Paroxysmal nocturnal hemoglobinuria: Pathophysiology, natural history and treatment options in the era of biological agents

Biologics: Targets and Therapy

Volumn 2, Issue 2, 2008, Pages 205-222

  Risitano, Antonio M ^a   Rotoli, Bruno ^a  

^a UNIVERSITY OF NAPLES FEDERICO II   (Italy)

Author keywords

Complement; Eculizumab; GPI AP; Paroxysmal nocturnal hemoglobinuria; PIG A

Indexed keywords

EID: 77956235735     PISSN: 11775475     EISSN: 11775491     Source Type: Journal    
DOI: 10.2147/btt.s1420     Document Type: Review

References (120)

1. Alfinito F, Del Vecchio L, Rocco S, et al. 1996. Blood cell flow cytometry in paroxysmal nocturnal hemoglobinuria: a tool for measuring the extent of the PNH clone. Leukemia, 10:1326-30.
2. Almeida AM, Murakami Y, Baker A, et al. 2007. Targeted therapy for inherited GPI deficiency. N Engl J Med, 356:1641-7.
3. Almeida AM, Murakami Y, Layton DM, et al. 2006. Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med, 12:846-51.
4. Araten DJ, Bessler M, McKenzie S, et al. 2002. Dynamics of hematopoiesis in paroxysmal nocturnal hemoglobinuria (PNH): no evidence for intrinsic growth advantage of PNH clones. Leukemia, 16:2243-8.
5. Araten DJ, Nafa K, Pakdeesuwan K, et al. 1999. Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria genotype and phenotype are present in normal individuals. Proc Natl Acad Sci USA, 96:5209-14.
6. Araten DJ, Swirsky D, Karadimitris A, et al. 2001. Cytogenetic and morphological abnormalities in paroxysmal nocturnal haemoglobinuria. Br J Haematol, 115:360-8.
7. Audebert HJ, Planck J, Eisenburg M, et al. 2005. Cerebral ischemic infarction in paroxysmal nocturnal hemoglobinuria: report of 2 cases and updated review of 7 previously published patients. J Neurol, 252:1379-86.
8. Bemba M, Guardiola P, Garderet L, et al. 1999. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol, 105:366-8.
9. Bessler M, Hillmen P, Longo L, et al. 1994. Genomic organization of the X-linked gene (PIG-A) that is mutated in paroxysmal nocturnal haemoglobinuria and of a related autosomal pseudogene mapped to 12q21. Hum Mol Genet, 3:751-7.
10. Boccuni P, Del Vecchio L, Di Noto R, et al. 2000. Glycosyl phosphatidylinositol (GPI)-anchored molecules and the pathogenesis of paroxysmal nocturnal hemoglobinuria. Crit Rev Oncol Hematol, 33:25-43.
11. Bourantas K. 1994. High-dose recombinant erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria. Acta Haematol, 91:62-5.
12. Brodsky RA, Mukhina GL, Li S, et al. 2000. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin Pathol, 114:459-66.
13. Brodsky RA, Young NS, Antonioli E, et al. 2008. Multicenter phase III study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood, 111:1840-7.
14. Burge J, Nicholson-Weller A, Austen KF. 1981. Isolation of C4-binding protein from guinea pig plasma and demonstration of its function as a control protein of the classical complement pathway C3 convertase. J Immunol, 126:232-5.
15. Cacciapuoti C, Terrazzano G, Barone L, et al. 2007. Glycosyl-phosphatidylinositol-defective granulocytes from paroxysmal nocturnal haemoglobinuria patients show increased bacterial ingestion but reduced respiratory burst induction. Am J Hematol, 82:98-107.
16. Chen G, Zeng W, Maciejewski JP, et al. 2005. Differential gene expression in hematopoietic progenitors from paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis/immune response in 'normal' phenotype cells. Leukemia, 19:862-8.
