Paroxysmal nocturnal haemoglobinuria: the disease and a hypothesis for a new treatment

Paroxysmal nocturnal haemoglobinuria (PNH) is a disease entity that presents with intravascular haemolysis and an increased tendency for venous thrombosis. In recent years there has been a major breakthrough in our understanding of the pathogenesis of PNH. Most of the different symptoms can be tracked down to the deficiency of glycophosphoinositol (GPI)-anchored proteins in cell lines deriving from a single haematopoietic stem cell. This deficiency is caused by a mutation in the X-chromosomal PIG-A gene whose product, a glycosyltransferase, participates in the first step of the GPI-anchor biosynthesis. Lack of GPI-linked complement inhibitors CD55 and CD59 predisposes red blood cells to lysis. The main unresolved question is why the stem cells lacking GPI-anchored surface proteins gain a growth advantage over their normal counterparts. So far, our progress in understanding the pathogenesis has not resulted in better treatment of PNH and new ideas are warranted. In this regard, we propose a new mode of treatment for PNH by exploiting the increased susceptibility of affected bone marrow precursor cells to complement and targeting complement attack against them by a specific complement-activating monoclonal antibody.