UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Aplastic anemia: Pathogenesis; clinical manifestations; and diagnosis

Author
Stanley L Schrier, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Alan G Rosmarin, MD

INTRODUCTION

Aplastic anemia (AA) is characterized by diminished or absent hematopoietic precursors in the bone marrow, most often due to injury to the pluripotent stem cell. The designation "aplastic anemia" is a misnomer because the disorder is defined as pancytopenia rather than anemia [1]. The disease is estimated to occur in two to four individuals per million population per year [1,2].

This topic will review the pathogenesis, etiology, clinical manifestations, diagnosis, and differential diagnosis of AA [3-5]. Prognosis and therapy are discussed separately. (See "Treatment of aplastic anemia in adults" and "Hematopoietic cell transplantation for aplastic anemia in adults".)

THE PLURIPOTENT STEM CELL

Following the atomic bombings in World War II, there was great interest in the effects of radiation. Lethally irradiated mice frequently died as a consequence of neutropenic infections and thrombocytopenic hemorrhage. Their marrow was found to be "aplastic." That is, the myeloid and erythroid precursors were absent, as were lymphocytes and megakaryocytes, leaving only fat cells, stromal elements, and blood vessels. Two striking observations in this model led to the discovery of the pluripotent hematopoietic stem cell, which could reconstitute all of hematopoiesis and lymphopoiesis:

The animals did not die if the spleen was exteriorized and shielded from irradiation [6]. Injection of a suspension of spleen cells could also minimize the pancytopenia and prevent death in lethally irradiated mice [7].

Injections of dilute suspensions of syngeneic bone marrow cells into lethally irradiated mice provided protection; in addition, microscopically visible colonies were present in the spleen (CFU-S) at 10 to 14 days [8]. Most of the colonies appeared to be purely erythroid or myeloid, although some were mixed. Injection of suspensions of "pure" differentiated colonies into lethally irradiated mice led to protection and reconstitution of hematopoiesis, with macroscopic spleen colonies showing the usual mix of "pure" and mixed lineages [9]. Experiments using karyotypic markers showed that each spleen colony was a clone (ie, derived from a single cell).

                            

