Hemolytic Anemia (Video Notes)

Hemolysis: Definition, Mechanisms, and Clinical Relevance

• Etymology and definition
  • Hemo- meaning blood, lysis- meaning to break open; the breaking open of blood and releasing of hemoglobin into the surrounding fluid (plasma, in vivo).
  • Hemolytic Anemia: anemia due to hemolysis, i.e., abnormal breakdown of red blood cells (RBCs).
• Hemolysis sites and classifications
  • Occurs either in the blood vessels (intravascular hemolysis) or elsewhere in the body (extravascular hemolysis).
  • The breakdown can be caused by a wide range of factors, from relatively harmless to life-threatening.
• Key framing of hemolytic anemia
  • General classification: acquired or inherited.
  • Treatment depends on the cause and nature of the breakdown.

RBC Lifespan, Removal, and Homeostasis

• Normal RBC lifespan and turnover
  • In a healthy person, RBCs survive on average 90-120 days in circulation.
  • About 1\% of RBCs break down each day.
• Removal and production balance
  • The spleen (part of the Reticulo-Endothelial System, RES) is the main organ that removes old and damaged RBCs from circulation.
  • In healthy individuals, the breakdown/removal is matched by production of new RBCs in the bone marrow.
• When hemolysis outpaces production
  • In conditions with increased RBC breakdown, the body initially compensates by producing more RBCs.
  • If breakdown exceeds the rate the bone marrow can produce RBCs, anemia develops.
  • Hemolysis leads to bilirubin formation from hemoglobin; bilirubin can accumulate, causing jaundice; bilirubin can be excreted in urine, giving urine a dark brown color.

Causes and Classification of Hemolytic Anemia

• Two broad classifications
  • Acquired
  • Inherited
• Key test question to distinguish types
  • Hereditary defects are in the RBCs themselves.
  • Acquired defects are outside the RBCs.

Diagnostic Cornerstones and Common Tests

• Diagnosis focuses on confirming hemolysis and its cause
  • Define hemolysis
  • Diagnose hemolysis (presence of hemolysis indicators)
  • Distinguish types of hemolytic anemia
  • Inheritance pattern:
  • Hereditary: defect is in the RBC
  • Acquired: defect outside the RBC
• Typical inherited defects (3 main types)
  • Membrane defects (e.g., hereditary spherocytosis; hereditary elliptocytosis)
  • Enzyme defects (e.g., G6PD deficiency, pyruvate kinase deficiency)
  • Hemoglobin defects (e.g., sickle cell anemia, thalassemia; Hemoglobin H disease as an example)
• Typical acquired causes of hemolysis (3 main types)
  • Immune-mediated (antibody-mediated) and non-immune mediated
  • Note: Dysplastic RBCs from any cause may have a shortened lifespan.

Inherited Hemolytic Anemias: Where the Defect Lies

• Hereditary defects in RBC membrane
  • Examples: Hereditary Spherocytosis, Hereditary Elliptocytosis
• Genetic defects in RBC metabolism (enzyme defects)
  • G6PD deficiency (G6PD or Favism)
  • Pyruvate kinase deficiency
• Genetic defects in hemoglobin
  • Sickle cell anemia
  • Thalassemias

