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6.1: Introduction to Hemolytic Anemias

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    Hemolytic anemia refers to a process where there is increased red blood cell destruction or decreased red blood cell survival (hemolysis) leading to a drop in the measured hemoglobin (anemia).1

    The type of hemolysis can be categorized into different categories based on the location of the hemolysis (intravascular or extravascular) or the cause (intrinsic or extrinsic).

    Intravascular and extravascular refers to the location of the hemolytic process, whether the process is taking place within the blood vessels (intra) or outside the blood vessels (extra).2

    Intrinsic and extrinsic refers to the cause of red blood cell destruction relative to the red blood cell itself. If the cause is due to an issue with the red blood cell (e.g. inherited defects of the RBC), it is referred to as being intrinsic. If the cause is due to factors from outside the red blood cell (e.g. environment), it is referred to as being extrinsic.2

    Compensated hemolysis refers to the ability of the bone marrow to increase red blood cell production in order to compensate for the rate of hemolysis. As a result, anemia does not develop.2

    Extravascular (Macrophage-mediated) Hemolysis (EVH)

    Process:1, 3-5

    1. RBCs are phagocytized in the spleen, bone marrow, or liver by macrophages.
    2. Hemoglobin is broken down into iron, globin, and the protoporphyrin ring.
    3. Iron is carried by transferrin to the bone marrow be reused or stored as ferritin or hemosiderin.
    4. Globin is broken down into amino acids to be recycled.
    5. The protoporphyrin ring is further is broken down to biliverdin and then to unconjugated bilirubin in the macrophage.
    6. Unconjugated bilirubin is then released and carried by albumin to the liver.
    7. In the liver, unconjugated bilirubin is converted to conjugated bilirubin (bilirubin diglucuronide).
    8. Conjugated bilirubin is excreted with bile into the intestines where it is converted into urobilinogen by bacteria.
    9. A majority of the urobilinogen is then excreted in feces, a small amount is reabsorbed by the kidney, and another portion is excreted into the urine.

    Intravascular (Fragmentation) Hemolysis (IVH)


    1. RBC hemolysis occurs in the blood vessels and hemoglobin is released into circulation.
    2. Hemoglobin dissociates into αβ dimers and is picked up by Haptoglobin where it is carried to the liver.
    3. Subsequent catabolic steps are the same as extravascular hemolysis from the liver onwards.
    4. If haptoglobin is not available, the αβ dimers become oxidized into methemoglobin where it is broken down into metheme and globin.
    5. Metheme is carried by hemopexin to the liver.
    6. If hemopexin is not available, metheme binds albumin instead to form methalbumin,.
    7. Methemalbumin continues to circulate the body until hemopexin becomes available.

    Table 1. Comparison of IVH and EVH Laboratory Findings1-3

    Test IVH EVH
    RBC, Hct, Hb Decreased Decreased
    Total Bilirubin Increased Increased
    LDH Increased Slightly Increased
    Haptoglobin Decreased Slightly Decreased
    Hemopexin Decreased Slightly Decreased
    Hemosiderinuria Present Absent
    Hemoglobinuria Present Absent
    RBC Morphology Schistocytes Spherocytes
    Examples PNH, PCH, MAHAs, Mechanical trauma, Bacterial Infections, Thermal Injury Thalassemia (Other hemoglobinopathies), Enzymopathies, Membranopathies, Megaloblastic anemia, Autoimmune hemolytic anemia, Drug-induced hemolytic anemia


    1. Barcellini W, Fattizzo B. Clinical Applications of Hemolytic Markers in the Differential Diagnosis and Management of Hemolytic Anemia. Dis Markers [Internet]. 2015 Dec 27 [cited 2018 Jun 26];2015:635670. Available from:

    2. McKenzie SB, Otto CN. Introduction to anemias. In: Clinical laboratory hematology. 3rd ed. New Jersey: Pearson; 2015. p.178–97.

    3. Doig K. Introduction to increased destruction of erythrocytes. In: Rodak’s hematology clinical applications and principles. 5th ed. St. Louis, Missouri: Saunders; 2015. p. 348-66.

    4. McKenzie SB. Hemoglobin. In: Clinical laboratory hematology. 3rd ed. New Jersey: Pearson; 2015. p. 77-96.

    5. Harmening DM. The red blood cell: structure and function. In: Clinical hematology and fundamentals of hemostasis. 5th ed. Philadelphia: F.A. Davis Company; 2009. p. 64-81.

    This page titled 6.1: Introduction to Hemolytic Anemias is shared under a CC BY-NC 4.0 license and was authored, remixed, and/or curated by Valentin Villatoro and Michelle To (Open Education Alberta) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request.