Update on paroxysmal nocturnal haemoglobinuria: On the long way to understand the principles of the disease

European Journal of Haematology

Volumn 94, Issue 6, 2015, Pages 464-473

  Schubert, Jörg ^a   Röth, Alexander ^b  

^a Internal Medicine II   (Germany)

^b UNIVERSITY HOSPITAL ESSEN   (Germany)

Author keywords

Clonal evolution; Complement inhibition; Eculizumab; Paroxysmal nocturnal haemoglobinuria; Stem cell disorder

Indexed keywords

CYANOCOBALAMIN; CYCLOSPORIN A; ECULIZUMAB; FOLIC ACID; IRON; PREDNISONE; THYMOCYTE ANTIBODY;

ALLOGENEIC STEM CELL TRANSPLANTATION; BONE MARROW APLASIA; CELL DIFFERENTIATION; CLONAL EVOLUTION; COMPLEMENT ACTIVATION; COMPLEMENT DEFICIENCY; DIET SUPPLEMENTATION; ERYTHROCYTE TRANSFUSION; GENE MUTATION; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; LIFE EXPECTANCY; MENINGOCOCCEMIA; PAROXYSMAL NOCTURNAL HEMOGLOBINURIA; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; THROMBOPHILIA; HEMOGLOBINURIA, PAROXYSMAL;

HEMOGLOBINURIA, PAROXYSMAL; HUMANS;

EID: 84929132804     PISSN: 09024441     EISSN: 16000609     Source Type: Journal    
DOI: 10.1111/ejh.12520     Document Type: Review

References (90)

