Skip to main content
SpringerLink
Log in

New Insights into Molecular Pathogenesis of Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria

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

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by the clonal expansion of hematopoietic stem cells with mutations of the phosphatidylinositol glycan-class A gene (PIGA). PNH clones then fail to generate glycosylphosphatidylinositol (GPI) or to express a series of GPI-linked membrane proteins including complement-regulatory proteins, resulting in complement-mediated intravascular hemolysis and thrombosis. Bone marrow failure is another characteristic feature of PNH. It is currently considered that immune-mediated injury of hematopoietic cells is implicated in PNH marrow failure as well as in aplastic anemia, a well-known PNH-related disorder. There is increasing evidence that the autoimmune attack allows PNH clones to selectively survive in the injured marrow, leading to clinical manifestations characteristic of PNH. As candidate molecules that trigger the immune attack on marrow cells, stress-inducible membrane proteins and Wilms’ tumor protein WT1 have been proposed. Among the stress-inducible proteins, GPI-linked proteins, such as cytomegalovirus glycoprotein UL16-binding protein, are distinct candidates that not only induce immune attack, but also allow PNH clones to survive the attack. Here, we overview the current understanding of the molecular pathogenesis of bone marrow failure in PNH.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Rotoli B, Luzzatto L. Paroxysmal nocturnal haemoglobinuria.Baillieres Clin Haematol. 1989;2:113–138.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  5. 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 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  9. 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 

  10. Fujioka S, Asai T. Prognostic features of paroxysmal nocturnal hemoglobinuria in Japan.Acta Haematol Jpn. 1989;52:1386–1394.

    CAS  Google Scholar 

  11. Rotoli B, Robledo R, Luzzatto L. Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria.Blood. 1982;60:157–159.

    PubMed  CAS  Google Scholar 

  12. Moore JG, Humphries RK, Frank MM, Young N. Characterization of the hematopoietic defect in paroxysmal nocturnal hemoglobinuria.Exp Hematol. 1986;14:222–229.

    PubMed  CAS  Google Scholar 

  13. Iwamoto N, Kawaguchi T, Horikawa K, et al. Preferential hematopoiesis by paroxysmal nocturnal hemoglobinuria clone engrafted in SCID mice.Blood. 1996;87:4944–4948.

    PubMed  CAS  Google Scholar 

  14. 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.

    PubMed  CAS  Google Scholar 

  15. Elebute MO, Rizzo S, Tooze JA, Marsh JC, Gordon-Smith EC, Gibson FM. Evaluation of the haemopoietic reservoir in de novo haemolytic paroxysmal nocturnal haemoglobinuria.Br J Haematol. 2003;123:552–560.

    Article  PubMed  Google Scholar 

  16. Nakakuma H, Nagakura S, Iwamoto N, et al. Paroxysmal nocturnal hemoglobinuria clone in bone marrow of patients with pancytopenia.Blood. 1995;85:1371–1376.

    PubMed  CAS  Google Scholar 

  17. Schubert J, Vogt HG, Zielinska-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.

    PubMed  CAS  Google Scholar 

  18. 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 

  19. Griscelli-Bennaceur A, Gluckman E, Scrobohaci ML, et al. Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link.Blood. 1995;85:1354–1363.

    PubMed  CAS  Google Scholar 

  20. De Lord C, Tooze JA, Saso R, Marsh JC, Gordon-Smith EC. Deficiency of glycosylphosphatidyl inositol-anchored proteins in patients with aplastic anaemia does not affect response to immunosuppressive therapy.Br J Haematol. 1998;101:90–93.

    Article  PubMed  Google Scholar 

  21. Azenishi Y, Ueda E, Machii T, et al. CD59-deficient blood cells and PIG-A gene abnormalities in Japanese patients with aplastic anaemia.Br J Haematol. 1999;104:523–529.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. Wang H, Chuhjo T, Yamazaki H, et al. Relative increase of granulocytes with a paroxysmal nocturnal haemoglobinuria phenotype in aplastic anaemia patients: the high prevalence at diagnosis.Eur J Haematol. 2001;66:200–205.