17. Christmas SE, de la Mata Espinosa CT, Halliday D, et al. 2006. Levels of expression of complement regulatory proteins CD46, CD55 and CD59 on resting and activated human peripheral blood leucocytes. Immunology, 119:522-8.
18. Dufour C, Corcione A, Svahn J, et al. 2001. Interferon gamma and tumour necrosis factor alpha are overexpressed in bone marrow T lymphocytes from paediatric patients with aplastic anaemia. Br J Haematol, 115:1023-31.
19. Dunn DE, Liu JM, Young NS. 2000. Paroxysmal nocturnal hemoglobinuria. In Young NS (ed). Bone Marrow Failure Syndromes. Philadelphia: WB Saunders Company. p 99-121.
20. Endo M, Ware RE, Vreeke TM, et al. 1996. Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria. Blood, 87:2546-57.
21. Gargiulo L, Lastraioli S, Cerruti G, et al. 2007. Highly homologous T-cell receptor beta sequences support a common target for autoreactive T cells in most patients with paroxysmal nocturnal hemoglobinuria. Blood, 109:5036-42.
22. Goebel J, Forrest K, Flynn D, et al. 2002. Lipid rafts, major histocompatibility complex molecules, and immune regulation. Hum Immunol, 63:813-20.
23. Hall C, Richards S, Hillmen P. 2003. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood, 102:3587-91.
24. Harrington WJ Sr, Kolodny R, Horstmann LL, et al. 1997. Danazol for paroxysmal nocturnal hemoglobinuria. Am J Hematol, 54:149-54.
25. Hauser AC, Brichta A, Pabinger-Fasching I, et al. 2003. Fibrinolytic therapy with rt-PA in a patient with paroxysmal nocturnal hemoglobinuria and Budd-Chiari syndrome. Ann Hematol, 82:299-302.
26. Hertenstein B, Wagner B, Bunjes D, et al. 1995. Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma. Blood, 86:1487-92.
27. Hill A, Hillmen P, Richards SJ, et al. 2005a. Sustained response and longterm safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood, 106:2559-65.
28. Hill A, Ridley SH, Esser D, et al. 2006. Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: a new approach to PNH therapy. Blood, 107:2131-7.
29. Hill A, Rother RP, Hillmen P. 2005b. Improvement in the symptoms ofsmooth muscle dystonia during eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Haematologica, 90:ECR40.
30. Hill A, Richards SJ, Hillmen P. 2007a. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol, 137:181-92.
31. Hill A, Richards SJ, Rother RP, et al. 2007b. Erythopoietin treatment during complement inhibition with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria. Haematologica, 92:ECR14.
32. Hillmen P, Hall C, Marsh JC, et al. 2004. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med, 350:552-9.
33. Hillmen P, Lewis SM, Bessler M, et al. 1995. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med, 333:1253-8.
34. Hillmen P, Muus P, Duhrsen U, et al. 2007. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood, 110:4123-8.
35. Hillmen P, Young NS, Schubert J, et al. 2006. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med, 355:1233-43.
36. Hirose S, Ravi L, Prince GM, et al. 1992. Synthesis of mannosylglucosaminylinositol phospholipids in normal but not paroxysmal nocturnal hemoglobinuria cells. Proc Natl Acad Sci USA, 89:6025-9.
37. Holguin MH, Wilcox LA, Bernshaw NJ, et al. 1989. Relationship between the membrane inhibitor of reactive lysis and the erythrocyte phenotypes of paroxysmal nocturnal hemoglobinuria. J Clin Invest, 84:1387-94.
38. Hu R, Mukhina GL, Piantadosi S, et al. 2005. PIG-A mutations in normal hematopoiesis. Blood, 105:3848-54.
39. Hugel B, Socié G, Vu T, et al. 1999. Elevated levels of circulating procoagulant microparticles in patients with paroxysmal nocturnal hemoglobinuria and aplastic anemia. Blood, 93:3451-6.
40. Issaragrisil S, Piankijagum A, Tang. Naitrisorana Y. Corticosteroid therapy in paroxysmal nocturnal hemoglobinuria. Am J Hematol, 25:77-83.
