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Paroxysmal nocturnal haemoglobinuria

Abstract

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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Figure 1: Clonal expansion in paroxysmal nocturnal haemoglobinuria.
Figure 2: Biosynthesis of glycosylphosphatidylinositol-anchored proteins.
Figure 3: Intravascular and extravascular haemolysis in paroxysmal nocturnal haemoglobinuria.
Figure 4: Complement cascade inhibition.

References

  1. 1

    Brodsky, R. A. Paroxysmal nocturnal hemoglobinuria. Blood 124, 2804–2811 (2014).

    Google Scholar 

  2. 2

    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).

    Google Scholar 

  3. 3

    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.

    Google Scholar 

  4. 4

    Enneking, J. Eine neue form intermittierender haemoglobinurie (haemoglobinuria paroxysmalis nocturia) [German]. Klin. Wochenschr. 7, 2045 (1928).

    Google Scholar 

  5. 5

    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).

    Google Scholar 

  6. 6

    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.

    Google Scholar 

  7. 7

    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).

    Google Scholar 

  8. 8

    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).

    Google Scholar 

  9. 9

    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.

    Google Scholar 

  10. 10

    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).

    Google Scholar 

  11. 11

    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).

    Google Scholar 

  12. 12

    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).

    Google Scholar 

  13. 13

    Schrezenmeier, H. et al. Baseline characteristics and disease burden in patients in the international paroxysmal nocturnal hemoglobinuria registry. Haematologica 99, 922–929 (2014).

    Google Scholar 

  14. 14

    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).

    Google Scholar 

  15. 15

    Naithani, R. et al. Paroxysmal nocturnal hemoglobinuria in childhood and adolescence — a retrospective analysis of 18 cases. Indian J. Pediatr. 75, 575–578 (2008).

    Google Scholar 

  16. 16

    Curran, K. J. et al. Paroxysmal nocturnal hemoglobinuria in pediatric patients. Pediatr. Blood Cancer 59, 525–529 (2012).

    Google Scholar 

  17. 17

    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).

    Google Scholar 

  18. 18

    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).

    Google Scholar 

  19. 19

    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).

    Google Scholar 

  20. 20

    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).

    Google Scholar 

  21. 21

    Hill, A., Kelly, R. J. & Hillmen, P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 121, 4985–4996 (2013).

    Google Scholar 

  22. 22

    Issaragrisil, S. et al. The epidemiology of aplastic anemia in Thailand. Blood 107, 1299–1307 (2006).

    Google Scholar 

  23. 23

    Young, N. S. & Kaufman, D. W. The epidemiology of acquired aplastic anemia. Haematologica 93, 489–492 (2008).

    Google Scholar 

  24. 24

    Socie, G. et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 348, 573–577 (1996).

    Google Scholar 

  25. 25

    de Latour, R. P. et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 112, 3099–3106 (2008).

    Google Scholar 

  26. 26

    Kelly, R. J. et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 117, 6786–6792 (2011).

    Google Scholar 

  27. 27

    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].

  28. 28

    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).

    Google Scholar 

  29. 29

    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).

    Google Scholar 

  30. 30

    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).

    Google Scholar 

  31. 31

    Hidaka, M. et al. Impaired glycosylation of glycosylphosphatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria leukocytes. Biochem. Biophys. Res. Commun. 191, 571–579 (1993).

    Google Scholar 

  32. 32

    Kinoshita, T. Biosynthesis and deficiencies of glycosylphosphatidylinositol. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 90, 130–143 (2014).

    Google Scholar 

  33. 33

    Kinoshita, T. & Fujita, M. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J. Lipid Res. 57, 6–24 (2016).

    Google Scholar 

  34. 34

    Saha, S., Anilkumar, A. A. & Mayor, S. GPI-anchored protein organization and dynamics at the cell surface. J. Lipid Res. 57, 159–175 (2016).

    Google Scholar 

  35. 35

    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).

    Google Scholar 

  36. 36

    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).

