Aplastic anemia resident survival guide: Difference between revisions

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==Definition==
==Overview==
[[Aplastic Anemia]] is a condition where the [[bone marrow]] and the bone marrow cells are damaged.  A deficiency of all the three cell types is seen which leads to [[pancytopenia]].
[[Aplastic Anemia]] is a condition where the [[bone marrow]] and the bone marrow cells are damaged .  A deficiency of all the three cell types is seen which leads to [[pancytopenia]] .
Decrease in [[red blood cells]] ([[Anemia]]) presents as [[pallor]], fatigue, dyspnea and leg pain.  Decrease in [[platelets]] ([[Thrombocytopenia]]) presents as mucosal bleeding, purpura and bruising.  Decrease in [[white blood cells]] ([[Neutropenia]]) manifests as recurrent infection.
Decrease in [[red blood cells]] ([[Anemia]]) presents as [[pallor]], fatigue , dyspnea and leg pain .  Decrease in [[platelets]] ([[Thrombocytopenia]]) presents as mucosal bleeding , purpura and bruising .  Decrease in [[white blood cells]] ([[Neutropenia]]) manifests as recurrent infection .


==Causes==
==Causes==
===Idiopathic ===
*( The most common cause - 50% of the causes )<ref name="Young-2002">{{Cite journal  | last1 = Young | first1 = NS. | title = Acquired aplastic anemia. | journal = Ann Intern Med | volume = 136 | issue = 7 | pages = 534-46 | month = Apr | year = 2002 | doi =  | PMID = 11926789 }}</ref><ref name="Shichishima-2002">{{Cite journal  | last1 = Shichishima | first1 = T. | last2 = Okamoto | first2 = M. | last3 = Ikeda | first3 = K. | last4 = Kaneshige | first4 = T. | last5 = Sugiyama | first5 = H. | last6 = Terasawa | first6 = T. | last7 = Osumi | first7 = K. | last8 = Maruyama | first8 = Y. | title = HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria. | journal = Blood | volume = 100 | issue = 1 | pages = 22-8 | month = Jul | year = 2002 | doi =  | PMID = 12070003 }}</ref><ref name="Saunthararajah-2002">{{Cite journal  | last1 = Saunthararajah | first1 = Y. | last2 = Nakamura | first2 = R. | last3 = Nam | first3 = JM. | last4 = Robyn | first4 = J. | last5 = Loberiza | first5 = F. | last6 = Maciejewski | first6 = JP. | last7 = Simonis | first7 = T. | last8 = Molldrem | first8 = J. | last9 = Young | first9 = NS. | title = HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. | journal = Blood | volume = 100 | issue = 5 | pages = 1570-4 | month = Sep | year = 2002 | doi =  | PMID = 12176872 }}</ref><ref name="Young-2006">{{Cite journal  | last1 = Young | first1 = NS. | last2 = Calado | first2 = RT. | last3 = Scheinberg | first3 = P. | title = Current concepts in the pathophysiology and treatment of aplastic anemia. | journal = Blood | volume = 108 | issue = 8 | pages = 2509-19 | month = Oct | year = 2006 | doi = 10.1182/blood-2006-03-010777 | PMID = 16778145 }}</ref>


===Drug History===
* Chemotherapy


{{familytree/start |summary= Aplastic anemia causes Algorithm}}
* Bone marrow suppressing drugs<ref name="Young-2002">{{Cite journal  | last1 = Young | first1 = NS. | title = Acquired aplastic anemia. | journal = Ann Intern Med | volume = 136 | issue = 7 | pages = 534-46 | month = Apr | year = 2002 | doi = | PMID = 11926789 }}</ref>
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | A01 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |A01 = '''Aplastic Anemia'''}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | |}}
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{{familytree | | | | | | | | | | | | | |,|-|-|-|-|-|v|-|-|-|-|-|+|-|-|-|-|-|v|-|-|-|-|-|.| | | | | | | | |}}
{{familytree | | | | | | | | | | | | | |!| | | | | |!| | | | | |!| | | | | |!| | | | | |!| | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | |!| | | | | |!| | | | | |!| | | | | |!| | | | | |!| | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | C01 | | | | C02 | | | | C03 | | | | C04 | | | | C05 | | | | | | | | | | | | | | | | | | | | | | | | | |C01='''Drug History''' |C02='''Radiation'''|C03='''Infection'''|C04='''Idiopathic'''<br>50% of the cases| C05='''Congential / Family history'''
<br>[[Fanconi's Anemia]] <br>98 % [[Autosomal recessive ]]<br> 2 % [[X-linked recessive]] }}
{{familytree | | | | | | | | | | | | | |!| | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
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{{familytree | | | | | | | | | | |,|-|-|^|-|-|.| | | | | |,|-|-|^|-|-|.| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | D01 | | | | D02 | | | | D03 | | | | D04 | | | | | | | | | | | | | | | | | | | | | | | | | | | | |D01='''Bone Marrow suppressing drugs'''<br> [[Chloramphenicol]] <br>[[carbamazepine]]<br> [[Felbamate]]<br> [[Phenylbutazone]]<br> [[Quinine]]<br>[[Phenytoin]] | D02='''Chemotherapy''' |D03='''Viral hepatitis'''|D04='''[[Parvovirus B19]] '''<br>in children}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}


