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 clonecoexists 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.

The Pathophysiology of Paroxysmal Nocturnal Hemoglobinuria – USMLE
Paroxysmal Nocturnal Hemoglobinuria
Advanced Understanding of PNH (paroxysmal nocturnal hemoglobinuria)
PNH is a rare but potentially serious blood disease affecting people of all ages. Although some of the features of this disease, such as hemolysis inside of the blood vessels or appearance of red urine, have been known for over 100 years, many aspects of PNH remain a mystery.