https://emedicine.medscape.

com/article/198759-treatment

Updated: Apr 04, 2017 Sameer Bakhshi, MD; Chief Editor: Emmanuel C Besa, MD

1. Breakey VR, Meyn S, Ng V, Allen C, Dokal I, Lansdorp PM, et al. Hepatitis-

associated aplastic anemia presenting as a familial bone marrow failure syndrome. J
Pediatr Hematol Oncol. 2009 Nov. 31(11):884-7. [Medline].
2. Gonzalez-Casas R, Garcia-Buey L, Jones EA, Gisbert JP, Moreno-Otero R.
Systematic review: hepatitis-associated aplastic anaemia--a syndrome associated with
abnormal immunological function. Aliment Pharmacol Ther. 2009 Sep 1. 30(5):436-
43. [Medline].
3. Miano M, Dufour C. The diagnosis and treatment of aplastic anemia: a review. Int J
Hematol. 2015 Jun. 101 (6):527-35. [Medline].
4. McCormack PL. Eltrombopag: a review of its use in patients with severe aplastic
anaemia. Drugs. 2015 Apr. 75 (5):525-31. [Medline].
5. [Guideline] Killick SB, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al.
Guidelines for the diagnosis and management of adult aplastic anaemia. Br J
Haematol. 2016 Jan. 172 (2):187-207. [Medline]. [Full Text].
6. [Guideline] Barone A, Lucarelli A, Onofrillo D, Verzegnassi F, Bonanomi S, et al.
Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from
the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian
Association (AIEOP). Blood Cells Mol Dis. 2015 Jun. 55 (1):40-7. [Medline].
7. Wu Y, Yu J, Zhang L, Luo Q, Xiao JW, Liu XM, et al. [Hematopoiesis support of
mesenchymal stem cells in children with aplastic anemia]. Zhongguo Dang Dai Er Ke
Za Zhi. 2008 Aug. 10(4):455-9. [Medline].
8. Scopes J, Daly S, Atkinson R, Ball SE, Gordon-Smith EC, Gibson FM. Aplastic
anemia: evidence for dysfunctional bone marrow progenitor cells and the corrective
effect of granulocyte colony-stimulating factor in vitro. Blood. 1996 Apr 15.
87(8):3179-85. [Medline].
9. Young NS. Pathophysiologic mechanisms in acquired aplastic anemia. Hematology
Am Soc Hematol Educ Program. 2006. 72-7. [Medline].
10. Liu H, Mihara K, Kimura A, Tanaka K, Kamada N. Induction of apoptosis in CD34+
cells by sera from patients with aplastic anemia. Hiroshima J Med Sci. 1999 Jun.
48(2):57-63. [Medline].
11. Marsh JC. Long-term bone marrow cultures in aplastic anaemia. Eur J Haematol
Suppl. 1996. 60:75-9. [Medline].
12. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM. The hematopoietic defect in
aplastic anemia assessed by long-term marrow culture. Blood. 1990 Nov 1.
76(9):1748-57. [Medline].
13. 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 May 15.
107(10):3983-91. [Medline]. [Full Text].
14. Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of
treated aplastic anemia. Semin Hematol. 2000 Jan. 37(1):91-101. [Medline].
15. Nakao S. Immune mechanism of aplastic anemia. Int J Hematol. 1997 Aug.
66(2):127-34. [Medline].
16. Frickhofen N, Kaltwasser JP, Schrezenmeier H, Raghavachar A, Vogt HG, Herrmann
F, et al. Treatment of aplastic anemia with antilymphocyte globulin and
methylprednisolone with or without cyclosporine. The German Aplastic Anemia
Study Group. N Engl J Med. 1991 May 9. 324(19):1297-304. [Medline].
17. Passweg JR, Pérez WS, Eapen M, Camitta BM, Gluckman E, Hinterberger W, et al.
Bone marrow transplants from mismatched related and unrelated donors for severe
aplastic anemia. Bone Marrow Transplant. 2006 Apr. 37(7):641-9. [Medline].
18. Bacigalupo A, Brand R, Oneto R, Bruno B, Socié G, Passweg J, et al. Treatment of
acquired severe aplastic anemia: bone marrow transplantation compared with
immunosuppressive therapy--The European Group for Blood and Marrow
Transplantation experience. Semin Hematol. 2000 Jan. 37(1):69-80. [Medline].
19. Hirano N, Butler MO, Von Bergwelt-Baildon MS, Maecker B, Schultze JL, O'Connor
KC, et al. Autoantibodies frequently detected in patients with aplastic anemia. Blood.
2003 Dec 15. 102(13):4567-75. [Medline].
20. Solomou EE, Gibellini F, Stewart B, Malide D, Berg M, Visconte V, et al. Perforin
gene mutations in patients with acquired aplastic anemia. Blood. 2007 Jun 15.
109(12):5234-7. [Medline]. [Full Text].
21. Solomou EE, Rezvani K, Mielke S, Malide D, Keyvanfar K, Visconte V, et al.
Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia.
Blood. 2007 Sep 1. 110(5):1603-6. [Medline]. [Full Text].
22. Scheinberg P, Cooper JN, Sloand EM, Wu CO, Calado RT, Young NS. Association
of telomere length of peripheral blood leukocytes with hematopoietic relapse,
malignant transformation, and survival in severe aplastic anemia. JAMA. 2010 Sep 22.
304(12):1358-64. [Medline].
23. Alter BP. Aplastic Anemia, Pediatric Aspects. Oncologist. 1996. 1(6):361-366.
[Medline].
24. Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia
and mutations in telomerase RNA. Lancet. 2002 Jun 22. 359(9324):2168-70.
[Medline].
25. Rothbaum R, Perrault J, Vlachos A, Cipolli M, Alter BP, Burroughs S, et al.
Shwachman-Diamond syndrome: report from an international conference. J Pediatr.
2002 Aug. 141(2):266-70. [Medline].
26. Doherty L, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Clinton C, et al.
Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-
Blackfan anemia. Am J Hum Genet. 2010 Feb 12. 86(2):222-8. [Medline]. [Full Text].
27. Zhang J, Yang T. [Meta-analysis of association between organophosphorus pesticides
and aplastic anemia]. Zhonghua Liu Xing Bing Xue Za Zhi. 2015 Sep. 36 (9):1005-9.
[Medline].
28. Young NS, Maciejewski JP, Sloand E, Chen G, Zeng W, Risitano A, et al. The
relationship of aplastic anemia and PNH. Int J Hematol. 2002 Aug. 76 Suppl 2:168-
72. [Medline].
29. Kaufman DW, Kelly JP, Levy M, Shapiro S. The Drug Etiology of Agranulocytosis
and Aplastic Anemia. New York: Oxford University Press; 1991.
30. Issaragrisil S, Sriratanasatavorn C, Piankijagum A, Vannasaeng S, Porapakkham Y,
Leaverton PE, et al. Incidence of aplastic anemia in Bangkok. The Aplastic Anemia
Study Group. Blood. 1991 May 15. 77(10):2166-8. [Medline].
31. Young NS, Shimamura A. Acquired bone marrow failure syndromes. Handen RI, Lux
SE, Stossel TP,. Blood: Principles & Practice of Hematology. 2nd ed. Philadelphia,
Pa: Lippincott Williams & Wilkins; 2003. 297.
32. Locasciulli A, Oneto R, Bacigalupo A, Socié G, Korthof E, Bekassy A, et al.
Outcome of patients with acquired aplastic anemia given first line bone marrow
transplantation or immunosuppressive treatment in the last decade: a report from the
European Group for Blood and Marrow Transplantation (EBMT). Haematologica.
2007 Jan. 92(1):11-8. [Medline].
33. Chan KW, McDonald L, Lim D, Grimley MS, Grayson G, Wall DA. Unrelated cord
blood transplantation in children with idiopathic severe aplastic anemia. Bone
Marrow Transplant. 2008 Nov. 42(9):589-95. [Medline].
34. Bunin N, Aplenc R, Iannone R, Leahey A, Grupp S, Monos D, et al. Unrelated donor
bone marrow transplantation for children with severe aplastic anemia: minimal
GVHD and durable engraftment with partial T cell depletion. Bone Marrow
Transplant. 2005 Feb. 35(4):369-73. [Medline].
35. Kang HJ, Shin HY, Choi HS, Ahn HS. Fludarabine, cyclophosphamide plus
thymoglobulin conditioning regimen for unrelated bone marrow transplantation in
severe aplastic anemia. Bone Marrow Transplant. 2004 Dec. 34(11):939-43.
[Medline].
36. Brodsky RA, Sensenbrenner LL, Smith BD, Dorr D, Seaman PJ, Lee SM, et al.
Durable treatment-free remission after high-dose cyclophosphamide therapy for
previously untreated severe aplastic anemia. Ann Intern Med. 2001 Oct 2. 135(7):477-
83. [Medline].
37. Horowitz MM. Current status of allogeneic bone marrow transplantation in acquired
aplastic anemia. Semin Hematol. 2000 Jan. 37(1):30-42. [Medline].
38. Kaito K, Kobayashi M, Katayama T, Masuoka H, Shimada T, Nishiwaki K, 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 Nov. 103(2):297-303.
[Medline].
39. Piaggio G, Podestà M, Pitto A, Sessarego M, Figari O, Fugazza G, et al. Coexistence
of normal and clonal haemopoiesis in aplastic anaemia patients treated with
immunosuppressive therapy. Br J Haematol. 1999 Dec. 107(3):505-11. [Medline].
40. Rosti V. The molecular basis of paroxysmal nocturnal hemoglobinuria.
Haematologica. 2000 Jan. 85(1):82-7. [Medline].
41. Orazi A, Czader MB. Myelodysplastic syndromes. Am J Clin Pathol. 2009 Aug.
132(2):290-305. [Medline].
42. Kulasekararaj AG, Jiang J, Smith AE, Mohamedali AM, Mian S, Gandhi S, et al.
Somatic mutations identify a sub-group of aplastic anemia patients that progress to
myelodysplastic syndrome. Blood. 2014 Aug 18. [Medline].
43. Arai Y, Kondo T, Yamazaki H, Takenaka K, Sugita J, Kobayashi T, et al. Allogeneic
unrelated bone marrow transplantation from older donors results in worse prognosis
in recipients with aplastic anemia. Haematologica. 2016 Feb 8. [Medline].
44. Vajdic CM, Mayson E, Dodds AJ, O'Brien T, Wilcox L, Nivison-Smith I, et al.
Second cancer risk and late mortality in adult Australians receiving allogeneic
haematopoietic stem cell transplantation: A population-based cohort study. Biol Blood
Marrow Transplant. 2016 Feb 6. [Medline].
45. Brodsky RA, Mukhina GL, Li S, Nelson KL, Chiurazzi PL, Buckley JT, et al.
Improved detection and characterization of paroxysmal nocturnal hemoglobinuria
using fluorescent aerolysin. Am J Clin Pathol. 2000 Sep. 114(3):459-66. [Medline].
46. Krauss JS. The laboratory diagnosis of paroxysmal nocturnal hemoglobinuria (PNH):
update 2010. Lab Medicine. 2012. 43:20-4. [Full Text].
47. Hosokawa K, Kajigaya S, Feng X, Desierto MJ, Fernandez Ibanez MD, Rios O, et al.
A plasma microRNA signature as a biomarker for acquired aplastic anemia.
Haematologica. 2017 Jan. 102 (1):69-78. [Medline]. [Full Text].
48. Brodsky RA. Acquired Aplastic Anemia. Greer JP, Arber DA, Glader B, List AF,
Means RT Jr, Paraskevas F, Rodgers GM, eds. Wintrobe's Clinical Hematology. 13th
ed. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins; 2014. 965-74.
49. Matcuk GR Jr, Siddiqi I, Cen S, Hagiya A, Isaacson R, Brynes R. Bone marrow
cellularity MRI calculation and correlation with bone marrow biopsy. Clin Imaging.
2016 May-Jun. 40 (3):392-7. [Medline].
50. Camitta BM, Thomas ED, Nathan DG, Gale RP, Kopecky KJ, Rappeport JM, et al. A
prospective study of androgens and bone marrow transplantation for treatment of
severe aplastic anemia. Blood. 1979 Mar. 53(3):504-14. [Medline].
51. Valdez JM, Scheinberg P, Young NS, Walsh TJ. Infections in patients with aplastic
anemia. Semin Hematol. 2009 Jul. 46(3):269-76. [Medline].
52. Jancel T, Penzak SR. Antiviral therapy in patients with hematologic malignancies,
transplantation, and aplastic anemia. Semin Hematol. 2009 Jul. 46(3):230-47.
[Medline].
53. Pournaras S, Iosifidis E, Roilides E. Advances in antibacterial therapy against
emerging bacterial pathogens. Semin Hematol. 2009 Jul. 46(3):198-211. [Medline].
54. Di Bona E, Rodeghiero F, Bruno B, Gabbas A, Foa P, Locasciulli A, et al. Rabbit
antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating
factor is an effective treatment for aplastic anaemia patients unresponsive to a first
course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo
Osseo (GITMO). Br J Haematol. 1999 Nov. 107(2):330-4. [Medline].
55. Bacigalupo A, Broccia G, Corda G, Arcese W, Carotenuto M, Gallamini A, et al.
Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in
patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA
Working Party. Blood. 1995 Mar 1. 85(5):1348-53. [Medline].
56. Dufour C, Ferretti E, Bagnasco F, Burlando O, Lanciotti M, Ramenghi U, et al.
Changes in cytokine profile pre- and post-immunosuppression in acquired aplastic
anemia. Haematologica. 2009 Dec. 94(12):1743-7. [Medline]. [Full Text].
57. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E,
et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells
than bone marrow in HLA-matched sibling donor transplants for young patients with
severe acquired aplastic anemia. Blood. 2007 Aug 15. 110(4):1397-400. [Medline].
[Full Text].
58. Kumar R, Kimura F, Ahn KW, Hu ZH, Kuwatsuka Y, et al. Comparing Outcomes
with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched
Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions.
Biol Blood Marrow Transplant. 2016 Jan 18. [Medline].
59. Locatelli F, Bruno B, Zecca M, Van-Lint MT, McCann S, Arcese W, et al.
Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host
disease prophylaxis in patients with severe aplastic anemia given allogeneic bone
marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT
randomized trial. Blood. 2000 Sep 1. 96(5):1690-7. [Medline].
60. George B, Mathews V, Viswabandya A, Kavitha ML, Srivastava A, Chandy M.
Fludarabine and cyclophosphamide based reduced intensity conditioning (RIC)
regimens reduce rejection and improve outcome in Indian patients undergoing
allogeneic stem cell transplantation for severe aplastic anemia. Bone Marrow
Transplant. 2007 Jul. 40(1):13-8. [Medline].
61. Anderlini P, Wu J, Gersten I, Ewell M, Tolar J, Antin JH, et al. Cyclophosphamide
conditioning in patients with severe aplastic anaemia given unrelated marrow
transplantation: a phase 1-2 dose de-escalation study. Lancet Haematol. 2015 Sep. 2
(9):e367-75. [Medline].
62. Kekre N, Zhang Y, Zhang MJ, Carreras J, Ahmed P, Anderlini P, et al. Effect of
antithymocyte globulin source on outcomes of bone marrow transplantation for severe
aplastic anemia. Haematologica. 2017 Mar 24. [Medline]. [Full Text].
63. Maury S, Balère-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K, et al.
Unrelated stem cell transplantation for severe acquired aplastic anemia: improved
outcome in the era of high-resolution HLA matching between donor and recipient.
Haematologica. 2007 May. 92(5):589-96. [Medline].
64. Yagasaki H, Takahashi Y, Hama A, et al. Comparison of matched-sibling donor BMT
and unrelated donor BMT in children and adolescent with acquired severe aplastic
anemia. Bone Marrow Transplant. 2010 Oct. 45(10):1508-13. [Medline].
65. Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, et al. Fludarabine-based
conditioning for marrow transplantation from unrelated donors in severe aplastic
anemia: early results of a cyclophosphamide dose deescalation study show life-
threatening adverse events at predefined cyclophosphamide dose levels. Biol Blood
Marrow Transplant. 2012 Jul. 18(7):1007-11. [Medline].
66. Samarasinghe S, Steward C, Hiwarkar P, Saif MA, Hough R, Webb D, et al.
Excellent outcome of matched unrelated donor transplantation in paediatric aplastic
anaemia following failure with immunosuppressive therapy: a United Kingdom
multicentre retrospective experience. Br J Haematol. 2012 May. 157(3):339-46.
[Medline].
67. Hamad N, Del Bel R, Messner HA, Kim D, Kuruvilla J, Lipton JH, et al. Outcomes of
Hematopoietic Cell Transplantation in Adult Patients with Acquired Aplastic Anemia
Using Intermediate-Dose Alemtuzumab-Based Conditioning. Biol Blood Marrow
Transplant. 2014 Jul 10. [Medline].
68. Clay J, Kulasekararaj AG, Potter V, Grimaldi F, McLornan D, Raj K, et al.
Nonmyeloablative Peripheral Blood Haploidentical Stem Cell Transplantation for
Refractory Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2014 Jul 10.
[Medline].
69. Peffault de Latour R, Rocha V, Socié G. Cord blood transplantation in aplastic
anemia. Bone Marrow Transplant. 2013 Feb. 48(2):201-2. [Medline].
70. MacMillan ML, Walters MC, Gluckman E. Transplant outcomes in bone marrow
failure syndromes and hemoglobinopathies. Semin Hematol. 2010 Jan. 47(1):37-45.
[Medline].
71. Chan KW, McDonald L, Lim D, Grimley MS, Grayson G, Wall DA. Unrelated cord
blood transplantation in children with idiopathic severe aplastic anemia. Bone
Marrow Transplant. 2008 Nov. 42(9):589-95. [Medline].
72. Yoshimi A, Kojima S, Taniguchi S, et al. Unrelated cord blood transplantation for
severe aplastic anemia. Biol Blood Marrow Transplant. 2008 Sep. 14(9):1057-63.
[Medline].
73. Schrezenmeier H, Korper S, Hochsmann B. Standard first-line immunosuppression
for acquired severe aplastic anemia in adults. Curr Drug Targets. 2015 Jun 30.
[Medline].
74. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte
globulin in acquired aplastic anemia. N Engl J Med. 2011 Aug 4. 365(5):430-8.
[Medline].
75. Risitano AM. Immunosuppressive therapies in the management of acquired immune-
mediated marrow failures. Curr Opin Hematol. 2012 Jan. 19(1):3-13. [Medline].
76. Doney K, Dahlberg SJ, Monroe D, Storb R, Buckner CD, Thomas ED. Therapy of
severe aplastic anemia with anti-human thymocyte globulin and androgens: the effect
of HLA-haploidentical marrow infusion. Blood. 1984 Feb. 63(2):342-8. [Medline].
77. Marsh JC, Hows JM, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC.
Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease
severity. Blood. 1987 Oct. 70(4):1046-52. [Medline].
78. Means RT Jr, Krantz SB, Dessypris EN, Lukens JN, Niblack GD, Greer JP, et al. Re-
treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum.
Am J Med. 1988 Apr. 84(4):678-82. [Medline].
79. Schrezenmeier H, Marin P, Raghavachar A, McCann S, Hows J, Gluckman E, et al.
Relapse of aplastic anaemia after immunosuppressive treatment: a report from the
European Bone Marrow Transplantation Group SAA Working Party. Br J Haematol.
1993 Oct. 85(2):371-7. [Medline].
80. 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 Jan. 23(1):81-7.
[Medline].
81. Stein RS, Means RT Jr, Krantz SB, Flexner JM, Greer JP. Treatment of aplastic
anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med
Sci. 1994 Dec. 308(6):338-43. [Medline].
82. Tichelli A, Passweg J, Nissen C, Bargetzi M, Hoffmann T, Wodnar-Filipowicz A, et
al. Repeated treatment with horse antilymphocyte globulin for severe aplastic
anaemia. Br J Haematol. 1998 Feb. 100(2):393-400. [Medline].
83. Maschan A, Bogatcheva N, Kryjanovskii O, Shneider M, Litvinov D, Mitiushkina T,
et al. Results at a single centre of immunosuppression with cyclosporine A in 66
children with aplastic anaemia. Br J Haematol. 1999 Sep. 106(4):967-70. [Medline].
84. Hayakawa J, Kanda J, Akahoshi Y, Harada N, Kameda K, Ugai T, et al. Meta-
analysis of treatment with rabbit and horse antithymocyte globulin for aplastic
anemia. Int J Hematol. 2017 Jan 11. [Medline].
85. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012 Aug 9.
120(6):1185-96. [Medline]. [Full Text].
86. Brodsky RA, Chen AR, Dorr D, et al. High-dose cyclophosphamide for severe
aplastic anemia: long-term follow-up. Blood. 2010 Mar 18. 115(11):2136-41.
[Medline]. [Full Text].
87. Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic
anaemia: a randomised trial. Lancet. 2000 Nov 4. 356(9241):1554-9. [Medline].
88. Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al.
Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J
Med. 2012 Jul 5. 367(1):11-9. [Medline]. [Full Text].
89. Promacta (eltrombopag) prescribing information [package insert]. Research Triangle
Park, NC 27709: GlaxoSmithKline. August 2014. Available at [Full Text].
90. Mandal PK, Baul S, Dolai TK, De R, Chakrabarti P. Outcome of Cyclosporine
Monotherapy in Patients of Aplastic Anemia: Experience of a Tertiary Care Hospital
in Eastern India. Indian J Hematol Blood Transfus. 2017 Mar. 33 (1):144-147.
[Medline].
91. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin
with or without cyclosporin A: 11-year follow-up of a randomized trial comparing
treatments of aplastic anemia. Blood. 2003 Feb 15. 101(4):1236-42. [Medline].
92. Führer M, Rampf U, Baumann I, Faldum A, Niemeyer C, Janka-Schaub G, et al.
Immunosuppressive therapy for aplastic anemia in children: a more severe disease
predicts better survival. Blood. 2005 Sep 15. 106(6):2102-4. [Medline].
 93. Deyell RJ, Shereck EB, Milner RA, Schultz KR. Immunosuppressive therapy without
hematopoietic growth factor exposure in pediatric acquired aplastic anemia. Pediatr
Hematol Oncol. 2011 Sep. 28(6):469-78. [Medline].

