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Arch Hellen Med, 26(2), March-April 2009, 206-229


Pathogenetic and pathophysiological mechanisms of the paroxysmal nocturnal hemoglobinuria

1First Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, “Laiko” General Hospital,
2Department of Medical Research, 251 General Air Force Hospital, Athens, Greece

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired stem cell disorder characterized by the unique triad of intravascular hemolysis, bone marrow failure and thrombosis. The hallmark of PNH at the cellular level is a deficiency in cell surface glycosylphosphatidylinositol (GPI) anchored proteins, due to somatic mutations in an X-linked gene, termed PIG-A (phosphatidyl inositol glycan group A). The reduction or absence of GPI-anchor biosynthesis results in a deficiency or absence of all GPI-anchored proteins on the cell surface. CD55 and CD59 are GPI-anchored complement regulatory proteins. Their absence on PNH red cells is responsible for the complement-mediated intravascular hemolysis, which is one of the main characteristics of the disease. However, rare PIG-A mutations can be found in virtually all healthy control subjects, leading to speculation that the presence of PIG-A mutation alone does not induce the expansion of the affected cell. Thus PNH only develops in patients who have a predisposition to such an expansion, in whom there is either a positive selection of the PIG-A gene mutant cells or a negative selection against the non-mutated cells (“dual pathogenesis” theory of PNH development). This review aims to summarize all available data to-date for the pathogenetic mechanisms that lead to the development of PNH.

Key words: CD55, CD59, DAF, Decay accelerating factor, GPI anchor, Membrane inhibitor of reactive lysis, MIRL, Paroxysmal nocturnal hemoglobinuria.

© Archives of Hellenic Medicine