Paroxysmal nocturnal hemoglobinuria pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Paroxysmal nocturnal hemoglobinuria is believed to be caused by a genetic mutation and complement mediated hemolysis. A mutation in PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is considered the main pathogenic factor in development of PNH because PIGA gene is responsible for the GPI anchor synthesis. The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes. Other genetic mutation may also cause PNH like TET2, SUZ12, U2AF1, and JAK2. The anemia in PNH is due to complement mediated hemolysis of RBCs which are defective in the CD59//CD55 markers which are important in inactivating the complement system and protecting the RBCs. Paroxysmal nocturnal hemoglobinuria may be associated with aplastic anemia, myelodysplastic syndrome, and acute myelogenous leukemia.

Pathophysiology

Physiology

• Normally, Red Blood Cells (RBCs), alike other cells in the body, have surface proteins that acts as a communicating signal between the cells and the environment.
• The signaling proteins are most commonly attached to the surface of the RBCs by glycolipids. The most common glycolipid is the glycosyl phosphatidylinositols (GPI).
• The attached proteins are also protective to the cells against destruction by the complement system.
• The RBCs are mainly protected by proteins called decay accelerating factor (DAF/CD55). The DAF or CD55 proteins prevent the formation of C3-convertase enzyme, the protectin (CD59), and the C9 which are components of the complement inflammatory system.

Pathogenesis

• It is understood that paroxysmal nocturnal hemoglobinuria is caused by genetic mutation and complement mediated hemolysis.

PIGA gene mutation and PNH

• The acquired gene mutation of PIGA gene (Posphatidylinositol Glycan anchor biosynthesis, class A) is the main pathogenic factor in developing PNH. The PIGA gene is responible for the GPI anchor synthesis.
• The PIGA gene is found on the X chromosome and that concludes the affection of all males who have the mutation in one allele. However, the females will be carrier if one allele affected and a second genetic "hit" must take place to develop the disease.
• The PIGA gene mutation is most common a frameshift mutation which results in a misfolded protein product which is nonfunctional proteins and degraded by proteasomes.
• It is believed the mutation mechanism is caused by exposure to radiation, chemotherapy, or DNA repair defects.
• Other mutations:
  • Lack of the CD59 on the RBCs surface membrane is strongly related to the clinical signs of PNH. It is related to the intravascular hemolysis and peripheral neuropathy.

Anemia

• The anemia in PNH is mainly due to complement induced hemolysis. However, other defects can cause anemia in the setting of paroxysmal nocturnal hemoglobinuria. These causes include bone marrow failure and iron deficiency.
• Different mechanisms of anemia in PNH include the following:
  • Complement mediated anemia:
    • The main cause of anemia in the patients of PNH and it can cause both intravascular and extravascular hemolysis. This type of hemolysis is non immune so, the patients with PNH will have a negative Coombs test.
    • Intravascular hemolysis: This type of hemolytic anemia in PNH is due to lack of CD59 marker as this marker is the main inhibitor of intravascular hemolysis normally.
    • Extravascular hemolysis occurs due to reduced expression of CD55 marker.
  • Aplastic anemia:
    • Aplastic anemia is defined as pancytopenia due to stem cell defect.
    • It may occur in already diagnosed PNH or before established diagnosis.

Genetics

Genes involved in the pathogenesis of paroxysmal nocturnal hemoglobinuria include:

• PIGA gene
• TET2
• SUZ12
• U2AF1
• JAK2

Associated Conditions

• However, paroxysmal nocturnal hemoglobinuria is usually associated with the following diseases:
  • Aplastic anemia
  • Myelodysplastic syndrome
  • Acute myelogenous leukemia