{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
** [[Chloramphenicol]]<ref name="Wallerstein-1969">{{Cite journal  | last1 = Wallerstein | first1 = RO. | last2 = Condit | first2 = PK. | last3 = Kasper | first3 = CK. | last4 = Brown | first4 = JW. | last5 = Morrison | first5 = FR. | title = Statewide study of chloramphenicol therapy and fatal aplastic anemia. | journal = JAMA | volume = 208 | issue = 11 | pages = 2045-50 | month = Jun | year = 1969 | doi =  | PMID = 5818983 }}</ref>
{{familytree/end}}
** [[Carbamazepine]]
** [[Felbamate]]<ref name="Brodie-1995">{{Cite journal  | last1 = Brodie | first1 = MJ. | last2 = Pellock | first2 = JM. | title = Taming the brain storms: felbamate updated. | journal = Lancet | volume = 346 | issue = 8980 | pages = 918-9 | month = Oct | year = 1995 | doi =  | PMID = 7564721 }}</ref>
** [[Phenylbutazone]]
** [[Quinine]]
** [[Phenytoin]]<ref name="Handoko-2006">{{Cite journal  | last1 = Handoko | first1 = KB. | last2 = Souverein | first2 = PC. | last3 = van Staa | first3 = TP. | last4 = Meyboom | first4 = RH. | last5 = Leufkens | first5 = HG. | last6 = Egberts | first6 = TC. | last7 = van den Bemt | first7 = PM. | title = Risk of aplastic anemia in patients using antiepileptic drugs. | journal = Epilepsia | volume = 47 | issue = 7 | pages = 1232-6 | month = Jul | year = 2006 | doi = 10.1111/j.1528-1167.2006.00596.x | PMID = 16886988 }}</ref>
** [[Gold]]<ref name="Kay-1976">{{Cite journal  | last1 = Kay | first1 = AG. | title = Myelotoxicity of gold. | journal = Br Med J | volume = 1 | issue = 6020 | pages = 1266-8 | month = May | year = 1976 | doi =  | PMID = 817772 }}</ref>
** [[Sulfonamides]]
** [[Nifedipine]]<ref name="Laporte-1998">{{Cite journal  | last1 = Laporte | first1 = JR. | last2 = Ibáñez | first2 = L. | last3 = Ballarín | first3 = E. | last4 = Pérez | first4 = E. | last5 = Vidal | first5 = X. | title = Fatal aplastic anaemia associated with nifedipine. | journal = Lancet | volume = 352 | issue = 9128 | pages = 619-20 | month = Aug | year = 1998 | doi = 10.1016/S0140-6736(98)24034-7 | PMID = 9746025 }}</ref>
 
*  Industrial chemicals<ref name="SCOTT-1959">{{Cite journal  | last1 = SCOTT | first1 = JL. | last2 = CARTWRIGHT | first2 = GE. | last3 = WINTROBE | first3 = MM. | title = Acquired aplastic anemia: an analysis of thirty-nine cases and review of the pertinent literature. | journal = Medicine (Baltimore) | volume = 38 | issue = 2 | pages = 119-72 | month = May | year = 1959 | doi =  | PMID = 13656164 }}</ref><ref name="Powars-1965">{{Cite journal  | last1 = Powars | first1 = D. | title = Aplastic anemia secondary to glue sniffing. | journal = N Engl J Med | volume = 273 | issue = 13 | pages = 700-2 | month = Sep | year = 1965 | doi = 10.1056/NEJM196509232731307 | PMID = 5827034 }}</ref> and insecticides eg , benzene hexachloride ( lindane )<ref name="LOGE-1965">{{Cite journal  | last1 = LOGE | first1 = JP. | title = APLASTIC ANEMIA FOLLOWING EXPOSURE TO BENZENE HEXACHLORIDE (LINDANE). | journal = JAMA | volume = 193 | issue =  | pages = 110-4 | month = Jul | year = 1965 | doi =  | PMID = 14304352 }}</ref>
 
