International Journal of Hematology

, Volume 77, Issue 2, pp 113–120

Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria: Present State and Future Problems

Progress in hematology

Abstract

The clinical pathology of paroxysmal nocturnal hemoglobinuria (PNH) involves 3 complications: hemolytic anemia, thrombosis, and hematopoietic deficiency. The first 2 are clearly the result of the cellular defect in PNH, the lack of proteins anchored to the membrane by the glycosylphosphatidylinositol anchor. The hemolytic anemia results in syndromes primarily related to the fact that the hemolysis is extracellular. Thrombosis is most significant in veins within the abdomen, although a number of other thrombotic syndromes have been described. The hematopoietic deficiency may be the same as that in aplastic anemia, a closely related disorder, and may not be due to the primary biochemical defect. The relationship to aplastic anemia suggests a nomenclature that emphasizes the predominant clinical manifestations in a patient. This relationship does not explain cases that appear to be related to myelodysplastic syndromes or the transition of some cases of PNH to leukemia. Treatment, except for bone marrow transplantation, remains noncurative and in need of improvement.

Key words

Paroxysmal nocturnal hemoglobinuria Hemolysis Thrombosis Aplastic anemia Myelodysplasia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gull WW. A case of intermittent haematinuria, with remarks.Guys Hosp Rep. 1866;12:381–392.Google Scholar
  2. 2.
    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
  3. 3.
    Nicholson-Weller A, March JE, 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 USA. 1983;80:5430.CrossRefGoogle Scholar
  4. 4.
    Holguin MH, Wilcox LA, Bernshaw NJ, Rosse WF, Parker CI. 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
  5. 5.
    Rosse WF, Dacie JV. Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria red blood cells, I: the sensitivity of PNH red cells to lysis by complement and specific antibody.J Clin Invest. 1966;45:736–748.PubMedCrossRefGoogle Scholar
  6. 6.
    Telen MJ, Green AM. The Inab phenotype: characterization of the membrane protein and complement regulatory defect.Blood. 1989;74:437–441.PubMedGoogle Scholar
  7. 7.
    Yamashina M, Ueda H, Kinoshita T, et al. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria.N Engl J Med. 1990,323:1184–1189.PubMedGoogle Scholar
  8. 8.
    Ohta M, Okada M, Yamashina I, Kawasaki T. The mechanism of carbohydrate-mediated complement activation by the serum mannan-binding protein.J Biol Chem. 1990;265:1980–1984.PubMedGoogle Scholar
  9. 9.
    Couturier C, Haeffner Cavaillon N, Caroff M, Kazatchkine MD. Binding sites for endotoxins (lipopolysaccharides) on human monocytes.J Immunol. 1991;147:1899–1904.PubMedGoogle Scholar
  10. 10.
    Simmons DL, Tan S, Tenen DG, Nicholson-Weller A, Seed B. Monocyte antigen CD14 is a phospholipid anchored membrane protein.Blood. 1989;73:284–289.PubMedGoogle Scholar
  11. 11.
    Jose MD, Lynn KB. Acute renal failure in a patient with paroxysmal nocturnal hemoglobinuria.Clin Nephrol. 2002;56:172–174.Google Scholar
  12. 12.
    Zupanska B, Uhrynowska M, Konopka L. Transfusion-related acute lung injury due to granulocyte-agglutinating antibody in a patient with paroxysmal nocturnal hemoglobinuria.Transfusion. 1999;39:944–977.PubMedCrossRefGoogle Scholar
  13. 13.