    Article  PubMed  CAS  Google Scholar 

  24. Iwanaga M, Furukawa K, Amenomori T, et al. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes.Br J Haematol. 1998;102:465–474.

    Article  PubMed  CAS  Google Scholar 

  25. Young N, ed.Bone Marrow Failure Syndromes. W S. Saunders; 2000.

  26. Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria.Blood. 2005;106:3699–3709.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Young NS. Acquired aplastic anemia.Ann Intern Med. 2002;136:534–546.

    Article  PubMed  Google Scholar 

  28. Kusminsky GD, Barazzutti L, Korin JD, Blasetti A, Tartas NE, Sanchez Avalos JC. Complete response to antilymphocyte globulin in a case of aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome.Am J Hematol. 1988;29:123.

    Article  PubMed  CAS  Google Scholar 

  29. Nakao S, Yamaguchi M, Takamatsu H, Shiobara S, Matusda T. Expansion of a paroxysmal nocturnal hemoglobinuria (PNH) clone after cyclosporine therapy for aplastic anemia/PNH syndrome.Blood. 1992;80:2943–2944.

    PubMed  CAS  Google Scholar 

  30. Van Kamp H, van Imhoff GW, de Wolf JT, Smit JW, Halie MR, Vellenga E. The effect of cyclosporine on haematological parameters in patients with paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1995;89:79–82.

    Article  PubMed  Google Scholar 

  31. 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;93:42–44.

    Article  PubMed  CAS  Google Scholar 

  32. Horikawa K, Fujisao S, Iwamoto N, et al. Cyclosporin-responsive pancytopenia and HLA class II alleles of a patient with paroxysmal nocturnal hemoglobinuria.Int J Hematol. 1996;63:165–166.

    Article  PubMed  CAS  Google Scholar 

  33. Paquette RL, Yoshimura R, Veiseh C, Kunkel L, Gajewski J, Rosen PJ. Clinical characteristics predict response to antithymocyte globulin in paroxysmal nocturnal haemoglobinuria.Br J Haematol. 1997;96:92–97.

    Article  PubMed  CAS  Google Scholar 

  34. Noji H, Shichishima T, Ishikawa S, Kai T, Saitoh Y, Maruyama Y. Effective treatment combining antithymocyte globulin, cyclosporin A, and granulocyte colony-stimulating factor for atypical paroxysmal nocturnal hemoglobinuria accompanied by bone marrow hypoplasia.Rinsho Ketsueki. 1999;40:240–243.

    PubMed  CAS  Google Scholar 

  35. Cheung WC, Lam CC, Kwong YL. Anti-thymocyte globulin treatment of marrow aplasia associated with paroxysmal nocturnal haemoglobinuria (PNH) resulted in haematological improvement due to an expansion of the PNH clone.Br J Haematol. 2003;120:325–328.

    Article  PubMed  CAS  Google Scholar 

  36. Boschetti C, Fermo E, Bianchi P, Vercellati C, Barraco F, Zanella A. Clinical and molecular aspects of 23 patients affected by paroxysmal nocturnal hemoglobinuria.Am J Hematol. 2004;77:36–44.

    Article  PubMed  CAS  Google Scholar 

  37. Chapuis B, Von Fliedner VE, Jeannet M, et al. Increased frequency of DR2 in patients with aplastic anaemia and increased DR sharing in their parents.Br J Haematol. 1986;63:51–57.

    Article  PubMed  CAS  Google Scholar 

  38. Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients.Blood. 1994;84:923–927.

    PubMed  CAS  Google Scholar 

  39. Maciejewski JP, Follmann D, Nakamura R, et al. Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome.Blood. 2001;98:3513–3519.

    Article  PubMed  CAS  Google Scholar 

  40. Shichishima T, Okamoto M, Ikeda K, et al. HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria.Blood. 2002;100:22–28.

    Article  PubMed  CAS  Google Scholar 

  41. Nakao S, Takamatsu H, Chuhjo T, et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia.Blood. 1994;84:4257–4261.

    PubMed  CAS  Google Scholar 

  42. Coluzzi S, Biffoni M, Pasqualetti D, et al. Production of interferon-gamma by lymphocytes from paroxysmal nocturnal haemoglobinuria patients: relationship with clinical status.Br J Haematol. 2004;124:685–690.