Practice Essentials
Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral
pancytopenia and marrow hypoplasia (see the image below). Although the anemia is
often normocytic, mild macrocytosis can also be observed in association with stress
erythropoiesis and elevated fetal hemoglobin levels.

Low power, H and E showing a hypocellular bone marrow with increased adipose
tissue and decreased hematopoietic cells

Signs and symptoms

The clinical presentation of patients with aplastic anemia includes symptoms related to the
decrease in bone marrow production of hematopoietic cells. The onset is insidious, and the
initial symptom is frequently related to anemia or bleeding, although fever or infections may
be noted at presentation.

Signs and symptoms of aplastic anemia may include the following:

 Pallor
 Headache
 Palpitations, dyspnea
 Fatigue
 Foot swelling
 Gingival bleeding, petechial rashes
 Overt and/or recurrent infections
 Oropharyngeal ulcerations

A subset of patients with aplastic anemia present with jaundice and evidence of clinical
hepatitis. [1, 2]
Diagnosis

Testing

Laboratory testing for suspected aplastic anemia includes the following:

 Complete blood count

 Peripheral blood smears
 Hemoglobin electrophoresis and blood-group testing
 Biochemical profile
 Serology for hepatitis and other viral entities
 Autoimmune-disease evaluation for evidence of collagen-vascular disease
 Fluorescence-activated cell sorter profiling
 Fluorescent-labeled inactive toxin aerolysin testing
 Diepoxybutane incubation
 Histocompatibility testing
 Kidney function studies
 Liver function studies
 Transaminase, bilirubin, and lactate dehydrogenase levels

Procedures

Bone marrow biopsy is performed in addition to aspiration to assess cellularity qualitatively

and quantitatively. Bone marrow culture may be useful in diagnosing mycobacterial and viral
infections; however, the yield is generally low.

See Workup for more detail.

