Hereditary Blood Disorders Quiz

Hemolytic Anemia

• Hemolytic anemia (HA) is a heterogeneous group of conditions characterized by premature destruction of red blood cells (RBCs), or a shortened RBC lifespan.
• Bone marrow (BM) can increase its output six to eight-fold to compensate for anemia. This corresponds to an RBC lifespan of 15-20 days.

Classification of Hemolytic Anemia

• Intracorpuscular Defects: Inherited defects affecting the red blood cell (RBC) itself.
  • Hereditary defects
    • Defects in the red blood cell membrane
    • Enzyme defects
    • Hemoglobinopathies
    • Thalassemia syndromes
  • Acquired defects
    • Paroxysmal nocturnal hemoglobinuria (PNH)
• Extracorpuscular Defects: Defects not intrinsic to the red blood cell, affecting the red cell exterior.
  • Immune hemolytic anemia
  • Infections
  • Exposure to chemicals and toxins
  • Exposure to physical agents
  • Microangiopathic and macroangiopathic hemolytic anemias
  • Splenic sequestration (hypersplenism)
  • General systemic disorders (in which hemolysis is not the dominant feature of the anemia)

Diagnosis of Hemolytic Anemia

• Tests reflecting increased red blood cell destruction:
  • Serum unconjugated (indirect) bilirubin
  • Hemoglobinemia
  • Hemoglobinuria (dark urine)
  • Hemosiderinuria (iron storage protein in urine)
  • Methemalbumin in the blood (Schumm's test)
  • Methemoglobinemia
  • Serum Hemopexin
  • Serum Haptoglobin
  • Urine urobilinogen and fecal stercobilinogen increased

Degradation of Hb After Intra- & Extra-vascular Hemolysis

• When present in high quantities, methemalbumin and hemopexin-heme complex impart a brownish colour to plasma.
• Diagrammatic representation of hemoglobin degradation after intravascular or extravascular destruction of red blood cells.
• Progressive urine samples in acute intravascular hemolysis showing hemoglobinuria of decreasing severity.

Tests Reflecting Increased Red Cell Production

• Reticulocyte count
• Reticulocyte production index (RPI)
• RPI >2.5-3.0 is indicative of hemolytic anemia
• Bone marrow (BM) erythroid hyperplasia; M:E ratio from 3-4:1 reduced to 1:1 or even reversed

Red Cell Membrane Structure

• Red blood cell deformability is determined by the biconcave disc shape and the surface area-to-volume ratio (SA:Volume).
• Cytoplasmic viscosity, determined by mean corpuscular hemoglobin concentration (MCHC).
• Viscoelastic properties depend on the integrity of the membrane skeleton.
• Diagrammatic illustrations of the red blood cell membrane skeleton network.
• Table of integral and peripheral proteins involved.

Hereditary Defects of the Red Cell Membrane

• Mutations affecting the membrane are numerous.
• Classifications into specific phenotypes:
  • Hereditary spherocytosis (HS)
  • Hereditary elliptocytosis (HE) & related disorders (e.g., hereditary pyropoikilocytosis or HPP and Southeast Asian ovalocytosis)
  • Hereditary stomatocytosis
  • Hereditary xerocytosis
  • Hereditary acanthocytosis

Hereditary Defects of RBC Membrane - Specifics

• Inheritance: Most are autosomal dominant.
• Red Cell Membrane Protein Defects: Gene mutations cause protein deficiencies leading to altered RBC shape and function: spectrin, ankyrin, band 3, protein 4.2
• Pathophysiology: Loss of surface area leads to spherocytes. Increased permeability to sodium.

Classification of RBC Membrane Defects

• Mutations affect RBC membrane, impacting the red blood cell's phenotype.
• Vertical and horizontal protein interactions within the RBC membrane dictate the cell's shape.

Hereditary Spherocytosis (HS)

• Inheritance: Autosomal dominant.
• Membrane Protein Defects: Protein deficiencies in spectrin, ankyrin, band 3, and protein 4.2 commonly implicated.
• Pathophysiology: Loss of membrane surface area leads to spherocytosis. Increased permeability to sodium.
• Clinical Manifestations: Jaundice, anemia, enlarged spleen (splenomegaly), aplastic and hemolytic crises. Potential for gallstones and leg ulcers.