    Brecher ME, Taswell HF. Paroxysmal nocturnal hemoglobinuria and the transfusion of washed red cells: a myth revisited.Transfusion. 1989;29:681–685.PubMedCrossRefGoogle Scholar
  14. 14.
    Marchiafava E. Anemia emolitica con emosiderinuria perpetua.Policlinico [Med]. 1992;35:109.Google Scholar
  15. 15.
    Micheli F. Anemia splcnomcgalia emolyitica con emoglobinuria-emosiderinuria tipo Marchiafava.Haematologica. 1931;12:101.Google Scholar
  16. 16.
    Mooraki A, Boroumand B, Mohammad Zadeh F, Ahmed SH, Bastani B. Acute reversible renal failure in a patient with paroxysmal nocturnal hemoglobinuria.Clin Nephrol. 1998;50:255–257.PubMedGoogle Scholar
  17. 17.
    Sechi LA, Marigliano A, Pala A, Tedde R. Acute renal failure in paroxysmal nocturnal haemoglobinuria with splanchnic venous thrombosis.Clin Lab Haematol. 1989;11:273–275.PubMedCrossRefGoogle Scholar
  18. 18.
    Crosby WH. Paroxysmal nocturnal hemoglobinuria: relation of the clinical manifestations to underlying pathogenic mechanisms.Blood. 1953;8:769–812.PubMedGoogle Scholar
  19. 19.
    Socie G, Mary J-Y, De Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long term follow-up and prognostic factors.Lancet. 1996;348:573–577.PubMedCrossRefGoogle Scholar
  20. 20.
    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
  21. 21.
    Hartmann RC, Luther AB, Jenkins DE Jr, Tenorio LE, Saba HI. Fulminant hepatic venous thrombosis (Budd-Chiari syndrome) in paroxysmal nocturnal hemoglobinuria: definition of a medical emergency.Johns Hopkins Med J. 1980;146:247–254.PubMedGoogle Scholar
  22. 22.
    Peytremann R, Rhodes RS, Hartmann RC. Thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) with particular reference to progressive, diffuse hepatic venous thrombosis.Ser Haematol. 1972;5:115–136.PubMedGoogle Scholar
  23. 23.
    Blum SF, Gardner FH. Intestinal infarction in paroxysmal nocturnal hemoglobinuria.N Engl J Med. 1966;274:1137–1138.Google Scholar
  24. 24.
    Grossman JA, McDermott WV Jr. Paroxysmal nocturnal hemoglobinuria associated with hepatic and portal venous thrombosis.Am J Surg. 1974;127:733–736.PubMedCrossRefGoogle Scholar
  25. 25.
    Zimmerman D, Bell WR. Venous thrombosis and splenic rupture in paroxysmal nocturnal hemoglobinuria.Am J Med. 1980;68:275–279.PubMedCrossRefGoogle Scholar
  26. 26.
    Donhowe SP, Lazaro RP. Durai sinus thrombosis in paroxysmal nocturnal hemoglobinuria.Clin Neurol. Neurosurg. 1984;86:149–152.PubMedCrossRefGoogle Scholar
  27. 27.
    Omardeen F, Wharfe G, St Omer L, Richards JS, Morgan OS. Cerebral sinovenous thrombosis in a patient with paroxysmal nocturnal haemoglobinuria.West Indian Med J. 1992;41:31–33.PubMedGoogle Scholar
  28. 28.
    Hauser D, Barzilai N, Zalish M, Oliver M, Pollack A. Bilateral papilledema with retinal hemorrhages in association with cerebral venous sinus thrombosis and paroxysmal nocturnal hemoglobinuria.Am J Ophthalmol. 1996;122:592–593.PubMedGoogle Scholar
  29. 29.
    Payne PR, Holt JM, Neame PB. Paroxysmal nocturnal haemoglobinuria parturition complicated by venous thrombosis.J Obstet Gynaecol Br Commonw. 1968;75:1066–1068.PubMedGoogle Scholar
  30. 30.
    Wozniak AJ, Kitchens CS. Prospective hemostatic studies in a patient having PNH pregnancy and cerebral venous thrombosis.Am J Obstet Gynecol. 1982;142:591–593.PubMedGoogle Scholar
  31. 31.
    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.Hemostasis. 2000;30:103–117.Google Scholar
  32. 32.
