Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, predominantly acquired hematological condition in which the premature destruction of erythrocytes results in a loss of hemoglobin through the urine. The darkened urine is particularly noticeable in the early morning after hemoglobin has accumulated in the bladder during the night. The symptoms of PNH tend to recur when various triggers stress the body, including physical exertion and infection.1

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Genetic Etiology of PNH

Mutations in the phosphatidylinositol glycan class A (PIGA) gene, located on the X chromosome, cause most cases of PNH.2 Rarely, variants in the phosphatidylinositol glycan class T (PIGT) gene, located on chromosome 20, result in an inflammatory form of PNH.2,3

Although mutated PIGA genes are found on the X chromosome, PIGA-mutant PNH is not an inherited sex-linked disorder.2 Patients in whom this type of PNH develops acquire somatic PIGA mutations within certain hematopoietic stem cells during their lifetime. Whereas unaffected hematopoietic stem cells produce normal blood cells, mutated stem cells produce abnormal, PNH blood cells.4 

In contrast, individuals with PNH due to PIGT mutations inherit a mutant allele of the PIGT gene from one parent and a normal PIGT allele from the other parent. A somatic mutation must develop in the second, normal PIGT allele before manifestations of PNH due to the PIGT mutation develop.2,5

The cause of PIGA mutations is unknown, but researchers speculate that immune system attacks on hematopoietic stem cells as a maladaptive response to an injury or infection may lead to the development of somatic mutations.2

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The Role of Clonal Expansion in PNH

In PNH, mutated hematopoietic stem cells replicate to form clones, and the number of abnormal hematopoietic stem cells producing PNH blood cells rapidly increases (nonmalignant clonal expansion). 

Although the exact cause of the selective clonal expansion of PIGA-mutated stem cells is unknown, evidence suggests 2 possible theories: either the PIGA mutation confers a proliferative advantage to the PNH clones over normal cells, or the PIGA mutation allows PNH clones to survive longer than normal cells.6,7 

The theory of conferred survival advantage of PNH clones is supported by the extended survival of PIGA-mutated stem cells in immune-mediated bone marrow disorders such as aplastic anemia, myelodysplastic syndrome, and PNH. Additionally, PIGA-mutated stem cells appear to be resistant to cytotoxic attacks by T lymphocytes and natural killer cells, further bolstering the survival theory.6

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The Function of GPI Anchor Proteins

PIGA and PIGT genes encode glycosylphosphatidyl inositol (GPI) anchor proteins, which normally cover the surface membranes of erythrocytes, leukocytes, and platelets derived from unmutated hematopoietic stem cells.8 

The GPI anchor proteins, especially CD59 (also known as membrane inhibitor of reactive lysis, or MIRL) and CD55 (also known as decay accelerating factor, or DAF), are complement regulatory proteins that inhibit various steps of the complement cascade. CD55 inhibits C3 and C5 convertases; C3 convertase cleaves complement component C3 into complement-activating fragments C3a and C3b, and C5 convertase cleaves C5 into complement-activating fragments C5a and C5b. CD59 blocks the fusion of C9 to the C5b-C8 complex, which is needed to form the membrane attack complex (MAC).8 

In PNH, mutated PIGA and PIGT genes in affected hematopoietic stem cells result in a lack of normally functioning GPI anchor proteins on the surface membranes of mature PNH progeny blood cells, such as erythrocytes, platelets, and leukocytes. The deficiency leads to an increase in complement activation, formation of the MAC on affected erythrocyte surface membranes, and eventually complement-mediated intravascular hemolysis of the affected erythrocytes. This sequence of events elevates the level of free hemoglobin in the peripheral blood, which ultimately is excreted through the urine, giving the urine its hallmark dark color.8 

It is predominantly erythrocytes that are affected by complement-mediated hemolysis. PNH leukocytes appear to be unaffected by hemolysis despite the lack of GPI anchor proteins. It is speculated that the leukocytes are protected by the presence of a non-GPI-linked complement inhibitor, CD46, on their surface.8 

Affected platelets lacking GPI anchor proteins may also undergo complement-mediated destruction, thereby contributing to another characteristic feature of PNH: a predisposition to thromboembolic events.8 

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  1. Paroxysmal nocturnal hemoglobinuria: description. Medline Plus. Accessed November 17, 2022.
  2. Paroxysmal nocturnal hemoglobinuria: causes. Medline Plus. Accessed November 17, 2022.
  3. PIGT phosphatidylinositol glycan anchor biosynthesis class T. NIH National Library of Medicine. Updated November 6, 2022. Accessed November 17, 2022.
  4. Luzzatto L. Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism. Curr Opin Genet Dev. 2006;16(3):317-322. doi:10.1016/j.gde.2006.04.015
  5. Brodsky RA. Paroxysmal nocturnal hemoglobinuria without GPI-anchor deficiency. J Clin Invest. 2019;129(12):5074-5076. doi:10.1172/JCI131647
  6. Nakakuma H, Kawaguchi T. Pathogenesis of selective expansion of PNH clones. Int J Hematol. 2003;77(2):121-124. doi:10.1007/BF02983210
  7. Inoue N, Izui-Sarumaru T, Murakami Y, et al. Molecular basis of clonal expansion of hematopoiesis in 2 patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood. 2006;108(13):4232-4236. doi:10.1182/blood-2006-05-025148
  8. Risitano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics. 2008;2(2):205-222. 

Reviewed by Hasan Avcu, MD, on 11/20/2022.