Management

Severe or very severe aplastic anemia is a hematologic emergency, and care should be
instituted promptly. Clinicians must stress the need for patient compliance with therapy. The
specific medications administered depend on the choice of therapy and whether it is
supportive care only, immunosuppressive therapy, or hematopoietic cell transplantation. [3]

Pharmacotherapy

The following medications are used in patients with aplastic anemia:

 Immunosuppressive agents (eg, cyclosporine, methylprednisolone, equine antithymocyte

globulin, rabbit antithymocyte globulin, cyclophosphamide, alemtuzumab)
 Hematopoietic growth factors (eg, eltrombopag [4] , sargramostim, filgrastim)
 Antimetabolite (purine) antineoplastic agents (eg, fludarabine)
 Chelating agents (eg, deferoxamine, deferasirox)

Nonpharmacotherapy

Nonpharmacologic management of aplastic anemia includes the following:

 Supportive care
  Blood transfusions with blood products that have undergone leukocyte reduction and
irradiation
 Hematopoietic cell transplantation

Surgical option

Central venous catheter placement is required before the administration of hematopoietic cell
transplantation.

See Treatment and Medication for more detail.

Background
Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he reported the case of a
pregnant woman who died of bone marrow failure. However, it was not until 1904 that
Anatole Chauffard named this disorder aplastic anemia. (See Etiology.)

The British Society for Standards in Haematology has issued guidelines on diagnosis and
management of aplastic anemia in adults. [5] The Pediatric Haemato-Oncology Italian
Association has issued guidelines on diagnosis and management of acquired aplastic anemia
in childhood. [6]

For more information, see the following Medscape articles:

 Anemia
 Chronic Anemia
 Megaloblastic Anemia
 Myelophthisic Anemia
 Hemolytic Anemia
 Sideroblastic Anemias

Etiology
The theoretical basis for marrow failure includes primary defects in or damage to the stem
cell or the marrow microenvironment. [7, 8, 9] The distinction between acquired and inherited
disease may present a clinical challenge, but more than 80% of cases are acquired. Clinical
and laboratory observations suggest that acquired aplastic anemia is an autoimmune disease.

On morphologic evaluation, the hematopoietic elements in the bone marrow are less than
25%, and they are largely replaced with fat cells. Flow cytometry shows that the CD34 cell
population, which contains the stem cells and the early committed progenitors, is
substantially reduced. [8, 10] Data from in vitro colony-culture assays suggest profound
functional loss of the hematopoietic progenitors, so much so that they are unresponsive even
to high levels of hematopoietic growth factors.

Previously, it had been hypothesized that aplastic anemia may be due to a defect at various
levels, such as an intrinsic defect of hematopoietic cells; external injury to hematopoietic
cells; and defective stroma, which is critical for normal proliferation and functioning of
hematopoietic cells. Theoretically, all of these mechanisms could be responsible for aplastic
anemia. This theory was the basis of many in vitro stem cell culture experiments using a
crossover design in which stem cells from patients with aplastic anemia were cultured with
normal stroma and vice versa. The conclusions from these studies led to the understanding
that stem cell defect is the central mechanism in the majority of patients with aplastic anemia.
[11, 12]

In patients with severe aplastic anemia, stromal cells have normal function, including growth
factor production. Adequate stromal function is implicit in the success of hematopoietic cell
transplantation (HCT) in aplastic anemia, because the stromal elements are almost entirely
(frequently) of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was
documented in a patient with aplastic anemia who failed to engraft after HCT. Mathe
proposed that the immunosuppressive regimen used for conditioning promoted the return of
normal marrow function. Since then, numerous studies have shown that, in approximately
70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow
function. [9, 13, 14, 15, 16]

Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure). [17, 18] Although the inciting antigens
that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte
antigen (HLA)-DR2 is overrepresented among European and United States patients with
aplastic anemia, and its presence is predictive of a better response to cyclosporine.

Suppression of hematopoiesis is likely mediated by an expanded population of CD8+ HLA-

DR+, cytotoxic T lymphocytes (CTLs) that are frequently detectable in the blood and bone
marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as
gamma-interferon and tumor necrosis factor, which can suppress progenitor cell growth.
Polymorphisms associated with an increased immune response are more prevalent in these
cytokine genes in patients with aplastic anemia. These cytokines suppress hematopoiesis by
affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis.

In addition, such cytokines induce nitric oxide synthase and nitric oxide production by
marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of
hematopoietic cells. Hirano et al reported that CD8+ cytotoxic T cells raised against kinectin-
derived peptides suppress colony forming units (CFUs) in an HLA class I–restricted fashion,
findings that suggest kinectin may be a candidate autoantigen in the pathophysiology of
aplastic anemia. [19]

Constitutive expression of Tbet, a transcriptional regulator that is critical to type 1 T helper

cell (Th1) polarization, occurs in a majority of aplastic anemia patients. [13] Perforin is a
cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells.
Mutations in the perforin gene are responsible for some cases of familial hemophagocytosis
[20]
; mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-
interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with
an aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein
levels are markedly diminished in some cases of acquired aplastic anemia.

The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell (Treg)
development and function, and Tregs play a role in autoimmunity. Tregs are decreased at
presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels
also are significantly lower in patients with this condition, whereas NFAT1 protein levels are
decreased or absent. [21]

Variations in telomere length have been reported in severe aplastic anemia, but their clinical
significance is unknown. However, although telomere length was unrelated to response, it
was associated with the risk of relapse, clonal evolution, and overall survival in patients with
severe aplastic anemia. [22]

Congenital or inherited causes

Congenital or inherited causes of aplastic anemia are responsible for at least 25% of children
with this condition and for perhaps up to 10% of adults. [23] Patients may have dysmorphic
features or physical stigmata, but marrow failure may be the initial presenting feature.
Several loci have been identified that are associated not only with increased susceptibility to
aplastic anemia but also with other physical findings.

Fanconi anemia

Fanconi anemia is characterized by the following:

 Multiple congenital anomalies (60-75%): Short stature, abnormal skin pigmentation,

malformations of the thumbs with or without dysplastic or absent radii, as well as
microphthalmos and malformations of the heart, kidneys, intestines, and ears
 Bone marrow failure: Thrombocytopenia, leukopenia, or aplastic anemia; most patients with
Fanconi anemia have bone marrow failure by adulthood
 Cancer: Hematologic malignancies are common with Fanconi anemia and myelodysplasia,
with acute myeloid leukemia (AML) being the most common; solid tumors such as those in
squamous cell head and neck cancer, female genital tumors, and liver tumors are also seen;
Fanconi anemia is associated with increased chromosomal breakage and abnormal sister
chromatid exchange in the presence of agents such as diepoxybutane or mitomycin C
 Predominantly autosomal recessive inheritance pattern: Fifteen genes are now known to be
causative for Fanconi anemia; only 1 of these— FANCB (X-lined recessive)—is not inherited
in an autosomal recessive manner
 Association between bone marrow progression and a complex pattern of recurrent
chromosomal abnormalities: Some chromosomal abnormalities are commonly found in non-
Fanconi anemia myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia
(eg, -7/7q or RUNX1 abnormalities), whereas others are specific for Fanconi anemia (eg, 1q+
and 3q+)

Dyskeratosis congenita

Dyskeratosis congenita is characterized by the diagnostic physical triad of dysplastic nails,

lacy reticular pigmentation of the upper torso, and oral leukoplakia. However, over the past
decade, it has been increasingly recognized that patients may have dyskeratosis congenita
without the triad. The following are also features of this condition:

 Some signs of premature aging, such as early graying of the hair

 Progressive bone marrow failure at any age, which can cause any combination of cytopenias,
including aplastic anemia
  Malignancy: Common; frequently MDS or AML; solid tumors such as head and neck cancer
or genital cancers can also be seen
 Pulmonary fibrosis
 Autosomal dominant, autosomal recessive, and X-linked inheritance patterns; 6 genes are
known to cause this disorder

Familial aplastic anemia

This is an isolated aplastic anemia. Mutations have been found in the TERC and TERT genes
and are thought to confer a susceptibility to aplastic anemia. These genes encode proteins that
are part of the telomerase apparatus that restores repeated regions in the telomere. [24]

Cartilage-hair hypoplasia

Cartilage-hair hypoplasia, which is caused by mutations in the RMRP gene, is inherited in an

autosomal recessive manner. This condition is characterized by the following:

 Short stature with short and bowed limbs

 Sparse, lightly pigmented hair
 Variably severe immune deficiency
 Anemia during childhood
 Hematopoietic malignancies, as well as malignancies of the skin, eyes, and liver
 Gastrointestinal malformations and malabsorption

Pearson syndrome

Pearson syndrome causes sideroblastic anemia and exocrine pancreatic dysfunction. This
condition results from mitochondrial deoxyribonucleic acid (DNA) deletions.

Thrombocytopenia-absent radius syndrome

Thrombocytopenia-absent radius (TAR) syndrome is characterized by deletions located at

chromosome 1q21.1 (which are typically about 200kb in size). Patients have bilateral absence
of the radii with presence of the thumbs, as well as thrombocytopenia. Other congenital
anomalies can also occur (eg, cardiac disease, skeletal anomalies, urogenital anomalies).

Shwachman-Diamond syndrome

Shwachman-Diamond syndrome is caused by mutations in the SBDS gene and is inherited in

an autosomal recessive manner. This disease is characterized by dysfunction of the exocrine
pancreas with malabsorption and growth failure, as well as cytopenias of single or multiple
lineage. Patients with Shwachman-Diamond syndrome also have an increased risk of MDS
and AML. [25]

Dubowitz syndrome

Dubowitz syndrome is caused by an as-yet unknown gene. This condition is characterized by

intrauterine growth retardation, extremely short stature, and wizened facial appearance.
Patients also have microcephaly and mild developmental delay. Dubowitz syndrome is also
associated with eczema, immune deficiency, and aplastic anemia. Malignancy is more
common with this disorder, particularly lymphoma and neuroblastoma.

Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is characterized by a normochromic macrocytic anemia

that can be isolated, or it can be associated with growth retardation or congenital
malformation in the upper limbs, heart, and genitourinary systems. In a small minority of
patients, DBA can progress to aplastic anemia. Nine genes have been found to be causative
for DBA, and they are inherited in an autosomal dominant manner. [26] Approximately 50% of
cases are inherited from a parent, and about 50% result from de novo mutations.

Acquired causes

Acquired causes of aplastic anemia (80%) include the following:

 Idiopathic factors
 Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), parvovirus, and mycobacteria
 Exposure to ionizing radiation
 Exposure to toxic chemicals, such as benzene or pesticides [27]
 Transfusional graft versus host disease (GVHD)
 Orthotopic liver transplantation for fulminant hepatitis
 Pregnancy
 Eosinophilic fasciitis
 Anorexia
 Severe nutritional deficiencies (B12, folate)
 Paroxysmal nocturnal hemoglobinuria (PNH)
 MDS
 Acute lymphoblastic leukemia (ALL)(rarely)

Drugs and elements (eg, chloramphenicol, phenylbutazone, gold) may cause aplasia of the
marrow. The immune mechanism does not account for the marrow failure in idiosyncratic
drug reactions. In such cases, direct toxicity may occur, perhaps due to genetically
determined differences in metabolic detoxification pathways. For example, the null
phenotype of certain glutathione transferases is overrepresented among patients with aplastic
anemia.

PNH is caused by an acquired genetic defect affecting the PIGA gene and limited to the stem
cell compartment. Mutations in the PIGA gene render cells of hematopoietic origin sensitive
to increased complement lysis. Approximately one third of patients with aplastic anemia have
evidence of PNH at presentation, as detected by means of flow cytometry. [28] Furthermore,
patients whose disease responds after immunosuppressive therapy may recover with clonal
hematopoiesis and PNH.

Epidemiology
United States statistics

No accurate prospective data are available regarding the incidence of aplastic anemia in the
United States. Findings from several retrospective studies usually overlap those from Europe
and suggest that the incidence is 0.6-6.1 cases per million population; this rate is largely
based on data from retrospective reviews of death registries.

International statistics

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic
studies, is 2 cases per million population. [29] Aplastic anemia is thought to be more common
in Asia than in the West. The incidence was accurately determined to be 4 cases per million
population in Bangkok, [30] but based on prospective studies, it may actually be closer to 6
cases per million population in the rural areas of Thailand. This increased incidence may be
related to environmental factors, such as increased exposure to toxic chemicals, rather than to
genetic factors, because this increase is not observed in people of Asian ancestry who are
living in the United States.