    Hartmann RC, Bruce ASC. Fetomaternal outcomes of pregnancy in paroxysmal nocturnal hemoglobinuria. In: Bern MM, ed.Hematologic Disorders in Maternal-Fetal Medicine. New York: WileyLiss; 1990:261–281.Google Scholar
  33. 33.
    Rietschel RL, Lewis CW, Simmons RA, Phyliky RL. Skin lesions in paroxysmal nocturnal hemoglobinuria.Arch Dermatol. 1978;134:560–563.CrossRefGoogle Scholar
  34. 34.
    Draelos ZK, Hansen RC. Hemorrhagic bullae in an anemic woman: Paroxysmal nocturnal hemoglobinuria (PNH).Arch Dermatol. 1986;122:1326–1327, 1329–1330.PubMedCrossRefGoogle Scholar
  35. 35.
    Hansen NE, Killmann SA. Paroxysmal nocturnal haemoglobinuria: a clinical study.Acta Med Scand. 1968;184:525–541.PubMedGoogle Scholar
  36. 36.
    Rosse WE. Paroxysmal nocturnal hemoglobinuria as a molecular disease.Medicine. 1997;76:63–94.PubMedCrossRefGoogle Scholar
  37. 37.
    Hamilton KK, Hattori R, Esmon CT, Sims PJ. Complement proteins C5b-9 induce vesiculation of the endothelial plasma membrane and expose catalytic surface for assembly of the prothrombinase enzyme complex.J Biol Chem. 1990;265:3809–3814.PubMedGoogle Scholar
  38. 38.
    Wiedmer T, Hall SE, Ortel TL, et al. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria.Blood. 1993;82:1192–1196PubMedGoogle Scholar
  39. 39.
    Hugel B, Socie G, Vu T, et al. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia.Blood. 1999;93:3451–3564.PubMedGoogle Scholar
  40. 40.
    Gilbert GE, Sims PJ, Wiedmer T, et al. Platelet-derived microparticles express high affinity receptors for factor VIII.J Biol Chem. 1991;266:17261–17268.PubMedGoogle Scholar
  41. 41.
    Ploug M, Pilesner T, Ronne F, et al. The receptor for urokinasetype plasminogen activator is delicient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria.Blood. 1992;79:1447–1455.PubMedGoogle Scholar
  42. 42.
    McMullin MF, Hillmen P, Jackson J, Ganly P, Luzzatto L. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal hemoglobinuria.J Intern Med. 1994;235:85–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Dacie JV, Lewis SM. Paroxysmal nocturnal haemoglobinuria: variation in clinical severity and association with bone marrow hypoplasia.Br J Haematol. 1961;7:442–457.PubMedCrossRefGoogle Scholar
  44. 44.
    Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome.Br J Haematol. 1967;13:236–251.PubMedCrossRefGoogle Scholar
  45. 45.
    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
  46. 46.
    Brubaker L, Essig LJ, Mengel CE. Neutrophil life span in paroxysmal nocturnal hemoglobinuria.Blood. 1977;50:657–662.PubMedGoogle Scholar
  47. 47.
    Dacie JV, Lewis SM. Paroxysmal nocturnal hemoglobinuria, clinical manifestations, hematology and nature of the disease.Ser Haemataol. 1972;5:3–23.Google Scholar
  48. 48.
    Nissen C, Tichelli A, Gratwohl A, et al. High incidence of transiently appearing complement-sensitive bone marrow precursor cells in patients with severe aplastic anemia: a possible role of high endogenous IL-2 in their suppression.Acta Haematol. 1999;101:165–172.PubMedCrossRefGoogle Scholar
  49. 49.
    Tichelli A, Gratwohl A, Nissen C, Speck B. Late clonal complications in severe aplastic anemia.Leak Lymphoma. 1994;12:167–175.CrossRefGoogle Scholar
  50. 50.
    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;23:81–87.PubMedGoogle Scholar
  51. 51.
    Sultan C, Marquet M, Joffroy Y. Etude de dysmyelopoieses acquises idiopathiques en culture de moelle in vitro.Nouv Rev Fr Hematol. 1973;13:431–426.PubMedGoogle Scholar