    Google Scholar 

  37. 37

    Yamada, N. et al. Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria. Blood 85, 885–892 (1995).

    Google Scholar 

  38. 38

    Pramoonjago, P. et al. Somatic mutations of PIG-A in Thai patients with paroxysmal nocturnal hemoglobinuria. Blood 86, 1736–1739 (1995).

    Google Scholar 

  39. 39

    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).

    Google Scholar 

  40. 40

    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).

    Google Scholar 

  41. 41

    Nishimura, J. et al. A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones. Blood 89, 3470–3476 (1997).

    Google Scholar 

  42. 42

    Nishimura, J., Murakami, Y. & Kinoshita, T. Paroxysmal nocturnal hemoglobinuria: an acquired genetic disease. Am. J. Hematol. 62, 175–182 (1999).

    Google Scholar 

  43. 43

    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).

    Google Scholar 

  44. 44

    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).

    Google Scholar 

  45. 45

    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).

    Google Scholar 

  46. 46

    Rotoli, B. & Luzzatto, L. Paroxysmal nocturnal haemoglobinuria. Baillieres Clin. Haematol. 2, 113–138 (1989).

    Google Scholar 

  47. 47

    Young, N. S. The problem of clonality in aplastic anemia: Dr. Dameshek's riddle, restated. Blood 79, 1385–1392 (1992).

    Google Scholar 

  48. 48

    Luzzatto, L., Bessler, M. & Rotoli, B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell 88, 1–4 (1997).

    Google Scholar 

  49. 49

    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).

    Google Scholar 

  50. 50

    Kinoshita, T. & Inoue, N. Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria. Int. J. Hematol. 75, 117–122 (2002).

    Google Scholar 

  51. 51

    Inoue, N., Murakami, Y. & Kinoshita, T. Molecular genetics of paroxysmal nocturnal hemoglobinuria. Int. J. Hematol. 77, 107–112 (2003).

    Google Scholar 

  52. 52

    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).

    Google Scholar 

  53. 53

    Hu, R. et al. PIG-A mutations in normal hematopoiesis. Blood 105, 3848–3854 (2005).

    Google Scholar 

  54. 54

    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).

    Google Scholar 

  55. 55

    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).

    Google Scholar 

  56. 56

    Kawagoe, K. et al. GPI-anchor deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria. Blood 87, 3600–3606 (1996).

    Google Scholar 

  57. 57

    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).

    Google Scholar 

  58. 58

    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).

    Google Scholar 

  59. 59

    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).

    Google Scholar 

  60. 60

    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).

    Google Scholar 

  61. 61

    Dingli, D., Luzzatto, L. & Pacheco, J. M. Neutral evolution in paroxysmal nocturnal hemoglobinuria. Proc. Natl Acad. Sci. USA 105, 18496–18500 (2008).

    Google Scholar 

  62. 62

    Young, N. S., Calado, R. T. & Scheinberg, P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 108, 2509–2519 (2006).

    Google Scholar 

  63. 63

    Murakami, Y. et al. Inefficient response of T lymphocytes to GPI-anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood 100, 4116–4122 (2002).

    Google Scholar 

  64. 64

    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).

    Google Scholar 

  65. 65

    Luzzatto, L. Recent advances in the pathogenesis and treatment of paroxysmal nocturnal hemoglobinuria. F1000Res. 5 (F1000 Faculty Rev.), 209 (2016).

    Google Scholar 

  66. 66

    Gargiulo, L. et al. Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood 121, 2753–2761 (2013).

    Google Scholar 

  67. 67

    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).

    Google Scholar 

  68. 68

    Nagakura, S. et al. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Blood 100, 1031–1037 (2002).

    Google Scholar 

  69. 69

    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).

    Google Scholar 

  70. 70

    Inoue, N. et al. Molecular basis of clonal expansion of hematopoiesis in two patients with paroxysmal nocturnal hemoglobinuria (PNH). Blood 108, 4232–4236 (2006).