===Infection===
* [[Viral Hepatitis]]<ref name="Goss-1997">{{Cite journal  | last1 = Goss | first1 = JA. | last2 = Schiller | first2 = GJ. | last3 = Martin | first3 = P. | last4 = Seu | first4 = P. | last5 = Stribling | first5 = R. | last6 = McDiarmid | first6 = SV. | last7 = Shackleton | first7 = CR. | last8 = Markowitz | first8 = JS. | last9 = Nuesse | first9 = BJ. | title = Aplastic anemia complicating orthotopic liver transplantation. | journal = Hepatology | volume = 26 | issue = 4 | pages = 865-9 | month = Oct | year = 1997 | doi = 10.1002/hep.510260410 | PMID = 9328306 }}</ref><ref name="Kurtzman-1989">{{Cite journal  | last1 = Kurtzman | first1 = G. | last2 = Young | first2 = N. | title = Viruses and bone marrow failure. | journal = Baillieres Clin Haematol | volume = 2 | issue = 1 | pages = 51-67 | month = Jan | year = 1989 | doi =  | PMID = 2537667 }}</ref><ref name="Brown-1997">{{Cite journal  | last1 = Brown | first1 = KE. | last2 = Tisdale | first2 = J. | last3 = Barrett | first3 = AJ. | last4 = Dunbar | first4 = CE. | last5 = Young | first5 = NS. | title = Hepatitis-associated aplastic anemia. | journal = N Engl J Med | volume = 336 | issue = 15 | pages = 1059-64 | month = Apr | year = 1997 | doi = 10.1056/NEJM199704103361504 | PMID = 9091802 }}</ref>
* [[Parvovirus B19]] in children
 
=== Congenital /Family History ===
* Fanconi's Anemia<ref name="Huck-2006">{{Cite journal  | last1 = Huck | first1 = K. | last2 = Hanenberg | first2 = H. | last3 = Gudowius | first3 = S. | last4 = Fenk | first4 = R. | last5 = Kalb | first5 = R. | last6 = Neveling | first6 = K. | last7 = Betz | first7 = B. | last8 = Niederacher | first8 = D. | last9 = Haas | first9 = R. | title = Delayed diagnosis and complications of Fanconi anaemia at advanced age--a paradigm. | journal = Br J Haematol | volume = 133 | issue = 2 | pages = 188-97 | month = Apr | year = 2006 | doi = 10.1111/j.1365-2141.2006.05998.x | PMID = 16611311 }}</ref><ref name="Li-1997">{{Cite journal  | last1 = Li | first1 = Y. | last2 = Youssoufian | first2 = H. | title = MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups. | journal = J Clin Invest | volume = 100 | issue = 11 | pages = 2873-80 | month = Dec | year = 1997 | doi = 10.1172/JCI119836 | PMID = 9389754 }}</ref> ( 98 % Autosomal recessive and 2 % X-linked recessive )
 
* Radiation<ref name="Young-2002">{{Cite journal  | last1 = Young | first1 = NS. | title = Acquired aplastic anemia. | journal = Ann Intern Med | volume = 136 | issue = 7 | pages = 534-46 | month = Apr | year = 2002 | doi =  | PMID = 11926789 }}</ref><ref name="LANGE-1955">{{Cite journal  | last1 = LANGE | first1 = RD. | last2 = WRIGHT | first2 = SW. | last3 = TOMONAGA | first3 = M. | last4 = KURASAKI | first4 = H. | last5 = MATSUOKE | first5 = S. | last6 = MATSUNAGA | first6 = H. | title = Refractory anemia occurring in survivors of the atomic bombing in Nagasaki, Japan. | journal = Blood | volume = 10 | issue = 4 | pages = 312-24 | month = Apr | year = 1955 | doi =  | PMID = 14363312 }}</ref>
 
===Miscellaneous===
* Thymoma
* Pregnancy<ref name="Walport-1982">{{Cite journal  | last1 = Walport | first1 = MJ. | last2 = Hubbard | first2 = WN. | last3 = Hughes | first3 = GR. | title = Reversal of aplastic anaemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide. | journal = Br Med J (Clin Res Ed) | volume = 285 | issue = 6344 | pages = 769-70 | month = Sep | year = 1982 | doi =  | PMID = 6810992 }}</ref><ref name="Nissen-1991">{{Cite journal  | last1 = Nissen | first1 = C. | title = The pathophysiology of aplastic anemia. | journal = Semin Hematol | volume = 28 | issue = 4 | pages = 313-8 | month = Oct | year = 1991 | doi =  | PMID = 1759172 }}</ref>
* Radiation<ref name="Young-2002">{{Cite journal  | last1 = Young | first1 = NS. | title = Acquired aplastic anemia. | journal = Ann Intern Med | volume = 136 | issue = 7 | pages = 534-46 | month = Apr | year = 2002 | doi =  | PMID = 11926789 }}</ref><ref name="LANGE-1955">{{Cite journal  | last1 = LANGE | first1 = RD. | last2 = WRIGHT | first2 = SW. | last3 = TOMONAGA | first3 = M. | last4 = KURASAKI | first4 = H. | last5 = MATSUOKE | first5 = S. | last6 = MATSUNAGA | first6 = H. | title = Refractory anemia occurring in survivors of the atomic bombing in Nagasaki, Japan. | journal = Blood | volume = 10 | issue = 4 | pages = 312-24 | month = Apr | year = 1955 | doi =  | PMID = 14363312 }}</ref>


