Paroxysmal Nocturnal Hemoglobinuria Quiz and Flashcards

Study Notes

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

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.

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.

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.

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.

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.

Paroxysmal Nocturnal Hemoglobinuria Overview