Race-, sex-, and age-related demographics

Although no racial predisposition for aplastic anemia is reported in the United States, the
prevalence is increased in the Far East. The male-to-female ratio for acquired aplastic anemia
is approximately 1:1, although there are data to suggest that a male preponderance may be
observed in the Far East.

Although aplastic anemia occurs in all age groups, a small peak in the incidence is observed
in childhood because of the inclusion of inherited marrow-failure syndromes. A second peak
is observed in people aged 20-25 years.

Prognosis
The outcome of patients with aplastic anemia has substantially improved because of
improved supportive care. The natural history of aplastic anemia suggests that a small
number of patients may spontaneously recover with supportive care [31] ; however,
observational and/or supportive care therapy alone is rarely indicated.

The estimated 10-year survival rate for the typical patient receiving immunosuppression is
68%, compared with 73% for hematopoietic cell transplantation (HCT). [32] However, there is
a significantly improved outcome for HCT over time, for matched sibling and alternative
donors, and with younger age. [32] In cases of immunosuppression, relapse and late clonal
disease are risks.

In a single-institution analysis of 183 patients who received immunosuppressive treatments

for severe aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated
to treatment response. [22] In a multivariate analysis, however, telomere length was associated
with risk of relapse, clonal evolution, and overall survival. [22] Additional studies are needed
to validate these findings and to determine how this information might be incorporated into
treatment algorithms.
Mortality/morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and
bleeding. Patients who undergo HCT have additional issues related to acute and chronic
toxicity from the conditioning regimen and graft versus host disease (GVHD), as well as a
potential for graft failure. [18, 33, 34, 35, 36, 37] In approximately 25-30% of patients with aplastic
anemia, the condition does not respond to immunosuppression. In cases with a treatment
response, relapse and late-onset clonal disease, such as paroxysmal nocturnal hemoglobinuria
(PNH), myelodysplastic syndrome (MDS), and leukemia, are risks—regardless of the
treatment response or degree of response. [14, 38, 39, 40, 41]

Kulasekararaj and colleagues reported that the presence of somatic mutations (including
ASXL1, DNMT3A, and BCOR) in patients with aplastic anemia for more than 6 months was
associated with 40% risk of transformation to MDS. Nearly a fifth of patients with aplastic
anemia have mutations in genes typically seen in myeloid malignancies that predicted for
later transformation to MDS. [42]

In a Japanese study of 427 patients (16-72 years old) with aplastic anemia who underwent
unrelated-donor bone marrow transplantation, outcome was significantly inferior in patients
whose donors were 40 years of age or older than in those with younger donors. In the older
donor group, overall survival was significantly inferior (adjusted hazard ratio, 1.64), the
incidence of fatal infection was significantly higher (13.7% vs. 7.5%), and primary
engraftment failure and acute GVHD occurred significantly more often (9.7% vs. 5.0% and
27.1% vs. 19.7%, respectively). [43]

An Australian population-based cohort study of adults receiving allogeneic HCT reported an

elevated secondary cancer risk in several patient groups, including those transplanted for
severe aplastic anemia. Overall, in patients alive 2 years after transplantation (n=1463), the
cumulative incidence of late mortality was 22.2% at 10 years and the risk of death relative to
the matched general population was 13.8. [44]

Blood Transfusion
Patients with aplastic anemia require transfusion support until the diagnosis is established and
specific therapy can be instituted. The British Committee for Standards in Haematology
recommends prophylactic transfusions in patients whose platelet counts fall below 10 × 109/L
(or <20 × 109/L in febrile patients). [5] However, it is important that transfusions be guided by
the patient’s clinical status and not by numbers alone. Avoiding transfusions from family
members is important because of possible sensitization against non-HLA (human leukocyte
antigen) tissue antigens of potential donors.

For patients in whom hematopoietic cell transplantation (HCT) may be attempted,

transfusions should be used judiciously because minimally transfused subjects have achieved
superior therapeutic outcomes.
If using blood-bank support, attempt to minimize the risk of cytomegalovirus (CMV)
infection. The blood products should, if possible, undergo leukocyte reduction to prevent
alloimmunization and CMV transmission and should be irradiated to prevent transfusion-
associated graft versus host disease (GVHD) in HCT candidates.

The British Committee for Standards in Haematology also recommends irradiated blood
products for all patients receiving antithymocyte globulin (ATG) therapy. In patients with
life-threatening neutropenic sepsis, the committee suggests consideration of irradiated
granulocyte transfusions. [5]

Development of a transfusion plan in consultation with a physician who is experienced in the

management of aplastic anemia is essential.

Treatment of Infections
Infections are a major cause of mortality in patients with aplastic anemia. [51, 52] Risk factors
include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal
infections, especially those due to Aspergillus species, pose a major risk. Patients should
maintain hygiene to reduce infection risk.

The British Committee for Standards in Haematology recommends prophylactic antibiotic

and antifungal agents for patients whose neutrophil counts are below 0.2 ×109/L. [5] Empirical
antibiotic therapy should be broad based, with gram-negative and staphylococcal coverage
based on local microbial sensitivities. Especially consider including antipseudomonal
coverage at the start of treatment for patients with febrile neutropenia; also consider early
introduction of antifungal agents for individuals with persistent fever.

However, the strategy of empiric antibiotic use has also resulted in the development of
resistant organisms and thus is not favored by some clinicians. [53]

Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-

macrophage colony-stimulating factor (GM-CSF) may be considered in refractory infections,
although this therapy should be weighed against its cost and efficacy. [8, 54, 55, 56] Discontinue
cytokine support after 1 week if the neutrophil count doesn’t rise. [5]

Hematopoietic Cell Transplantation

Central venous catheter placement is required prior to hematopoietic cell transplantation
(HCT). Note that the following recommendations do not apply to patients with Fanconi
anemia and other types of inherited marrow failure; [5] these patients require special
consideration.

HCT using an HLA-matched sibling donor

Human leukocyte antigen (HLA)-matched sibling-donor HCT is the treatment of choice for a
young patient with severe or very severe aplastic anemia (SAA or VSAA, respectively),
being generally accepted for patients younger than 40 years. [5] Persons undergoing this
procedure do not require irradiation-based conditioning regimens. [5]
A study of 692 German patients with SAA who received transplants from HLA-matched
siblings, noted that bone-marrow grafts were preferable to peripheral blood progenitor cell
(PBPC) grafts in patients younger than 20 years. [57] A multinational study of patients with
SAA who received HCT from an HLA-matched sibling donor concluded that although bone
marrow should definitely be the preferred graft source for these patients, PBPCs may be an
acceptable alternative in countries with limited resources where patients present later in their
disease course and risks of graft failure and infective complications are high. [58]

Although evidence suggests that stem cells from bone marrow afford better outcomes
compared with PBPCs, an additional consideration is the perspective of the donor, who must
be informed of the difference between the methods of harvesting. Bone marrow harvesting is
usually performed with the donor under general anesthesia, while with PBPC harvesting the
donor is awake and connected via large-bore intravenous catheters to an apheresis machine,
which separates out the stem cells (for descriptions of the two methods, see Bone Marrow
Donor Procedure).

Along with the risks associated with anesthesia, bone marrow donors typically experience
moderate pain for several days following the procedure. PBPC donors usually experience
bone pain, which may be severe, from the filgrastim-induced bone marrow stimulation used
to mobilize stem cells in advance of the procedure.

One of the major problems of HCT in aplastic anemia is the high rate of rejection (10%;
range, 5-50%). This is positively correlated with the number of transfusions the patient
received and the duration of his or her disease, prior to transplantation.

Previously, a higher stem cell dose, as well as the addition of total body irradiation to
cyclophosphamide conditioning, was tried. Although it was associated with a reduced
incidence of graft rejection, the benefit was negated by high transplant-related mortality
(TRM) due to an increase in graft versus host disease (GVHD).

Currently, antithymocyte globulin (ATG) with cyclophosphamide is a commonly used

conditioning regimen for transplantations in aplastic anemia. The addition of ATG to
cyclophosphamide for conditioning has resulted in infrequent graft rejections, as well as
improved overall survival. [16, 54, 55, 59]

Umbilical Cord Blood Transplantation

Umbilical cord blood transplantation (CBT) is not yet recommended as first- or second-line
therapy for aplastic anemia. This treatment should be used as experimental therapy for
patients who do not have a human leukocyte antigen (HLA)–matched donor and who have 1-
2 courses of failed immunosuppressive therapy, and it should be evaluated only through
prospective clinical trials. [69] Controlled trials are needed to better define the role and timing
of CBT in aplastic anemia. [70, 71, 72]

Immunosuppressive Therapy
Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine is
associated with an overall response rate of 60-80% and a 5-year survival rate of 75% in most
reports, but event-free survival rates are in the range of 35-50%.
Immunosuppressive therapy using ATG plus cyclosporine is being administered as first-line
therapy [73] for patients with severe or very severe aplastic anemia (SAA or VSAA,
respectively) who are older than 40 years and as second-line therapy in younger patients with
SAA or VSAA if a human leukocyte antigen (HLA)–matched sibling donor is not available.
Immunosuppressive therapy is also recommended in patients with nonsevere aplastic anemia
who are transfusion dependent. [5]

Central venous catheter placement may be required before the administration of

immunosuppressive therapy, and patients with these catheters should be treated as inpatients.
Patients may require blood product support during ATG therapy, as well as close monitoring
for allergic or anaphylactic signs and symptoms and for prophylaxis and treatment of fevers.
[5]

ATG and cyclosporine

Scheinberg et al reported that a large difference was observed in patients with aplastic anemia
in the rate of hematologic response at 6 months in favor of horse ATG (68%), as compared
with rabbit ATG (37%). [74] Overall survival at 3 years also differed, with a survival rate of
96% in the horse-ATG group, compared with 76% in the rabbit-ATG group when data were
censored at the time of stem-cell transplantation, and 94% versus 70% in the respective
groups when stem-cell–transplantation events were not censored. [74]

A review by Risitano also demonstrated that immunosuppression with rabbit ATG, as well as
cyclophosphamide and alemtuzumab, in patients with aplastic anemia or immune-mediated
bone marrow failure syndromes had an inferior outcome relative to horse ATG. [75] Therefore,
rabbit ATG, cyclophosphamide, and alemtuzumab are not recommended as first-line therapy
in these patients. [75]

In other studies of ATG, responses have been defined as complete responses (CRs) when all
blood counts return to normal, and as partial responses (PRs) when there is an improvement
in blood counts with transfusion independence. In these analyses, response to ATG is slow,
usually taking 10-12 weeks for a response to occur; and the response may also continue to
improve or occur later. If the patient has not responded to a first course of ATG, then a
second course may be given, using either the same preparation or another one.
Approximately 30-60% of patients may respond to a second course of ATG. [76, 77, 78, 79, 80, 81,
82]

In one study, response rates to cyclosporine alone were 45% overall, 16% for VSSA, 47% for
SAA, and 85% for moderate aplastic anemia. [83] Therefore, the only predictor of response to
cyclosporine was an absolute neutrophil count (ANC) of less than 200/mm3. Adding
granulocyte colony-stimulating factor (G-CSF) to ATG and cyclosporine in patients with an
ANC of over 200/mm3 does not provide any additional advantage in reducing the infection
rate or in increasing survival or therapeutic responses.

A meta-analysis by Hayakawa et al of 13 studies comparing horse ATG with rabbit ATG for
immunosuppressive therapy in severe aplastic anemia concluded that horse ATG results in a
higher respnse rate (p=0.015); further, a sensitivity analysis showed that there was higher
early mortality with rabbit ATG. [84] Hence, horse ATG is the preferred choice in this setting.
Time to response and relapse

The treatment response in aplastic anemia, unlike in other autoimmune diseases, is slow. At
least 4-12 weeks is usually needed to observe early improvement, and the patient may
continue to improve slowly thereafter. About 50% of patients respond by 3 months after ATG
administration, and about 75% respond by 6 months. Most patients improve and become
transfusion independent, but many still have evidence of hypoproliferative bone marrow.

