International Journal of Hematology

, Volume 77, Issue 2, pp 125–132

Management Issues in Paroxysmal Nocturnal Hemoglobinuria

Progress in hematology


Paroxysmal nocturnal hemoglobinuria (PNH) arises in the setting of bone marrow injury. Thus, management decisions must take into account whether symptoms are a consequence of the underlying marrow failure or of the expansion of the clone of thePIG-A mutant hematopoietic cells. The primary clinical manifestations of PNH are intravascular hemolysis and thrombophilia. Currently available options for treatment of the hemolysis of PNH are unsatisfactory, but the recent development of specific inhibitors of complement for use in treating human disease should make possible effective management of this pathology. The fundamental basis of the thrombophilia of PNH has not been elucidated. Currently, empiric anticoagulant therapy is the foundation for treating the thromboembolic complications of PNH. The role of warfarin prophylaxis, however, remains an area of active debate. Pregnancy in a patient with PNH presents special concerns about fetal/maternal well-being because of the high potential for thromboembolic complications. Bone marrow transplantation can be considered curative, but the decision to recommend this treatment must take into account factors related both to PNH and to comorbid conditions. Refining the technology for both gene therapy (by transducing stem cells with a functionalPIG-A gene) and autotransplantation (by using stem cells selected for the expression of glycosyl phosphatidylinositol-anchored proteins) remain challenges for the future.