==Investigations==
==Investigations==
{{familytree/start |summary= Aplastic anemia investigation Algorithm}}
{{familytree/start |summary= Aplastic anemia investigation Algorithm}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | A01 | | | | | | | | | | | | | | | | | | | | | | | |A01 = '''Aplastic anemia'''}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | A01 | | | | | | | | | | | | | | | | | | | | | | | |A01 = Symptoms of dyspnea , fatigue , bleeding and recurrent infection}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
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{{familytree | | | | | | | | | | | |!| | | | | | }}
{{familytree | | | | | | | | | | | |!| | | | | | }}
{{familytree | | | |,|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|.| | | }}
{{familytree | | | |,|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|.| | | }}
{{familytree | | | B01 | | | | | | B02 | | | | | | B03 | | | | | | | |B01='''Moderate'''<br>1. Bone marrow cellularity < 30 % <br>2. Absence of severe pancytopenia<br>3. Depression of atleast 2 / 3rd blood elements |B02='''Severe'''<br>1. Bone Marrow cellularity < 25 %  OR <br>2. Bone Marrow cellularity < 50 % out of which < 30 % cells are hematopeotic and atleast 2 out of the following : <br>a. Absolute reticulocyte count < 40000 / ul.<br>b. ANC < 500 / ul<br>c. Platelet < 10,000 / ul  |B03= '''Very Severe'''<br>Same as Severe + <br>Absolute neutrophil count < 200 / ul}}
{{familytree | | | B01 | | | | | | B02 | | | | | | B03 | | | | | | | |B01='''Moderate'''<br>1. Bone marrow cellularity < 30 % <br>2. Absence of severe pancytopenia<br>3. Depression of atleast 2 / 3rd blood elements |B02='''Severe<ref name="Rozman-1987">{{Cite journal  | last1 = Rozman | first1 = C. | last2 = Marín | first2 = P. | last3 = Nomdedeu | first3 = B. | last4 = Montserrat | first4 = E. | title = Criteria for severe aplastic anaemia. | journal = Lancet | volume = 2 | issue = 8565 | pages = 955-7 | month = Oct | year = 1987 | doi =  | PMID = 2889870 }}</ref>
'''<br>1. Bone Marrow cellularity < 25 %  OR <br>2. Bone Marrow cellularity < 50 % out of which < 30 % cells are hematopeotic and atleast 2 out of the following : <br>a. Absolute reticulocyte count < 40000 / ul.<br>b. ANC < 500 / ul<br>c. Platelet < 10,000 / ul  |B03= '''Very Severe'''<br>Same as Severe + <br>Absolute neutrophil count < 200 / ul}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | }}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | }}
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{{familytree | | | | | | | | | | |,|-|-|-|-|-|-|-|-|-|-|-|^|-|-|-|-|-|-|-|-|-|-|-|.| | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | |,|-|-|-|-|-|-|-|-|-|-|-|^|-|-|-|-|-|-|-|-|-|-|-|.| | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | | | | | | B01 | | | | | | | | | | | | | | | | | | | | | | B02 | | | | | | | | | | | | | | | | | | | | |B01='''Hematopoietic stem cell transplantation(HSCT)'''|B02='''Immunotherapy'''}}
{{familytree | | | | | | | | | | B01 | | | | | | | | | | | | | | | | | | | | | | B02 | | | | | | | | | | | | | | | | | | | | |B01='''Hematopoietic stem cell transplantation(HSCT)<ref name="Gupta-2010">{{Cite journal  | last1 = Gupta | first1 = V. | last2 = Eapen | first2 = M. | last3 = Brazauskas | first3 = R. | last4 = Carreras | first4 = J. | last5 = Aljurf | first5 = M. | last6 = Gale | first6 = RP. | last7 = Hale | first7 = GA. | last8 = Ilhan | first8 = O. | last9 = Passweg | first9 = JR. | title = Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. | journal = Haematologica | volume = 95 | issue = 12 | pages = 2119-25 | month = Dec | year = 2010 | doi = 10.3324/haematol.2010.026682 | PMID = 20851870 }}</ref><ref name="Scheinberg-2012">{{Cite journal  | last1 = Scheinberg | first1 = P. | last2 = Young | first2 = NS. | title = How I treat acquired aplastic anemia. | journal = Blood | volume = 120 | issue = 6 | pages = 1185-96 | month = Aug | year = 2012 | doi = 10.1182/blood-2011-12-274019 | PMID = 22517900 }}</ref><ref name="Young-2013">{{Cite journal  | last1 = Young | first1 = ME. | last2 = Potter | first2 = V. | last3 = Kulasekararaj | first3 = AG. | last4 = Mufti | first4 = GJ. | last5 = Marsh | first5 = JC. | title = Haematopoietic stem cell transplantation for acquired aplastic anaemia. | journal = Curr Opin Hematol | volume = 20 | issue = 6 | pages = 515-20 | month = Nov | year = 2013 | doi = 10.1097/MOH.0b013e328365af83 | PMID = 24104412 }}</ref>
'''|B02='''Immunotherapy'''}}
{{familytree | | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| | | | | | | | | | |,|-|-|-|-|-|+|-|-|-|-|-|.| | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| | | | | | | | | | |,|-|-|-|-|-|+|-|-|-|-|-|.| | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | C01 | | | | | C02 | | | | | C03 | | | | | | | | | C04 | | | | C05 | | | | C06 | | | |C01=Severe and very severe Aplastic anemia|C02=Patients < 40 yrs old |C03= HLA  match|C04=Moderate Aplastic anemia |C05=Patients > 40 Yrs old| C06=HLA not matched hence not a candidate for HSCT }}
{{familytree | | | C01 | | | | | C02 | | | | | C03 | | | | | | | | | C04 | | | | C05 | | | | C06 | | | |C01=Severe and very severe Aplastic anemia|C02=Patients < 40 yrs old |C03= HLA  match|C04=Moderate Aplastic anemia |C05=Patients > 40 Yrs old| C06=HLA not matched hence not a candidate for HSCT }}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |  | |}}
{{familytree | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |  | |}}
{{familytree/end}}
{{familytree/end}}