41. Jasinski M, Keller P, Fujiwara Y, et al. 2001. GATA1-Cre mediates Piga gene inactivation in the erythroid/megakaryocytic lineage and leads to circulating red cells with a partial deficiency in glycosyl phosphatidylinositol-linked proteins (paroxysmal nocturnal hemoglobinuria type II cells). Blood, 98:2248-55.
42. Karadimitris A, Manavalan JS, Thaler HT, et al. 2000. Abnormal T-cell repertoire is consistent with immune process underlying the pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood, 96:2613-20.
43. Katayama Y, Hiramatsu Y, Kohriyama H. 2001. Monitoring of CD59 expression in paroxysmal nocturnal hemoglobinuria treated with danazol. Am J Hematol, 68:280-3.
44. Keller P, Payne JL, Tremml G, et al. 2001. FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hematopoietic stem cells in the bone marrow. J Exp Med, 194:581-9.
45. Kook H, Risitano AM, Zeng W, et al. 2002 Changes in T-cell receptor VB repertoire in aplastic anemia: effects of different immunosuppressive regimens. Blood, 99:3668-75.
46. Luzzatto L, Bessler M. 1996. The dual pathogenesis of paroxysmal nocturnal hemoglobinuria. Curr Opin Hematol, 3:101-10.
47. Luzzatto L, Bessler M, Rotoli B. 1997. Somatic mutations in paroxysmal nocturnal hemoglobinuria: a blessing in disguise? Cell, 88:1-4.
48. Maciejewski JP, Sloand EM, Sato T, et al. 1997. Impaired hematopoiesis in paroxysmal nocturnal hemoglobinuria/aplastic anemia is not associated with a selective proliferative defect in the glycosylphosphatidylinositolanchored protein-deficient clone. Blood, 89:1173-81.
49. Mahoney JF, Urakaze M, Hall S, et al. 1992. Defective glycosylphosphatidylinositol anchor synthesis in paroxysmal nocturnal hemoglobinuria granulocytes. Blood, 79:1400-3.
50. Matis LA and Rollins SA.1995. Complement-specific antibodies: designing novel anti-inflammatories. Nat Med, 1:839-42.
51. McMullin MF, Hillmen P, Elder GE, et al. 1996. Serum erythropoietin level in paroxysmal nocturnal hemoglobinuria: implications for therapy. Br J Haematol, 92:815-7.
52. McMullin MF, Hillmen P, Jackson J, et al. 1994. Tissue plasminogen activator for hepatic vein thrombosis in paroxysmal nocturnal haemoglobinuria. J Intern Med, 235:85-9.
53. Medof ME, Kinoshita T, Nussenzweig V. 1984. Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J Exp Med, 160:1558-78.
54. Miyata T, Takeda J, Iida Y, et al. 1993. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science, 259:1318-20.
55. Moyo VM, Mukhina GL, Garrett ES, et al. 2004. Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol, 126:133-8.
56. Murakami Y, Kosaka H, Maeda Y, et al. 2002. Inefficient response of T lymphocytes to glycosylphosphatidylinositol anchor-negative cells: implications for paroxysmal nocturnal hemoglobinuria. Blood, 100:4116-22.
57. Nafa K, Bessler M, Deeg HJ, et al. 1998. New somatic mutation in the PIG-A gene emerges at relapse of paroxysmal nocturnal hemoglobinuria. Blood, 92:3422-7.
58. Nafa K, Bessler M, Mason P, et al. 1996. Factor V Leiden mutation investigated by amplification created restriction enzyme site (ACRES) in PNH patients with and without thrombosis. Haematologica, 81:540-2.
59. Nagakura S, Ishihara S, Dunn DE, et al. 2002. Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro. Blood, 100:1031-7.
60. Nakao S, Takami A, Takamatsu H, et al. 1997. Isolation of a T-cell clone showing HLA-DRB1*0405-restricted cytotoxicity for hematopoietic cells in a patient with aplastic anemia. Blood, 89:3691-9.