Key words

PNH Hemolysis Thrombosis Complement Therapy 


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  1. 1.
    Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria.Cell. 1993;73:703–711.PubMedCrossRefGoogle Scholar
  2. 2.
    Schubert J, Vogt HG, Ziclinska-Skowronek M, et al. Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia.Blood. 1994;83:2323–2328.PubMedGoogle Scholar
  3. 3.
    Twanaga M, Furukawa K, Amenomori T, et al. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes.Br J Haemalol. 1998;102:465–474.CrossRefGoogle Scholar
  4. 4.
    Dunn DE, Tanawattanacharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.Ann Intern Med. 1999;131:401–408.PubMedGoogle Scholar
  5. 5.
    Mukhina GL, Buckley JT, Barber JP, Jones RJ, Brodsky RA. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia.Br J Haemalol. 2001;115:476–482.CrossRefGoogle Scholar
  6. 6.
    Wang H, Chuhjo T, Yasue S, Omine M, Nakao S. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome.Blood. 2002;100:3897–3902.PubMedCrossRefGoogle Scholar
  7. 7.
    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;115:1015–1022.PubMedCrossRefGoogle Scholar
  8. 8.
    Bessler M, Hillmen P. Somatic mutation and clonal selection in the pathogenesis and in the control of paroxysmal nocturnal hemoglobinuria.Semin Hematol. 1998;35:149–167.PubMedGoogle Scholar
  9. 9.
    Dunn DE, Liu JM, Young NS. Bone marrow failure in PNH. In: Young NS, Moss J, eds.Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol-Linked Proteins. San Diego, Calif: Academic Press; 2000:113–138.Google Scholar
  10. 10.
    Luzzatto L, Bessler M. The dual pathogenesis of paroxysmal nocturnal hemoglobinuria.Curr Opin Hematol. 1996;3:101–110.PubMedCrossRefGoogle Scholar
  11. 11.
    Parker CJ. Hemolysis in PNH. In: Young NS, Moss J, eds.Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol-Linked Proteins. San Diego, Calif: Academic Press; 2000:49–100.Google Scholar
  12. 12.
    Rosse WF. Paroxysmal nocturnal hemoglobinuria: present status and future prospects.West J Med. 1980;132:219–228.PubMedGoogle Scholar
  13. 13.
    Endo M, Ware RE, Vreeke TM, et al. Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria.Blood. 1996;87:2546–2557.PubMedGoogle Scholar
  14. 14.
    Holguin MH, Wilcox LA, Bernshaw NJ, Rosse WF, Parker CJ. Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria.J Clin Invest. 1989;84:1387–1394.PubMedCrossRefGoogle Scholar
  15. 15.
    Clark DA, Butler SA, Braren V, Hartmann RC, Jenkins DE Jr. The kidneys in paroxysmal nocturnal hemoglobinuria.Blood. 1981;57:83–89.PubMedGoogle Scholar
  16. 16.
    Balleari E, Gatti AM, Mareni C, Massa G, Marmont AM, Ghio R. Recombinant human erythropoietin for long-term treatment of anemia in paroxysmal nocturnal hemoglobinuria.Haematologica. 1996;81:143–147.PubMedGoogle Scholar
  17. 17.
    McMullin MF, Hillmen P Elder GE, Lappin TR, Luzzatto L. Serum erythropoietin levels in paroxysmal nocturnal haemoglobinuria: implications for therapy.Br J Haematol. 1996;92:815–817.PubMedCrossRefGoogle Scholar
  18. 18.
    Stebler C, Tichelli A, Dazzi H, Gratwohl A, Nissen C, Speck B. High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study.Exp Hematol. 1990;18:1204–1208.PubMedGoogle Scholar
  19. 19.
    Rosse WF. Treatment of paroxysmal nocturnal hemoglobinuria.Blood. 1982;60:20–23.PubMedGoogle Scholar
  20. 20.
    Rosse WF. Paroxysmal nocturnal hemoglobinuria. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds.Hematology: Basic Principles and Practice. 3rd ed. New York, NY: Churchill Livingstone; 2000:331–342.Google Scholar
  21. 21.
    Zhao M, Shao Z, Li K, et al. Clinical analysis of 78 cases of paroxysmal nocturnal hemoglobinuria diagnosed in the past ten years.Chin Med J (Engl). 2002;115:398–401.Google Scholar
  22. 22.
    Bourantas K. High-dose recombinant human erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria.Acta Haematol. 1994;91:62–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Issaragrisil S, Piankijagum A, Tang-naitrisorana Y. Corticosteroids therapy in paroxysmal nocturnal hemoglobinuria.Am J Hematol. 1987;25:77–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Brecher ME, Taswell HF. Paroxysmal nocturnal hemoglobinuria and the transfusion of washed red cells: a myth revisited.Transfusion. 1989;29:681–685.PubMedCrossRefGoogle Scholar
  25. 25.
    Parker CJ. An overview of the development of specific inhibitors of complement: opportunites for therapy of paroxysmal nocturnal hemoglobinuria. In: Omine M, Kinoshita T, eds.Paroxysmal Nocturnal Hemoglobinuria and Related Disorders: Molecular Aspects of Pathogenesis. Tokyo, Japan: Springer-Verlag; 2002:11–23.Google Scholar
  26. 26.
    Hillmen P, Hall C, Marsh J, et al. Eculizumab, a C5 complement-blocking antibody, abolishes hemolysis and renders hemolytic patients with paroxysmal nocturnal hemoglobinuria (PNH) transfusion independent [abstract].Blood. 2002;100:44a.Google Scholar
  27. 27.
    Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis.Blood. 2000;96:823–833.PubMedGoogle Scholar
  28. 28.
    Sloand EM, Young NS. Thrombotic complications in PNH. In: Young NS, Moss J, eds.Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol-Linked Proteins. San Diego, Calif: Academic Press; 2000:101–112.Google Scholar
  29. 29.
    Devine DV, Siegel RS, Rosse WF. Interactions of the platelets in paroxysmal nocturnal hemoglobinuria with complement: relationship to defects in the regulation of complement and to platelet survival in vivo.J Clin Invest. 1987;79:131–137.PubMedCrossRefGoogle Scholar