==Drugs used in Immunotherapy==
==Drugs used in Immunotherapy==
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{{familytree | | B01 | | | | | B02 | | | | | B03 |B01='''Horse ATG'''<br>( 20 mg / kg x 4 days )<br> + <br> '''Cyclosporine (CSA)'''<br> ( 12 - 15 mg / kg in divided doses b.i.d x 6 months |B02='''Granulocyte colony-stimulating factor ( G-CSF)'''<br> (5 µg / kg/ day x 90 days)|B03= For relapsing and in countries where ATG is unavailable }}
{{familytree | | B01 | | | | | B02 | | | | | B03 |B01='''Horse ATG'''<br>( 20 mg / kg x 4 days )<br> + <br> '''Cyclosporine (CSA)'''<br> ( 12 - 15 mg / kg in divided doses b.i.d x 6 months |B02='''Granulocyte colony-stimulating factor ( G-CSF)'''<br> (5 µg / kg/ day x 90 days)|B03= For relapsing and in countries where ATG is unavailable }}
{{familytree | | | | | | | | | | | | | | | | |!| | }}
{{familytree | | | | | | | | | | | | | | | | |!| | }}
{{familytree | | | | | | | | | | | | | | | | C01 | |C01='''Cyclophosphamide (CTX) '''<br>( 30 mg / kg IV x 4 days over 1 hr )<br> + <br>''' Cyclosporin (CSA)''' <br> (3 mg / kg / day )<br> Starting on day 11 to maintain trough and peak blood levels of 150 - 250 mg/ml and  700 - 1000 mg / ml respectively for 180 days  }}
{{familytree | | | | | | | | | | | | | | | | C01 | |C01='''Cyclophosphamide ( CTX ) '''<br>( 30 mg / kg IV x 4 days over 1 hr )<br> + <br>''' Cyclosporin (CSA)''' <br> (3 mg / kg / day )<br> Starting on day 11 to maintain trough and peak blood levels of 150 - 250 mg/ml and  700 - 1000 mg / ml respectively for 180 days  }}
{{familytree | | | | | | | | | | | | | | | | | | | }}
{{familytree | | | | | | | | | | | | | | | | | | | }}
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==Do's==
==Do's==
* Take detailed history of all patients presenting with anemia.
* Take detailed history of all patients presenting with anemia .
* Have a high suspicion and look for any identifiable causes.
* Have a high suspicion and look for any identifiable causes .
* When treating with ATG keep the platelet count >20,000 / microL at all times. Keep platelets and leukoreduced irradiated blood products readily available.
* When treating with ATG keep the platelet count >20,000 / microL at all times . Keep platelets and leukoreduced irradiated blood products readily available .
* Secure a central line which would help in blood drawing, infusing blood products and other fluids.
* Secure a central line which would help in blood drawing , infusing blood products and other fluids .
* When treating with cyclosporine check levels regularly , renal function ( creatinine levels ), blood pressure and for signs of neurotoxicity. Cyclosporine should be   given for six months but doasge should be tapered right from the first month to maintain levels of 200 to 250 ng/ml.
* When treating with [[cyclosporine]] check levels regularly , renal function ( creatinine levels ), blood pressure and for signs of neurotoxicity . Cyclosporine should be given for six months but dosage should be tapered right from the first month to maintain levels of 200 to 250 ng / ml .
* In previously untreated adults use horse ATG than rabbit ATG.
* In previously untreated adults use horse ATG instead of rabbit ATG .


