Skip to main content
Log in

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

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Gull WW. A case of intermittent haematinuria, with remarks.Guys Hosp Rep. 1866;12:381–392.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Telen MJ, Green AM. The Inab phenotype: characterization of the membrane protein and complement regulatory defect.Blood. 1989;74:437–441.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  9. Couturier C, Haeffner Cavaillon N, Caroff M, Kazatchkine MD. Binding sites for endotoxins (lipopolysaccharides) on human monocytes.J Immunol. 1991;147:1899–1904.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  11. Jose MD, Lynn KB. Acute renal failure in a patient with paroxysmal nocturnal hemoglobinuria.Clin Nephrol. 2002;56:172–174.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  13. Brecher ME, Taswell HF. Paroxysmal nocturnal hemoglobinuria and the transfusion of washed red cells: a myth revisited.Transfusion. 1989;29:681–685.

    Article  PubMed  CAS  Google Scholar 

  14. Marchiafava E. Anemia emolitica con emosiderinuria perpetua.Policlinico [Med]. 1992;35:109.

    Google Scholar 

  15. Micheli F. Anemia splcnomcgalia emolyitica con emoglobinuria-emosiderinuria tipo Marchiafava.Haematologica. 1931;12:101.

    Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  18. Crosby WH. Paroxysmal nocturnal hemoglobinuria: relation of the clinical manifestations to underlying pathogenic mechanisms.Blood. 1953;8:769–812.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  23. Blum SF, Gardner FH. Intestinal infarction in paroxysmal nocturnal hemoglobinuria.N Engl J Med. 1966;274:1137–1138.

    Article  Google Scholar 

  24. Grossman JA, McDermott WV Jr. Paroxysmal nocturnal hemoglobinuria associated with hepatic and portal venous thrombosis.Am J Surg. 1974;127:733–736.

    Article  PubMed  CAS  Google Scholar 

  25. Zimmerman D, Bell WR. Venous thrombosis and splenic rupture in paroxysmal nocturnal hemoglobinuria.Am J Med. 1980;68:275–279.

    Article  PubMed  CAS  Google Scholar 

  26. Donhowe SP, Lazaro RP. Durai sinus thrombosis in paroxysmal nocturnal hemoglobinuria.Clin Neurol. Neurosurg. 1984;86:149–152.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  29. Payne PR, Holt JM, Neame PB. Paroxysmal nocturnal haemoglobinuria parturition complicated by venous thrombosis.J Obstet Gynaecol Br Commonw. 1968;75:1066–1068.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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. Rietschel RL, Lewis CW, Simmons RA, Phyliky RL. Skin lesions in paroxysmal nocturnal hemoglobinuria.Arch Dermatol. 1978;134:560–563.

    Article  Google Scholar 

  34. Draelos ZK, Hansen RC. Hemorrhagic bullae in an anemic woman: Paroxysmal nocturnal hemoglobinuria (PNH).Arch Dermatol. 1986;122:1326–1327, 1329–1330.

    Article  PubMed  CAS  Google Scholar 

  35. Hansen NE, Killmann SA. Paroxysmal nocturnal haemoglobinuria: a clinical study.Acta Med Scand. 1968;184:525–541.

    Article  PubMed  CAS  Google Scholar 

  36. Rosse WE. Paroxysmal nocturnal hemoglobinuria as a molecular disease.Medicine. 1997;76:63–94.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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;82:1192–1196

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  44. Lewis SM, Dacie JV. The aplastic anaemia-paroxysmal nocturnal haemoglobinuria syndrome.Br J Haematol. 1967;13:236–251.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Brubaker L, Essig LJ, Mengel CE. Neutrophil life span in paroxysmal nocturnal hemoglobinuria.Blood. 1977;50:657–662.

    Article  PubMed  CAS  Google Scholar 

  47. Dacie JV, Lewis SM. Paroxysmal nocturnal hemoglobinuria, clinical manifestations, hematology and nature of the disease.Ser Haemataol. 1972;5:3–23.

    CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  49. Tichelli A, Gratwohl A, Nissen C, Speck B. Late clonal complications in severe aplastic anemia.Leak Lymphoma. 1994;12:167–175.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  54. Young NS. The problem of clonality in aplastic anemia: Dr. Dameshek’s riddle, restated.Blood. 1992;79:1385–1392.

    Article  PubMed  CAS  Google Scholar 

  55. Luzzatto L, Bessler M. The dual pathogenesis of paroxysmal nocturnal hemoglobinuria.Curr Opin Hematol. 1996;3:101–110.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia.N Engl J Med. 1997;336:1365–1372.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  62. Lewis SM, Petit JE, Tattersall MH, Pepys MB. Myelosclerosis and paroxysmal nocturnal haemoglobinuria.Scand J Haematol. 1971:8:451–460.

    Article  PubMed  CAS  Google Scholar 

  63. Hansen NE, Killman SA. Paroxysmal nocturnal hemoglobinuria in myelofibrosis.Blood. 1970;36:428–431.

    Article  PubMed  CAS  Google Scholar 

  64. Lewis SM, Verwilghen RL. Dyserythropoiesis and dyserythropoietic anemias.Prog Hematol. 1973;8:99–128.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. Holden D, Lichtman H. Paroxysmal nocturnal hemoglobinuria with acute leukemia.Blood. 1969;33:283–286.

    Article  PubMed  CAS  Google Scholar 

  69. Jenkins DF, Jr, Hartmann RC. Paroxysmal nocturnal hemoglobinuria terminating in acute myeloblastic leukemia.Blood. 1969;33:274–282.

    Article  PubMed  Google Scholar 

  70. Kaufmann RW, Schechter G, McFarland W. Paroxysmal nocturnal hemoglobinuria terminating in acute granulocytic leukemia.Blood. 1969;22:287–291.

    Article  Google Scholar 

  71. Harris JW, Koscick R, Lazarus HM, Eschleman JR, Medof ME. Leukemia arising out of paroxysmal nocturnal hemoglobinuria.Lenk Lymphoma. 1999;32:401–426.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  78. Strubing P. Paroxysmale Hämoglobinurie.Dtsch Med, Wochenschr. 1882;8:1–8.

    Article  Google Scholar 

  79. Rosse WF, Gutterman LA. The effect of iron therapy in paroxysmal nocturnal hemoglobinuria.Blood. 1970;36:559–565.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  81. Tichelli A, Gratwohl A, Nissen C, Speck B. Late haematological complications in severe aplastic anaemia.Br J Haematol. 1988;69:413–418.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  86. Kawahara K, Witherspoon RP, Storb R. Marrow transplantation for paroxysmal nocturnal hemoglobinuria.Am. J Hematol. 1992;39:283–288.

    Article  PubMed  CAS  Google Scholar 

  87. Raiola AM, van Lint MT, Lamparelli T, et al. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria.Haematologica. 2000;85:59–62.

    PubMed  CAS  Google Scholar 

  88. Suenaga K, Kanda Y, Niiya H, et al. Successful application of nonmyeloablative transplantation for paroxysmal nocturnal hemoglobinuria.Exp Hematol. 2001;29:639–642.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wendell F. Rosse.

About this article

Cite this article

Rosse, W.F., Nishimura, J. Clinical Manifestations of Paroxysmal Nocturnal Hemoglobinuria: Present State and Future Problems. Int J Hematol 77, 113–120 (2003). https://doi.org/10.1007/BF02983209

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02983209

Key words

Navigation