Hereditary Hemolytic

Overview of Hemolytic Anemias

Definition: Anemia caused by increased red blood cell (RBC) destruction (hemolysis), either intravascularly (within the blood vessels) or extravascularly (primarily in the spleen and liver)
Hallmarks:
- Shortened RBC lifespan
- Increased erythropoiesis (increased reticulocyte count)
- Accumulation of hemoglobin breakdown products (e.g., bilirubin, LDH)
Classification:
- Intrinsic (Inherited) Hemolytic Anemias:
  - Result from defects within the RBC itself
  - Include membrane defects, enzyme deficiencies, and hemoglobinopathies
- Extrinsic (Acquired) Hemolytic Anemias:
  - Result from external factors that cause RBC destruction
  - Include immune-mediated hemolysis, mechanical trauma, infections, and chemical injury

Intrinsic Hemolytic Anemias: Membrane Defects

General Pathophysiology:
- Defects in RBC membrane proteins disrupt the structural integrity and flexibility of the membrane
- Abnormally shaped RBCs are more susceptible to splenic sequestration and destruction
Common Features:
- Splenomegaly (due to increased splenic workload)
- Jaundice (due to elevated bilirubin levels)
- Increased osmotic fragility
Specific Membrane Defects:
- Hereditary Spherocytosis (HS):
  - Defect: Primarily caused by mutations in genes encoding spectrin, ankyrin, band 3, or protein 4.2
    - These proteins are essential for maintaining the biconcave shape and flexibility of RBCs
  - Pathophysiology: Protein deficiencies lead to loss of membrane surface area, resulting in spherical-shaped RBCs (spherocytes)
    - Spherocytes have decreased deformability and are trapped and destroyed in the spleen
  - Clinical Findings:
    - Anemia (variable severity)
    - Jaundice
    - Splenomegaly
    - Bilirubin gallstones (cholelithiasis)
  - Laboratory Findings:
    - CBC:
      - Normal to decreased HGB and HCT
      - Normal or decreased MCV (may be falsely low due to spherocytes)
      - Increased MCHC (often >36 g/dL)
      - Increased RDW
    - Peripheral Blood Smear:
      - Spherocytes (hallmark finding)
      - Polychromasia (increased reticulocytes)
      - Absence of central pallor in spherocytes
    - Reticulocyte Count: Elevated
    - Direct Antiglobulin Test (DAT): Negative (unless there is a coexisting autoimmune process)
    - Osmotic Fragility Test: Increased osmotic fragility (RBCs lyse more readily in hypotonic solutions)
  - Treatment:
    - Splenectomy: Mainstay of treatment for severe HS
      - Reduces hemolysis and improves anemia
      - Increases risk of infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)
      - Patients require vaccination before splenectomy
    - Folic acid supplementation
    - Blood transfusions (in severe cases)
- Hereditary Elliptocytosis (HE):
  - Defect: Primarily caused by mutations in genes encoding spectrin, protein 4.1, or glycophorin C
  - Pathophysiology: Protein defects disrupt the horizontal interactions in the RBC cytoskeleton, leading to elliptical-shaped RBCs (elliptocytes)
  - Clinical Findings:
    - Most patients are asymptomatic
    - Variable degrees of anemia, splenomegaly, and jaundice
    - Severe forms (e.g., hereditary pyropoikilocytosis) can cause significant hemolysis
  - Laboratory Findings:
    - CBC:
      - Normal to decreased HGB and HCT
      - Normal MCV
      - Normal MCHC
    - Peripheral Blood Smear:
      - Elliptocytes (hallmark finding, >25% of RBCs)
      - Poikilocytosis (in severe forms)
    - Reticulocyte Count: Normal to slightly elevated
    - Osmotic Fragility Test: Usually normal
  - Treatment:
    - Most patients require no treatment
    - Splenectomy: May be considered in patients with severe hemolysis
    - Folic acid supplementation
    - Blood transfusions (in severe cases)
- Hereditary Pyropoikilocytosis (HPP):
  - Defect: A severe form of hereditary elliptocytosis with compound heterozygosity for spectrin mutations
  - Pathophysiology: Marked spectrin deficiency leads to extreme poikilocytosis (abnormal RBC shapes) and heat sensitivity
    - RBCs fragment at temperatures that are normally well-tolerated
  - Clinical Findings:
    - Severe microcytic hemolytic anemia
    - Marked poikilocytosis
    - Splenomegaly
  - Laboratory Findings:
    - CBC:
      - Decreased HGB and HCT
      - Very low MCV
      - Increased RDW
    - Peripheral Blood Smear:
      - Extreme poikilocytosis (hallmark finding)
      - Microspherocytes, elliptocytes, fragmented cells
    - Reticulocyte Count: Elevated
  - Treatment:
    - Splenectomy: Mainstay of treatment
    - Folic acid supplementation
    - Blood transfusions (often required)
- Hereditary Stomatocytosis:
  - Defect: Mutations affecting membrane cation permeability, particularly the PIEZO1 and stomatin (band 7) proteins
  - Pathophysiology: Altered cation permeability leads to changes in RBC volume and shape
    - Overhydrated Hereditary Stomatocytosis (OHS): Increased influx of sodium and water into RBCs, leading to swelling and stomatocytes (mouth-like appearance)
    - Dehydrated Hereditary Stomatocytosis (DHS): Increased efflux of potassium and water from RBCs, leading to dehydration and spiculated cells (e.g., echinocytes)
  - Clinical Findings:
    - Variable degrees of hemolytic anemia
    - Splenomegaly
    - Jaundice
  - Laboratory Findings:
    - CBC:
      - Variable HGB and HCT (depending on the severity of hemolysis)
      - Increased MCV (in OHS) or decreased MCV (in DHS)
    - Peripheral Blood Smear:
      - Stomatocytes (in OHS): RBCs with a slit-like area of central pallor
      - Spiculated cells (echinocytes) (in DHS)
    - Reticulocyte Count: Elevated
    - Osmotic Fragility Test: Variable (increased in OHS, decreased in DHS)
  - Treatment:
    - Splenectomy: May be considered in severe cases of OHS, but carries a risk of thrombosis
    - Iron overload: Can occur in DHS due to increased iron absorption
    - Folic acid supplementation
    - Blood transfusions (in severe cases)

