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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Dosing Patterns of Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Ravulizumab in the United States: A Retrospective Claims-Based Analysis
Advances in Therapy Open Access 24 November 2023
Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry
Annals of Hematology Open Access 05 September 2023
Pegcetacoplan for Treating Paroxysmal Nocturnal Haemoglobinuria: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
PharmacoEconomics - Open Open Access 17 May 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 1 digital issues and online access to articles
$99.00 per year
only $99.00 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Brodsky, R. A. Paroxysmal nocturnal hemoglobinuria. Blood 124, 2804–2811 (2014).
Hillmen, P., Lewis, S. M., Bessler, M., Luzzatto, L. & Dacie, J. V. Natural history of paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 333, 1253–1258 (1995).
Oni, S. B., Osunkoya, B. O. & Luzzatto, L. Paroxysmal nocturnal hemoglobinuria: evidence for monoclonal origin of abnormal red cells. Blood 36, 145–152 (1970). This is the first paper to demonstrate that PNH is a clonal haematopoietic disease.
Enneking, J. Eine neue form intermittierender haemoglobinurie (haemoglobinuria paroxysmalis nocturia) [German]. Klin. Wochenschr. 7, 2045 (1928).
Ham, T. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria. A study of the mechanism of hemolysisin relation to acid-base equilibrium. N. Engl. J. Med. 217, 915–917 (1937).
Rother, R. P., Rollins, S. A., Mojcik, C. F., Brodsky, R. A. & Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256–1264 (2007). This outstanding review provides the rationale for targeting C5 to treat PNH.
Kinoshita, T., Medof, M. E., Silber, R. & Nussenzweig, V. Distribution of decay-accelerating factor in the peripheral blood of normal individuals and patients with paroxysmal nocturnal hemoglobinuria. J. Exp. Med. 162, 75–92 (1985).
Richards, S. J., Norfolk, D. R., Swirsky, D. M. & Hillmen, P. Lymphocyte subset analysis and glycosylphosphatidylinositol phenotype in patients with paroxysmal nocturnal hemoglobinuria. Blood 92, 1799–1806 (1998).
Takeda, J. et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell 73, 703–711 (1993). This seminal paper links PIGA mutations to GPI anchor deficiency in PNH.
Socie, G. et al. Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories; an analysis of the International PNH Registry. Intern. Med. J. 46, 1044–1053 (2016).
Yu, F., Du, Y. & Han, B. A comparative analysis of clinical characteristics of patients with paroxysmal nocturnal hemoglobinuria between Asia and Europe/America. Int. J. Hematol. 103, 649–654 (2016).
Munoz-Linares, C. et al. Paroxysmal nocturnal hemoglobinuria: a single Spanish center's experience over the last 40 yr. Eur. J. Haematol. 93, 309–319 (2014).
Schrezenmeier, H. et al. Baseline characteristics and disease burden in patients in the international paroxysmal nocturnal hemoglobinuria registry. Haematologica 99, 922–929 (2014).
Ware, R. E., Hall, S. E. & Rosse, W. F. Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence. N. Engl. J. Med. 325, 991–996 (1991).
Naithani, R. et al. Paroxysmal nocturnal hemoglobinuria in childhood and adolescence — a retrospective analysis of 18 cases. Indian J. Pediatr. 75, 575–578 (2008).
Curran, K. J. et al. Paroxysmal nocturnal hemoglobinuria in pediatric patients. Pediatr. Blood Cancer 59, 525–529 (2012).
van den Heuvel-Eibrink, M. M. et al. Childhood paroxysmal nocturnal haemoglobinuria (PNH), a report of 11 cases in the Netherlands. Br. J. Haematol. 128, 571–577 (2005).
Mukhina, G. L., Buckley, J. T., Barber, J. P., Jones, R. J. & Brodsky, R. A. Multilineage glycosylphosphatidylinositol anchor deficient hematopoiesis in untreated aplastic anemia. Br. J. Haematol. 115, 476–482 (2001).
Sugimori, C. et al. Minor population of CD55−, CD59−, blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood 107, 1308–1314 (2006).