61. Nicholson-Weller A, March JP, Rosenfeld SI, et al. 1983. Affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria are deficient in the complement regulatory protein, decay accelerating factor. Proc Natl Acad Sci USA, 80:5066-70.
62. Nicholson-Weller A, Spicer DB, Austen KF, et al. 1985. Deficiency of the complement regulatory protein, decay-accelerating factor, on membranes of granulocytes, monocytes, and platelets in paroxysmal nocturnal hemoglobinuria. N Engl J Med, 312:1091-7.
63. Ninomiya H, Hasegawa Y, Nagasawa T, et al. 1997. Excess soluble urokinase-type plasminogen activator receptor in the plasma of patients with paroxysmal nocturnal hemoglobinuria inhibits cell-associated fibrinolytic activity. Int J Hematol, 65:285-91.
64. Nishimura Ji J, Hirota T, Kanakura Y, et al. 2002. Long-term support of hematopoiesis by a single stem cell clone in patients with paroxysmal nocturnal hemoglobinuria. Blood, 99:2748-51.
65. Nishimura J, Kanakura Y, Ware RE, et al. 2004. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore), 83:193-207.
66. Okada N, Harada R, Okada H. 1990. Erythrocytes of patients with paroxysmal nocturnal haemoglobinuria acquire resistance to complement attack by purified 20-kD homologous restriction factor. Clin Exp Immunol, 80:109-13.
67. Olsen SB, Tang DB, Jackson MR, et al. 1996. Enhancement of platelet deposition by cross-linked hemoglobin in a rat carotid endarterectomy model. Circulation, 93:327-32.
68. Oni BS, Osunkoya BO, Luzzatto L. 1970. Paroxysmal nocturnal hemoglobinuria: evidence for monoclonal origin of abnormal red cells. Blood, 36:145-52.
69. Parker C, Omine M, Richards S, et al; International PNH Interest Group. 2005. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood, 106:3699-709.
70. Peffault de Latour R, Mary JY, Salanoubat C, et al. 2006. Paroxysmal Nocturnal Hemoglobinuria (PNH): Long-Term Epidemiological Study. Blood, 108:291a.
71. Plasilova M, Risitano A, Maciejewski JP. 2003. Application of the molecular analysis of the T-cell receptor repertoire in the study of immunemediated hematologic diseases. Hematology, 8:173-81.
72. Plasilova M, Risitano AM, O'Keefe CL, et al. 2004. Shared and individual specificities of immunodominant cytotoxic T cell clones in Paroxysmal Nocturnal Hemoglobinuria as determined by molecular analysis. Exp Hematol, 32:261-9.
73. Poggi A, Negrini S, Zocchi MR, et al. 2005. Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors. Blood, 106:2399-408.
74. Pramoonjago P, Pakdeesuwan K, Siripanyaphinyo U, et al. 1999. Genotypic, immunophenotypic and clinical features of Thai patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol, 105:497-504.
75. Raiola AM, Van Lint MT, Lamparelli T, et al. 2000. Bone marrow transplantation for paroxysmal nocturnal hemoglobinuria. Haematologica, 85:59-62.
76. Richards SJ, Rawstron AC, Hillmen P. 2000. Application of flow cytometry to the diagnosis of paroxysmal nocturnal hemoglobinuria. Cytometry, 42:223-33.
77. Risitano AM, Hill A, Ricci P, et al. 2007. Paroxysmal nocturnal hemoglobinuria (PNH) in the eculizumab era: the bedside and beyond. Haematologica, 92(s3):89a.
78. Risitano AM, Hillmen P, Barbano F, et al. 2006. The complement inhibitor eculizumab to treat paroxysmal nocturnal hemoglobinuria patients: a single center experience within the Triumph, Shepherd and Extension studies. Haematologica, 91(s3):135a.
