Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:

Subscribers log in here

Diagnosis and treatment of paroxysmal nocturnal hemoglobinuria


Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder characterized by a defect in the glycosylphosphatidylinositol (GPI) anchor, due to an acquired abnormality in the PIG-A gene. This leads to partial or complete absence of all GPI-linked proteins, particularly CD59 (membrane inhibitor of reactive lysis) and CD55 (decay accelerating factor), resulting in an increased sensitivity of the affected cells to the action of complement [1]. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)

The clinical manifestations of PNH are primarily related to abnormalities in the hematopoietic system, including hemolytic anemia, a hypercoagulable state, and diminished hematopoiesis. Progression to aplastic anemia, myelodysplasia, and acute leukemia can also occur. In the past, the treatment of PNH had been largely empirical. As with most medical disorders, therapy is largely given to ameliorate the symptoms or complications rather than the cause of the disease. However, with improved understanding of the underlying pathogenesis, more rational therapies are emerging, such as the use of eculizumab. (See 'Eculizumab' below.)

The diagnosis and treatment of PNH will be reviewed here [1-4]. The clinical manifestations of this disorder are discussed separately. (See "Clinical manifestations of paroxysmal nocturnal hemoglobinuria".)


Clinical presentation of the classic disease — The diagnosis of PNH should be considered in a patient with any of the following manifestations:

Evidence of acquired hemolysis, specifically with a negative direct antiglobulin (Coombs) test of the red cells.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Aug 2014. | This topic last updated: Mar 3, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
  1. Rosse WF. Paroxysmal nocturnal hemoglobinuria as a molecular disease. Medicine (Baltimore) 1997; 76:63.
  2. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood 2005; 106:3699.
  3. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol 2007; 137:181.
  4. Luzzatto L, Gianfaldoni G, Notaro R. Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol 2011; 153:709.
  5. Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121:4985.
  6. Townsley DM, Young NS. Blood consult: paroxysmal nocturnal hemoglobinuria and its complications. Blood 2013; 122:2795.
  7. Hartmann RC, Jenkins DE. The "sugar-water" test for paroxysmal nocturnal hemoglobinuria. N Engl J Med 1966; 275:155.
  9. Rosse WF. Dr Ham's test revisited. Blood 1991; 78:547.
  10. Brodsky RA. Narrative review: paroxysmal nocturnal hemoglobinuria: the physiology of complement-related hemolytic anemia. Ann Intern Med 2008; 148:587.
  11. Preis M, Lowrey CH. Laboratory tests for paroxysmal nocturnal hemoglobinuria. Am J Hematol 2014; 89:339.
  12. Hernández-Campo PM, Almeida J, Acevedo MJ, et al. Detailed immunophenotypic characterization of different major and minor subsets of peripheral blood cells in patients with paroxysmal nocturnal hemoglobinuria. Transfusion 2008; 48:1403.
  13. Hall SE, Rosse WF. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 1996; 87:5332.
  14. Shichishima T, Terasawa T, Saitoh Y, et al. Diagnosis of paroxysmal nocturnal haemoglobinuria by phenotypic analysis of erythrocytes using two-colour flow cytometry with monoclonal antibodies to DAF and CD59/MACIF. Br J Haematol 1993; 85:378.
  15. Mukhina GL, Buckley JT, Barber JP, et al. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia. Br J Haematol 2001; 115:476.
  16. 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.
  17. Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol 2000; 114:459.
  18. Borowitz MJ, Craig FE, Digiuseppe JA, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom 2010; 78:211.
  19. Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995; 333:1253.
  20. Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet 1996; 348:573.
  21. 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.
  22. Sears DA, Anderson PR, Foy AL, et al. Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases. Blood 1966; 28:708.
  23. Rosse WF, Gutterman LA. The effect of iron therapy in paroxysmal nocturnal hemoglobinuria. Blood 1970; 36:559.
  24. Dacie JV, Firth D. Blood transfusion in nocturnal haemoglobinuria. Br Med J 1943; i:626.
  25. HEFFERNAN CK, JASWON N. A case of paroxysmal nocturnal haemoglobinuria associated with secondary haemochromatosis, a lower nephron nephrosis, and a megaloblastic anaemia. J Clin Pathol 1955; 8:211.
  26. HEITZMAN EJ, CAMPBELL JS, STEFANINI M. Paroxysmal nocturnal hemoglobinuria with hemosiderin nephrosis. Am J Clin Pathol 1953; 23:975.
  28. DACIE JV. Transfusion of saline-washed red cells in nocturnal haemoglobinuria (Marchiafava-Micheli disease). Clin Sci (Lond) 1948; 7:65.
  29. Dacie JV. Paroxysmal nocturnal hemoglobinuria. In: The Haemolytic Anaemias — Congenital and Acquired, 2nd ed, Dacie JV (Ed), Grune & Stratton, New York 1967. p.1128.
  30. FUNDENBERG H, PALMER WL, KIRSNER JB. Paroxysmal nocturnal hemoglobinuria; report of a case with rare hemoglobinuria treated with corticotropin. Am J Med Sci 1954; 227:32.
  31. Firkin F, Goldberg H, Firkin BG. Glucocorticoid management of paroxysmal nocturnal haemoglobinuria. Australas Ann Med 1968; 17:127.
  32. Rosse WF. Treatment of paroxysmal nocturnal hemoglobinuria. Blood 1982; 60:20.
  33. Hartmann RC, Jenkins DE Jr, McKee LC, Heyssel RM. Paroxysmal nocturnal hemoglobinuria: clinical and laboratory studies relating to iron metabolism and therapy with androgen and iron. Medicine (Baltimore) 1966; 45:331.
  34. Parker C. Eculizumab for paroxysmal nocturnal haemoglobinuria. Lancet 2009; 373:759.
  35. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350:552.
  36. Hill A, Hillmen P, Richards SJ, et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005; 106:2559.
  37. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355:1233.
  38. 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.
  39. 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.
  40. Schubert J, Hillmen P, Röth A, et al. Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2008; 142:263.
  41. 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.
  42. 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.
  43. Kelly RJ, Hill A, Arnold LM, et al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 2011; 117:6786.
  44. Brodsky RA, Hillmen P, Schubert J, et al. Safety and efficacy of eculizumab in paroxysmal nocturnal hemoglobinuria evolving from patients with myelodysplastic syndrome and aplastic anemia (abstract). J Clin Oncol 2007; 25:365s.
  45. Kelly R, Arnold L, Richards S, et al. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2010; 149:446.
  46. Marasca R, Coluccio V, Santachiara R, et al. Pregnancy in PNH: another eculizumab baby. Br J Haematol 2010; 150:707.
  47. Peffault de Latour R, Schrezenmeier H, Bacigalupo A, et al. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012; 97:1666.
  48. Lindorfer MA, Pawluczkowycz AW, Peek EM, et al. A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement. Blood 2010; 115:2283.
