Acquired Aplastic Anemia.docx
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AcquiredAplasticAnemia
AcquiredAplasticAnemia
Young,NealS.MD
AuthorInformation
FromtheNationalHeart,Lung,andBloodInstitute,NationalInstitutesofHealth,Bethesda,Maryland.
Forauthoraffiliationandcurrentaddress,seeendoftext.
Acknowledgments:
TheauthorthanksDrs.JaroslawMaciejewski,JohnBarrett,ElaineSloand,andCynthiaDunbarfortheircarefulreadingofthemanuscript.
GrantSupport:
Dr.YoungissupportedentirelybyintramuralfundsfromtheNationalHeart,Lung,andBloodInstitute.
RequestsforSingleReprints:
NealS.Young,MD,Building10,Room7C103,NationalInstitutesofHealth,9000RockvillePike,Bethesda,MD20892-1652.
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Abstract
Inaplasticanemia,hematopoiesisfails:
Bloodcellcountsareextremelylow,andthebonemarrowappearsempty.Thepathophysiologyofaplasticanemiaisnowbelievedtobeimmune-mediated,withactivedestructionofblood-formingcellsbylymphocytes.Theaberrantimmuneresponsemaybetriggeredbyenvironmentalexposures,suchastochemicalsanddrugsorviralinfectionsand,perhaps,endogenousantigensgeneratedbygeneticallyalteredbonemarrowcells.Inpatientswithpost-hepatitisaplasticanemia,antibodiestotheknownhepatitisvirusesareabsent;theunknowninfectiousagentmaybemorecommonindevelopingcountries,whereaplasticanemiaoccursmorefrequentlythanitdoesintheWest.
Thesyndromeparoxysmalnocturnalhemoglobinuria(PNH)isintimatelyrelatedtoaplasticanemiabecausemanypatientswithbonemarrowfailurehaveanincreasedpopulationofabnormalcells.InPNH,anentireclassofproteinsisnotdisplayedonthecellsurfacebecauseofanacquiredX-chromosomegenemutation.ThePNHcellsmayhaveaselectiveadvantageinresistingimmuneattack.Incontrast,thediseasemyelodysplasiacanbeconfusedwithaplasiaandcanalsoevolvefromaplasticanemia.Theoccurrenceofcytogeneticabnormalitiesinpatientsyearsafterpresentationimpliesthatgenomicinstabilityisafeatureofthisimmune-mediateddisease.
Aplasticanemiacanbeeffectivelytreatedbystem-celltransplantationorimmunosuppressivetherapy.Transplantationiscurativebutisbestusedforyoungerpatientswhohavehistocompatiblesiblingdonors.Antithymocyteglobulinandcyclosporinerestorehematopoiesisinapproximatelytwothirdsofpatients.However,recoveryofbloodcellcountisoftenincomplete,recurrentpancytopeniarequiresretreatment,andsomepatientsdeveloplatecomplications(especiallymyelodysplasia).
Aplasticanemia’slonghistory,fromitsearlydescriptionbyEhrlich
(1)attheendofthe19thcentury,andthesimplicityofitspathology,anemptybonemarrow,havemadeittheparadigmofhematopoieticfailuresyndromes.Aplasticanemiaisnowincreasinglyrecognizedasbeingcloselyrelatedtootherhematologicdiseases(Figure1).Erythrocytes,granulocytes,andplatelets,whicharenormallyproducedinthebonemarrow,decreasetodangerouslylowlevels.Bloodcellcountsdeterminepresentationandprognosis.Anemialeadstofatigue,dyspnea,andcardiacsymptoms;thrombocytopeniatobruisingandmucosalbleeding;andneutropeniatosharplyincreasedsusceptibilitytoinfection.Whenpatientsaretreatedwithtransfusionsandantibioticsalone,survivalratesarepoorandrelatedtotheseverityofthepancytopenia,asdefinedbythepresenceoftwoofthreecriteria:
aneutrophilcountlessthan0.5×109cells/L,aplateletcountlessthan20×109cells/L,andareticulocytecountlessthan1%.Whentheneutrophilcountislessthan0.2×109cells/L,thediseaseischaracterizedasverysevere.Intheearly20thcentury,patientsoftendiedquicklyofheartfailure,profusehemorrhage,oroverwhelminginfection.Inthemoderneraoferythrocyteandplatelettransfusions,themostcommoncausesofdeatharerecurrentbacterialsepsisorfungalinvasionofcriticalorganssecondarytorefractorygranulocytopenia.
Figure1
Historically,aplasticanemiahasbeenstronglyassociatedwithexposuretochemicalsanddrugsintheenvironment,givingthediseaseasocialimpactdisproportionatetoitsincidence
(2).TherecognitionofbonemarrowfailureinworkersexposedtobenzeneledtoheroicindustrialhygienecrusadesbyAliceHamiltonandHarrisonMartlandintheUnitedStatesinthe1920sand1930s.Inthelate1940sandearly1950s,anepidemicofaplasticanemiaappearedtofollowtheintroductionofchloramphenicol,andthediseasehasbeenlinkedtomanyclassesofpharmaceuticalswidelyusedinmedicalpractice(Table).Becauseaplasticanemiahasbecomesuchafeareddisorderasaresultofitsassociationwithcommondruguse,evenafewcasescanhaveaprofoundeffectonnewdrugdevelopmentbythepharmaceuticalindustry.Also,thisbelievedassociationwithnumerous,diversepossiblecauses,fromchemicalsanddrugstohepatitis,infectiousmononucleosis,pregnancy,andcollagenvascularprocesses(forexample,eosinophilicfasciitis),hasledtothebeliefthattherealsoarenumerousanddifferentmechanismsofdisease.