1. Rosse WF, Nishimura J. Clinical manifestations of paroxysmal nocturnal hemoglobinuria: present state and future problems. Int J Hematol 2003;77:113-20.
2. Luzzatto L, Gianfaldoni G. Recent advances in biological and clinical aspects of paroxysmal nocturnal hemoglobinuria. Int J Hematol 2006;84:104-12.
3. Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014;124:2804-11.
4. Meyers G, Weitz I, Lamy T, Cahn JY, Kroon HA, Severino B, Uranga MT, Alonso MS, Vela JAG, Hill A. Disease-related symptoms reported across a broad population of patients with paroxysmal nocturnal hemoglobinuria. Blood 2007;110:3683.
5. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005;106:3699-709.
6. Hill A, Rother RP, Wang X, 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 2010;149:414-25.
7. Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995;333:1253-8.
8. Araten DJ, Thaler HT, Luzzatto L. High incidence of thrombosis in African-American and Latin-American patients with paroxysmal nocturnal haemoglobinuria. Thromb Haemost 2005;93:88-91.
9. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013;121:4985-96.
10. Schubert J, Vogt HG, Zielinska-Skowronek M, Freund M, Kaltwasser JP, Hoelzer D, Schmidt RE. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia. Blood 1994;83:2323-8.
11. Schrezenmeier H, Hertenstein B, Wagner B, Raghavachar A, Heimpel H. A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins. Exp Hematol 1995;23:81-7.
12. Pu JJ, Mukhina G, Wang H, Savage WJ, Brodsky RA. Natural history of paroxysmal nocturnal hemoglobinuria clones in patients presenting as aplastic anemia. Eur J Haematol 2011;87:37-45.
13. Young NS. The problem of clonality in aplastic anemia: Dr Dameshek's riddle, restated. Blood 1992;79:1385-92.
14. Dunn DE, Tanawattanacharoen P, Boccuni P, Nagakura S, Green SW, Kirby MR, Kumar MS, Rosenfeld S, Young NS. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999;131:401-8.
15. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol 2001;115:1015-22.
16. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol 2014;164:546-54.
17. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 2005;293:1653-62.
18. Nicholson-Weller A, March JP, Rosenfeld SI, Austen KF. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci U S A 1983;80:5066-70.
19. Schubert J, Ostendorf T, Nischan C, Schmidt RE. Die paroxysmale nächtliche Hämoglobinurie - ein erworbener genetischer Defekt der hämatopoietischen Stammzelle. Dtsch Med Wochenschr 1995;120:31-4.
20. Miyata T, Yamada N, Iida Y, Nishimura J, Takeda J, Kitani T, Kinoshita T. Abnormalities of PIG-A transcripts in granulocytes from patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 1994;330:249-55.
21. Bessler M, Mason PJ, Hillmen P, Miyata T, Yamada N, Takeda J, Luzzatto L, Kinoshita T. Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene. EMBO J 1994;13:110-7.
22. Ostendorf T, Nischan C, Schubert J, Grussenmeyer T, Scholz C, Zielinska-Skowronek M, Schmidt RE. Heterogeneous PIG-A mutations in different cell lineages in paroxysmal nocturnal hemoglobinuria. Blood 1995;85:1640-6.
23. Armstrong C, Schubert J, Ueda E, Knez JJ, Gelperin D, Hirose S, Silber R, Hollan S, Schmidt RE, Medof ME. 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 1992;267:25347-51.
24. Miyata T, Takeda J, Iida Y, Yamada N, Inoue N, Takahashi M, Maeda K, Kitani T, Kinoshita T. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science 1993;259:1318-20.
25. Mortazavi Y, Merk B, McIntosh J, Marsh JC, Schrezenmeier H, Rutherford TR. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Blood 2003;101:2833-41.
26. Yamashina M, Ueda E, Kinoshita T, Takami T, Ojima A, Ono H, Tanaka H, Kondo N, Orii T, Okada N. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1990;323:1184-9.
27. Krawitz PM, Höchsmann B, Murakami Y, et al. A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood 2013;122:1312-5.
28. Bessler M, Mason P, Hillmen P, Luzzatto L. Somatic mutations and cellular selection in paroxysmal nocturnal haemoglobinuria. Lancet 1994;343:951-3.
29. Tremml G, Dominguez C, Rosti V, Zhang Z, Pandolfi PP, Keller P, Bessler M. Increased sensitivity to complement and a decreased red blood cell life span in mice mosaic for a nonfunctional Piga gene. Blood 1999;94:2945-54.
30. Hu R, Mukhina GL, Piantadosi S, Barber JP, Jones RJ, Brodsky RA. PIG-A mutations in normal hematopoiesis. Blood 2005;105:3848-54.
31. Araten DJ, 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 U S A 1999;96:5209-14.
32. Dameshek W. Riddle: what do aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH) and "hypoplastic" leukemia have in common? Blood 1967;30:251-4.
33. Luzzatto L, Bessler M, Rotoli B. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell 1997;88:1-4.
34. Maciejewski JP, Follmann D, Nakamura R, Saunthararajah Y, Rivera CE, Simonis T, Brown KE, Barrett JA, Young NS. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome. Blood 2001;98:3513-9.
35. Murakami Y, Kinoshita T, Maeda Y, Nakano T, Kosaka H, Takeda J. Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria. Blood 1999;94:2963-70.
36. Sugimori C, Padron E, Caceres G, et al. Paroxysmal nocturnal hemoglobinuria and concurrent JAK2(V617F) mutation. Blood Cancer J 2012;2:e63.
37. Longo L, Bessler M, Beris P, Swirsky D, Luzzatto L. Myelodysplasia in a patient with pre-existing paroxysmal nocturnal haemoglobinuria: a clonal disease originating from within a clonal disease. Br J Haematol 1994;87:401-3.
38. 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;108:4232-6.
39. Shen W, Clemente MJ, Hosono N, et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest 2014;124:4529-38.
40. Kulasekararaj AG, Jiang J, Smith AE, Mohamedali AM, Mian S, Gandhi S, Gaken J, Czepulkowski B, Marsh JC, Mufti GJ. Somatic mutations identify a sub-group of aplastic anemia patients that progress to myelodysplastic syndrome. Blood 2014;124:2698-704.
41. Dumitriu B, Feng X, Townsley DM, Ueda Y, Yoshizato T, Calado RT, Yang Y, Wakabayashi Y, Kajigaya S, Ogawa S, Zhu J, Young NS. Telomere attrition and candidate gene mutations preceeding monosomy 7 in aplastic anemia. Blood 2015;125:706-9.
42. Karadimitris A, Luzzatto L. The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria. Leukemia 2001;15:1148-52.
43. Devine DV, Gluck WL, Rosse WF, Weinberg JB. Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone. J Clin Invest 1987;79:314-7.
