Recent advances in pathogenesis of paroxysmal nocturnal hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired hemolytic anemia with a unique clinical picture: intravascular hemolysis (with hemoglobinuria), high risk of thrombosis and pancytopenia. In PNH the progeny of a hematopoetic stem cell (HSC) with a somatic mutation of the X-linked PIGA gene are unable to synthesize the glycosylphosphatidylinositol (GPI) molecule, which serves to tether various proteins to the cell membrane. The absence of the GPI-linked complement regulators CD55 and CD59 make PNH cells unable to cope complement activation: this explains hemolysis and, likely, thrombosis. Targeting complement activation by eculizumab, a monoclonal antibody against complement 5 (C5), has proven to be effective in abrogating intravascular hemolysis, reducing blood transfusion and reducing the risk of thrombosis in most patients with hemolytic PNH. However, few patients remain transfusion-dependent, as a fraction of PNH red cells become coated with C3 and can undergo extravascular hemolysis. Despite GPI deficiency plays a central role in PNH pathogenesis, it does not explain neither the pancitopenia nor the expansion of PNH (GPI-negative) blood cells. In fact, PIGA gene inactivation in mice HSC does not provide growth advantage; moreover, rare PNH blood cells are always present in healthy people. A reasonable model to explain the paradoxical expansion of PNH blood cells is that the mutated HSC expands by escaping the attack of autoreactive T cells against normal (GPI-positive) hematopoiesis. In keeping with this model, deranged populations of T cells have been found in PNH patients. Here we review some recent findings about the diverse pathogenic mechanisms involved in shaping the multifaceted clinical features of PNH.