  30. 30.
    Wiedmer T, Hall SE, Ortel TL, Kane WH, Rosse WF, Sims PI. Com-plement-induced vesiculation and exposure of membrane pro-thrombinase sites in platelets of paroxysmal nocturnal hemoglo-binuria.Blood. 1993;82:1192–1196.PubMedGoogle Scholar
  31. 31.
    Ninomiya H, Kawashima Y, Hasegawa Y, Nagasawa T. Complement-induced procoagulant alteration of red blood cell membranes with microveside formation in paroxysmal nocturnal haemoglobinuria (PNH): implication for thrombogenesis in PNH.BrJ Haematol. 1999:106:224–231.CrossRefGoogle Scholar
  32. 32.
    Hugcl B, Socie G, Vu T, et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood. 1999;93:3451–3456.Google Scholar
  33. 33.
    Socie G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology.Lancet. 1996:348:573–577.PubMedCrossRefGoogle Scholar
  34. 34.
    Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural history of paroxysmal nocturnal hemoglobinuria.N Engl J Med. 1995;333: 1253–1258.PubMedCrossRefGoogle Scholar
  35. 35.
    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.Haetnostasis. 2000;30:103–117.Google Scholar
  36. 36.
    Fujioka S, Takayoshi T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan.Acta Haematol Japan. 1989;52:1386–1394.Google Scholar
  37. 37.
    Le XF, Yang TY, Yang XY, Wang XM. Characteristics of paroxysmal nocturnal hemoglobinuria in China: clinical analysis of 476 cases.Chin Med J (Engl). 1990;103:885–889.Google Scholar
  38. 38.
    Gongora Bianchi RA. Paroxysmal nocturnal hemoglobinuria: the Mexican experience.Rev Invest Clin. 1997;49(suppl):85S-88S.Google Scholar
  39. 39.
    Moyo VM, Mukhina GL, Garrett ES, Brodsky RA. Correlation between thrombosis and the percentage of glycosylphosphatidylinositol (GPI) anchor deficient cells in PNH.Blood. 2002;100:230a.CrossRefGoogle Scholar
  40. 40.
    Hall C, Richards S, Hillmen P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal haemoglobinuria (PNH).Blood. 2001;98:220a.CrossRefGoogle Scholar
  41. 41.
    Nafa K, Bessler M, Mason P, et al. Factor V Leiden mutation investigated by amplification created restriction enzyme site (ACRES) in PNH patients with and without thrombosis.Haematologica. 1996;81:540–542.PubMedGoogle Scholar
  42. 42.
    Ninomiya H, Kawashima Y, Nagasawa T. Inhibition of complementmediated haemolysis in paroxysmal nocturnal haemoglobinuria by heparin or low-molecular weight heparin.BrJ Haematol. 2000;109:875–881.CrossRefGoogle Scholar
  43. 43.
    McMullin MF, Hillmen Jackson J, Ganly P, Luzzatto L. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria.J. Intern Med. 1994;235:85–89.PubMedCrossRefGoogle Scholar
  44. 44.
    de Planque MM, Bacigalupo A, Wursch A, et al. Long-term follow-up of severe aplastic anaemia patients treated with antithymocytc globulin: Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT).BrJ Haematol. 1989:73:121–126.CrossRefGoogle Scholar
  45. 45.
    Tichelli A, Gratwohl A, Nissen C, Speck B. Late donal complications in severe aplastic anemia.Leak Lymphoma. 1994:12:167–175.CrossRefGoogle Scholar
  46. 46.
    Horikawa K, Kawaguchi T, Ishihara S, et al. Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria.Blood. 2002;99:24–29.PubMedCrossRefGoogle Scholar
  47. 47.
    Brodsky RA, Sensenbrenner LL, Smith BD, et al. Durable treatment-free remission after high-dose cyclophosphamide therapy for previously untreated severe aplastic anemia.Ann Inlern Med.. 2001;135:477–483.Google Scholar
  48. 48.
    Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamidc in severe aplastic anaemia: a randomised trial.Lancet. 2000:356:1554–1559.PubMedCrossRefGoogle Scholar
  49. 49.
    Tisdale JF, Maciejewski JP, Nunez O, Rosenfeld S.T, Young NS. Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial.Blood. 2002;100:4668–4670.PubMedCrossRefGoogle Scholar
  50. 50.
    Endo M, Beatty PG, Vreeke TM, Wittwer CT, Singh SP, Parker CJ. 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. 1996:88:742–750.PubMedGoogle Scholar
  51. 51.
    Takahashi Y, McCoy JP Carvallo C, et al. PNH cells are not resistant to allogeneic immune attack and can be eradicated following nonmyeloablative allogeneic stem cell transplantation (NST).Blood. 2002;100:9aGoogle Scholar
  52. 52.
    Araten DJ, Luzzatto L. Allogeneic bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.Haematologica. 2000;85:1–2.PubMedGoogle Scholar
  53. 53.
    Prince GM, Nguyen M, Lazarus HM, Brodsky RA, Tcrstappcn LW, Medof ME. Peripheral blood harvest of unaffected CD34+CD38 hematopoietic precursors in paroxysmal nocturnal hemoglobinuria.Blood. 1995;86:3381–3386.PubMedGoogle Scholar
  54. 54.
    Sloand EM, Fuhrer M, Maciejewski JP, et al. When cytogenetic abnromalities occur in patients with paroxysmal nocturnal hemoglobinuira (PNH), they primarily affect the glycosylphosphatidylinositol (GPI)-positive cell clones.Blood. 2002;100:229a.Google Scholar
  55. 55.
    Nishimura J, Phillips KL, Ware RE, 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;97:3004–3010.CrossRefGoogle Scholar
  56. 56.
    Hall SE, Rosse WH The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria.Blood. 1996;87:5332–5340.PubMedGoogle Scholar
  57. 57.
    Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin.Am J Clin Pathol. 2000;114:459–466.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  1. 1.Divisions of Hematology and Medical OncologyUniversity of Utah School of Medicine and VA Medical CenterSalt Lake CityUSA

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