  52. 52.
    Chen R, Nagarajan S, Prince GM, et al. Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria.J Clin Invest. 2000;106:689–696.PubMedCrossRefGoogle Scholar
  53. 53.
    Maciejewski JP, Sloand EM, Sato T, Anderson S, Young NS. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria/ aplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositol-anchored protein-deficient clone.Blood. 1997;89:1173–1181.PubMedGoogle Scholar
  54. 54.
    Young NS. The problem of clonality in aplastic anemia: Dr. Dameshek’s riddle, restated.Blood. 1992;79:1385–1392.PubMedGoogle Scholar
  55. 55.
    Luzzatto L, Bessler M. The dual pathogenesis of paroxysmal nocturnal hemoglobinuria.Curr Opin Hematol. 1996;3:101–110.PubMedCrossRefGoogle Scholar
  56. 56.
    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 USA. 1999;96:5209–5214.PubMedCrossRefGoogle Scholar
  57. 57.
    Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997;336:1365–1372.PubMedCrossRefGoogle Scholar
  58. 58.
    Brodsky RA, Vala MS, Barber JP, Medof ME, Jones RJ. Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria.Proc Natl Acad Sci USA. 1997;94:8756–8760.PubMedCrossRefGoogle Scholar
  59. 59.
    Horikawa K, Nakakuma H, Kawagauchi T, et al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome.Blood. 1997;90:2716–2722.PubMedGoogle Scholar
  60. 60.
    Ware RE, Nishimura J, Moody MA, et al. The PIG-A mutation and absence of glycosylphosphatidylinositol-linked proteins do not confer resistance to apoptosis in paroxysmal nocturnal hemoglobinuria.Blood. 1998;92:2541–2550.PubMedGoogle Scholar
  61. 61.
    Kawagoe K, Kitamura T, Okabe M, et al. Glycosylphosphatidylinositol-anchor-deficient mice: implications for clonal dominance of mutant cells in paroxysmal nocturnal hemoglobinuria.Blood. 1996;87:3600–3606.PubMedGoogle Scholar
  62. 62.
    Lewis SM, Petit JE, Tattersall MH, Pepys MB. Myelosclerosis and paroxysmal nocturnal haemoglobinuria.Scand J Haematol. 1971:8:451–460.PubMedGoogle Scholar
  63. 63.
    Hansen NE, Killman SA. Paroxysmal nocturnal hemoglobinuria in myelofibrosis.Blood. 1970;36:428–431.PubMedGoogle Scholar
  64. 64.
    Lewis SM, Verwilghen RL. Dyserythropoiesis and dyserythropoietic anemias.Prog Hematol. 1973;8:99–128.PubMedGoogle Scholar
  65. 65.
    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;87:401–403.PubMedCrossRefGoogle Scholar
  66. 66.
    Nagakura S, Kawaguchi T, Fujimoto K, et al. Sequential development of myelodysplasia and paroxysmal nocturnal hemoglobinuria in a patient with preceding aplastic anemia.Int J Hematol. 1997;65:187–189.PubMedCrossRefGoogle Scholar
  67. 67.
    Dunn DE, Tanawattancharoen P, Boccuni P, et al. Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.Ann Intern Med. 1999;21:467–468.Google Scholar
  68. 68.
    Holden D, Lichtman H. Paroxysmal nocturnal hemoglobinuria with acute leukemia.Blood. 1969;33:283–286.PubMedGoogle Scholar
  69. 69.
    Jenkins DF, Jr, Hartmann RC. Paroxysmal nocturnal hemoglobinuria terminating in acute myeloblastic leukemia.Blood. 1969;33:274–282.PubMedGoogle Scholar
  70. 70.
    Kaufmann RW, Schechter G, McFarland W. Paroxysmal nocturnal hemoglobinuria terminating in acute granulocytic leukemia.Blood. 1969;22:287–291.Google Scholar
  71. 71.
    Harris JW, Koscick R, Lazarus HM, Eschleman JR, Medof ME. Leukemia arising out of paroxysmal nocturnal hemoglobinuria.Lenk Lymphoma. 1999;32:401–426.Google Scholar