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Sep 08 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Young NS. Acquired aplastic anemia. Ann Intern Med 2002; 136:534.
  2. Wallerstein RO, Condit PK, Kasper CK, et al. Statewide study of chloramphenicol therapy and fatal aplastic anemia. JAMA 1969; 208:2045.
  3. Marsh JC, Ball SE, Cavenagh J, et al. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol 2009; 147:43.
  4. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120:1185.
  5. Rovó A, Tichelli A, Dufour C, SAA-WP EBMT. Diagnosis of acquired aplastic anemia. Bone Marrow Transplant 2013; 48:162.
  6. JACOBSON LO, MARKS EK. The role of the spleen in radiation injury. Proc Soc Exp Biol Med 1949; 70:740.
  7. FORD CE, HAMERTON JL, BARNES DW, LOUTIT JF. Cytological identification of radiation-chimaeras. Nature 1956; 177:452.
  8. TILL JE, McCULLOCH EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14:213.
  9. Jurásková V, Tkadlecek L. Character of primary and secondary colonies of haematopoiesis in the spleen of irradiated mice. Nature 1965; 206:951.
  10. Baum CM, Weissman IL, Tsukamoto AS, et al. Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A 1992; 89:2804.
  11. Goss JA, Schiller GJ, Martin P, et al. Aplastic anemia complicating orthotopic liver transplantation. Hepatology 1997; 26:865.
  12. Walport MJ, Hubbard WN, Hughes GR. Reversal of aplastic anaemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide. Br Med J (Clin Res Ed) 1982; 285:769.
  13. Nissen C. The pathophysiology of aplastic anemia. Semin Hematol 1991; 28:313.
  14. Oosterkamp HM, Brand A, Kluin-Nelemans JC, Vandenbroucke JP. Pregnancy and severe aplastic anaemia: causal relation or coincidence? . Br J Haematol 1998; 103:315.
  15. LANGE RD, WRIGHT SW, TOMONAGA M, et al. Refractory anemia occurring in survivors of the atomic bombing in Nagasaki, Japan. Blood 1955; 10:312.
  16. Kay AG. Myelotoxicity of gold. Br Med J 1976; 1:1266.
  17. Brodie MJ, Pellock JM. Taming the brain storms: felbamate updated. Lancet 1995; 346:918.
  18. Laporte JR, Ibáñez L, Ballarín E, et al. Fatal aplastic anaemia associated with nifedipine. Lancet 1998; 352:619.
  19. Handoko KB, Souverein PC, van Staa TP, et al. Risk of aplastic anemia in patients using antiepileptic drugs. Epilepsia 2006; 47:1232.
  20. Calado RT, Garcia AB, Falcão RP. Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic anaemia: possible pathophysiologic implications. Br J Haematol 1998; 102:1157.
  21. Calado RT, Garcia AB, Gallo DA, Falcão RP. Reduced function of the multidrug resistance P-glycoprotein in CD34+ cells of patients with aplastic anaemia. Br J Haematol 2002; 118:320.
  22. Muir KR, Chilvers CE, Harriss C, et al. The role of occupational and environmental exposures in the aetiology of acquired severe aplastic anaemia: a case control investigation. Br J Haematol 2003; 123:906.
  23. SCOTT JL, CARTWRIGHT GE, WINTROBE MM. Acquired aplastic anemia: an analysis of thirty-nine cases and review of the pertinent literature. Medicine (Baltimore) 1959; 38:119.
  24. Powars D. Aplastic anemia secondary to glue sniffing. N Engl J Med 1965; 273:700.
  25. LOGE JP. APLASTIC ANEMIA FOLLOWING EXPOSURE TO BENZENE HEXACHLORIDE (LINDANE). JAMA 1965; 193:110.
  26. Issaragrisil S, Kaufman DW, Anderson T, et al. The epidemiology of aplastic anemia in Thailand. Blood 2006; 107:1299.
  27. Babushok DV, Li Y, Roth JJ, et al. Common polymorphic deletion of glutathione S-transferase theta predisposes to acquired aplastic anemia: Independent cohort and meta-analysis of 609 patients. Am J Hematol 2013; 88:862.
  28. Kurtzman G, Young N. Viruses and bone marrow failure. Baillieres Clin Haematol 1989; 2:51.
  29. Brown KE, Tisdale J, Barrett AJ, et al. Hepatitis-associated aplastic anemia. N Engl J Med 1997; 336:1059.
  30. Lu J, Basu A, Melenhorst JJ, et al. Analysis of T-cell repertoire in hepatitis-associated aplastic anemia. Blood 2004; 103:4588.
  31. Ikawa Y, Nishimura R, Kuroda R, et al. Expansion of a liver-infiltrating cytotoxic T-lymphocyte clone in concert with the development of hepatitis-associated aplastic anaemia. Br J Haematol 2013; 161:599.
  32. Locasciulli A, Bacigalupo A, Bruno B, et al. Hepatitis-associated aplastic anaemia: epidemiology and treatment results obtained in Europe. A report of The EBMT aplastic anaemia working party. Br J Haematol 2010; 149:890.
  33. Mary JY, Baumelou E, Guiguet M. Epidemiology of aplastic anemia in France: a prospective multicentric study. The French Cooperative Group for Epidemiological Study of Aplastic Anemia. Blood 1990; 75:1646.
  34. 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.
  35. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood 2002; 100:1570.
  36. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood 2006; 108:2509.