Although the initial response rate is good, durable responses with no relapse or clonal
evolution are observed in 50% of the patients. [85] To reduce the risk of relapse, continue
cyclosporine for a minimum of 12 months after achieving maximal hematologic response,
with a very slow tapering thereafter. [5] Approximately one third of patients have a relapse,
most of whom have a relapse at the time of cyclosporine taper. About one third of responders
are cyclosporine dependent. Of patients without a response or who relapse, 40-50% respond
to a second course of immunosuppressive therapy.

In rare cases, full hematologic recovery is observed, but most patients improve to a functional
hematologic recovery that obviates further transfusion support. Furthermore, the risk of some
form of clonal disease other than paroxysmal nocturnal hemoglobinuria (PNH) is 15-30% and
may be due to the inability of these therapies to completely correct bone marrow function, a
missed diagnosis of myelodysplastic syndrome (MDS), or the fact that the stem cells under
proliferative stress may be more prone than other cells to mutation.

Investigational immunosuppressive therapy

At present, the use of high-dose cyclophosphamide should be limited to clinical trials. [85]
Preliminary data have suggested that high-dose cyclophosphamide may result in durable
remissions in some patients with aplastic anemia. However, some of these patients develop
PNH and cytogenetic abnormalities on follow-up. When investigators conducted a
prospective, randomized study based on the above preliminary report by using
cyclophosphamide versus ATG plus CSA, the study was terminated early because of very
high mortality and fungal infections in the cyclophosphamide arm. [86, 87]

Up to 50% of patients with aplastic anemia demonstrate small PNH clones in the absence of
evidence of hemolysis. [5] In patients with a history of PNH-associated thrombosis, use of
ATG is not recommended. In addition, because abnormal cytogenetic clones can occur in up
to 12% of patients with aplastic anemia, the presence of some clones in otherwise typical
cases of aplastic anemia does not necessarily signify a diagnosis of myelodysplastic
syndrome (MDS) or acute myeloid leukemia (AML). [5] However, an exception is when the
monosomy 7 clone is present, in which case there is a high risk of transformation to MDS or
AML. [5]

Other promising investigational immunosuppressive therapies include alemtuzumab

(monoclonal anti-CD52 antibody) and daclizumab (anti ̶ interleukin-2 receptor or CD-25
antibody). Mycophenolate mofetil and sirolimus have also been used but did not result in
treatment responses.

Except in the setting of prospective clinical trials, hematopoietic growth factors (eg,
recombinant human erythropoietin [rHuEPO], granulocyte colony-stimulating factor [G-
CSF]) is not recommended for routine long-term use following ATG and CSA therapy. [5]
Diet and Activity
The diet for the patient with aplastic anemia who has neutropenia or who is receiving
immunosuppressive therapy should be tailored carefully to exclude raw meats, dairy
products, or fruits and vegetables that are likely to be colonized by bacteria, fungus, or molds.
Furthermore, a salt-limited diet is recommended during therapy with steroids or cyclosporin-
A (CSA).

The patient should avoid any activity that increases the risk of trauma during periods of
thrombocytopenia. Menstruating women are also advised to be on hormonal pills to avoid
menstrual cycles that are likely to be heavy due to thrombocytopenia.

Inform patients of the increased risk of community-acquired infections during periods of

neutropenia and lymphopenia. Patients should maintain hygiene to reduce the risks of
infection.

Patients Refractory to Immunosuppressive Therapy

In patients with aplastic anemia that is refractory to immunosuppressive therapy (IST),
treatment with eltrombopag (Promacta) may be considered. Eltrombopag, a thrombopoietin
receptor agonist, was approved in August 2014 for severe aplastic anemia in patients who fail
to respond adequately to at least one prior IST regimen. Approval was supported by a phase
II study in which 41% of patients experienced a hematologic response in at least one lineage
(ie, platelets, red blood cells, neutrophils) after 12 weeks of treatment with eltrombopag. [88,
89]

In the extension phase of the study, three patients achieved a multi-lineage response. Four of
those patients subsequently tapered off treatment and maintained the response (median
followup 8.1 months, range 7.2-10.6 months). [88,

Medication Summary
The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity and
prevent complications.

As describe in Treatment, options in immunosuppressive treatment include combination

therapy, including antithymocyte globulin (ATG), cyclosporine, and methylprednisolone,
with or without cytokine support. ATG or cyclosporine alone may also produce a response in
aplastic anemia, but the combination improves the likelihood of a response. Nevertheless, a
prospective study from India concluded that for resource-poor patients, cyclosporine
monotherapy, in a dosage of 5 mg/kg/day, is a relatively safe treatment option for aplastic
anemia. [90]

Hematopoietic support with eltrombopag, granulocyte colony-stimulating factor (G-CSF) and

granulocyte-macrophage colony-stimulating factor (GM-CSF) may be considered in
refractory infections, although this therapy should be weighed against cost and efficacy. [8, 54,
55, 56, 88, 89]
Signs and symptoms

Presentasi klinis pasien dengan anemia aplastik mencakup gejala yang terkait dengan
penurunan produksi sumsum tulang sel hematopoietik. Awitannya sangat berbahaya, dan
gejala awal sering dikaitkan dengan anemia atau perdarahan, walaupun demam atau infeksi
dapat dicatat pada saat presentasi.

Tanda dan gejala anemia aplastik bisa meliputi:

• Pucat
• Sakit kepala
• Palpitasi, dyspnea
• Kelelahan
• Kaki bengkak
• Perdarahan gingiva, ruam petechial
• Infeksi terbalik dan / atau rekuren
• Ulserasi Oropharyngeal
Sebuah subset dari pasien dengan anemia aplastik hadir dengan ikterus dan bukti hepatitis
klinis.

Diagnosa
Pengujian
Pengujian laboratorium untuk anemia aplastik yang dicurigai meliputi:
• hitung darah lengkap
• Pemeriksaan darah perifer
• Elektroforesis hemoglobin dan pengujian golongan darah
• Profil biokimia
• Serologi untuk hepatitis dan entitas virus lainnya
• Evaluasi penyakit autoimun untuk bukti penyakit kolagen-vaskular
• Penyortir selotip selektif fluoresensi
• Pengujian aerolinin toksin tanpa label yang tidak aktif
• Diepoxybutane inkubasi
• Pengujian histokompatibilitas
• Penelitian fungsi ginjal
• Penelitian fungsi hati
• Tingkat transaminase, bilirubin, dan laktat dehidrogenase
Prosedur
Biopsi sumsum tulang dilakukan selain aspirasi untuk menilai seluler secara kualitatif dan
kuantitatif. Kultur sumsum tulang mungkin bermanfaat dalam mendiagnosis infeksi
mikobakteri dan virus; Namun, imbal hasil umumnya rendah.

Pengelolaan
Anemia aplastik berat atau sangat parah adalah keadaan darurat hematologi, dan perawatan
harus segera dilakukan. Dokter harus menekankan perlunya kepatuhan pasien terhadap terapi.
Pengobatan spesifik yang diberikan tergantung pada pilihan terapi dan apakah hanya
perawatan suportif, terapi imunosupresif, atau transplantasi sel hematopoietik. [3]
Farmakoterapi
Obat berikut digunakan pada pasien dengan anemia aplastik:
• Agen imunosupresif (misalnya, siklosporin, metilprednisolon, globulin antitimokinida,
globulin antithymocyte kelinci, siklofosfamid, alemtuzumab)
• Faktor pertumbuhan hematopoietik (misalnya eltrombopag [4], sargramostim, filgrastim)
• Agen antineoplastik antimetabolit (purin) (misalnya, fludarabin)
• Agen Chelating (misalnya deferoxamine, deferasirox)
Nonfarmakoterapi
Pengelolaan nonfarmakologis anemia aplastik meliputi:
• Perawatan suportif
• Transfusi darah dengan produk darah yang telah mengalami pengurangan dan iradiasi
leukosit
• Transplantasi sel hematopoietik
Bedah pilihan
Penempatan kateter vena sentral diperlukan sebelum pemberian transplantasi sel
hematopoietik.

Latar Belakang
Paul Ehrlich memperkenalkan konsep anemia aplastik pada tahun 1888 saat dia melaporkan
kasus seorang wanita hamil yang meninggal karena gagal sumsum tulang. Namun, baru pada
1904 Anatole Chauffard menamakan gangguan ini anemia aplastik. (Lihat Etiologi.)
Masyarakat Inggris untuk Standar Hematologi telah mengeluarkan pedoman untuk diagnosis
dan pengelolaan anemia aplastik pada orang dewasa. [5] Asosiasi Italia Pediatric Haemato-
Oncology telah mengeluarkan panduan untuk diagnosis dan pengelolaan anemia aplastik
yang didapat di masa kanak-kanak. [6]
Etiologi
Dasar teoritis untuk kegagalan sumsum mencakup kerusakan primer atau kerusakan pada sel
punca atau lingkungan mikro sumsum. [7, 8, 9] Perbedaan antara penyakit yang diakuisisi
dan yang diwariskan dapat menimbulkan tantangan klinis, namun lebih dari 80% kasus
diperoleh. Observasi klinis dan laboratorium menunjukkan bahwa anemia aplastik yang
didapat adalah penyakit autoimun.
Pada evaluasi morfologis, unsur hematopoietik di sumsum tulang kurang dari 25%, dan
sebagian besar diganti dengan sel lemak. Flow cytometry menunjukkan bahwa populasi sel
CD34, yang mengandung sel punca dan nenek moyang awal yang dilakukan sebelumnya,
secara substansial berkurang. [8, 10] Data dari tes budaya koloni in vitro menunjukkan
hilangnya fungsional yang signifikan dari nenek moyang hematopoietik, sedemikian rupa
sehingga tidak responsif bahkan pada faktor pertumbuhan hematopoietik tingkat tinggi.

Sebelumnya, telah dihipotesiskan bahwa anemia aplastik mungkin disebabkan oleh cacat
pada berbagai tingkat, seperti defek intrinsik sel hematopoietik; cedera eksternal pada sel
hematopoietik; dan stroma yang rusak, yang sangat penting untuk proliferasi normal dan
fungsi sel hematopoietik. Secara teoritis, semua mekanisme ini dapat menyebabkan anemia
aplastik. Teori ini adalah dasar dari banyak percobaan kultur sel induk in vitro dengan
menggunakan desain crossover dimana sel induk dari pasien dengan anemia aplastik dikultur
dengan stroma normal dan sebaliknya. Kesimpulan dari penelitian ini mengarah pada
pemahaman bahwa defek sel induk merupakan mekanisme sentral pada sebagian besar pasien
dengan anemia aplastik. [11, 12]