79. Risitano AM, Kook H, Zeng W, et al. 2002. Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by Vβ CDR3 spectratyping and flow cytometry. Blood, 100:178-83.
80. Risitano AM, Maciejewski JP, Green S, et al. 2004. In vivo dominant immune responses in aplastic anemia patients: molecular tracking of putatively pathogenic T cells by TCRβ-CDR3 sequencing. Lancet, 364:353-63.
81. Risitano AM, Maciejewski JP, Muranski P, et al. 2005. Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal hemoglobinuria (PNH) patients. Leukemia, 19:217-22.
82. Rosenfeld SI, Jenkins DE Jr, Leddy JP. 1985. Enhanced reactive lysis of paroxysmal nocturnal hemoglobinuria erythrocytes by C5b-9 does not involve increased C7 binding or cell-bound C3b. J Immunol, 134:506-11.
83. Rosse WF. 1982. Treatment of paroxysmal nocturnal hemoglobinuria. Blood, 60:20-3.
84. Rosse WF. 1990. Phosphatidylinositol-linked proteins and paroxysmal nocturnal hemoglobinuria. Blood, 75:1595-601.
85. Rosse WF. 1996. Epidemiology of PNH. Lancet, 348:573-7.
86. Rosse WF, Dacie JV. 1966. Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. I. The sensitivity of PNH red cells to lysis by complement and specific antibody. J Clin Invest, 45:736-48.
87. Rosti V, Tremml G, Soares V, et al. 1997. Murine embryonic stem cells without pig-a gene activity are competent for hematopoiesis with the PNH phenotype but not for clonal expansion. J Clin Invest, 100:1028-36.
88. Rother RP, Bell L, Hillmen P, et al. 2005. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA, 293:1653-62.
89. Rother RP, Rollins SA, Mojcik CF, et al. 2007. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol, 25:1256-64.
90. Rotoli B, Bessler M, Alfinito F, et al. 1993. Membrane proteins in paroxysmal nocturnal haemoglobinuria. Blood Rev, 7:75-86.
91. Rotoli B, Luzzatto L. 1989. Paroxysmal nocturnal haemoglobinuria. Baillieres Clin Haematol, 2:113-38.
92. Rotoli B, Robledo R, Luzzatto L. 1982. Decreased number of circulating BFU-Es in paroxysmal nocturnal hemoglobinuria. Blood, 60:157-9.
93. Rotoli B, Robledo R, Scarpato N, et al. 1984. Two populations of erythroid cell progenitors in paroxysmal nocturnal hemoglobinuria. Blood, 64:847-51.
94. Rotoli B, Nafa D, Risitano AM. 2006. Paroxysmal nocturnal hemoglobinuria. In: Runge MD and Patterson C, ed. Principles of Molecolar Medicine, 2nd edition. Philadelphia, Humana Press. p 838-47.
95. Sanchez-Valle E, Morales-Polanco MR, Gomez-Morales E, et al. 1993. Treatment of paroxysmal nocturnal hemoglobinuria with antilymphocyte globulin. Rev Invest Clin, 45:457-61.
96. Santarone S, Di Bartolomeo E, Bacigalupo, et al. 2008. Long-term results of a GITMO retrospective study on haematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinura. Bone Marrow Transplant, 41(S1):19.
97. Saso R, Marsh J, Cevreska L, et al. 1999. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol, 104:392-6.
98. Sato T, Selleri C, Anderson S, et al. 1997. Expression and modulation of cellular receptors for interferon-gamma, tumour necrosis factor, and Fas on human bone marrow CD34+ cells. Br J Haematol, 97:356-65.
99. Schafer A, Wiesmann F, Neubauer S, et al. 2004. Rapid regulation of platelet activation in vivo by nitric oxide. Circulation, 109:1819-22.
100. Selvaraj P, Rosse WF, Silber R, et al. 1988. The major Fc receptor in blood has a phosphatidylinositol anchor and is deficient in paroxysmal nocturnal haemoglobinuria. Nature, 333:565-7.