==Don'ts==
==Don'ts==
* G-CSF should not be used as a primary therapy because that will only delay the onset of effective therapy (Immunosuppressive therapy) . There is an increased incidence of MDS/AML as well as poor outcome in relapsing patients who were treated with G-CSF.
* [[G-CSF]] should not be used as a primary therapy because that will only delay the onset of effective therapy ( Immunosuppressive therapy ) . There is an increased incidence of MDS / AML as well as poor outcome in relapsing patients who were treated with G-CSF .
*  There is no evidence to use high dose intravenous cyclophosphamide (total dose 200 mg/kg given over four days), with or without cyclosporine in the initial treatment of  severe aplastic anemia (SAA) . However, this regimen can  be used in patients who did not respond to immunosuppressive therapy.
*  There is no evidence to use high dose intravenous [[cyclophosphamide]] ( total dose 200 mg / kg given over four days ) , with or without cyclosporine in the initial treatment of  severe aplastic anemia ( SAA ) . However, this regimen can  be used in patients who did not respond to immunosuppressive therapy .
 
 


==References==
==References==

Latest revision as of 11:50, 13 March 2014


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Chetan Lokhande, M.B.B.S [2]


Overview

Aplastic Anemia is a condition where the bone marrow and the bone marrow cells are damaged . A deficiency of all the three cell types is seen which leads to pancytopenia . Decrease in red blood cells (Anemia) presents as pallor, fatigue , dyspnea and leg pain . Decrease in platelets (Thrombocytopenia) presents as mucosal bleeding , purpura and bruising . Decrease in white blood cells (Neutropenia) manifests as recurrent infection .

Causes

Idiopathic

Drug History

  • Chemotherapy
  • Bone marrow suppressing drugs[1]
  • Industrial chemicals[10][11] and insecticides eg , benzene hexachloride ( lindane )[12]

Infection

Congenital /Family History

  • Fanconi's Anemia[16][17] ( 98 % Autosomal recessive and 2 % X-linked recessive )

Miscellaneous

Investigations

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptoms of dyspnea , fatigue , bleeding and recurrent infection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Check routine Labs,
CBC and smear
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pancytopenia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
{{{ }}}
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate / Biopsy
 
 
 
 
 
 
 
 
 
1. Chest X-ray
2. Liver function tests
3. Vit B12 / Folate
 
 
 
 
 
 
 
 
 
Genetic / Cytology

1. Chromosomal breakpoint for Fanconi's Anemia
2. Mutational Analysis for Inherited Bone Marrow Failure Syndrome (IBMFS)
3. Flow cytometry for Paroxysmal Nocturnal Hemoglobinuria (PNH).
Check CD55 and CD59 expression on RBC for PNH.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
{{{ }}}
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
{{{ }}}
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypocellular
Diagnostic criteria of Aplastic Anemia includes
1. Increased fat / Stroma
2. No Malignant / Fibrotic infiltration
3. Normal Residual hematopoeitic cells with megaloblastic cells
Once diagnosed as Aplastic anemia rule out the common causes of Aplastic anemia.
 
 
 
 
 
 
 
 
 
 
 
Variable / Infiltrated / Hypercellular
Causes are :
1. Myelodysplastic Syndrome
2. Leukemia
3. Hodgkins
4. Storage disorder
5. Anorexia Nervosa
6. Nutritional deficiency
7. Myelofibrosis
8. Solid tumors
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Grading

 
 
 
 
 
 
 
 
 
 
Aplastic anemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moderate
1. Bone marrow cellularity < 30 %
2. Absence of severe pancytopenia
3. Depression of atleast 2 / 3rd blood elements
 
 
 
 
 
Severe[21]
1. Bone Marrow cellularity < 25 % OR
2. Bone Marrow cellularity < 50 % out of which < 30 % cells are hematopeotic and atleast 2 out of the following :
a. Absolute reticulocyte count < 40000 / ul.
b. ANC < 500 / ul
c. Platelet < 10,000 / ul
 
 
 
 
 
Very Severe
Same as Severe +
Absolute neutrophil count < 200 / ul
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Management

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aplastic Anemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematopoietic stem cell transplantation(HSCT)[22][23][24]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunotherapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe and very severe Aplastic anemia
 
 
 