Table.DrugsAssocia...
However,wenowhaveaplausible,unifiedmodelofthepathophysiologyofaplasticanemia,drawnfrombothcompellingclinicalobservationsoftherapeuticefficacyandsystematiclaboratoryexperimentation.Theearly,successfuluseofbonemarrowtransplantationtocureaplasticanemiaimplicatedastem-celldeficiency.Later,responsestoimmunosuppressivetherapiespointedtoanimmunemechanismofhematopoieticfailure.Asaplasticanemiaisprogressivelydemystified,questionsofsomebiologicalinterestemerge.Thesearerelevanttobonemarrowfailureaswellastoourconceptionsofautoimmunediseasesofotherorgansystemsandtotherelationshipofimmunemechanismstomalignanttransformation.
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ImmunePathophysiologyofAplasticAnemia
MostcasesofacquiredaplasticanemiacanbepathophysiologicallycharacterizedasT-cell–mediated,organ-specificdestructionofbonemarrowhematopoieticcells(4).Inanindividualpatient,theaberrantimmuneresponsecansometimesbelinkedtoaviralinfectionortodrugorchemicalexposure(Figure2).Thereismuchlessevidenceforothermechanisms,suchasdirecttoxicityforstemcellsoradeficiencyofstromal-cellorhematopoieticgrowthfactorfunction.Furthermore,thevariabilityinclinicalcourseandresponsetotreatmentcanbeexplainedbythequantitativedegreeofstem-celldestructionandqualitativevariationsinimmuneresponse.
Figure2
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HematopoieticFailure
Thatfailureofbloodcellproductionwasresponsiblefortheemptybonemarrowwasaprescientconclusionoftheearliestobserversofthe“yellowfat”ofthebonyspacesandtheabsenceofthemorphologicallydiverseprecursorsofmaturebloodelements—stillsostrikingonexaminationofbonemarrowaspiratesmearsorcorebiopsyspecimens(5).Magneticresonanceimagingofthevertebraeshowsuniformreplacementofmarrowwithfat.Immaturehematopoieticcellscanalsobequantitatedbyfluorescent-activatedflowcytometry,whichcandetecttheCD34cellantigen,anadhesionproteinpresentonlessthan1%ofnormalbonemarrow.CD34cellsarealmostabsentinaplasticanemia.Progenitorcellscapableofformingerythroid,myeloid,andmegakaryocyticcoloniesintissueculturearegreatlyreduced,andassaysofveryprimitive,quiescent,hematopoieticcellsthatarecloselyrelatedifnotidenticaltostemcellsshowasimilarconsistentandseveredeficit.Byextrapolationfromsuchfunctionalstudiesofaplasticbonemarrow,itislikelythatpatientspresentwithpancytopeniawhenstem-cellandprogenitor-cellpopulationshavedecreasedtoapproximately1%orlessofnormal.Suchaprofounddeficiencyhasimportantqualitativeconsequences,asreflectedintheshortenedtelomerelengthofgranulocytesofpatientswithaplasticanemia(6).
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ImmuneDestruction
Theefficiencyofimmunesystemdestructionofblood-formingcellsisobviousin“runtdisease”inanimalsandintransfusion-associatedgraft-versus-hostdisease(GVHD)inhumans(7).Inthesesyndromes,smallnumbersofalloreactiveTcellsproducefatalaplasticanemia,andinthemousemodel,weknowthatstem-celldestructionisrapidandalmostcomplete.Muchlaboratorydatasupportthehypothesisthat,inmostpatientswithacquiredaplasticanemia,lymphocytesareresponsibleforthedestructionofthehematopoieticcellcompartment(4).
Earlyexperimentsshowedthatthepatients’lymphocytessuppressedhematopoiesis.Thesecellsproducedasoluble,inhibitoryfactorthatwaseventuallyidentifiedasinterferon-[gamma].ActivationofaTH1-typeT-cellresponsehasbeeninferredfromimmunophenotypiccharacterizationofTcellsandexcessiveproductionofinterferon,tumornecrosisfactor,andinterleukin-2.Detectionofintracellularinterferon-[gamma]inpatientsamplesbyflowcytometrymaycorrelatewithresponsivenesstoimmunosuppressivetherapyandmaypredictrelapse(8).Alteredimmunityresultsindestruction,specificallyFas-mediatedCD34celldeath,andinactivationofintracellularpathwaysleadingtocell-cyclearrest.Immunityislocalandhasbeenmodeledintissueculturewhenlowconcentrationsofinterferon-[gamma]aresecretedintothemarrowmicroenvironment.Inananimalmodel,bonemarrowfailureafterinjectionofalloreactivelymphocytescanbepreventedbytreatmentwithamonoclonalantibodytointerferon-[gamma](9).
Thenatureoftheantigenorantigensdrivingthepathologicimmuneresponseisunknown.Atthemolecularlevel,lymphocytesinaplasticanemiashowsimilaritytoTcellsinmultiplesclerosis,diabetes,andotherrelatedillnesses.Characterizat