Acquired Hemolytic Anemia: Immune vs Non-immune Mediated

• Immune-mediated hemolytic anemia (direct Coombs test is positive)
  • Autoimmune hemolytic anemia (AIHA)
  • Warm antibody AIHA
    • Idiopathic
    • Associated with systemic lupus erythematosus (SLE)
    • Evans’ syndrome (antiplatelet antibodies and hemolytic antibodies)
  • Cold antibody AIHA
    • Idiopathic cold agglutinin syndrome
    • Infectious mononucleosis and atypical pneumonia (mycoplasma)
    • Paroxysmal cold hemoglobinuria (rare)
  • Alloimmune hemolytic anemia
  • Hemolytic disease of the newborn (HDN)
    • Rh disease (Rh D)
    • ABO hemolytic disease of the newborn
    • Anti-Kell, Rh C, Rh E, Rh c, Rh Duffy, Rh Kidd, MN, P and others
  • Alloimmune transfusion reactions (from non-compatible blood)
  • Drug-induced immune-mediated hemolytic anemia
  • Penicillin (high dose)
  • Methyldopa
• Non-immune mediated hemolytic anemia
  • Drugs and other ingested substances causing direct action on RBCs (e.g., ribavirin)
  • Toxins (e.g., snake venom)
  • Trauma causing RBC destruction (mechanical, e.g., prosthetic heart valves, extensive vascular surgery)
  • Microangiopathic hemolytic anemia subtypes (e.g., TTP, HUS, DIC, HELLP syndrome)
  • Infections (direct Coombs test may be positive in infection-related hemolysis; examples include malaria, babesiosis, septicaemia)
  • Membrane disorders such as Paroxysmal nocturnal hemoglobinuria (rare acquired clonal disorder affecting RBC surface proteins)
  • Liver disease

Morphology and Laboratory Hallmarks of Hemolysis

• Blood film findings associated with hemolysis
  • Damaged RBCs in the blood film; examples include spherocytes and fragmented cells
• Marrow response to anemia
  • Reticulocytosis indicates active marrow response to hemolysis
• RBC breakdown products in plasma
  • Unconjugated bilirubin
  • Lactate dehydrogenase (LDH)
  • Haptoglobin: decreased in intravascular hemolysis
• Other tests
  • Some other diagnostic tests exist but are generally less useful than the core markers listed above

Quick Reference: Diagnosis and Classification Summary

• Hemolysis diagnosis framework
  • Define hemolysis
  • Demonstrate hemolysis with supportive labs and smear findings
• Inheritance distinction
  • Hereditary vs Acquired: where the defect resides (RBC vs outside RBC)
• Common inherited defects (3 categories, with examples)
  • Membrane defects: hereditary spherocytosis, hereditary elliptocytosis
  • Enzyme defects: G6PD deficiency, pyruvate kinase deficiency
  • Hemoglobin defects: sickle cell anemia, thalassemias
• Common acquired etiologies (immune and non-immune)
  • Immune: warm AIHA, cold AIHA, alloimmune conditions (HDN, transfusion reactions), drug-induced AIHA
  • Non-immune: drugs/toxins, trauma, microangiopathic processes, infections, membrane disorders, liver disease

Key Takeaways and Connections

• Hemolysis as a central process can be intravascular or extravascular, with distinct clinical and laboratory features.
• The balance between RBC destruction and bone marrow production determines whether anemia develops; when destruction outstrips production, anemia results.
• The spleen plays a central role in removing old/damaged RBCs, but other organs and pathways contribute depending on the mechanism.
• Lab clues (reticulocytosis, bilirubin, LDH, haptoglobin, smear findings) help differentiate the type and cause of hemolysis.
• Understanding whether a defect is hereditary (RBC-intrinsic) or acquired (RBC-extrinsic) guides diagnostic work-up and therapy.
• Clinically, hemolytic processes can be autoimmune, alloimmune, drug-induced, traumatic, infectious, or related to membrane/enzyme/hemoglobin defects; each has characteristic, testable features such as Coombs positivity and specific RBC morphologies.

ext{RBC lifespan}
ightarrow 90-120 ext{ days}
ext{Daily RBC breakdown fraction}
ightarrow 1 ext{ extperthousand?} \, ext{(approx }1\% ext{ per day)}
ext{Bone marrow compensation capacity}
ightarrow 6-8 imes ext{ normal rate of hemolysis}
ext{Intravascular hemolysis markers}
ightarrow ext{decreased haptoglobin, increased LDH, unconjugated bilirubin}
ext{Hemolysis causes}
ightarrow ext{Inherited (membrane/enzyme/hemoglobin) or Acquired (immune/non-immune)}