 
Patients < 40 yrs old
 
 
 
 
HLA match
 
 
 
 
 
 
 
 
Moderate Aplastic anemia
 
 
 
Patients > 40 Yrs old
 
 
 
HLA not matched hence not a candidate for HSCT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
{{{ }}}
 

Drugs used in Immunotherapy

 
 
 
 
 
 
 
 
Immunotherapy in Aplastic anemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Horse ATG
( 20 mg / kg x 4 days )
+
Cyclosporine (CSA)
( 12 - 15 mg / kg in divided doses b.i.d x 6 months
 
 
 
 
Granulocyte colony-stimulating factor ( G-CSF)
(5 µg / kg/ day x 90 days)
 
 
 
 
For relapsing and in countries where ATG is unavailable
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide ( CTX )
( 30 mg / kg IV x 4 days over 1 hr )
+
Cyclosporin (CSA)
(3 mg / kg / day )
Starting on day 11 to maintain trough and peak blood levels of 150 - 250 mg/ml and 700 - 1000 mg / ml respectively for 180 days
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Do's

  • Take detailed history of all patients presenting with anemia .
  • Have a high suspicion and look for any identifiable causes .
  • When treating with ATG keep the platelet count >20,000 / microL at all times . Keep platelets and leukoreduced irradiated blood products readily available .
  • Secure a central line which would help in blood drawing , infusing blood products and other fluids .
  • When treating with cyclosporine check levels regularly , renal function ( creatinine levels ), blood pressure and for signs of neurotoxicity . Cyclosporine should be given for six months but dosage should be tapered right from the first month to maintain levels of 200 to 250 ng / ml .
  • In previously untreated adults use horse ATG instead of rabbit ATG .

Don'ts

  • G-CSF should not be used as a primary therapy because that will only delay the onset of effective therapy ( Immunosuppressive therapy ) . There is an increased incidence of MDS / AML as well as poor outcome in relapsing patients who were treated with G-CSF .
  • There is no evidence to use high dose intravenous cyclophosphamide ( total dose 200 mg / kg given over four days ) , with or without cyclosporine in the initial treatment of severe aplastic anemia ( SAA ) . However, this regimen can be used in patients who did not respond to immunosuppressive therapy .