    Google Scholar 

  71. 71

    Fusco, A. & Fedele, M. Roles of HMGA proteins in cancer. Nat. Rev. Cancer 7, 899–910 (2007).

    Google Scholar 

  72. 72

    Cavazzana-Calvo, M. et al. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Nature 467, 318–322 (2010).

    Google Scholar 

  73. 73

    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).

    Google Scholar 

  74. 74

    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).

    Google Scholar 

  75. 75

    Sugimori, C. et al. Paroxysmal nocturnal hemoglobinuria and concurrent JAK2V617F mutation. Blood Cancer J. 2, e63 (2012).

    Google Scholar 

  76. 76

    Shen, W. et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J. Clin. Invest. 124, 4529–4538 (2014).

    Google Scholar 

  77. 77

    Nangalia, J. et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 369, 2391–2405 (2013).

    Google Scholar 

  78. 78

    Yoshida, K. et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat. Genet. 45, 1293–1299 (2013).

    Google Scholar 

  79. 79

    Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010).

    Google Scholar 

  80. 80

    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).

    Google Scholar 

  81. 81

    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.

    Google Scholar 

  82. 82

    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).

    Google Scholar 

  83. 83

    Rittirsch, D., Flierl, M. A. & Ward, P. A. Harmful molecular mechanisms in sepsis. Nat. Rev. Immunol. 8, 776–787 (2008).

    Google Scholar 

  84. 84

    Clark, A. et al. Evidence for non-traditional activation of complement factor C3 during murine liver regeneration. Mol. Immunol. 45, 3125–3132 (2008).

    Google Scholar 

  85. 85

    Amara, U. et al. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 (2010).

    Google Scholar 

  86. 86

    Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006).

    Google Scholar 

  87. 87

    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).

    Google Scholar 

  88. 88

    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.

    Google Scholar 

  89. 89

    Lin, Z. et al. Complement C3dg-mediated erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood 126, 891–894 (2015).

    Google Scholar 

  90. 90

    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).

    Google Scholar 

  91. 91

    Hochsmann, B. et al. Paroxysmal nocturnal haemoglobinuria treatment with eculizumab is associated with a positive direct antiglobulin test. Vox Sang. 102, 159–166 (2012).

    Google Scholar 

  92. 92

    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).

    Google Scholar 

  93. 93

    Risitano, A. M. et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia 19, 217–222 (2005).

    Google Scholar 

  94. 94

    Parker, C. et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 106, 3699–3709 (2005).

    Google Scholar 

  95. 95

    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).

    Google Scholar 

  96. 96

    Brodsky, R. A. How I treat paroxysmal nocturnal hemoglobinuria. Blood 113, 6522–6527 (2009).

    Google Scholar 

  97. 97

    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.

    Google Scholar 

  98. 98

    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).

    Google Scholar 

  99. 99

    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).

    Google Scholar 

  100. 100

    Araten, D. J. et al. Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 115, 360–368 (2001).

    Google Scholar 

  101. 101

    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).

    Google Scholar 

  102. 102

    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).

    Google Scholar 

  103. 103

    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).

    Google Scholar 

  104. 104

    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).

    Google Scholar 

  105. 105

    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).

    Google Scholar 

  106. 106

    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).

    Google Scholar 

  107. 107

    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).

    Google Scholar 

  108. 108

    Bunn, H. F. et al. Pulmonary hypertension and nitric oxide depletion in sickle cell disease. Blood 116, 687–692 (2010).

    Google Scholar 

  109. 109

    Saso, R. et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 104, 392–396 (1999).

    Google Scholar 

  110. 110

    Peffault de Latour, R. et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 97, 1666–1673 (2012).

    Google Scholar 

  111. 111

    Brodsky, R. A. Stem cell transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica 95, 855–856 (2010).

    Google Scholar 

  112. 112

    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).

    Google Scholar 

  113. 113

    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).

    Google Scholar 

  114. 114

    Hill, A. et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 106, 2559–2565 (2005).

    Google Scholar 

  115. 115

    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.

