Paroxysmal Nocturnal Hemoglobinuria Overview

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Most normal individuals have small numbers of bone marrow cells with PIGA mutations, similar to those that cause PNH.
• These cells increase in numbers and produce clinically evident PNH only in rare instances where they have a selective advantage, such as in autoimmune reactions against GPI-linked antigens.

PNH and Aplastic Anemia

• PNH is frequently associated with aplastic anemia, a marrow failure syndrome that has an autoimmune basis in many individuals.

GPI-Linked Proteins

• PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity:
  • Decay-accelerating factor (CD55)
  • Membrane inhibitor of reactive lysis (CD59)
  • C8-binding protein
• CD59 is the most important, as it prevents the spontaneous activation of the alternative complement pathway.

Hemolysis and Anemia

• Red cells deficient in GPI-linked factors are abnormally susceptible to lysis or injury by complement.
• This manifests as intravascular hemolysis, caused by the C5b-C9 membrane attack complex.
• Hemolysis is paroxysmal and nocturnal in only 25% of cases, while chronic hemolysis without dramatic hemoglobinuria is more typical.
• The anemia is variable but usually mild to moderate in severity.

Iron Deficiency and Thrombosis

• The loss of heme iron in the urine (hemosiderinuria) eventually leads to iron deficiency, which can exacerbate the anemia if untreated.
• Thrombosis is the leading cause of disease-related death in individuals with PNH, with about 40% of patients suffering from venous thrombosis, often involving the hepatic, portal, or cerebral veins.

Diagnosis and Complications

• PNH is diagnosed by flow cytometry, which detects red cells that are deficient in GPI-linked proteins such as CD59.
• About 5% to 10% of patients eventually develop acute myeloid leukemia or a myelodysplastic syndrome, indicating that PNH may arise in the context of genetic damage to hematopoietic stem cells.

Genetics of PNH

• PNH results from acquired mutations in the phosphatidylinositol glycan complementation group A gene (PIGA), an enzyme essential for the synthesis of GPI-linked proteins.
• PIGA is X-linked and subject to lyonization, which means a single acquired mutation in the active PIGA gene of any given cell is sufficient to produce a deficiency state.
• The causative mutations occur in a hematopoietic stem cell, and all of its clonal progeny (red cells, white cells, and platelets) are deficient in GPI-linked proteins.