Acquired Aplastic Anemia.docx

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