Pada pasien dengan anemia aplastik berat, sel stroma memiliki fungsi normal, termasuk
faktor pertumbuhan produksi. Fungsi stroma yang memadai tersirat dalam keberhasilan
transplantasi sel hematopoietik (HCT) pada anemia aplastik, karena unsur stroma hampir
seluruhnya (sering) berasal dari host.
Peran disfungsi kekebalan disarankan pada tahun 1970, saat pemulihan autolog
didokumentasikan pada pasien dengan anemia aplastik yang gagal masuk setelah HCT.
Mathe mengusulkan agar rejimen imunosupresif yang digunakan untuk pengkondisian
mendorong kembalinya fungsi sumsum normal. Sejak itu, banyak penelitian telah
menunjukkan bahwa, pada sekitar 70% pasien dengan anemia aplastik yang didapat, terapi
imunosupresif memperbaiki fungsi sumsum. [9, 13, 14, 15, 16]
Imunitas diatur secara genetis (oleh gen respon kekebalan), dan juga dipengaruhi oleh
lingkungan (misalnya nutrisi, penuaan, paparan sebelumnya). [17, 18] Meskipun antigen
yang menghasut yang melanggar toleransi kekebalan dengan autoimmunity berikutnya tidak
diketahui, antigen leukosit manusia (HLA) -DR2 terlalu banyak diwakili oleh pasien Eropa
dan Amerika Serikat dengan anemia aplastik, dan kehadirannya merupakan prediksi respons
yang lebih baik terhadap siklosporin. .
Penekanan hematopoiesis kemungkinan dimediasi oleh populasi CD8 + HLA-DR + yang
diperluas, limfosit T sitotoksik (CTLs) yang sering terdeteksi di dalam darah dan sumsum
tulang pasien anemia aplastik. Sel-sel ini menghasilkan sitokin penghambat, seperti faktor
gamma-interferon dan tumor necrosis, yang dapat menekan pertumbuhan sel progenitor.
Polimorfisme yang terkait dengan peningkatan respons imun lebih banyak terjadi pada gen
sitokin ini pada pasien dengan anemia aplastik. Sitokin ini menekan hematopoiesis dengan
mempengaruhi siklus mitosis dan pembusukan sel dengan mendorong apoptosis yang
dimediasi Fas.
Sebagai tambahan, sitokin tersebut menginduksi oksida nitrat oksida dan produksi oksida
nitrat oleh sel sumsum, yang berkontribusi terhadap sitotoksisitas yang dimediasi oleh
kekebalan dan penghapusan sel hematopoietik. Hirano dkk melaporkan bahwa sel T
sitotoksik CD8 + yang diturunkan terhadap peptida yang diturunkan kinectin menekan unit
pembentuk koloni (CFU) dalam mode HLA class I-restricted, temuan yang menyarankan
kinectin dapat menjadi kandidat autoantigen pada patofisiologi anemia aplastik. [19]
Ekspresi konstitutif Tbet, regulator transkripsional yang sangat penting untuk polarisasi sel T
T 1 (Th1), terjadi pada mayoritas pasien anemia aplastik. [13] Perforin adalah protein sitolitik
yang diekspresikan terutama pada limfosit sitotoksik aktif dan sel pembunuh alami. Mutasi
pada gen perforin bertanggung jawab atas beberapa kasus hemofagositosis keluarga [20];
mutasi di SAP, pengkodean gen untuk protein modulasi kecil yang menghambat produksi
interferon yang tidak terdefinisi, mendasari limfoproliferasi terkait-X, penyakit fatal yang
terkait dengan respons kekebalan yang menyimpang terhadap virus herpes dan anemia
aplastik. Tingkat protein perforin dan SAP secara nyata berkurang pada beberapa kasus
anemia aplastik yang didapat.
Faktor transkripsi FOXP3 dan NFAT1 memiliki peran kunci dalam pengembangan dan
fungsi sel T (Treg), dan Treg berperan dalam autoimunitas. Treg menurun pada presentasi
hampir di semua pasien anemia aplastik; Tingkat protein dan mRNA FOXP3 juga secara
signifikan lebih rendah pada pasien dengan kondisi ini, sedangkan kadar protein NFAT1
menurun atau tidak ada. [21]
Variasi panjang telomer telah dilaporkan pada anemia aplastik parah, namun signifikansi
klinisnya tidak diketahui. Namun, walaupun panjang telomere tidak terkait dengan respons,
hal itu terkait dengan risiko kambuh, evolusi klonal, dan kelangsungan hidup secara
keseluruhan pada pasien dengan anemia aplastik berat. [22]

Penyebab bawaan atau bawaa

penyebab anemia aplastik bawaan atau bawaan bertanggung jawab atas setidaknya 25% anak
dengan kondisi ini dan mungkin sampai 10% orang dewasa. [23] Pasien mungkin memiliki
fitur dismorfik atau stigmata fisik, namun kegagalan sumsum mungkin merupakan fitur
penyajian awal. Beberapa lokus telah diidentifikasi yang terkait tidak hanya dengan
peningkatan kerentanan terhadap anemia aplastik tetapi juga dengan temuan fisik lainnya.

Anemia fanconi
Anemia fanconi ditandai dengan:
• Anomali kongenital multipel (60-75%): Perawakan pendek, pigmentasi kulit tidak normal,
malformasi jempol dengan atau tanpa radius displastik atau tidak ada, serta mikrofthalmos
dan malformasi jantung, ginjal, usus, dan telinga.
• Gagal sumsum tulang: Trombositopenia, leukopenia, atau anemia aplastik; Sebagian besar
pasien dengan anemia Fanconi mengalami kegagalan sumsum tulang pada usia dewasa
• Kanker: Keganasan hematologi umum terjadi pada anemia Fanconi dan myelodysplasia,
dengan leukemia myeloid akut (AML) yang paling umum; Tumor padat seperti kanker sel
skuamosa dan kanker leher, tumor genital wanita, dan tumor hati juga terlihat; Anemia
fanconi dikaitkan dengan peningkatan kerusakan kromosom dan pertukaran kromatid
adrenalin abnormal dengan adanya agen seperti diepoxybutane atau mitomycin C
• Pola pewarisan resesif autosomal dominan: Lima belas gen sekarang diketahui penyebab
anemia Fanconi; hanya 1 dari ini - FANCB (berlapis X resesif) - tidak diwariskan secara
autosomal resesif
• Asosiasi antara perkembangan sumsum tulang dan pola kompleks kelainan kromosom
rekuren: Beberapa kelainan kromosom umumnya ditemukan pada sindrom myelodysplastic
anemia non-Fanconi dan kelainan myeloid leukemia akut (misalnya, -7 / 7q atau RUNX1),
sedangkan yang lainnya khusus untuk anemia Fanconi (misalnya, 1q + dan 3q +)
Disperatosis kongenita
Dyskeratosis kongenita ditandai dengan triad fisik diagnostik dari kuku displastik, pigmentasi
retikuler berenda pada batang atas, dan leukoplakia oral. Namun, selama dekade terakhir,
sudah semakin diketahui bahwa penderita congenita mungkin mengalami dyskeratosis tanpa
triad. Berikut ini adalah fitur dari kondisi ini:
• Beberapa tanda penuaan dini, seperti awal beruban dari rambut
• Kegagalan sumsum tulang progresif pada usia berapapun, yang dapat menyebabkan
kombinasi sitopeni, termasuk anemia aplastik
• Keganasan: Umum; sering MDS atau AML; Tumor padat seperti kanker kepala dan leher
atau kanker genital juga bisa terlihat
• Fibrosis paru
• pola dominan autosomal dominan, autosomal resesif, dan X-linked; 6 gen diketahui
menyebabkan gangguan ini
Anemia aplastik keluarga
Ini adalah anemia aplastik yang terisolasi. Mutasi telah ditemukan pada gen TERC dan TERT
dan dianggap memberi kerentanan terhadap anemia aplastik. Gen ini mengkodekan protein
yang merupakan bagian dari aparatus telomerase yang mengembalikan daerah berulang di
telomer. [24]
Hipoplasia rambut kartilago
Hipoplasia rambut kartilago, yang disebabkan oleh mutasi pada gen RMRP, diwarisi secara
autosomal resesif. Kondisi ini ditandai dengan:
• Perawakan pendek dengan tungkai pendek dan tertekuk
• Rambut jarang berpigmen tipis
• Defisiensi imun yang sangat parah
• Anemia selama masa kanak-kanak
• Keganasan hematopoietik, serta keganasan kulit, mata, dan hati
• Malformasi gastrointestinal dan malabsorpsi
Sindrom Pearson
Sindrom Pearson menyebabkan anemia sideroblastik dan disfungsi pankreas eksokrin.
Kondisi ini diakibatkan oleh penghapusan asam deoksiribonukleat (DNA) mitokondria.
Sindrom radius trombositopenia tidak ada
Sindrom trombositopenia-absen radius (TAR) ditandai dengan delesi yang terletak pada
kromosom 1q21.1 (yang biasanya berukuran sekitar 200kb). Pasien memiliki ketiadaan radius
bilateral dengan kehadiran ibu jari, serta trombositopenia. Anomali kongenital lainnya juga
dapat terjadi (misalnya, penyakit jantung, anomali kerangka, anomali urogenital).
Sindrom Shwachman-Diamond
Sindrom Shwachman-Diamond disebabkan oleh mutasi pada gen SBDS dan diwarisi secara
autosomal resesif. Penyakit ini ditandai dengan disfungsi pankreas eksokrin dengan
malabsorpsi dan kegagalan pertumbuhan, serta sitopeni dari satu atau beberapa garis
keturunan. Pasien dengan sindrom Shwachman-Diamond juga memiliki peningkatan risiko
MDS dan AML. [25]
Sindrom Dubowitz
Sindrom Dubowitz disebabkan oleh gen yang belum diketahui. Kondisi ini ditandai dengan
retardasi pertumbuhan intrauterine, perawakannya sangat pendek, dan penampilan wajah
yang melengkung. Pasien juga mengalami microcephaly dan keterlambatan perkembangan
ringan. Sindrom Dubowitz juga terkait dengan eksim, defisiensi imun, dan anemia aplastik.
Keganasan lebih sering terjadi pada kelainan ini, terutama limfoma dan neuroblastoma.
Anemia Diamond-Blackfan
Anemia Diamond-Blackfan (DBA) ditandai dengan anemia makrositik normokromik yang
dapat diisolasi, atau dapat dikaitkan dengan retardasi pertumbuhan atau malformasi
kongenital pada sistem tungkai atas, jantung, dan genitourinari. Pada sebagian kecil pasien,
DBA dapat berkembang menjadi anemia aplastik. Sembilan gen telah ditemukan menjadi
penyebab DBA, dan mereka diwarisi secara dominan autosomal. [26] Sekitar 50% kasus
diwarisi dari orang tua, dan sekitar 50% hasil dari de novo mu

