B Paroxysmal Nocturnal Hemoglobinuria | Anatomy2Medicine
B Paroxysmal Nocturnal Hemoglobinuria Types

B Paroxysmal Nocturnal Hemoglobinuria

 

  • Paroxysmal nocturnal hemoglobinuria (PNH)

 

    • It results from acquired mutations in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme that is essential for the synthesis of certain cell surface proteins. (MCQ)
    • it is the only hemolytic anemia caused by an acquired genetic defect (MCQ)
    • Proteins are anchored into the lipid bilayer in two ways.

 

  • Transmembrane proteins

 

        • Most have a hydrophobic region that spans the cell membrane
      • others are attached to the cell membrane through a covalent linkage to a specialized phospholipid called glycosylphosphatidylinositol (GPI).( MCQ)
    • In PNH, these GPI-linked proteins are deficient because of somatic mutations that inactivate PIGA.
    • PIGA is X-linked and subject to lyonization (MCQ)
      • As a result, a single acquired mutation in the active PIGA gene of any given cell is sufficient to produce a deficiency state.
    • Because the causative mutations occur in a hematopoietic stem cell, all of its clonal progeny (red cells, white cells, and platelets) are deficient in GPI-linked proteins.
      • Typically the mutant clone coexists with the progeny of normal stem cells that are not PIGA deficient.
    • PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity

 

  • decay–accelerating factor, or CD55 (MCQ)
  • membrane inhibitor of reactive lysis, or CD59 (MCQ)

 

      • C8 binding protein.

 

  • CD59 deficiency (MCQ)

 

      • most important

 

  • a potent inhibitor of C3 convertase that prevents the spontaneous activation of the alternative complement pathway.

 

    • Red cells, platelets, and granulocytes deficient in these GPI-linked factors are abnormally susceptible to lysis or injury by complement.

 

  • intravascular hemolysis

 

      • caused by the C5b-C9 membrane attack complex (MCQ)
      • The hemolysis is paroxysmal and nocturnal in only 25% of cases
      • chronic hemolysis without dramatic hemoglobinuria is more typical.
      • Why is there a tendency for red cells to lyse at night (MCQ)

 

  • There is  slight decrease in blood pH during sleep, which increases the activity of complement.

 

      • Hemosiderinuria eventually leads to iron deficiency
    • Thrombosis is the leading cause of disease-related death in individuals with PNH. (MCQ)

 

  • About 40% of patients suffer from venous thrombosis, often involving the hepatic, portal, or cerebral veins

 

      • Factors that contribute to the prothrombotic state
        • Dysfunction of platelets due to the absence of certain GPI-linked proteins(MCQ)

 

  • absorption of NO by free hemoglobin
  • Acute myeloid leukemia or a myelodysplastic syndrome(MCQ)

 

      • Develop in 5% to 10% of patients  

 

  • PNH is diagnosed by flow cytometry(MCQ)

 

      • provides a sensitive means for detecting red cells that are deficient in GPI-linked proteins such as CD59
    • Infusion of a monoclonal antibody inhibitor of C5a (MCQ)
      • greatly reduces the hemolysis
      • exposes patients to an increased risk of serious or fatal meningococcal infections (as is true of individuals with inherited complement defects).
    • Immunosuppressive drugs are sometimes beneficial for those with evidence of marrow aplasia.

 

  • The only cure is bone marrow transplantation.