44. Tanaka H, Imamura N, Oguma N, Shintani T, Tanaka K, Hyodo H, Oda K, Kimura A. Acute myelogenous leukemia with PIG-A gene mutation evolved from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome. Int J Hematol 2001;73:206-12.
45. Araten DJ, Krejci O, Ditata K, Wunderlich M, Sanders KJ, Zamechek L, Mulloy JC. The rate of spontaneous mutations in human myeloid cells. Mutat Res 2013;749:49-57.
46. de Latour RP, Mary JY, Salanoubat C, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008;112:3099-106.
47. Bessler M. Paroxysmal nocturnal hemoglobinuria: the price for a chance. Schweiz Med Wochenschr 1996;126:1912-21.
48. Hirano N, Butler MO, Bergwelt-Baildon MS, Maecker B, Schultze JL, O'Connor KC, Schur PH, Kojima S, Guinan EC, Nadler LM. Autoantibodies frequently detected in patients with aplastic anemia. Blood 2003;102:4567-75.
49. Alahmad A, Preuss KD, Schenk J, Fureder W, Schrezenmeier H, Muller-Lantzsch N, Schubert J, Pfreundschuh M. Desmoplakin and KIF20B as target antigens in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2010;151:273-80.
50. Hall SE, Rosse WF. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 1996;87:5332-40.
51. Brodsky RA, Mukhina GL, Li S, Nelson KL, Chiurazzi PL, Buckley JT, Borowitz MJ. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000;114:459-66.
52. Borowitz MJ. Flow cytometry testing in PNH. How much is enough? Cytometry 2000;42:221-2.
53. Schrezenmeier H, Bettelheim P, Panse J, Schubert J, Höchsmann B, Röth A, Nebe T. Recommendations for the diagnosis of paroxysmal nocturnal hemoglobinuria: a German-Austrian consensus. J Lab Med 2011;35:315-27.
54. Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999;104:392-6.
55. Peffault dL, Schrezenmeier H, Bacigalupo A, et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012;97:1666-73.
56. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009;147:43-70.
57. Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant 2010;16:S119-25.
58. Schrezenmeier H, Brümmendorf TH, Deeg HJ, Höchsmann B, Linkesch W, Röth A, Schubert J. Onkopedia Leitlinie Aplastische Anämie - Diagnostik und Therapie der erworbenen Aplastischen Anämie. 2012.
59. Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria. Exp Hematol 2001;29:639-42.
60. Hegenbart U, Niederwieser D, Forman S, et al. Hematopoietic cell transplantation from related and unrelated donors after minimal conditioning as a curative treatment modality for severe paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant 2003;9:689-97.
61. Brecher ME, Taswell HF. Paroxysmal nocturnal hemoglobinuria and the transfusion of washed red cells. A myth revisited. Transfusion 1989;29:681-5.
62. Röth A, Hock C, Konik A, Christoph S, Dührsen U. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol 2011;93:704-14.
63. Issaragrisil S, Piankijagum A, Tang-naitrisorana Y. Corticosteroids therapy in paroxysmal nocturnal hemoglobinuria. Am J Hematol 1987;25:77-83.
64. Bourantas K. High-dose recombinant human erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria. Acta Haematol 1994;91:62-5.
65. Zhao M, Shao Z, Liu H, et al. Yang T [In vitro effects of low-molecular weight heparin and dexamethasone on the hemolysis of red blood cells from paroxysmal nocturnal hemoglobinuria patients]. Zhonghua Xue Ye Xue Za Zhi 2002;23:80-2.
66. Luzzatto L, Gianfaldoni G, Notaro R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol 2011;153:709-20.
67. Socie G, Mary JY, de Gramont A, Rio B, Leporrier M, Rose C, Heudier P, Rochant H, Cahn JY, Gluckman E. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996;348:573-7.
68. Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004;83:193-207.
69. Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 2004;126:133-8.
70. McMullin MF, Hillmen P, Jackson J, Ganly P, Luzzatto L. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria. J Intern Med 1994;235:85-9.
71. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 2003;102:3587-91.
72. Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am J Hematol 2009;84:699-701.
73. Hillmen P, Muus P, Dührsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007;110:4123-8.
74. Ninomiya H, Kawashima Y, Nagasawa T. Inhibition of complement-mediated haemolysis in paroxysmal nocturnal haemoglobinuria by heparin or low-molecular weight heparin. Br J Haematol 2000;109:875-81.
75. Thomas TC, Rollins SA, Rother RP, Giannoni MA, Hartman SL, Elliott EA, Nye SH, Matis LA, Squinto SP, Evans MJ. Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv. Mol Immunol 1996;33:1389-401.
76. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 2007;25:1256-64.
77. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006;355:1233-43.
78. Brodsky RA, Young NS, Antonioli E, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 2008;111:1840-7.
79. Schubert J, Röth A, Bettelheim P, Stüssi G, Brümmendorf TH, Schrezenmeier H. Onkopedia Leitlinie Paroxysmale nächtliche Hämoglobinurie (PNH). 2013.
80. Parker CJ. The pathophysiology of paroxysmal nocturnal hemoglobinuria. Exp Hematol 2007;35:523-33.
81. Kelly RJ, Hill A, Arnold LM, Brooksbank GL, Richards SJ, Cullen M, Mitchell LD, Cohen DR, Gregory WM, Hillmen P. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011;117:6786-92.
82. Hill A, Kelly RJ, Kulasekararaj AG, et al. Eculizumab in paroxysmal nocturnal hemoglobinuria (PNH): a report of all 153 patients treated in the UK. Blood 2012;120:3472.
83. Hillmen P, Muus P, Röth A, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013;162:62-73.
84. Risitano AM, Notaro R, Marando L, et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 2009;113:4094-100.
85. Röth A, Peine S, Dührsen U. Paroxysmal nocturnal hemoglobinuria turning Coombs-positive. Int J Hematol 2010;91:159-60.
86. Risitano AM, Ricklin D, Huang Y, et al. Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria. Blood 2014;123:2094-101.
87. Risitano AM, Notaro R, Pascariello C, et al. The complement receptor 2/factor H fusion protein TT30 protects paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and C3 fragment. Blood 2012;119:6307-16.
88. Lai S, Venugopal P, Leslie W. Long-term remission of paroxysmal nocturnal hemoglobinuria following chemoimmunotherapy for non-Hodgkin lymphoma. Clin Adv Hematol Oncol 2012;10:134-6.
89. Hillmen P, Elebute M, Kelly R, et al. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Am J Hematol 2010;85:553-9.
90. Luzzatto L. Paroxysmal nocturnal hemoglobinuria: an acquired X-linked genetic disease with somatic-cell mosaicism. Curr Opin Genet Dev 2006;16:317-22.