Penyebab yang diakuisisi

Penyebab anemia aplastik yang didapat (80%) meliputi:
• Faktor idiopatik
• Penyebab infeksi, seperti virus hepatitis, virus Epstein-Barr (EBV), human
immunodeficiency virus (HIV), parvovirus, dan mycobacteria
• Paparan radiasi pengion
• Paparan bahan kimia beracun, seperti benzena atau pestisida [27]
• Cangkok transfusi versus penyakit inang (GVHD)
• Transplantasi hati Orthotopic untuk hepatitis fulminan
• Kehamilan
• Eosinofilik fasciitis
• Anoreksia
• Defisiensi nutrisi yang parah (B12, folat)
• Hemoglobinuria nokturnal paroxysmal (PNH)
• MDS
• Leukemia limfoblastik akut (ALL) (jarang)
Obat dan unsur (misalnya, kloramfenikol, fenilbutazon, emas) dapat menyebabkan aplasia
sumsum. Mekanisme kekebalan tubuh tidak memperhitungkan kegagalan sumsum dalam
reaksi obat istimewa. Dalam kasus tersebut, toksisitas langsung dapat terjadi, mungkin karena
perbedaan yang ditentukan secara genetik dalam jalur detoksifikasi metabolik. Sebagai
contoh, fenotipe null dari transferase glutathione tertentu terlalu banyak diwakili oleh pasien
dengan anemia aplastik.
PNH disebabkan oleh defek genetik yang didapat yang mempengaruhi gen PIGA dan terbatas
pada kompartemen sel induk. Mutasi pada gen PIGA membuat sel asal hematopoietik peka
terhadap peningkatan lisis komplemen. Sekitar sepertiga pasien dengan anemia aplastik
memiliki bukti PNH saat presentasi, seperti yang dideteksi dengan cara flow cytometry. [28]
Selanjutnya, pasien yang penyakitnya merespons setelah terapi imunosupresif dapat sembuh
dengan hematopoiesis klonal dan PNH.
Epidemiologi
Statistik Amerika Serikat
Tidak ada data prospektif yang akurat mengenai kejadian anemia aplastik di Amerika Serikat.
Temuan dari beberapa penelitian retrospektif biasanya menimpa orang-orang dari Eropa dan
menunjukkan bahwa kejadian tersebut adalah 0,6-6,1 kasus per juta penduduk; Tingkat ini
sebagian besar didasarkan pada data dari tinjauan retrospektif terhadap daftar pendaftar
kematian.
Statistik internasional
Kejadian anemia aplastik tahunan di Eropa, seperti yang dijelaskan dalam studi epidemiologi
formal yang besar, adalah 2 kasus per juta penduduk. [29] Anemia aplastik diperkirakan lebih
sering terjadi di Asia daripada di Barat. Insidensi tersebut secara akurat ditentukan menjadi 4
kasus per juta penduduk di Bangkok, [30] namun berdasarkan studi prospektif, sebenarnya
dapat mendekati 6 kasus per juta penduduk di daerah pedesaan Thailand. Kejadian yang
meningkat ini mungkin terkait dengan faktor lingkungan, seperti meningkatnya paparan
bahan kimia beracun, dan bukan pada faktor genetik, karena kenaikan ini tidak diamati pada
orang-orang keturunan Asia yang tinggal di Amerika Serikat.
Demografi ras, seks, dan usia terkait
Meskipun tidak ada predisposisi rasial untuk anemia aplastik yang dilaporkan di Amerika
Serikat, prevalensinya meningkat di Timur Jauh. Rasio laki-laki terhadap perempuan untuk
anemia aplastik diperoleh sekitar 1: 1, walaupun ada data yang menunjukkan bahwa
perkiraan pria dapat diamati di Timur Jauh.
Meskipun anemia aplastik terjadi pada semua kelompok usia, puncak kecil pada kejadian
diamati pada masa kanak-kanak karena dimasukkannya sindrom kegagalan sumsum warisan.
Puncak kedua diamati pada orang berusia 20-25 tahun.
Prognosa
Hasil dari pasien dengan anemia aplastik telah meningkat secara substansial karena
perawatan suportif membaik. Riwayat alami anemia aplastik menunjukkan bahwa sejumlah
kecil pasien dapat pulih secara spontan dengan perawatan suportif [31]; Namun, terapi
perawatan observasional dan / atau pendukung saja jarang ditunjukkan.
Tingkat kelangsungan hidup 10 tahun yang diperkirakan untuk pasien yang mendapat
imunosupresi biasa adalah 68%, dibandingkan dengan 73% untuk transplantasi sel
hematopoietik (HCT). [32] Namun, ada hasil yang meningkat secara signifikan untuk HCT
dari waktu ke waktu, untuk saudara kandung dan donor alternatif, dan dengan usia lebih
muda. [32] Dalam kasus imunosupresi, kambuh dan penyakit klonal terlambat adalah risiko.
Dalam analisis satu institusi terhadap 183 pasien yang mendapat pengobatan imunosupresif
untuk anemia aplastik berat, panjang sel leukosit darah perifer tidak terkait dengan respons
pengobatan. [22] Dalam analisis multivariat, bagaimanapun, panjang telomere dikaitkan
dengan risiko kambuh, evolusi klonal, dan kelangsungan hidup secara keseluruhan.
Diperlukan penelitian tambahan untuk memvalidasi temuan ini dan untuk menentukan
bagaimana informasi ini dimasukkan ke dalam algoritma pengobatan.
Kematian / morbiditas
Penyebab utama morbiditas dan mortalitas dari anemia aplastik meliputi infeksi dan
perdarahan. Pasien yang menjalani HCT memiliki masalah tambahan terkait toksisitas akut
dan kronis dari rejimen pengkondisian dan penyakit graft versus host (GVHD), serta potensi
kegagalan graft. [18, 33, 34, 35, 36, 37] Pada kira-kira 25-30% pasien dengan anemia
aplastik, kondisinya tidak merespons imunosupresi. Pada kasus dengan respons pengobatan,
kambuh dan penyakit klon akhir-akhir, seperti hemoglobinuria nokturnal paroksismal (PNH),
sindrom myelodysplastic (MDS), dan leukemia, adalah risiko - terlepas dari respons
pengobatan atau tingkat responsnya. [14, 38, 39, 40, 41]
Kulasekararaj dan rekannya melaporkan bahwa adanya mutasi somatik (termasuk ASXL1,
DNMT3A, dan BCOR) pada pasien dengan anemia aplastik selama lebih dari 6 bulan
dikaitkan dengan 40% risiko transformasi menjadi MDS. Hampir seperlima pasien anemia
aplastik mengalami mutasi pada gen yang biasanya terlihat pada keganasan myeloid yang
diprediksi untuk transformasi selanjutnya ke MDS. [42]
Dalam sebuah penelitian di Jepang terhadap 427 pasien (16-72 tahun) dengan anemia aplastik
yang menjalani transplantasi sumsum tulang donor yang tidak terkait, hasilnya secara
signifikan lebih rendah pada pasien yang donornya berusia 40 tahun atau lebih tua daripada
mereka yang memiliki donor muda. Pada kelompok donor yang lebih tua, kelangsungan
hidup secara keseluruhan lebih rendah secara inferior (rasio hazard yang disesuaikan, 1,64),
kejadian infeksi fatal secara signifikan lebih tinggi (13,7% vs 7,5%), dan kegagalan
engraftment primer dan GVHD akut terjadi secara signifikan lebih sering (9,7% vs 5,0% dan
27,1% vs 19,7%, masing-masing). [43]
Studi kohort berbasis populasi di Australia terhadap orang dewasa yang menerima HCT
allogeneic melaporkan peningkatan risiko kanker sekunder pada beberapa kelompok pasien,
termasuk yang ditransplantasikan untuk anemia aplastik berat. Secara keseluruhan, pada
pasien yang hidup 2 tahun setelah transplantasi (n = 1463), kejadian kumulatif kematian dini
adalah 22,2% pada 10 tahun dan risiko kematian relatif terhadap populasi umum yang sesuai
adalah 13,8. [44]

Transfusi darah
Pasien dengan anemia aplastik memerlukan dukungan transfusi sampai diagnosis ditetapkan
dan terapi spesifik dapat dilakukan. Komite Inggris untuk Standar Hematologi
merekomendasikan transfusi profilaksis pada pasien yang jumlah trombositnya di bawah 10 ×
109 / L (atau <20 × 109 / L pada pasien demam). [5] Namun, penting bahwa transfusi
dipandu oleh status klinis pasien dan bukan oleh angka saja. Menghindari transfusi dari
anggota keluarga penting karena kemungkinan sensitisasi terhadap antigen jaringan non-HLA
(human leukocant antigen) dari donor potensial.
Untuk pasien yang memerlukan transplantasi sel hematopoietik (HCT), transfusi harus
digunakan dengan bijaksana karena subjek dengan transfusi minimal telah mencapai hasil
terapeutik yang superior.
Jika menggunakan dukungan darah-bank, usahakan meminimalkan risiko infeksi
sitomegalovirus (CMV). Produk darah harus, jika mungkin, mengalami pengurangan leukosit
untuk mencegah penularan alloimunisasi dan CMV dan harus diiradiasi untuk mencegah
penyakit graft versus host (GVHD) terkait transfusi pada kandidat HCT.
Komite Inggris untuk Standar Hematologi juga merekomendasikan produk darah iradiasi
untuk semua pasien yang menerima terapi antithymocyte globulin (ATG). Pada pasien
dengan sepsis neutropenia yang mengancam jiwa, panitia menyarankan pertimbangan
transfusi granulosit yang diiradiasi. [5]
Pengembangan rencana transfusi dengan berkonsultasi dengan dokter yang berpengalaman
dalam pengelolaan anemia aplastik sangat penting.
Pengobatan Infeksi
Infeksi merupakan penyebab utama kematian pada pasien dengan anemia aplastik. [51, 52]
Faktor risiko termasuk neutropenia berkepanjangan dan kateter tinggal yang digunakan untuk
terapi spesifik. Infeksi jamur, terutama yang disebabkan oleh spesies Aspergillus,
menimbulkan risiko besar. Pasien harus menjaga kebersihan untuk mengurangi risiko infeksi.
Komite Inggris untuk Standar Hematologi merekomendasikan antibiotik profilaksis dan agen
antijamur untuk pasien yang jumlah neutrofilnya di bawah 0,2 × 109 / L. [5] Terapi antibiotik
empiris harus berbasis luas, dengan cakupan gram negatif dan staphylococcal berdasarkan
sensitivitas mikroba lokal. Terutama mempertimbangkan termasuk cakupan antipseudomonal
pada awal pengobatan untuk pasien dengan febrile neutropenia; Juga pertimbangkan
pengenalan awal agen antijamur untuk individu dengan demam terus-menerus.
Namun, strategi penggunaan antibiotik empiris juga telah menghasilkan pengembangan
organisme tahan dan oleh karena itu tidak disukai oleh beberapa klinisi. [53]
Dukungan sitokin dengan faktor stimulasi koloni granulosit (G-CSF) dan faktor stimulasi
koloni granulosit-makrofag (GM-CSF) dapat dipertimbangkan pada infeksi refrakter,
walaupun terapi ini harus dipertimbangkan terhadap biaya dan khasiatnya. [8, 54, 55, 56]
Hentikan dukungan sitokin setelah 1 minggu jika jumlah neutrofil tidak meningkat. [5]
Transplantasi Sel Hematopoietik
Penempatan kateter vena sentral diperlukan sebelum transplantasi sel hematopoietik (HCT).
Perhatikan bahwa rekomendasi berikut ini tidak berlaku untuk pasien dengan anemia Fanconi
dan jenis kegagalan sumsum lainnya yang diwariskan; [5] Pasien-pasien ini memerlukan
pertimbangan khusus.
HCT menggunakan donor sibir HLA yang cocok
HCT leukosit manusia-leukosit (HLA) -terkaitan dengan donor kandung kemih HCT adalah
pengobatan pilihan untuk pasien muda dengan anemia aplastik berat atau sangat parah (SAA
atau VSAA, masing-masing), yang umumnya diterima untuk pasien yang berusia kurang dari
40 tahun. [5] Orang yang menjalani prosedur ini tidak memerlukan regimen pengkondisian
berbasis iradiasi. [5]
Sebuah penelitian terhadap 692 pasien Jerman dengan SAA yang menerima transplantasi dari
saudara kandung HLA, mencatat bahwa cangkok sumsum tulang lebih disukai daripada
cangkok sel induk darah perifer (PBPC) pada pasien berusia di bawah 20 tahun. [57] Studi
multinasional terhadap pasien dengan SAA yang menerima HCT dari donor sibir HLA-cocok
menyimpulkan bahwa meskipun sumsum tulang pasti merupakan sumber cangkok yang lebih
disukai untuk pasien ini, PBPC dapat menjadi alternatif yang dapat diterima di negara-negara
dengan sumber daya terbatas di mana pasien hadir. Kemudian dalam perjalanan penyakit
mereka dan risiko kegagalan korupsi dan komplikasi infeksi tinggi. [58]
Meskipun bukti menunjukkan bahwa sel induk dari sumsum tulang menghasilkan hasil yang
lebih baik dibandingkan dengan PBPC, pertimbangan tambahan adalah perspektif donor,
siapa yang harus diberitahu mengenai perbedaan antara metode pemanenan. Penangkapan
sumsum tulang biasanya dilakukan dengan donor dengan anestesi umum, sementara dengan
PBPC memanen donor terjaga dan terhubung melalui kateter intravena yang besar ke mesin
apheresis, yang memisahkan sel induk (untuk deskripsi kedua metode tersebut, lihat Bone
Prosedur Donor Marak).
Seiring dengan risiko yang terkait dengan anestesi, donor sumsum tulang biasanya
mengalami nyeri sedang selama beberapa hari setelah prosedur ini berlangsung. Pendeta
PBPC biasanya mengalami nyeri tulang, yang mungkin parah, dari stimulasi sumsum tulang
yang disebabkan oleh filgrastim yang digunakan untuk memobilisasi sel induk sebelum
prosedur tersebut. Salah satu masalah utama HCT pada anemia aplastik adalah tingginya
tingkat penolakan (10%; range, 5-50% ). Ini berkorelasi positif dengan jumlah transfusi yang
diterima dan durasi penyakitnya sebelum transplantasi. Sebelumnya, dosis sel induk yang
lebih tinggi, serta penambahan penyiraman total tubuh ke pengkondisian siklofosfamid, telah
dicoba. Meskipun dikaitkan dengan berkurangnya kejadian penolakan graft, manfaatnya
ditiadakan oleh kematian terkait transplantasi (TRM) karena peningkatan penyakit graft
versus host (GVHD). Saat ini, globulin antithymocyte (ATG) dengan siklofosfamid adalah
yang umum digunakan rejimen pengkondisian untuk transplantasi pada anemia aplastik.
Penambahan ATG ke siklofosfamid untuk pengkondisian telah mengakibatkan penolakan
graft yang jarang terjadi, serta peningkatan ketahanan hidup secara keseluruhan. [16, 54, 55,
59]

Transplantasi Darah Tali Pusat

Transplantasi darah tali pusat (CBT) belum direkomendasikan sebagai terapi lini pertama
atau kedua untuk anemia aplastik. Pengobatan ini harus digunakan sebagai terapi
eksperimental untuk pasien yang tidak memiliki donor antigen leukosit manusia (HLA) dan
memiliki 1-2 terapi gagal imunosupresif, dan harus dievaluasi hanya melalui uji klinis
prospektif. [69] Uji coba terkontrol diperlukan untuk menentukan peran dan waktu CBT pada
anemia aplastik dengan lebih baik. [70, 71, 72]
Terapi Imunosupresif
Terapi imunosupresif dengan menggunakan antithymocyte globulin (ATG) dan siklosporin
dikaitkan dengan tingkat respons keseluruhan 60-80% dan tingkat ketahanan hidup 5 tahun
sebesar 75% di sebagian besar laporan, namun tingkat kelangsungan hidup bebas kejadian
berada pada kisaran 35-50 %.
Terapi imunosupresif dengan menggunakan ATG plus siklosporin diberikan sebagai terapi
lini pertama [73] untuk pasien dengan anemia aplastik berat atau sangat parah (SAA atau
VSAA, masing-masing) yang berusia lebih dari 40 tahun dan sebagai terapi lini kedua pada
pasien yang lebih muda dengan SAA atau VSAA jika donor sibuk leukosit manusia (HLA)
yang tidak sesuai tidak tersedia. Terapi imunosupresif juga dianjurkan pada pasien dengan
anemia aplastik nonseves yang bergantung pada transfusi. [5]
Penempatan kateter vena sentral mungkin diperlukan sebelum pemberian terapi
imunosupresif, dan pasien dengan kateter ini harus diperlakukan sebagai pasien rawat inap.
Pasien mungkin memerlukan dukungan produk darah selama terapi ATG, serta pemantauan
ketat untuk tanda dan gejala alergi dan anafilaksis dan untuk profilaksis dan pengobatan
demam.