    Google Scholar 

  116. 116

    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.

    Google Scholar 

  117. 117

    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).

    Google Scholar 

  118. 118

    Kelly, R. J. et al. Eculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. 373, 1032–1039 (2015).

    Google Scholar 

  119. 119

    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).

    Google Scholar 

  120. 120

    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).

    Google Scholar 

  121. 121

    Babushok, D. V. et al. Clonal replacement underlies spontaneous remission in paroxysmal nocturnal haemoglobinuria. Br. J. Haematol. 176, 487–490 (2017).

    Google Scholar 

  122. 122

    Nishimura, J. et al. Genetic variants in C5 and poor response to eculizumab. N. Engl. J. Med. 370, 632–639 (2014).

    Google Scholar 

  123. 123

    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).

    Google Scholar 

  124. 124

    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).

    Google Scholar 

  125. 125

    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.

    Google Scholar 

  126. 126

    Emadi, A. & Brodsky, R. A. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am. J. Hematol. 84, 699–701 (2009).

    Google Scholar 

  127. 127

    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).

    Google Scholar 

  128. 128

    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).

    Google Scholar 

  129. 129

    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).

    Google Scholar 

  130. 130

    Hall, C., Richards, S. & Hillmen, P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 102, 3587–3591 (2003).

    Google Scholar 

  131. 131

    Hugel, B. et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood 93, 3451–3456 (1999).

    Google Scholar 

  132. 132

    Hoekstra, J. et al. Paroxysmal nocturnal hemoglobinuria in Budd–Chiari syndrome: findings from a cohort study. J. Hepatol. 51, 696–706 (2009).

    Google Scholar 

  133. 133

    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).

    Google Scholar 

  134. 134

    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).

    Google Scholar 

  135. 135

    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).

    Google Scholar 

  136. 136

    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).

    Google Scholar 

  137. 137

    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).

    Google Scholar 

  138. 138

    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).

    Google Scholar 

  139. 139

    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).

    Google Scholar 

  140. 140

    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).

    Google Scholar 

  141. 141

    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).

    Google Scholar 

  142. 142

    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).

    Google Scholar 

  143. 143

    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).

    Google Scholar 

  144. 144

    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).

    Google Scholar 

  145. 145

    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).

    Google Scholar 

  146. 146

    Risitano, A. M. & Marotta, S. Therapeutic complement inhibition in complement-mediated hemolytic anemias: past, present and future. Semin. Immunol. 28, 223–240 (2016).

    Google Scholar 

  147. 147

    Roversi, P. et al. The structure of OMCI, a novel lipocalin inhibitor of the complement system. J. Mol. Biol. 369, 784–793 (2007).

    Google Scholar 

  148. 148

    Magotti, P. et al. Structure–kinetic relationship analysis of the therapeutic complement inhibitor compstatin. J. Mol. Recognit. 22, 495–505 (2009).

    Google Scholar 

  149. 149

    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).

    Google Scholar 

  150. 150

    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).

    Google Scholar 

  151. 151

    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).

    Google Scholar 

  152. 152

    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).

    Google Scholar 

  153. 153

    Lublin, D. M. & Atkinson, J. P. Decay-accelerating factor: biochemistry, molecular biology, and function. Annu. Rev. Immunol. 7, 35–58 (1989).

    Google Scholar 

  154. 154

    Holguin, M. H. & Parker, C. J. Membrane inhibitor of reactive lysis. Curr. Top. Microbiol. Immunol. 178, 61–85 (1992).

    Google Scholar 

  155. 155

    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).

    Google Scholar 

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Acknowledgements

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.).

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Introduction (R.A.B.); Epidemiology (A.E.D.); Mechanisms/pathophysiology (T.K.); Diagnosis, screening and prevention (R.A.B.); Management (A.H. and R.A.B.); Quality of life (A.E.D.); Outlook (R.A.B.); Overview of the Primer (R.A.B.).

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Correspondence to Robert A. Brodsky.

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Competing interests

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.

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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

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