. MRI for PNH-related complications.
7. MANAGEMENT & TREATMENT¶
Management depends on etiology: splenectomy for HS, corticosteroids/rituximab for AIHA, eculizumab for PNH, and transfusions for severe anemia. Iron chelation is required for chronic transfusion-dependent cases.
Table 105-9: PNH Treatment Options¶
| Therapy | Mechanism | Use |
|---|---|---|
| Eculizumab | C5 inhibitor | Prevent MAC formation |
| Ravulizumab | C5 inhibitor | Longer half-life |
| Pegcetacoplan | C3 inhibitor | Block complement cascade |
| Iptacopan | Factor B inhibitor | Prevent C3 convertase |
7.1 Inherited Hemolytic Anemias¶
HS: Splenectomy (4–6 years), folic acid. G6PD deficiency: Avoid triggers (fava beans, oxidants). PNH: Eculizumab, complement inhibitors.
7.2 Acquired Hemolytic Anemias¶
AIHA: Corticosteroids, rituximab, splenectomy. Drug-induced: Discontinue agent, transfusion if needed.
8. PROGNOSIS & COMPLICATIONS¶
Prognosis varies: HS is generally benign with splenectomy, while PNH has high thrombotic risk. Complications include gallstones, iron overload, and renal failure. PNH may progress to aplastic anemia.
8.1 Complications¶
Gallstones, iron overload, thrombosis, renal failure, splenic dysfunction.
8.2 Prognostic Factors¶
Severity of hemolysis, presence of complications, response to therapy.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Monitor for hemolysis, avoid fava beans. Pediatrics: HS may present with jaundice. Elderly: Consider drug-induced hemolysis. PNH: Anticoagulation for thrombosis prevention.
9.1 Pregnancy¶
Monitor for hemolysis, avoid G6PD triggers. Splenectomy may be required for severe HS.
9.2 Pediatric Considerations¶
HS may present with neonatal jaundice. PNH may be diagnosed in children with hemoglobinuria.
10. KEY POINTS & CLINICAL PEARLS¶
- Hemolytic anemias are classified into intracorpuscular and extracorpuscular defects. 2. G6PD deficiency is a common X-linked disorder causing oxidative hemolysis. 3. PNH is diagnosed by flow cytometry (CD59/CD55 deficiency). 4. AIHA is managed with corticosteroids and rituximab. 5. Splenectomy is indicated for severe HS but carries thrombotic risks.