Pathogenesis of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired GPI deficiency caused by somatic mutation of the PIGA gene in one or several hematopoietic stem cells. Recently, PNH caused by somatic mutation of one allele of the PIGT gene in combination with a germline mutation of the other allele was reported, showing that PIGA is not the only gene responsible for PNH, though other causes are rare. These mutant cells become GPI deficient, expand clonally and differentiate into all of the hematopoietic lineages. When GPI deficient erythrocytes increase in proportion, massive hemolysis occurs due to activated complement attack during infection. As the complement regulatory proteins such as CD59 and DAF are GPI anchored proteins, they are defective on GPI deficient erythrocytes and these abnormal erythrocytes are thereby left unprotected from complement attack. Hemolytic anemia, venous thrombosis, and bone marrow failure are thus the resulting triad of symptoms. Clonal expansion does not occur with PIGA deficiency alone. We hypothesize that PIGA deficient cells acquire a proliferative phenotype via additional gene mutations within the associated environment of bone marrow failure. This hypothesis will be explained by introducing recent reports.