  37. Hoffman R, Young N, Ershler WB, et al. Diffuse fasciitis and aplastic anemia: a report of four cases revealing an unusual association between rheumatologic and hematologic disorders. Medicine (Baltimore) 1982; 61:373.
  38. de Masson A, Bouaziz JD, Peffault de Latour R, et al. Severe aplastic anemia associated with eosinophilic fasciitis: report of 4 cases and review of the literature. Medicine (Baltimore) 2013; 92:69.
  39. Risitano AM, Kook H, Zeng W, et al. 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.
  40. Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet 2004; 364:355.
  41. Gargiulo L, Papaioannou M, Sica M, et al. Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria. Blood 2013; 121:2753.
  42. Solomou EE, Wong S, Visconte V, et al. Decreased TCR zeta-chain expression in T cells from patients with acquired aplastic anaemia. Br J Haematol 2007; 138:72.
  43. Solomou EE, Keyvanfar K, Young NS. T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood 2006; 107:3983.
  44. Li J, Zhao Q, Xing W, et al. Interleukin-27 enhances the production of tumour necrosis factor-α and interferon-γ by bone marrow T lymphocytes in aplastic anaemia. Br J Haematol 2011; 153:764.
  45. Nisticò A, Young NS. gamma-Interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994; 120:463.
  46. Sloand E, Kim S, Maciejewski JP, et al. Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood 2002; 100:1185.
  47. Solomou EE, Gibellini F, Stewart B, et al. Perforin gene mutations in patients with acquired aplastic anemia. Blood 2007; 109:5234.
  48. Solomou EE, Rezvani K, Mielke S, et al. Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia. Blood 2007; 110:1603.
  49. de Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood 2010; 116:4175.
  50. Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic anemia. Blood 2012; 119:2033.
  51. Shi J, Ge M, Lu S, et al. Intrinsic impairment of CD4(+)CD25(+) regulatory T cells in acquired aplastic anemia. Blood 2012; 120:1624.
  52. Maciejewski JP, Selleri C, Sato T, et al. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol 1995; 91:245.
  53. Dufour C, Capasso M, Svahn J, et al. Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol 2004; 126:682.
  54. Ismail M, Gibson FM, Gordon-Smith EC, Rutherford TR. Bcl-2 and Bcl-x expression in the CD34+ cells of aplastic anaemia patients: relationship with increased apoptosis and upregulation of Fas antigen. Br J Haematol 2001; 113:706.
  55. Tripathy NK, Nityanand S. Massive apoptosis of bone marrow cells in aplastic anaemia. Br J Haematol 2002; 117:993.
  56. Xu JL, Nagasaka T, Nakashima N. Involvement of cytotoxic granules in the apoptosis of aplastic anaemia. Br J Haematol 2003; 120:850.
  57. Hirano N, Butler MO, Von Bergwelt-Baildon MS, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood 2003; 102:4567.
  58. 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.
  59. Luther-Wyrsch A, Nissen C, Wodnar-Filipowicz A. Intracellular Fas ligand is elevated in T lymphocytes in severe aplastic anaemia. Br J Haematol 2001; 114:884.
  60. Zeng W, Maciejewski JP, Chen G, et al. Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol 2002; 119:803.
  61. Hanaoka N, Nakakuma H, Horikawa K, et al. NKG2D-mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes. Br J Haematol 2009; 146:538.
  62. Hirano N, Butler MO, Guinan EC, et al. Presence of anti-kinectin and anti-PMS1 antibodies in Japanese aplastic anaemia patients. Br J Haematol 2005; 128:221.
  63. Takamatsu H, Feng X, Chuhjo T, et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia. Blood 2007; 109:2514.
  64. Goto M, Kuribayashi K, Takahashi Y, et al. Identification of autoantibodies expressed in acquired aplastic anaemia. Br J Haematol 2013; 160:359.
  65. Wagatsuma M, Kimura M, Suzuki R, et al. Ezrin, radixin and moesin are possible auto-immune antigens in rheumatoid arthritis. Mol Immunol 1996; 33:1171.
  66. Gu Y, Hu X, Liu C, et al. Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 and tumour necrosis factor-alpha in aplastic anaemia. Br J Haematol 2008; 142:109.
  67. Zeng W, Chen G, Kajigaya S, et al. Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. Blood 2004; 103:325.
  68. Mukhina GL, Buckley JT, Barber JP, et al. Multilineage glycosylphosphatidylinositol anchor-deficient haematopoiesis in untreated aplastic anaemia. Br J Haematol 2001; 115:476.
  69. Maciejewski JP, Rivera C, Kook H, et al. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol 2001; 115:1015.
  70. Sugimori C, Mochizuki K, Qi Z, et al. Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure. Br J Haematol 2009; 147:102.
  71. Wlodarski MW, Gondek LP, Nearman ZP, et al. Molecular strategies for detection and quantitation of clonal cytotoxic T-cell responses in aplastic anemia and myelodysplastic syndrome. Blood 2006; 108:2632.