Hereditary Elliptocytosis (HE)

• Inheritance: Usually autosomal dominant.
• Defects: Defects in spectrin dimerization.
• Clinical Features: Often asymptomatic.
• Types: Hereditary pyropoikilocytosis (HPP); spherocytic HE
• **Southeast Asian ovalocytosis (SA0):**Oval-shaped cells

Hereditary Pyropoikilocytosis (HPP)

• Features: Relatively rare with severe hemolysis; showing microspherocytes, micropoikilocytosis, and fragments (few elliptocytes).
• Diagnosis: Heterozygotes frequently exhibit defective spectrin.

Spherocytic HE

• A hybrid of HE and HS, exhibiting clinical courses similar to HS.

Hereditary Stomatocytosis (Hydrocytosis) & Hereditary Xerocytosis

• Inheritance: Often AD (autosomal dominant) inheritance patterns.
• Defects: Defects in sodium & potassium; causes abnormal membrane permeability, affecting swell/shrink characteristics
• Etiology: Defects in Na+/K+ permeability in Hst, K+ permeability leading to dehydration in Hxe
• Clinical Features: Often asymptomatic or mild hemolysis.

Hereditary Acanthocytosis (Abetalipoproteinemia)

• Inheritance: Autosomal recessive.
• Features: Mild anemia, steatorrhea, neurological problems, and retinal abnormalities. Acnthocytes (spiky red blood cells) compose 50-100% of erythrocytes. Abnormal plasma lipid levels, lacking serum B lipoprotein, required for lipid transport.
• Diagnostic features: Increased cholesterol: lecithin ratio in the membrane.

RBC Metabolic Pathway Disorders

• Components of glycolytic pathway: Main glycolytic pathway and three ancillary pathways.
• Specific enzymopathies: Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency and Pyruvate Kinase (PK) deficiency.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• Inheritance: Sex-linked.
• Defect: Deficiency in the enzyme leads to reduced glutathione levels. This leads to methemoglobin (Fe3+) formation.
• Clinical Findings: The majority of patients are asymptomatic. Oxidant stress (drugs, infections, fava beans) trigger hemolysis (Favism).
• Diagnosis: Decreased G6PD activity.
• Variants: Gd B (normal), Gd Med, GdA+(normal), GdA-, Gd Canton

Pyruvate Kinase (PK) Deficiency

• Inheritance: Autosomal recessive.
• Defect: Lack of ATP (adenosine triphosphate) due to PK deficiency affects cation pumps, impairing intracellular sodium and potassium concentrations.
• Clinical Course: Decreased erythrocyte deformability shortens RBC lifespan. Severe hemolytic anemia with reticulocytosis, and echinocytes
• Diagnosis: Blood film; moderate increase in serum unconjugated bilirubin; quantitative PK assay; Osmotic fragility; Coombs test

Methemoglobin Reductase Deficiency

• Inheritance: AR (autosomal recessive).
• Diagnosis: Deficiency in the reductase enzyme responsible for converting methemoglobin (Fe3+) to hemoglobin (Fe2+) through a diagnostic enzyme assay.
• Deficiency causes: Methemoglobinemia (cyanosis).

Assessment Questions

• Q1: Common characteristics of hereditary spherocytosis, hereditary elliptocytosis, hereditary stomatocytosis, and paroxysmal nocturnal hemoglobinuria.
• Q2: Least likely situations for hemolytic episodes in patients with G6PD deficiency.
• Q3: Most likely condition causing a severe hemolytic episode after exposure to anti-malarials inducing red cell inclusions formed by denatured globin.
• Q4: Characteristic defect in hereditary pyropoikilocytosis.
• Q5: Reason for hemolytic crisis following primaquine drug exposure in a 32-year-old African American male.
• Detailed patient information required for accurate differential diagnosis.

Test your knowledge on hereditary blood disorders such as hereditary pyropoikilocytosis, Southeast Asian ovalocytosis, and hereditary elliptocytosis. This quiz covers characteristic lab findings, red blood cell morphology changes, and associated defects. Perfect for students and professionals in hematology.