Hemolytic anemia

Etiology

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By RBC pathology

• Intrinsic hemolytic anemia
  • Increased destruction of RBCs due to a defect within the RBC
• Extrinsic hemolytic anemia
  • Abnormal breakdown of normal RBCs

By location of RBC breakdown

• Intravascular hemolytic anemia
  • Increased destruction of RBCs within the blood vessels
• Extravascular hemolytic anemia
  • Increased destruction of RBCs by the reticuloendothelial system (primarily the spleen)

Diagnostics

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Feature	Intravascular Hemolytic Anemia	Extravascular Hemolytic Anemia
Pathophysiology	RBCs are destroyed within blood vessels.	RBCs are removed from circulation by macrophages in the spleen and liver (reticuloendothelial system).
Key Lab Findings	- ↓↓ Haptoglobin (binds free Hb) - ↑ LDH (released from RBCs) - Hemoglobinemia & Hemoglobinuria (free Hb in plasma & urine) - Hemosiderinuria (iron in urine, chronic) - ↑ Unconjugated Bilirubin (mild to moderate)	- ↓ Haptoglobin (mildly decreased or normal) - ↑ LDH - No Hemoglobinemia/Hemoglobinuria - ↑↑ Unconjugated Bilirubin (more significant) - ↑ Urine/Fecal Urobilinogen
Peripheral Smear	Schistocytes (fragmented RBCs).	Spherocytes (common in hereditary spherocytosis and autoimmune hemolysis).
Clinical Presentation	Often acute and dramatic, may include fever, chills, back pain, and red-brown urine.	Often chronic, presenting with anemia, jaundice, and splenomegaly.
Common Causes	- Microangiopathic Hemolytic Anemias (TTP, HUS, DIC) - Mechanical destruction (e.g., prosthetic heart valves) - Paroxysmal Nocturnal Hemoglobinuria (PNH) - ABO-incompatible transfusion - Certain infections (e.g., Clostridium, Malaria) - Oxidative damage (e.g., G6PD deficiency)	- Hereditary Spherocytosis - Autoimmune Hemolytic Anemia (AIHA) (most are warm agglutinin type) - Sickle Cell Anemia - Hypersplenism

• Indirect (unconjugated) bilirubin
  • Hemolysis → Hb release → heme catabolized to indirect bilirubin
  • More prominent in extravascular hemolysis
    • Heme needs to be catabolized to indirect bilirubin. Macrophages within the reticuloendothelial system (80% in the spleen and 20% in the bone marrow) are predominantly responsible for heme breakdown.
• Hemoglobinuria, Hemosiderinuria
  • More prominent in intravascular hemolysis
    • Free Hb can’t be catabolized, so they are excreted in urine.
• Lactate dehydrogenase (LDH)
  • Nonspecific parameter; indicates increased cellular breakdown
  • More prominent in intravascular hemolysis
• Peripheral blood smear
  • Intravascular hemolysis
    • ↑ Reticulocytes
    • Heinz bodies and bite cells in G6PD deficiency
    • Schistocytes in MAHA or macroangiopathic hemolysis
    • Intracellular organisms (e.g., in malaria , babesiosis , bartonellosis )
  • Extravascular hemolysis
    • ↑ Reticulocytes
    • Spherocytes in hereditary spherocytosis and immune-mediated hemolysis (e.g., warm AIHA, hemolytic transfusion reactions)
      • Spherocytes are typically found in warm AIHA due to splenic macrophages partially ingesting IgG-coated RBC membranes. A positive DAT and negative family history can distinguish warm AIHA from hereditary spherocytosis.
    • RBC agglutination in cold agglutinin disease (CAD)
    • Sickle cells in sickle cell disease
    • Target cells in HbC disease, Asplenia, Liver disease, Thalassemia
      • A type of pathologic red blood cell with a bullseye appearance due to an overabundance of membrane.
      • “HALT,” said the hunter to his target
    • Teardrop cells in thalassemia
    • Hb crystals within RBCs in hemoglobin C disease
    • Smudge cells (Gumprecht shadows) in chronic lymphocytic leukemia (CLL)