  72. 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.
  73. 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.
  74. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol 2014; 164:546.
  75. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 2009; 144:206.
  76. Yoshida N, Yagasaki H, Takahashi Y, et al. Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia. Br J Haematol 2008; 142:427.
  77. Timeus F, Crescenzio N, Lorenzati A, et al. Paroxysmal nocturnal haemoglobinuria clones in children with acquired aplastic anaemia: a prospective single centre study. Br J Haematol 2010; 150:483.
  78. Tutelman PR, Aubert G, Milner RA, et al. Paroxysmal nocturnal haemoglobinuria phenotype cells and leucocyte subset telomere length in childhood acquired aplastic anaemia. Br J Haematol 2014; 164:717.
  79. Huck K, Hanenberg H, Gudowius S, et al. Delayed diagnosis and complications of Fanconi anaemia at advanced age--a paradigm. Br J Haematol 2006; 133:188.
  80. Li Y, Youssoufian H. MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups. J Clin Invest 1997; 100:2873.
  81. Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia and mutations in telomerase RNA. Lancet 2002; 359:2168.
  82. Marrone A, Stevens D, Vulliamy T, et al. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood 2004; 104:3936.
  83. Ly H, Calado RT, Allard P, et al. Functional characterization of telomerase RNA variants found in patients with hematologic disorders. Blood 2005; 105:2332.
  84. Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 2005; 352:1413.
  85. Fibbe WE. Telomerase mutations in aplastic anemia. N Engl J Med 2005; 352:1481.
  86. Xin ZT, Beauchamp AD, Calado RT, et al. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood 2007; 109:524.
  87. Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood 2008; 111:4446.
  88. Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304:1358.
  89. Townsley DM, Dumitriu B, Liu D, et al. Danazol Treatment for Telomere Diseases. N Engl J Med 2016; 374:1922.
  90. Walne AJ, Dokal A, Plagnol V, et al. Exome sequencing identifies MPL as a causative gene in familial aplastic anemia. Haematologica 2012; 97:524.
  91. Dasouki MJ, Rafi SK, Olm-Shipman AJ, et al. Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 2013; 122:3440.
  92. Torres HA, Bodey GP, Rolston KV, et al. Infections in patients with aplastic anemia: experience at a tertiary care cancer center. Cancer 2003; 98:86.
  93. Valdez JM, Scheinberg P, Nunez O, et al. Decreased infection-related mortality and improved survival in severe aplastic anemia in the past two decades. Clin Infect Dis 2011; 52:726.
  94. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. Blood 2016; 128:337.
  95. Abkowitz JL. Clone wars--the emergence of neoplastic blood-cell clones with aging. N Engl J Med 2014; 371:2523.
  96. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med 2015; 373:35.
  97. Maciejewski JP, Risitano A, Sloand EM, et al. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood 2002; 99:3129.
  98. Gurion R, Gafter-Gvili A, Paul M, et al. Hematopoietic growth factors in aplastic anemia patients treated with immunosuppressive therapy-systematic review and meta-analysis. Haematologica 2009; 94:712.
  99. Tichelli A, Schrezenmeier H, Socié G, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood 2011; 117:4434.
  100. Tichelli A, Socié G, Henry-Amar M, et al. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Ann Intern Med 1999; 130:193.
  101. Kaito K, Kobayashi M, Katayama T, et al. Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol 1998; 103:297.
  102. Ohara A, Kojima S, Hamajima N, et al. Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia. Blood 1997; 90:1009.
  103. Socié G, Henry-Amar M, Bacigalupo A, et al. Malignant tumors occurring after treatment of aplastic anemia. European Bone Marrow Transplantation-Severe Aplastic Anaemia Working Party. N Engl J Med 1993; 329:1152.
  104. Peinemann F, Bartel C, Grouven U. First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia. Cochrane Database Syst Rev 2013; :CD006407.
  105. Socie G, Mary JY, Schrezenmeier H, et al. Granulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT). Blood 2007; 109:2794.
  106. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med 2012; 367:11.
  107. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood 2014; 123:1818.
  108. Rozman C, Marín P, Nomdedeu B, Montserrat E. Criteria for severe aplastic anaemia. Lancet 1987; 2:955.
  109. Yoshimi A, Niemeyer C, Baumann I, et al. High incidence of Fanconi anaemia in patients with a morphological picture consistent with refractory cytopenia of childhood. Br J Haematol 2013; 160:109.