Nishimura, J. et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 83, 193–207 (2004).
Hill, A., Kelly, R. J. & Hillmen, P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 121, 4985–4996 (2013).
Issaragrisil, S. et al. The epidemiology of aplastic anemia in Thailand. Blood 107, 1299–1307 (2006).
Young, N. S. & Kaufman, D. W. The epidemiology of acquired aplastic anemia. Haematologica 93, 489–492 (2008).
Socie, G. et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 348, 573–577 (1996).
de Latour, R. P. et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 112, 3099–3106 (2008).
Kelly, R. J. et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 117, 6786–6792 (2011).
de Fontebrune, F. S. & Socie, G. Long-term issues after immunosuppressive therapy for aplastic anemia. Curr. Drug Targets 2 May 2016 [epub ahead of print].
Armstrong, C. et al. Affected paroxysmal nocturnal hemoglobinuria T lymphocytes harbor a common defect in assembly of N-acetyl-d-glucosamine inositol phospholipid corresponding to that in class A Thy-1- murine lymphoma mutants. J. Biol. Chem. 267, 25347–25351 (1992).
Takahashi, M. et al. Deficient biosynthesis of N-acetylglucosaminyl phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria. J. Exp. Med. 177, 517–521 (1993).
Hillmen, P., Bessler, M., Mason, P. J., Watkins, W. M. & Luzzatto, L. Specific defect in N-acetylglucosamine incorporation in the biosynthesis of the glycosylphosphatidylinositol anchor in cloned cell lines from patients with paroxysmal nocturnal hemoglobinuria. Proc. Natl Acad. Sci. USA 90, 5272–5276 (1993).
Hidaka, M. et al. Impaired glycosylation of glycosylphosphatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria leukocytes. Biochem. Biophys. Res. Commun. 191, 571–579 (1993).
Kinoshita, T. Biosynthesis and deficiencies of glycosylphosphatidylinositol. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 90, 130–143 (2014).
Kinoshita, T. & Fujita, M. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J. Lipid Res. 57, 6–24 (2016).
Saha, S., Anilkumar, A. A. & Mayor, S. GPI-anchored protein organization and dynamics at the cell surface. J. Lipid Res. 57, 159–175 (2016).
Kostova, Z., Rancour, D. M., Menon, A. K. & Orlean, P. Photoaffinity labelling with P3-(4-azidoanilido)uridine 5′-triphosphate identifies gpi3p as the UDP-GlcNAc-binding subunit of the enzyme that catalyses formation of GlcNAc-phosphatidylinositol, the first glycolipid intermediate in glycosylphosphatidylinositol synthesis. Biochem. J. 350, 815–822 (2000).
Nishimura Ji, J. et al. Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria. Blood 99, 2748–2751 (2002).
Yamada, N. et al. Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 85, 885–892 (1995).
Pramoonjago, P. et al. Somatic mutations of PIG-A in Thai patients with paroxysmal nocturnal hemoglobinuria. Blood 86, 1736–1739 (1995).
Nafa, K., Mason, P. J., Hillmen, P., Luzzatto, L. & Bessler, M. Mutations in the PIG-A gene causing paroxysmal nocturnal hemoglobinuria are mainly of the frameshift type. Blood 86, 4650–4655 (1995).
Nafa, K., Bessler, M., Castro-Malaspina, H., Jhanwar, S. & Luzzatto, L. The spectrum of somatic mutations in the PIG-A gene in paroxysmal nocturnal hemoglobinuria includes large deletions and small duplications. Blood Cells Mol. Dis. 24, 370–384 (1998).
Nishimura, J. et al. A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones. Blood 89, 3470–3476 (1997).
Nishimura, J., Murakami, Y. & Kinoshita, T. Paroxysmal nocturnal hemoglobinuria: an acquired genetic disease. Am. J. Hematol. 62, 175–182 (1999).
Krawitz, P. M. et al. A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood 122, 1312–1315 (2013).
Ohishi, K., Inoue, N. & Kinoshita, T. PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. EMBO J. 20, 4088–4098 (2001).