  72. 72.
    Wasi P, Kruetrachue M, Na-Nakorn S. Aplastic anemia paroxysmal nocturnal hemoglobinuria syndrome-acute leukemia in the same patients: the first record of such occurrence.J Med Assoc Thai. 1970;53:656–663.PubMedGoogle Scholar
  73. 73.
    Hiroshige Y, Marsumoto N, Harima K, et al. An autopsy case of aplastic anemia-PNH syndrome terminating in acute granulocytic leukemia.Nippon Ketsueki Gakkai Zasshi. 1977;40:16–23.PubMedGoogle Scholar
  74. 74.
    van Kamp H, Smit JW, van den Berg E, Roud-Halle M, Vellenga E. Myelodysplasia following paroxysmal nocturnal haemoglobinuria: evidence for the emergence of a separate clone.Br J Haematol. 1994;87:399–400.PubMedCrossRefGoogle Scholar
  75. 75.
    Jin J-Y, Tooze JA, Marsh JC, Mathhey F, Gordon-Smith EC. Myelodysplasia following aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome after treatment with immuno-suppression and G-CSF: evidence for the emergence of a separate clone.Br J Haematol. 1996;94:510–512.PubMedCrossRefGoogle Scholar
  76. 76.
    Nakakuma H, Nagakura S, Iwamoto N, et al. Paroxysmal nocturnal hemoglobinuria clone in bone marrow of patients with pancytopenia.Blood. 1995;85:1371–1376.PubMedGoogle Scholar
  77. 77.
    Sears DA, Anderson PR, Foy AL, Williams HL, Crosby WH. Urinary iron excretion and renal metabolism of hemoglobin in hemolytic diseases.Blood. 1966;28:708–725.PubMedGoogle Scholar
  78. 78.
    Strubing P. Paroxysmale Hämoglobinurie.Dtsch Med, Wochenschr. 1882;8:1–8.Google Scholar
  79. 79.
    Rosse WF, Gutterman LA. The effect of iron therapy in paroxysmal nocturnal hemoglobinuria.Blood. 1970;36:559–565.PubMedGoogle Scholar
  80. 80.
    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. 1966;45:331–363.PubMedCrossRefGoogle Scholar
  81. 81.
    Tichelli A, Gratwohl A, Nissen C, Speck B. Late haematological complications in severe aplastic anaemia.Br J Haematol. 1988;69:413–418.PubMedCrossRefGoogle Scholar
  82. 82.
    Rosenfeld SJ, Kimball J, Vining D, Young NS. Intensive immuno-suppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia.Blood. 1995;85:3058–3065.PubMedGoogle Scholar
  83. 83.
    Brodsky RA, Sensenbrenner L, Jones RJ. Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation.Blood. 1996;87:491–494.PubMedGoogle Scholar
  84. 84.
    Fefer A, Freeman H, Storb R, et al. Paroxysmal nocturnal hemoglobinuria and marrow failure treated by infusion of marrow from an identical twin.Ann Intern Med. 1976;84:692–695.PubMedGoogle Scholar
  85. 85.
    Antin JR, 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;66:1247–1250.PubMedGoogle Scholar
  86. 86.
    Kawahara K, Witherspoon RP, Storb R. Marrow transplantation for paroxysmal nocturnal hemoglobinuria.Am. J Hematol. 1992;39:283–288.PubMedCrossRefGoogle Scholar
  87. 87.
    Raiola AM, van Lint MT, Lamparelli T, et al. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.Haematologica. 2000;85:59–62.PubMedGoogle Scholar
  88. 88.
    Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria.Exp Hematol. 2001;29:639–642.PubMedCrossRefGoogle Scholar
  89. 89.
    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

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  1. 1.Divisions of HematologyDuke University Medical CenterDurham
  2. 2.Medical Oncology-Bone Marrow Transplantation, Department of MedicineDuke University Medical CenterDurham

Personalised recommendations