Pathogenesis of paroxysmal nocturnal hemoglobinuria: Absence of the GPI anchor

INTRODUCTION

Paroxysmal nocturnal hemoglobinuria (PNH) was one of the first hematologic disorders given a clear clinical description, because the defining symptom, dark urine at night, was distinctive and easily observed. It was subsequently realized that the pigment was hemoglobin, which resulted from the breakdown or hemolysis of red cells.

The hemolysis was found to be due to the action of complement on abnormal red cells [1,2]. Compared with normal cells, PNH cells were lysed more readily when complement was activated by antibody. This property was used for many years to define the abnormal red cells [3].

The recognition that the red cells among patients with PNH were abnormal led to many attempts to determine its biochemical basis. The first red cell abnormalities found were the deficiency of two enzymes, leukocyte alkaline phosphatase [4] and erythrocyte acetylcholinesterase [5]; however, the absence of neither protein explained the clinical symptoms of PNH. Subsequently, decay accelerating factor (DAF), a complement regulatory protein that is now called CD55, was also found to be absent, a finding which helped explain the unusual sensitivity of the red cells to the hemolytic action of complement [6].

All three of these proteins are tethered to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. This finding uncovered the fundamental pathogenic defect in PNH: the inability to produce the GPI anchor [7].

This topic review will discuss the role of absence of the GPI anchor in PNH, beginning with a brief discussion of the biochemistry and genetics of this protein [8,9]. The role of the missing cell proteins, such as CD55, in the pathogenesis of PNH is presented separately. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria: Missing cell proteins".) A detailed history of our evolving understanding of this disorder has been published [10].