    Article  PubMed  CAS  Google Scholar 

  43. Shichishima T, Noji H, Ikeda K, Akutsu K, Maruyama Y. The frequency of HLA class I alleles in Japanese patients with bone marrow failure.Haematologica. 2006;91:856–857.

    PubMed  CAS  Google Scholar 

  44. Nakakuma H, Nagakura S, Kawaguchi T, et al. Markedly high plasma erythropoietin and granulocyte-colony stimulating factor levels in patients with paroxysmal nocturnal hemoglobinuria.Int J Hematol. 1997;66:451–457.

    Article  PubMed  CAS  Google Scholar 

  45. Risitano AM, Maciejewski JP, Muranski P, et al. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients.Leukemia. 2005;19:217–222.

    Article  PubMed  CAS  Google Scholar 

  46. Wlodarski MW, Gondek LP, Nearman ZP, Plasilova M, Kalaycio M, Maciejewski JP. Molecular strategies for detection and quantitation of clonal cytotoxic T cell responses in aplastic anemia and myelodysplastic syndrome.Blood. 2006;108:2632–2641.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Karadimitris A, Manavalan JS, Thaler HT, et al. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria.Blood. 2000;96:2613–2620.

    PubMed  CAS  Google Scholar 

  48. Risitano AM, Kook H, Zeng W, Chen G, Young NS, Maciejewski JP. Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by V beta CDR3 spectratyping and flow cytometry.Blood. 2002;100:178–183.

    Article  PubMed  CAS  Google Scholar 

  49. Vivier E, Malissen B. Innate and adaptive immunity: specificities and signaling hierarchies revisited.Nat Immunol. 2005;6:17–21.

    Article  PubMed  CAS  Google Scholar 

  50. Maciejewski JP, Hibbs JR, Anderson S, Katevas P, Young NS. Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure.Exp Hematol. 1994;22:1102–1110.

    PubMed  CAS  Google Scholar 

  51. Nagakura S, Ishihara S, Dunn DE, et al. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro.Blood. 2002;100:1031–1037.

    Article  PubMed  CAS  Google Scholar 

  52. Hanaoka N, Kawaguchi T, Horikawa K, Nagakura S, Mitsuya H, Nakakuma H. Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP.Blood. 2006;107:1184–1191.

    Article  PubMed  CAS  Google Scholar 

  53. Poggi A, Negrini S, Zocchi MR, et al. Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors.Blood. 2005;106:2399–2408.

    Article  PubMed  CAS  Google Scholar 

  54. Karadimitris A, Luzzatto L. The cellular pathogenesis of paroxysmal nocturnal haemoglobinuria.Leukemia. 2001;15:1148–1152.

    Article  PubMed  CAS  Google Scholar 

  55. Horikawa K, Nakakuma H, Kawaguchi T, et al. Apoptosis resistance of blood cells from patients with paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome.Blood. 1997;90:2716–2722.

    PubMed  CAS  Google Scholar 

  56. Yamamoto T, Shichishima T, Shikama Y, Saitoh Y, Ogawa K, Maruyama Y. Granulocytes from patients with paroxysmal nocturnal hemoglobinuria and normal individuals have the same sensitivity to spontaneous apoptosis.Exp Hematol. 2002;30:187–194.

    Article  PubMed  CAS  Google Scholar 

  57. 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 

  58. Chen G, Kirby M, Zeng W, Young NS, Maciejewski JP. Superior growth of glycophosphatidy linositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo.Exp Hematol. 2002;30:774–782.

    Article  PubMed  CAS  Google Scholar 

  59. Ismail MM, Tooze JA, Flynn JA, et al. Differential apoptosis and Fas expression on GPI-negative and GPI-positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria.Br J Haematol. 2003;123:545–551.

    Article  PubMed  CAS  Google Scholar 

  60. Murakami Y, Kosaka H, Maeda Y, et al. Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria.Blood. 2002;100:4116–4122.