References

  1. 1.0 1.1 1.2 1.3 Young, NS. (2002). "Acquired aplastic anemia". Ann Intern Med. 136 (7): 534–46. PMID 11926789. Unknown parameter |month= ignored (help)
  2. Shichishima, T.; Okamoto, M.; Ikeda, K.; Kaneshige, T.; Sugiyama, H.; Terasawa, T.; Osumi, K.; Maruyama, Y. (2002). "HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria". Blood. 100 (1): 22–8. PMID 12070003. Unknown parameter |month= ignored (help)
  3. Saunthararajah, Y.; Nakamura, R.; Nam, JM.; Robyn, J.; Loberiza, F.; Maciejewski, JP.; Simonis, T.; Molldrem, J.; Young, NS. (2002). "HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome". Blood. 100 (5): 1570–4. PMID 12176872. Unknown parameter |month= ignored (help)
  4. Young, NS.; Calado, RT.; Scheinberg, P. (2006). "Current concepts in the pathophysiology and treatment of aplastic anemia". Blood. 108 (8): 2509–19. doi:10.1182/blood-2006-03-010777. PMID 16778145. Unknown parameter |month= ignored (help)
  5. Wallerstein, RO.; Condit, PK.; Kasper, CK.; Brown, JW.; Morrison, FR. (1969). "Statewide study of chloramphenicol therapy and fatal aplastic anemia". JAMA. 208 (11): 2045–50. PMID 5818983. Unknown parameter |month= ignored (help)
  6. Brodie, MJ.; Pellock, JM. (1995). "Taming the brain storms: felbamate updated". Lancet. 346 (8980): 918–9. PMID 7564721. Unknown parameter |month= ignored (help)
  7. Handoko, KB.; Souverein, PC.; van Staa, TP.; Meyboom, RH.; Leufkens, HG.; Egberts, TC.; van den Bemt, PM. (2006). "Risk of aplastic anemia in patients using antiepileptic drugs". Epilepsia. 47 (7): 1232–6. doi:10.1111/j.1528-1167.2006.00596.x. PMID 16886988. Unknown parameter |month= ignored (help)
  8. Kay, AG. (1976). "Myelotoxicity of gold". Br Med J. 1 (6020): 1266–8. PMID 817772. Unknown parameter |month= ignored (help)
  9. Laporte, JR.; Ibáñez, L.; Ballarín, E.; Pérez, E.; Vidal, X. (1998). "Fatal aplastic anaemia associated with nifedipine". Lancet. 352 (9128): 619–20. doi:10.1016/S0140-6736(98)24034-7. PMID 9746025. Unknown parameter |month= ignored (help)
  10. SCOTT, JL.; CARTWRIGHT, GE.; WINTROBE, MM. (1959). "Acquired aplastic anemia: an analysis of thirty-nine cases and review of the pertinent literature". Medicine (Baltimore). 38 (2): 119–72. PMID 13656164. Unknown parameter |month= ignored (help)
  11. Powars, D. (1965). "Aplastic anemia secondary to glue sniffing". N Engl J Med. 273 (13): 700–2. doi:10.1056/NEJM196509232731307. PMID 5827034. Unknown parameter |month= ignored (help)
  12. LOGE, JP. (1965). "APLASTIC ANEMIA FOLLOWING EXPOSURE TO BENZENE HEXACHLORIDE (LINDANE)". JAMA. 193: 110–4. PMID 14304352. Unknown parameter |month= ignored (help)
  13. Goss, JA.; Schiller, GJ.; Martin, P.; Seu, P.; Stribling, R.; McDiarmid, SV.; Shackleton, CR.; Markowitz, JS.; Nuesse, BJ. (1997). "Aplastic anemia complicating orthotopic liver transplantation". Hepatology. 26 (4): 865–9. doi:10.1002/hep.510260410. PMID 9328306. Unknown parameter |month= ignored (help)
  14. Kurtzman, G.; Young, N. (1989). "Viruses and bone marrow failure". Baillieres Clin Haematol. 2 (1): 51–67. PMID 2537667. Unknown parameter |month= ignored (help)
  15. Brown, KE.; Tisdale, J.; Barrett, AJ.; Dunbar, CE.; Young, NS. (1997). "Hepatitis-associated aplastic anemia". N Engl J Med. 336 (15): 1059–64. doi:10.1056/NEJM199704103361504. PMID 9091802. Unknown parameter |month= ignored (help)
  16. Huck, K.; Hanenberg, H.; Gudowius, S.; Fenk, R.; Kalb, R.; Neveling, K.; Betz, B.; Niederacher, D.; Haas, R. (2006). "Delayed diagnosis and complications of Fanconi anaemia at advanced age--a paradigm". Br J Haematol. 133 (2): 188–97. doi:10.1111/j.1365-2141.2006.05998.x. PMID 16611311. Unknown parameter |month= ignored (help)
  17. Li, Y.; Youssoufian, H. (1997). "MxA overexpression reveals a common genetic link in four Fanconi anemia complementation groups". J Clin Invest. 100 (11): 2873–80. doi:10.1172/JCI119836. PMID 9389754. Unknown parameter |month= ignored (help)
  18. 18.0 18.1 LANGE, RD.; WRIGHT, SW.; TOMONAGA, M.; KURASAKI, H.; MATSUOKE, S.; MATSUNAGA, H. (1955). "Refractory anemia occurring in survivors of the atomic bombing in Nagasaki, Japan". Blood. 10 (4): 312–24. PMID 14363312. Unknown parameter |month= ignored (help)
  19. Walport, MJ.; Hubbard, WN.; Hughes, GR. (1982). "Reversal of aplastic anaemia secondary to systemic lupus erythematosus by high-dose intravenous cyclophosphamide". Br Med J (Clin Res Ed). 285 (6344): 769–70. PMID 6810992. Unknown parameter |month= ignored (help)
  20. Nissen, C. (1991). "The pathophysiology of aplastic anemia". Semin Hematol. 28 (4): 313–8. PMID 1759172. Unknown parameter |month= ignored (help)
  21. Rozman, C.; Marín, P.; Nomdedeu, B.; Montserrat, E. (1987). "Criteria for severe aplastic anaemia". Lancet. 2 (8565): 955–7. PMID 2889870. Unknown parameter |month= ignored (help)
  22. Gupta, V.; Eapen, M.; Brazauskas, R.; Carreras, J.; Aljurf, M.; Gale, RP.; Hale, GA.; Ilhan, O.; Passweg, JR. (2010). "Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors". Haematologica. 95 (12): 2119–25. doi:10.3324/haematol.2010.026682. PMID 20851870. Unknown parameter |month= ignored (help)
  23. Scheinberg, P.; Young, NS. (2012). "How I treat acquired aplastic anemia". Blood. 120 (6): 1185–96. doi:10.1182/blood-2011-12-274019. PMID 22517900. Unknown parameter |month= ignored (help)
  24. Young, ME.; Potter, V.; Kulasekararaj, AG.; Mufti, GJ.; Marsh, JC. (2013). "Haematopoietic stem cell transplantation for acquired aplastic anaemia". Curr Opin Hematol. 20 (6): 515–20. doi:10.1097/MOH.0b013e328365af83. PMID 24104412. Unknown parameter |month= ignored (help)