Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-.

Nieves Perdigones,Mariela Morales,Philip Mason,Monica Bessler

doi:10.12688/f1000research.4980.2

Abstract

We describe a case of paroxysmal nocturnal hemoglobinuria (PNH) in a woman who is heterozygous for the glucose-6-phosphate dehydrogenase A- ( G6PDA-) allele. PNH is associated with one or more clones of cells that lack complement inhibition due to loss of function somatic mutations in the PIGA gene. PIGA encodes the enzyme phosphatidylinositol glycan anchor biosynthesis, class A, which catalyses the first step of glycosylphosphatidylinisotol ( GPI) anchor synthesis. Two GPI anchored red cell surface antigens regulate complement lysis. G6PD catalyses the first step of the pentose phosphate pathway and enzyme variants, frequent in some populations have been selected because they confer resistance to malaria, are associated with hemolysis in the presence of oxidizing agents including several drugs. The patient had suffered a hemolytic attack after taking co-trimoxazole, a drug that precipitates hemolysis in G6PD deficient individuals. Since both G6PD and PIGA are X-linked we hypothesized that the PIGA mutation was on the X-chromosome carrying the G6PDA- allele. Investigations showed that in fact the PIGA mutation was on the X-chromosome carrying the normal G6PD B allele. We speculate that complement activation on G6PD A- red cells exposed to Bactrim might have triggered complement activation inducing the lysis of G6PD B PNH Type II red blood cells or that the patient may have had a PNH clone expressing G6PDA- at the time of the hemolytic episode.

Highlights

In paroxysmal nocturnal hemoglobinuria (PNH) one or more clones of blood cells develops from stem cells that have an acquired mutation in the X-linked PIGA gene[1]
We were interested to find out whether she might have both, and whether her PNH might have been responsible for her Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency and thereby explain the hemolysis precipitated by co-trimoxazole as noted by an obervant emergency physician
While developing our hypothesis, which turned out to be incorrect, we considered whether PNH/G6PDA- cells might have high levels of oxidative stress since both G6PD deficiency and PNH have been shown to be associated with elevated levels of reactive oxygen species[11,13]

Summary

Introduction

In paroxysmal nocturnal hemoglobinuria (PNH) one or more clones of blood cells develops from stem cells that have an acquired mutation in the X-linked PIGA gene[1]. PNH usually develops in patients with aplastic anemia (AA) and it is thought that PNH cells have a growth or survival advantage over the AA cells the mechanism is not known[2]. PNH cells can be completely deficient in GPI anchored proteins (Type III) or partially deficient due to residual activity of the PIGA protein (Type II), while PNH Type I cells express GPI-linked proteins normally. The use of a complement inhibitor, eculizumab has greatly improved the quality of life of PNH patients as it causes a dramatic reduction in the hemolysis and thrombotic episodes, improvement in anemia, with a stabilization of the hemoglobin levels and reduced transfusion requirements. The use of a complement inhibitor, eculizumab has greatly improved the quality of life of PNH patients as it causes a dramatic reduction in the hemolysis and thrombotic episodes, improvement in anemia, with a stabilization of the hemoglobin levels and reduced transfusion requirements3. eculizumab leads to an increase in the number of circulating red blood cells that otherwise are subject to complement-mediated hemolysis[4]

Methods

Results

Conclusion