The characteristic, defining defect in paroxysmal nocturnal hemoglobinuria
is the somatic mutation of the PIG-A gene (essential to the biosynthesis of
the glycosylphosphatidylinositol moiety that affixes a number of proteins
to the cellular surface) in hematopoietic cells. These cells thus lack the
proteins usually held in place by this anchor. The absence of these protein
s is the most reliable diagnostic criterion of the disease and is responsib
le for many of the clinical manifestations of PNH. The current hypothesis e
xplaining the disorder suggests that there are two components: (1) hematopo
ietic stem cells with the characteristic defect are present in the marrow o
f many if not all normal individuals in very small numbers; (2) some aplast
ogenic influence suppresses the normal stem cells but does not suppress the
defective stem cells, thus allowing the proportion of these cells to incre
ase. Current research attempts to substantiate this hypothesis and design t
herapy consistent with the hypothesis. Paroxysmal nocturnal hemoglobinuria
(PNH) is an acquired stem cell disorder characterized by intravascular hemo
lysis, hypercoagulability, and relative bone marrow failure [1]. It is char
acterized by a somatic mutation in the gene encoding the alpha1-6-N-acetyl-
glucosaminyltransferase necessary for the formation of the glycosylphosphat
idylinositol (GPI) anchor that binds certain proteins to the membrane surfa
ce (Fig. 1) [2,3(.)]. Whereas many of the manifestations can be accounted f
or by the absence of these proteins on the cells of the hematopoietic syste
m, it is not entirely clear whether this defect is sufficient to make the d
isease manifest. In this paper, the author reviews recent clinical observat
ions and relates them to the underlying pathophysiology of the disease. (C)
2001 Lippincott Williams & Wilkins, Inc.