101. Shichishima T, Saitoh Y, Terasawa T, et al. 1999. Complement sensitivity of erythrocytes in a patient with inherited complete deficiency of CD59 or with the Inab phenotype. Br J Haematol, 104:303-6.
102. Shin ML, Hänsch G, Hu VW, et al. 1986. Membrane factors responsible for homologous species restriction of complement-mediated lysis: evidence for a factor other than DAF operating at the stage of C8 and C9. J Immunol, 136:1777-82.
103. Simak J, Holada K, Risitano AM, et al. 2004. Elevated counts of circulating endothelial membrane microparticles in paroxysmal nocturnal hemoglobinuria indicate inflammatory status and ongoing stimulation of vascular endothelium. Br J Hemat, 125:804-13.
104. Sloand E, Maciejewski JP, Tisdale J, et al. 2002. Intracellular Interferon-γ (IFN-γ) in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood, 100:3129-35.
105. Sloand EM, More K, Shah S, et al. 2006. Soluble urokinase plasminogen activator receptor is increased in patients with paroxysmal nocturnal hemoglobinuria (PNH) and thrombosis and inhibits plasmin generation in vitro and promotes thrombosis in the mouse model. Blood, 108:422a.
106. Socie G, Mary JY, de Gramont A, et al. 1996. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. French Society of Haematology. Lancet, 348:573-7.
107. Stebler C, Tichelli A, Dazzi H, et al. 1990. High-dose recombinant human erythropoietin for treatment of anemia in myelodysplastic syndromes and paroxysmal nocturnal hemoglobinuria: a pilot study. Exp Hematol, 18:1204-8.
108. Sutherland DR, Kuek N, Davidson J, et al. 2007. Diagnosing PNH with FLAER and multiparameter flow cytometry. Cytometry B Clin Cytom, 72:167-77.
109. Takahashi M, Takeda J, Hirose S, et al. 1993. Deficient biosynthesis of N-acetylglucosaminyl-phosphatidylinositol, the first intermediate of glycosyl phosphatidylinositol anchor biosynthesis, in cell lines established from patients with paroxysmal nocturnal hemoglobinuria. J Exp Med, 177:517-21.
110. Takeda J, Miyata T, Kawagoe K, et al. 1992. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell, 73:703-11.
111. Tichelli A, Gratwohl A, Nissen C, et al. 1992. Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin. Blood, 80:337-45.
112. van der Schoot CE, Huizinga TW, van 't Veer-Korthof ET, et al. 1990. Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay. Blood, 76:1853-9.
113. Wiedmer T, Hall SE, Ortel TL, et al. 1993. Complement-induced vesiculation and exposure of membrane prothrombinase sites in platelets of paroxysmal nocturnal hemoglobinuria. Blood, 82:1192-6.
114. Wilcox LA, Ezzell JL, Bernshaw NJ, et al. 1991. Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum. Blood, 78:820-9.
115. Yamashina M, Ueda E, Kinoshita T, et al. 1990. Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria. N Engl J Med, 323:1184-9.
116. Young NS, Maciejewski JP. 2000. Genetic and environmental effects in paroxysmal nocturnal hemoglobinuria: this little PIG-A goes Why? Why? Why?. J Clin Invest, 106:637-41.
117. Zalman LS, Wood LM, Müller-Eberhard HJ. 1986. Isolation of a human erythrocyte membrane protein capable of inhibiting expression of homologous complement transmembrane channels. Proc Natl Acad Sci USA, 83:6975-9.
118. Zalman LS, Wood LM, Frank MM, et al. 1987. Deficiency of the homologous restriction factor in paroxysmal nocturnal hemoglobinuria. J Exp Med, 165:572-7.
119. Zeng W, Maciejewski JP, Chen G, et al. 2001. Limited heterogeneity of T-cell receptor VB usage in aplastic anemia. J Clin Invest, 108:765-73.
120. Zoumbos N, Gascon P, Trost S, et al. 1985. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med, 312:257-65.