  49. Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010; 95:567.
  50. 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.
  51. Risitano AM, Notaro R, Luzzatto L, et al. Paroxysmal nocturnal hemoglobinuria--hemolysis before and after eculizumab. N Engl J Med 2010; 363:2270.
  52. Berzuini A, Montanelli F, Prati D. Hemolytic anemia after eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2010; 363:993.
  53. Risitano AM, Marando L, Seneca E, Rotoli B. Hemoglobin normalization after splenectomy in a paroxysmal nocturnal hemoglobinuria patient treated by eculizumab. Blood 2008; 112:449.
  54. 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.
  55. Rondelli T, Risitano AM, Peffault de Latour R, et al. Polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with paroxysmal nocturnal hemoglobinuria. Haematologica 2014; 99:262.
  56. Brodsky RA. How I treat paroxysmal nocturnal hemoglobinuria. Blood 2009; 113:6522.
  57. Dmytrijuk A, Robie-Suh K, Cohen MH, et al. FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Oncologist 2008; 13:993.
  58. Nishimura J, Yamamoto M, Hayashi S, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med 2014; 370:632.
  59. Balleari E, Gatti AM, Mareni C, et al. Recombinant human erythropoietin for long-term treatment of anemia in paroxysmal nocturnal hemoglobinuria. Haematologica 1996; 81:143.
  60. Schubert J, Scholz C, Geissler RG, et al. G-CSF and cyclosporin induce an increase of normal cells in hypoplastic paroxysmal nocturnal hemoglobinuria. Ann Hematol 1997; 74:225.
  61. Hill A, Ridley SH, Esser D, et al. Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: a new approach to PNH therapy. Blood 2006; 107:2131.
  62. 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.
  63. Ray JG, Burows RF, Ginsberg JS, Burrows EA. Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient. Haemostasis 2000; 30:103.
  64. McMullin MF, Hillmen P, Jackson J, et al. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria. J Intern Med 1994; 235:85.
  65. Sholar PW, Bell WR. Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria. Ann Intern Med 1985; 103:539.
  66. Araten DJ, Notaro R, Thaler HT, et al. Thrombolytic therapy is effective in paroxysmal nocturnal hemoglobinuria: a series of nine patients and a review of the literature. Haematologica 2012; 97:344.
  67. Emadi A, Brodsky RA. Successful discontinuation of anticoagulation following eculizumab administration in paroxysmal nocturnal hemoglobinuria. Am J Hematol 2009; 84:699.
  68. Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 2003; 102:3587.
  69. Baglin TP, Keeling DM, Watson HG, British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition--2005 update. Br J Haematol 2006; 132:277.
  70. Graham ML, Rosse WF, Halperin EC, et al. Resolution of Budd-Chiari syndrome following bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1996; 92:707.
  71. Antin JH, Ginsburg D, Smith BR, et al. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria: eradication of the PNH clone and documentation of complete lymphohematopoietic engraftment. Blood 1985; 66:1247.
  72. Kawahara K, Witherspoon RP, Storb R. Marrow transplantation for paroxysmal nocturnal hemoglobinuria. Am J Hematol 1992; 39:283.
  73. Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol 1999; 104:392.
  74. Santarone S, Bacigalupo A, Risitano AM, et al. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Haematologica 2010; 95:983.
  75. Endo M, Beatty PG, Vreeke TM, et al. Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal hemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage. Blood 1996; 88:742.
  76. Nafa K, Bessler M, Deeg HJ, Luzzatto L. New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria. Blood 1998; 92:3422.
  77. Flotho C, Strahm B, Kontny U, et al. Stem cell transplantation for paroxysmal nocturnal haemoglobinuria in childhood. Br J Haematol 2002; 118:124.
  78. Ware RE, Hall SE, Rosse WF. Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence. N Engl J Med 1991; 325:991.
  79. Johnson RJ, Rawstron AC, Richards S, et al. Circulating primitive stem cells in paroxysmal nocturnal hemoglobinuria (PNH) are predominantly normal in phenotype but granulocyte colony-stimulating factor treatment mobilizes mainly PNH stem cells. Blood 1998; 91:4504.
  80. Stoppa AM, Vey N, Sainty D, et al. Correction of aplastic anaemia complicating paroxysmal nocturnal haemoglobinuria: absence of eradication of the PNH clone and dependence of response on cyclosporin A administration. Br J Haematol 1996; 93:42.
  81. van Kamp H, van Imhoff GW, de Wolf JT, et al. The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 1995; 89:79.
  82. Paquette RL, Yoshimura R, Veiseh C, et al. Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria. Br J Haematol 1997; 96:92.
  83. Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes. Ann Intern Med 1999; 131:401.
  84. Nishimura J, Smith CA, Phillips KL, et al. Paroxysmal nocturnal hemoglobinuria: molecular pathogenesis and molecular therapeutic approaches. Hematopathol Mol Hematol 1998; 11:119.
  85. Phillips KL, Ware RE, Hall S, et al. Efficient retrovirus-mediated PIG-A gene transfer and stable restoration of GPI-anchored protein expression in cells with the PNH phenotype. Blood 2001; 97:3004.
  86. Bessler M, Hillmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal hemoglobinuria. Semin Hematol 1998; 35:149.
  87. Sloand EM, Maciejewski JP, Dunn D, et al. Correction of the PNH defect by GPI-anchored protein transfer. Blood 1998; 92:4439.