Murakami, Y. et al. Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. J. Biol. Chem. 287, 6318–6325 (2012).
Rotoli, B. & Luzzatto, L. Paroxysmal nocturnal haemoglobinuria. Baillieres Clin. Haematol. 2, 113–138 (1989).
Young, N. S. The problem of clonality in aplastic anemia: Dr. Dameshek's riddle, restated. Blood 79, 1385–1392 (1992).
Luzzatto, L., Bessler, M. & Rotoli, B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell 88, 1–4 (1997).
Young, N. S. & Maciejewski, J. P. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes “Why? Why? Why?”. J. Clin. Invest. 106, 637–641 (2000).
Kinoshita, T. & Inoue, N. Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria. Int. J. Hematol. 75, 117–122 (2002).
Inoue, N., Murakami, Y. & Kinoshita, T. Molecular genetics of paroxysmal nocturnal hemoglobinuria. Int. J. Hematol. 77, 107–112 (2003).
Terstappen, L. W. M. M., Nguyen, M., Huang, S. & Lazarus, H. M. Defective and normal haematopoietic stem cells in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 84, 504–514 (1993).
Hu, R. et al. PIG-A mutations in normal hematopoiesis. Blood 105, 3848–3854 (2005).
Rondelli, T. et al. The frequency of granulocytes with spontaneous somatic mutations: a wide distribution in a normal human population. PLoS ONE 8, e54046 (2013).
Araten, D. J., Nafa, K., Pakdeesuwan, K. & Luzzatto, L. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc. Natl Acad. Sci. USA 96, 5209–5214 (1999).
Kawagoe, K. et al. GPI-anchor deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 87, 3600–3606 (1996).
Rosti, V. et al. Murine embryonic stem cells without Pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion. J. Clin. Invest. 100, 1028–1036 (1997).
Keller, P., Tremml, G., Rosti, V. & Bessler, M. X inactivation and somatic cell selection rescue female mice carrying a Piga-null mutation. Proc. Natl Acad. Sci. USA 96, 7479–7483 (1999).
Murakami, Y. et al. Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by model mice of paroxysmal nocturnal hemoglobinuria. Blood 94, 2963–2970 (1999).
Tremml, G. et al. Increased sensitivity to complement and a decreased red cell life span in mice mosaic for a non-functional Piga gene. Blood 94, 2945–2954 (1999).
Dingli, D., Luzzatto, L. & Pacheco, J. M. Neutral evolution in paroxysmal nocturnal hemoglobinuria. Proc. Natl Acad. Sci. USA 105, 18496–18500 (2008).
Young, N. S., Calado, R. T. & Scheinberg, P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108, 2509–2519 (2006).
Murakami, Y. et al. Inefficient response of T lymphocytes to GPI-anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood 100, 4116–4122 (2002).
DeZern, A. E. et al. Detection of paroxysmal nocturnal hemoglobinuria clones to exclude inherited bone marrow failure syndromes. Eur. J. Haematol. 92, 467–470 (2014).
Luzzatto, L. Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria. F1000Res. 5 (F1000 Faculty Rev.), 209 (2016).
Gargiulo, L. et al. Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood 121, 2753–2761 (2013).
Gargiulo, L. et al. Highly homologous T-cell receptor beta sequences support a common target for autoreactive T cells in most patients with paroxysmal nocturnal hemoglobinuria. Blood 109, 5036–5042 (2007).
Nagakura, S. et al. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Blood 100, 1031–1037 (2002).
Hanaoka, N. et al. Occupancy of whole blood cells by a single PIGA-mutant clone with HMGA2 amplification in a paroxysmal nocturnal haemoglobinuria patient having blood cells with NKG2D ligands. Br. J. Haematol. 160, 114–116 (2013).
Inoue, N. et al. Molecular basis of clonal expansion of hematopoiesis in two patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood 108, 4232–4236 (2006).
Fusco, A. & Fedele, M. Roles of HMGA proteins in cancer. Nat. Rev. Cancer 7, 899–910 (2007).
Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318–322 (2010).
Ikeda, K., Mason, P. J. & Bessler, M. 3’UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice. Blood 117, 5860–5869 (2011).
Murakami, Y. et al. Deregulated expression of HMGA2 is implicated in clonal expansion of PIGA deficient cells in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 156, 383–387 (2012).
Sugimori, C. et al. Paroxysmal nocturnal hemoglobinuria and concurrent JAK2V617F mutation. Blood Cancer J. 2, e63 (2012).
Shen, W. et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J. Clin. Invest. 124, 4529–4538 (2014).
Nangalia, J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 369, 2391–2405 (2013).
Yoshida, K. et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat. Genet. 45, 1293–1299 (2013).
Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010).
Ferreira, V. P. & Pangburn, M. K. Factor H mediated cell surface protection from complement is critical for the survival of PNH erythrocytes. Blood 110, 2190–2192 (2007).
Hillmen, P. et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 110, 4123–4128 (2007). This article demonstrates that terminal complement inhibition prevents thrombosis in PNH.
Ritis, K. et al. A novel C5a receptor–tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J. Immunol. 177, 4794–4802 (2006).
Rittirsch, D., Flierl, M. A. & Ward, P. A. Harmful molecular mechanisms in sepsis. Nat. Rev. Immunol. 8, 776–787 (2008).
Clark, A. et al. Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Mol. Immunol. 45, 3125–3132 (2008).
Amara, U. et al. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 (2010).
Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006).
Thoman, M. L., Meuth, J. L., Morgan, E. L., Weigle, W. O. & Hugli, T. E. C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation. J. Immunol. 133, 2629–2633 (1984).
Risitano, A. M. et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 113, 4094–4100 (2009). This seminal paper shows that extravascular haemolysis in patients with PNH receiving eculizumab treatment is caused by the accumulation of C3 fragments (opsonins) on the surviving PNH erythrocytes.
Lin, Z. et al. Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 126, 891–894 (2015).
Hill, A. et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 95, 567–573 (2010).
Hochsmann, B. et al. Paroxysmal nocturnal haemoglobinuria treatment with eculizumab is associated with a positive direct antiglobulin test. Vox Sang. 102, 159–166 (2012).
Karadimitris, A. et al. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood 96, 2613–2620 (2000).
Risitano, A. M. et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia 19, 217–222 (2005).
Parker, C. et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 106, 3699–3709 (2005).
Hall, S. E. & Rosse, W. F. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 87, 5332–5340 (1996).
Brodsky, R. A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 113, 6522–6527 (2009).
Brodsky, R. A. et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am. J. Clin. Pathol. 114, 459–466 (2000). This is the first description of FLAER reagent for the diagnosis of PNH.
Borowitz, M. J. et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin. Cytom. 78, 211–230 (2010).
Pu, J. J. et al. The small population of PIG-A mutant cells in myelodysplastic syndromes do not arise from multipotent hematopoietic stem cells. Haematologica 97, 1225–1233 (2012).
Araten, D. J. et al. Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 115, 360–368 (2001).
Matsui, W. H., Brodsky, R. A., Smith, B. D., Borowitz, M. J. & Jones, R. J. Quantitative analysis of bone marrow CD34 cells in aplastic anemia and hypoplastic myelodysplastic syndromes. Leukemia 20, 458–462 (2006).
Pu, J. J., Mukhina, G., Wang, H., Savage, W. J. & Brodsky, R. A. Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia. Eur. J. Haematol. 87, 37–45 (2011).
Moyo, V. M., Mukhina, G. L., Garrett, E. S. & Brodsky, R. A. Natural history of paroxysmal nocturnal hemoglobinuria using modern diagnostic assays. Br. J. Haematol. 126, 133–138 (2004).
Rother, R. P., Bell, L., Hillmen, P. & Gladwin, M. T. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293, 1653–1662 (2005).
Hillmen, P. et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 85, 553–559 (2010).
Hill, A. et al. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 149, 414–425 (2010).
Hill, A. et al. Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function. Br. J. Haematol. 158, 409–414 (2012).
