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Paroxysmal nocturnal hemoglobinuria (PNH) manifests by clonal expansion of mutant hematopoietic stem cells (HSCs) bearing a somatic mutation in the X-linked PIGA gene. PIGA mutations cause defective biosynthesis of GPI and cell surface deficiency of GPI-anchored proteins such as DAF and CD59, leading to intravascular hemolysis and thrombosis. These two major symptoms of PNH can be controlled by eculizumab, an anti-C5 monoclonal antibody. Bone marrow failure, the third major symptom of PNH, is autoimmune-mediated and contributes to the clonal expansion of GPI-defective HSCs by selectively attacking GPI-positive wild-type HSCs. GPI-defective erythrocytes, being protected from intravascular hemolysis by eculizumab, accumulate C3-derived fragments, C3b, iC3b, and C3dg, because of DAF deficiency and in turn become susceptible to CR3-mediated phagocytosis by spleen macrophages. Approximately 3% of Japanese patients with PNH are refractory to eculizumab therapy. Approximately 3% of Japanese people are heterozygous for a single nucleotide polymorphism that changes an amino acid near the eculizumab binding site. New therapeutic measures are needed to solve these issues.


Taroh Kinoshita. Molecular genetics, biochemistry, and biology of PNH. [Rinsho ketsueki] The Japanese journal of clinical hematology. 2017;58(4):353-362

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PMID: 28484166

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