ATG dan siklosporin

Scheinberg dkk melaporkan bahwa perbedaan yang besar diamati pada pasien dengan anemia
aplastik pada tingkat respon hematologi pada 6 bulan yang mendukung ATG kuda (68%),
dibandingkan dengan ATG kelinci (37%). [74] Kelangsungan hidup keseluruhan pada usia 3
tahun juga berbeda, dengan tingkat kelangsungan hidup 96% pada kelompok kuda-ATG,
dibandingkan dengan 76% pada kelompok kelinci-ATG saat data disensor pada saat
transplantasi sel induk, dan 94 % versus 70% pada kelompok masing-masing saat
transplantasi sel induk tidak disensor. [74]
Sebuah tinjauan oleh Risitano juga menunjukkan bahwa imunosupresi dengan ATG kelinci,
serta siklofosfamid dan alemtuzumab, pada pasien dengan anemia aplastik atau sindrom
kegagalan sumsum tulang yang dimediasi oleh kekebalan tubuh memiliki hasil inferior yang
relatif terhadap ATG kuda. [75] Oleh karena itu, ATG kelinci, siklofosfamid, dan
alemtuzumab tidak direkomendasikan sebagai terapi lini pertama pada pasien ini. [75]
Dalam penelitian ATG lainnya, tanggapan telah didefinisikan sebagai tanggapan lengkap
(complete response / CRs) ketika semua jumlah darah kembali normal, dan sebagai
tanggapan parsial (PRs) ketika terjadi peningkatan jumlah darah dengan independensi
transfusi. Dalam analisis ini, respons terhadap ATG lambat, biasanya membutuhkan waktu
10-12 minggu untuk merespons terjadinya; dan respon juga bisa terus membaik atau terjadi
nantinya. Jika pasien tidak menanggapi rangkaian ATG pertama, maka kursus kedua dapat
diberikan, dengan menggunakan persiapan yang sama atau yang lain. Sekitar 30-60% pasien
mungkin merespons ATG kedua. [76, 77, 78, 79, 80, 81, 82]
Dalam sebuah penelitian, tingkat respons terhadap siklosporin saja adalah 45% secara
keseluruhan, 16% untuk VSSA, 47% untuk SAA, dan 85% untuk anemia aplastik sedang.
[83] Oleh karena itu, satu-satunya prediktor respons terhadap siklosporin adalah jumlah
neutrofil absolut (ANC) kurang dari 200 / mm3. Menambahkan granulocyte colony-
stimulating factor (G-CSF) ke ATG dan siklosporin pada pasien dengan ANC lebih dari 200 /
mm3 tidak memberikan keuntungan tambahan dalam mengurangi tingkat infeksi atau dalam
meningkatkan kelangsungan hidup atau tanggapan terapeutik.
Sebuah meta-analisis oleh Hayakawa dkk dari 13 penelitian membandingkan ATG kuda
dengan ATG kelinci untuk terapi imunosupresif pada anemia aplastik berat menyimpulkan
bahwa ATG kuda menghasilkan tingkat respnse yang lebih tinggi (p = 0,015); Selanjutnya,
analisis sensitivitas menunjukkan bahwa ada angka kematian dini yang lebih tinggi dengan
ATG kelinci. [84] Oleh karena itu, kuda ATG adalah pilihan yang lebih disukai dalam setting
ini.
Waktunya merespons dan kambuh
Respon pengobatan pada anemia aplastik, tidak seperti penyakit autoimun lainnya, lambat.
Setidaknya 4-12 minggu biasanya diperlukan untuk mengamati peningkatan dini, dan pasien
mungkin terus membaik perlahan setelahnya. Sekitar 50% pasien merespons 3 bulan setelah
pemberian ATG, dan sekitar 75% merespon dengan 6 bulan. Kebanyakan pasien membaik
dan menjadi transfusi independen, namun masih banyak yang memiliki bukti sumsum tulang
hipoproliferatif.
Meskipun tingkat respons awal adalah tanggapan yang baik dan awet tanpa kambuh atau
evolusi klonal diamati pada 50% pasien. [85] Untuk mengurangi risiko kambuh, lanjutkan
siklosporin minimal 12 bulan setelah mencapai respons hematologis maksimal, dengan
kondisi yang sangat lambat setelahnya. [5] Sekitar sepertiga pasien mengalami kekambuhan,
sebagian besar mengalami kambuh pada saat lancip siklosporin. Sekitar sepertiga responden
bergantung pada siklosporin. Dari pasien tanpa tanggapan atau yang kambuh, 40-50%
menanggapi terapi imunosupresif kedua.
Dalam kasus yang jarang terjadi, pemulihan hematologis penuh diamati, namun sebagian
besar pasien membaik pada pemulihan hematologis fungsional yang meniadakan dukungan
transfusi lebih lanjut. Selain itu, risiko beberapa jenis penyakit klonal selain hemoglobinuria
nokturnal paroxysmal (PNH) adalah 15-30% dan mungkin karena ketidakmampuan terapi ini
memperbaiki fungsi sumsum tulang sepenuhnya, diagnosis sindrom myelodysplastic (MDS)
yang tidak terjawab, atau fakta bahwa sel induk di bawah tekanan proliferatif mungkin lebih
rentan daripada sel lainnya terhadap mutasi.
Terapi imunosupresif investigatif
Saat ini, penggunaan siklofosfamid dosis tinggi harus dibatasi pada uji klinis. [85] Data awal
menunjukkan bahwa siklofosfamid dosis tinggi dapat menyebabkan remisi yang tahan lama
pada beberapa pasien dengan anemia aplastik. Namun, beberapa dari pasien ini
mengembangkan kelainan PNH dan sitogenesis saat menindaklanjuti. Ketika peneliti
melakukan penelitian acak prospektif berdasarkan laporan awal di atas dengan menggunakan
siklofosfamid versus ATG dan CSA, penelitian dihentikan lebih awal karena kematian dan
infeksi jamur yang sangat tinggi pada kelompok siklofosfamid. [86, 87]
Sampai 50% pasien dengan anemia aplastik menunjukkan klon PNH kecil tanpa adanya
hemolisis. [5] Pada pasien dengan riwayat trombosis terkait PNH, penggunaan ATG tidak
dianjurkan. Selain itu, karena klon cytogenetic yang abnormal dapat terjadi pada hingga 12%
pasien dengan anemia aplastik, adanya beberapa klon dalam typ Kasus anemia aplastik tidak
selalu berarti diagnosis sindrom myelodysplastic (MDS) atau leukemia myeloid akut (acute
myeloid leukemia / AML). [5] Namun, pengecualian adalah ketika monosomi 7 klon hadir,
dalam hal ini ada risiko tinggi transformasi ke MDS atau AML. [5] Terapi imunosupresif
yang menjanjikan lainnya mencakup alemtuzumab (antibodi anti-CD52 monoklonal) dan
daclizumab (reseptor anti-interleukin-2 atau antibodi CD-25). Mycophenolate mofetil dan
sirolimus juga telah digunakan namun tidak menghasilkan respons pengobatan. Kecuali
dalam uji coba klinis prospektif, faktor pertumbuhan hematopoietik (misalnya eritropoietin
manusia rekombinan [rHuEPO], faktor stimulasi koloni granulosit (G-CSF)) adalah tidak
dianjurkan untuk penggunaan jangka panjang rutin mengikuti terapi ATG dan CSA. [5]

Diet dan Aktivitas

Diet untuk pasien dengan anemia aplastik yang memiliki neutropenia atau yang menerima
terapi imunosupresif harus disesuaikan dengan hati-hati untuk menyingkirkan daging mentah,
produk susu, atau buah-buahan dan sayuran yang kemungkinan besar akan dijajah oleh
bakteri, jamur, atau jamur. Selanjutnya, diet terbatas garam dianjurkan selama terapi dengan
steroid atau siklosporin-A (CSA).
Pasien harus menghindari aktivitas yang meningkatkan risiko trauma selama periode
trombositopenia. Menstruasi wanita juga disarankan untuk memakai pil hormonal untuk
menghindari siklus menstruasi yang cenderung berat akibat trombositopenia.
Informasikan kepada pasien tentang peningkatan risiko infeksi yang didapat masyarakat
selama periode neutropenia dan limfopenia. Pasien harus menjaga kebersihan untuk
mengurangi risiko infeksi.
Pasien Tahan terhadap Terapi Imunosupresif
Pada pasien dengan anemia aplastik yang tahan terhadap terapi imunosupresif (IST),
pengobatan dengan eltrombopag (Promacta) dapat dipertimbangkan. Eltrombopag, agonis
reseptor trombopoietin, disetujui pada Agustus 2014 untuk anemia aplastik berat pada pasien
yang gagal merespons secara memadai setidaknya satu rejimen IST sebelumnya. Persetujuan
didukung oleh penelitian fase II di mana 41% pasien mengalami respons hematologi pada
setidaknya satu garis keturunan (yaitu platelet, sel darah merah, neutrofil) setelah 12 minggu
pengobatan dengan eltrombopag. [88, 89]
Pada tahap penyuluhan, tiga pasien mencapai respons multi-garis keturunan. Empat dari
pasien tersebut kemudian meruncingkan pengobatan dan mempertahankan responnya
(median follow up 8,1 bulan, kisaran 7,2-10,6 bulan). [88,
Ringkasan Obat
Tujuan farmakoterapi dalam kasus anemia aplastik adalah untuk mengurangi morbiditas dan
mencegah komplikasi.
Seperti yang dijelaskan dalam Pengobatan, pilihan pengobatan imunosupresif termasuk terapi
kombinasi, termasuk antithymocyte globulin (ATG), siklosporin, dan metilprednisolon,
dengan atau tanpa dukungan sitokin. ATG atau siklosporin saja mungkin juga menghasilkan
respons pada anemia aplastik, namun kombinasi tersebut meningkatkan kemungkinan
respons. Namun demikian, sebuah penelitian prospektif dari India menyimpulkan bahwa
untuk pasien dengan sumber daya yang miskin, monoterapi siklosporin, dengan dosis 5 mg /
kg / hari, merupakan pilihan pengobatan yang relatif aman untuk anemia aplastik. [90]
Dukungan hematopoietik dengan eltrombopag, faktor stimulasi koloni granulosit (G-CSF)
dan faktor stimulasi koloni granulosit-makrofag (GM-CSF) dapat dipertimbangkan pada
infeksi refrakter, walaupun terapi ini harus dipertimbangkan terhadap biaya dan kemanjuran.
[8, 54, 55, 56, 88, 89]