Bunn, H. F. et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116, 687–692 (2010).
Saso, R. et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 104, 392–396 (1999).
Peffault de Latour, R. et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 97, 1666–1673 (2012).
Brodsky, R. A. Stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica 95, 855–856 (2010).
Brodsky, R. A. et al. Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 42, 523–527 (2008).
Takahashi, Y. et al. In vitro and in vivo evidence of PNH cell sensitivity to immune attack after nonmyeloablative allogeneic hematopoietic cell transplantation. Blood 103, 1383–1390 (2004).
Hill, A. et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 106, 2559–2565 (2005).
Hillmen, P. et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 355, 1233–1243 (2006). A report of the pivotal randomized, double-blind, placebo-controlled trial that led to FDA approval of eculizumab for the treatment of PNH.
Brodsky, R. A. et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 111, 1840–1847 (2008). A report of an open-label phase III trial of eculizumab for the treatment of PNH.
Hillmen, P. et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 350, 552–559 (2004).
Kelly, R. J. et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 373, 1032–1039 (2015).
Fijen, C. A. et al. Protection against meningococcal serogroup ACYW disease in complement-deficient individuals vaccinated with the tetravalent meningococcal capsular polysaccharide vaccine. Clin. Exp. Immunol. 114, 362–369 (1998).
Platonov, A. E., Vershinina, I. V., Kuijper, E. J., Borrow, R. & Kayhty, H. Long term effects of vaccination of patients deficient in a late complement component with a tetravalent meningococcal polysaccharide vaccine. Vaccine 21, 4437–4447 (2003).
Babushok, D. V. et al. Clonal replacement underlies spontaneous remission in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 176, 487–490 (2017).
Nishimura, J. et al. Genetic variants in C5 and poor response to eculizumab. N. Engl. J. Med. 370, 632–639 (2014).
Hillmen, P. et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 162, 62–73 (2013).
DeZern, A. E., Dorr, D. & Brodsky, R. A. Predictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur. J. Haematol. 90, 16–24 (2013).
Harder, M. J. et al. Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 129, 970–980 (2017). This article demonstrates that strong complement activation may lead to breakthrough haemolysis in patients with PNH receiving eculizumab treatment owing to conformational changes on C5.
Emadi, A. & Brodsky, R. A. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 84, 699–701 (2009).
Ross, S. C. & Densen, P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore) 63, 243–273 (1984).
Kuo, G. P., Brodsky, R. A. & Kim, H. S. Catheter-directed thrombolysis and thrombectomy for the Budd–Chiari syndrome in paroxysmal nocturnal hemoglobinuria in three patients. J. Vasc. Interv. Radiol. 17, 383–387 (2006).
Singer, A. L. et al. Successful liver transplantation for Budd–Chiari syndrome in a patient with paroxysmal nocturnal hemoglobinuria treated with the anti-complement antibody eculizumab. Liver Transpl. 15, 540–543 (2009).
Hall, C., Richards, S. & Hillmen, P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 102, 3587–3591 (2003).
Hugel, B. et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 93, 3451–3456 (1999).
Hoekstra, J. et al. Paroxysmal nocturnal hemoglobinuria in Budd–Chiari syndrome: findings from a cohort study. J. Hepatol. 51, 696–706 (2009).
Audebert, H. J., Planck, J., Eisenburg, M., Schrezenmeier, H. & Haberl, R. Cerebral ischemic infarction in paroxysmal nocturnal hemoglobinuria report of 2 cases and updated review of 7 previously published patients. J. Neurol. 252, 1379–1386 (2005).
Araten, D. J. et al. Thrombolytic therapy is effective in paroxysmal nocturnal hemoglobinuria: a series of nine patients and a review of the literature. Haematologica 97, 344–352 (2012).
Ray, J. G., Burows, R. F., Ginsberg, J. S. & Burrows, E. A. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 30, 103–117 (2000).
Bais, J., Pel, M., von dem Borne, A. & van der Lelie, H. Pregnancy and paroxysmal nocturnal hemoglobinuria. Eur. J. Obstet. Gynecol. Reprod. Biol. 53, 211–214 (1994).