Intrinsic Hemolytic Anemias: Enzyme Deficiencies

General Pathophysiology:
- Deficiencies in enzymes essential for RBC metabolism disrupt energy production or antioxidant defenses
- Leads to premature RBC destruction, especially under conditions of stress
Common Features:
- Hemolytic anemia
- Elevated reticulocyte count
- Elevated indirect bilirubin
- Decreased haptoglobin
Specific Enzyme Deficiencies:
- Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency:
  - Defect: Deficiency of G6PD, an enzyme in the pentose phosphate pathway (hexose monophosphate shunt)
  - Pathophysiology:
    - G6PD is essential for producing NADPH, which protects RBCs from oxidative damage
    - Without NADPH, RBCs are vulnerable to oxidative stress from infections, drugs, or certain foods (e.g., fava beans)
    - Oxidative stress leads to hemoglobin denaturation and formation of Heinz bodies (denatured hemoglobin precipitates)
    - Heinz bodies damage the RBC membrane, leading to intravascular and extravascular hemolysis
  - Inheritance: X-linked recessive; more common in males
  - Clinical Findings:
    - Most individuals are asymptomatic until exposed to an oxidative stressor
    - Acute hemolytic anemia:
      - Sudden onset of jaundice, dark urine, and fatigue
      - Symptoms usually resolve within a few weeks after the oxidative stressor is removed
    - Chronic nonspherocytic hemolytic anemia (in some severe variants)
  - Laboratory Findings:
    - CBC:
      - Decreased HGB and HCT
    - Peripheral Blood Smear:
      - Bite cells (RBCs with a portion removed by splenic macrophages)
      - Heinz bodies (require special stain, e.g., crystal violet or brilliant green)
      - Polychromasia
    - Reticulocyte Count: Elevated
    - G6PD Assay:
      - Decreased G6PD enzyme activity (may be normal during acute hemolytic episodes due to increased reticulocytes)
  - Treatment:
    - Avoidance of oxidative stressors (certain drugs, foods, and infections)
    - Supportive care during hemolytic episodes:
      - Hydration
      - Blood transfusions (in severe cases)
    - Folic acid supplementation
- Pyruvate Kinase (PK) Deficiency:
  - Defect: Deficiency of pyruvate kinase (PK), an enzyme in the glycolytic pathway (Embden-Meyerhof pathway)
  - Pathophysiology:
    - PK is essential for generating ATP, which is required to maintain RBC shape, membrane integrity, and ion transport
    - Without sufficient ATP, RBCs become rigid, dehydrated, and prone to splenic sequestration
    - Results in chronic hemolytic anemia
  - Inheritance: Autosomal recessive
  - Clinical Findings:
    - Chronic hemolytic anemia
    - Jaundice
    - Splenomegaly
    - Gallstones (cholelithiasis)
  - Laboratory Findings:
    - CBC:
      - Decreased HGB and HCT
      - Normal to decreased MCV (can be slightly macrocytic in some cases)
      - Normal MCHC
    - Peripheral Blood Smear:
      - Normal shape or slight poikilocytosis
      - No spherocytes
    - Reticulocyte Count: Markedly elevated
    - Pyruvate Kinase (PK) Assay:
      - Decreased PK enzyme activity
  - Treatment:
    - Blood transfusions (may be needed, especially in severe cases)
    - Splenectomy: May reduce transfusion requirements but increases the risk of thrombosis
    - Folic acid supplementation

General Laboratory Findings in Hemolytic Anemias

Increased Red Blood Cell Destruction:
- Elevated indirect (unconjugated) bilirubin
- Elevated lactate dehydrogenase (LDH)
- Decreased haptoglobin (due to binding with free hemoglobin)
- Hemoglobinuria (hemoglobin in the urine) in intravascular hemolysis
- Hemosiderinuria (iron in the urine) in chronic intravascular hemolysis
Increased Red Blood Cell Production:
- Elevated reticulocyte count
- Polychromasia on peripheral blood smear

Key Terms

Hemolytic Anemia: Anemia caused by increased red blood cell destruction
Intrinsic Hemolytic Anemia: Hemolysis due to defects within the red blood cell
Extrinsic Hemolytic Anemia: Hemolysis due to external factors
Spherocytes: Spherical-shaped red blood cells (hallmark of hereditary spherocytosis)
Elliptocytes: Elliptical-shaped red blood cells (hallmark of hereditary elliptocytosis)
Stomatocytes: Red blood cells with a mouth-like appearance (seen in hereditary stomatocytosis)
Heinz Bodies: Denatured hemoglobin precipitates (seen in G6PD deficiency)
Osmotic Fragility: A measure of the resistance of red blood cells to lysis in hypotonic solutions
Reticulocyte: Immature red blood cell
Haptoglobin: Protein that binds free hemoglobin
Bilirubin: Product of heme breakdown
Enzyme Deficiency: Lack of a specific enzyme needed for proper red blood cell metabolism
Splenectomy: Surgical removal of the spleen

Normocytic

Acquired Hemolytic