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Nat Rev Dis Primers. 2017 May 18;3:17028. doi: 10.1038/nrdp.2017.28.

Paroxysmal nocturnal haemoglobinuria.

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Department of Haematology, St. James' University Hospital, Leeds, UK.
Division of Hematology, Johns Hopkins Department of Medicine, Johns Hopkins University, Ross Research Building, Room 1025, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.
Laboratory of Immunoglycobiology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Department of Immunoregulation Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.


Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haematopoietic stem cell (HSC) disease that presents with haemolytic anaemia, thrombosis and smooth muscle dystonias, as well as bone marrow failure in some cases. PNH is caused by somatic mutations in PIGA (which encodes phosphatidylinositol N-acetylglucosaminyltransferase subunit A) in one or more HSC clones. The gene product of PIGA is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors; thus, PIGA mutations lead to a deficiency of GPI-anchored proteins, such as complement decay-accelerating factor (also known as CD55) and CD59 glycoprotein (CD59), which are both complement inhibitors. Clinical manifestations of PNH occur when a HSC clone carrying somatic PIGA mutations acquires a growth advantage and differentiates, generating mature blood cells that are deficient of GPI-anchored proteins. The loss of CD55 and CD59 renders PNH erythrocytes susceptible to intravascular haemolysis, which can lead to thrombosis and to much of the morbidity and mortality of PNH. The accumulation of anaphylatoxins (such as C5a) from complement activation might also have a role. The natural history of PNH is highly variable, ranging from quiescent to life-threatening. Therapeutic strategies include terminal complement blockade and bone marrow transplantation. Eculizumab, a monoclonal antibody complement inhibitor, is highly effective and the only licensed therapy for PNH.

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