    Article  PubMed  CAS  Google Scholar 

  61. Kinoshita T, Inoue N. Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria.Int J Hematol. 2002;75:117–122.

    Article  PubMed  Google Scholar 

  62. Takami A, Nakao S, Tatsumi Y, et al. High inducibility of heat shock protein 72 (hsp72) in peripheral blood mononuclear cells of aplastic anaemia patients: a reliable marker of immune-mediated aplastic anaemia responsive to cyclosporine therapy.Br J Haematol. 1999;106:377–384.

    Article  PubMed  CAS  Google Scholar 

  63. Hirano N, Butler MO, Von Bergwelt-Baildon MS, et al. Autoanti-bodies frequently detected in patients with aplastic anemia.Blood. 2003;102:4567–4575.

    Article  PubMed  CAS  Google Scholar 

  64. Feng X, Chuhjo T, Sugimori C, et al. Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells.Blood. 2004;104:2425–2431.

    Article  PubMed  CAS  Google Scholar 

  65. Cosman D, Mullberg J, Sutherland CL, et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.Immunity. 2001;14:123–133.

    Article  PubMed  CAS  Google Scholar 

  66. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells.Nat Immunol. 2001;2:255–260.

    Article  PubMed  CAS  Google Scholar 

  67. Vivier E,Tomasello E, Paul P. Lymphocyte activation via NKG2D: towards a new paradigm in immune recognition?Curr Opin Immunol. 2002;14:306–311.

    Article  PubMed  CAS  Google Scholar 

  68. 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.

    PubMed  CAS  Google Scholar 

  69. Nishimura J, Inoue N, Wada H, et al. A patient with paroxysmal nocturnal hemoglobinuria bearing four independent PIG-A mutant clones.Blood. 1997;89:3470–3476.

    PubMed  CAS  Google Scholar 

  70. 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;94:2963–2970.

    PubMed  CAS  Google Scholar 

  71. Tremml G, Dominguez C, Rosti V, et al. Increased sensitivity to complement and a decreased red blood cell life span in mice mosaic for a nonfunctional Piga gene.Blood. 1999;94:2945–2954.

    PubMed  CAS  Google Scholar 

  72. 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;96:5209–5214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Nakakuma H, Kawaguchi T. Pathogenesis of selective expansion of PNH clones.Int J Hematol. 2003;77:121–124.

    Article  PubMed  Google Scholar 

  74. Sugimori C, Chuhjo T, Feng X, et al. Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia.Blood. 2006;107:1308–1314.

    Article  PubMed  CAS  Google Scholar 

  75. Hertenstein B, Wagner B, Bunjes D, et al. Emergence of CD52-,phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma.Blood. 1995;86:1487–1492.

    PubMed  CAS  Google Scholar 

  76. Araten DJ, Swirsky D, Karadimitris A, et al. Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria.Br J Haematol. 2001;115:360–368.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  78. Ishihara S, Nakakuma H, Kawaguchi T, et al. Two cases showing clonal progression with full evolution from aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome to myelodysplastic syndromes and leukemia.Int J Hematol. 2000;72:206–209.

    PubMed  CAS  Google Scholar 

  79. 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.

    Article  PubMed  CAS  Google Scholar 

  80. Lyakisheva A, Felda O, Ganser A, Schmidt RE, Schubert J. Paroxysmal nocturnal hemoglobinuria: Differential gene expression of EGR-1 andTAXREB107.Exp Hematol. 2002;30:18–25.

    Article  PubMed  CAS  Google Scholar 

  81. 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;108:4232–4236.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria.N Engl J Med. 2006;355:1233–1243.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Honjo 1-1-1, Kumamoto 860-8556, Japan

    Tatsuya Kawaguchi

  2. Department of Hematology/Oncology, Wakayama Medical University, Wakayama City, Japan

    Hideki Nakakuma

Authors
  1. Tatsuya Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideki Nakakuma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tatsuya Kawaguchi.

About this article

Cite this article

Kawaguchi, T., Nakakuma, H. New Insights into Molecular Pathogenesis of Bone Marrow Failure in Paroxysmal Nocturnal Hemoglobinuria. Int J Hematol 86, 27–32 (2007). https://doi.org/10.1532/IJH97.07029

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.07029

Key words

Search

Navigation