Paroxysmal nocturnal haemoglobinuria: A replacement of haematopoietic tissue?

Acquired somatic mutations of the PIG-A gene lead to deficient expression o f glycosyl-phosphatidyl-inositol-anchored proteins (GPI-AP) by haematopoiet ic cells and play a causative role in the pathogenesis of paroxysmal noctur nal haemoglobinuria (PNH). However, PIG-A mutations do not explain how the defective PNH clone can expand. It was hypothesized that a selection proces s conferring a relative advantage to the GPI-AP-deficient population is req uired. Since GPI-AP-deficient cells are also detectable in a substantial pr oportion of patients with otherwise typical aplastic anaemia (AA), the mech anisms inducing bone marrow failure might selectively spare the GPI-deficie nt cells. In order to examine the growth characteristics of GPI-AP-deficien t cells in more detail, we performed repeated analyses of GPI-AP expression on peripheral blood cells in 41 patients with AA. We observed four pattern s of the course of GPI-AP-deficient populations: (1) 13 patients showed nor mal expression of GPI-AP in the first analysis and in at least two follow-u p studies at a median time of 709 days after the first analysis. (2) Second ary evolution of a GPI-AP-deficient population was a rare event, Only 4 pat ients with initially normal GPI-AP expression developed a GPI-AP-deficient population during follow up after immunosuppressive treatment. (3) Persiste nce of GPI-AP-deficient cells was observed in 16 patients during a median f ollow-up time of 774 days. However, in some patients, the size of the GPI-A P-deficient population increased substantially. (4) Disappearance of a GPI- AP-deficient population was observed in 8 patients. The time course of GPI- AP expression in relation to the treatment suggests that therapeutic interv entions might modulate the ratio of normal versus GPI-AP-deficient haematop oiesis. Overall, these data argue against an 'absolute growth advantage' of GPI-AP-deficient cells. Our data are consistent with the hypothesis that h aematopoietic failure caused by damage to normal haematopoiesis allows the outgrowth of a GPI-AP-deficient population. Thus, in at least some patients GPI-AP-deficient cells might pre-exist at a very low percentage and replac e haematopoiesis after an insult to the normal cells. Copyright (C) 2000 S. Karger AG. Basel.