Fieni, S., Bonfanti, L., Gramellini, D., Benassi, L. & Delsignore, R. Clinical management of paroxysmal nocturnal hemoglobinuria in pregnancy: a case report and updated review. Obstet. Gynecol. Surv. 61, 593–601 (2006).
Young, N. S., Meyers, G., Schrezenmeier, H., Hillmen, P. & Hill, A. The management of paroxysmal nocturnal hemoglobinuria: recent advances in diagnosis and treatment and new hope for patients. Semin. Hematol. 46, S1–S16 (2009).
Yellen, S. B., Cella, D. F., Webster, K., Blendowski, C. & Kaplan, E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J. Pain Symptom Manage. 13, 63–74 (1997).
Aaronson, N. K. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85, 365–376 (1993).
Osoba, D., Rodrigues, G., Myles, J., Zee, B. & Pater, J. Interpreting the significance of changes in health-related quality-of-life scores. J. Clin. Oncol. 16, 139–144 (1998).
Cella, D. et al. What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J. Clin. Epidemiol. 55, 285–295 (2002).
Cella, D., Eton, D. T., Lai, J. S., Peterman, A. H. & Merkel, D. E. Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J. Pain Symptom Manage. 24, 547–561 (2002).
Weitz, I. et al. Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern. Med. J. 43, 298–307 (2013).
Bacigalupo, A. et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy — The European Group for Blood and Marrow Transplantation experience. Semin. Hematol. 37, 69–80 (2000).
Risitano, A. M. & Marotta, S. Therapeutic complement inhibition in complement-mediated hemolytic anemias: past, present and future. Semin. Immunol. 28, 223–240 (2016).
Roversi, P. et al. The structure of OMCI, a novel lipocalin inhibitor of the complement system. J. Mol. Biol. 369, 784–793 (2007).
Magotti, P. et al. Structure–kinetic relationship analysis of the therapeutic complement inhibitor compstatin. J. Mol. Recognit. 22, 495–505 (2009).
Risitano, A. M. et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 123, 2094–2101 (2014).
Yuan, X. et al. Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 102, 466–475 (2017).
Bolanos-Meade, J. et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 120, 4285–4291 (2012).
DeZern, A. E. et al. Alternative donor transplantation with high-dose post-transplantation cyclophosphamide for refractory severe aplastic anemia. Biol. Blood Marrow Transplant. 23, 498–504 (2017).
Lublin, D. M. & Atkinson, J. P. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu. Rev. Immunol. 7, 35–58 (1989).
Holguin, M. H. & Parker, C. J. Membrane inhibitor of reactive lysis. Curr. Top. Microbiol. Immunol. 178, 61–85 (1992).
Bajic, G., Yatime, L., Sim, R. B., Vorup-Jensen, T. & Andersen, G. R. Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3. Proc. Natl Acad. Sci. USA 110, 16426–16431 (2013).
This work was supported in part by a grant from the Aplastic Anemia and MDS International Foundation and the US NIH R01HL133113 (R.A.B.).
A.H. has received honoraria from and consulted for Akari Therapeutics, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, Ra Pharmaceuticals and Roche. T.K. has received honoraria and speakers fees from and consulted for Alexion Pharmaceuticals. R.A.B is on the scientific advisory boards of Alexion Pharmaceuticals, Apellis Pharmaceuticals and Achillion Pharmaceuticals; R.A.B. also receives grant funding from Alexion. A.E.D. declares no competing interests.
About this article
Cite this article
Hill, A., DeZern, A., Kinoshita, T. et al. Paroxysmal nocturnal haemoglobinuria. Nat Rev Dis Primers 3, 17028 (2017). https://doi.org/10.1038/nrdp.2017.28
This article is cited by
Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up
Advances in Therapy (2023)
Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry
Annals of Hematology (2023)
Interim analysis of post-marketing surveillance of ravulizumab for paroxysmal nocturnal hemoglobinuria in Japan
International Journal of Hematology (2023)
Virchows Archiv (2023)