內(nèi)科學溶血(英文)

Hemolysis

1LearningObjectivesDistinguishextravascularfromintravascularhemolysisRecognizehemolyticanemiabyitsclinicalandlaboratoryfeaturesDiagnosethecommontypesofhemolyticanemias2NormalHypoproliferativeMaturationabnormality

HemolyticMarrowRedcelllifespan–120daysMarrow/CirculatingRedCellRelationshipsInDisturbancesOfTheErythron3Thedistinguishingfeatureofthehemolyticanemiasistheincreasedrateofdestructionofcirculatingredcells.HemolyticanemiasarerecognizedbyanemiawithsignsofincreasedredcellproductionwhichoccursasthenormalbonemarrowattemptstocompensatefortheacceleratedlossofRBC’s.Peripheralsmear–polychromasiaReticulocytosiswithanelevatedRPIChangesinRBCmorphologyElevatedLDHfromredcellbreakdownIncreaseinhemoglobinbreakdownpigmentsAccompaniedbyintenseerythroidhyperplasiaofthemarrow4Howdowediagnosehemolyticanemia?WestartwiththehistoryandphysicalexamWedoacarefulexaminationoftheperipheralsmearWemeasurethereticulocytecountandcalculatethereticulocyteproductionindex(RPI).>3(with1beingbaseline)Wesearchforhemoglobinbreakdownpigmentsindicativeofhemolysis5ScleralIcterusJaundice

duetoincreasedbilipigment–bestseeninthesclerae6SplenomegalyOneofthemostconstantfeaturesofextravascularhemolysisItiscausedbyaccelerateddestructionofredcells,mediatedbymacrophagesinthespleen,andsometimestheliver7PigmentedGallStonesFromincreasedbilirubincontentofthebile,iftheprocessischronic.8PolychromasiaReticulocytescontainalargeamountofRNAwhichstainsbluishredonastandardbloodsmear.BecausethereisashiftofmarrowreticsintothePB,thereispolychromasia.Alsolookforshapechanges.9AfterexaminingtheperipheralsmearandcalculatingthereticulocyteindexWemeasure

LDHBilirubinTheunconjugatedbilirubiniselevatedwithextravascularhemolysis10Whatisthepredominantsiteofredcellbreakdowninhemolysis?Extravascular–outsidethebloodvesselsWithinmacrophagesintheSpleenLiverCauseshyperbilirubinemiaIntravascular–withinbloodvesselsPlayslittleornoroleinnormalredcelldestruction,butplaysamajorroleincertaintypesofhemolyticanemiaCauseshemoglobinuriaand/orhemosiderinuria11RedCellDestructionbytheReticuloendothelialSystemRBCRECellHbUrobilinogenCO(expired)BilirubinLiverFeTransferrinGlobinAminoAcidPool12FecalUrobilinogenHemoglobinTetramerHemoglobinDimerHEPATOCYTEFeBilirubinHaptoglobinMethemalbuminHemopexinRBCIntravascularRedCellHemolysisMethemoglobinHemeGlobinHemosiderinHemoglobinMethemoglobiemosiderinuriaIntravascularHemolyticEventLEVELTIME(d)SerumHaptoglobinHemoglobinuria14IndicatorsofIntravascularHemolysisAbsenceofhaptoglobinPresenceoffreehemoglobininserumHemoglobinuria(acute)Hemosiderinuria(chronic)AbsenceofhemopexinPresenceofmethemalbumin15So,oncewehavedeterminedthathemolysisiscausingtheanemia,

howdowedeterminewhatiscausingthehemolysis?

Isitaproblemintrinsictotheredcell,oristheredcellmerelyaninnocentbystanderinahostileenvironment?16ClassificationofHemolyticAnemiasIntracellularDefectsMembranedefectMetabolicdefectHemoglobinabnormality17Case#1

A55yomanwasseenforincreasingfatigueoverseveralmonthsHiswifenoticedhehadyelloweyesHisphysiciannotedthathisspleenwaspalpable5cmbelowtheLCBHisHgbwas8gmandhisreticctwas15%.Bilirubinwas3.0T,2.5Ind(elevated)1852?Complicationspostsplenectomy407101215AnemiaSplenectomyIntermittentjaundiceGallstones192021CardinalFeaturesofHereditarySpherocytosisIncreasedrateofredcelldestructionSpherocytosisSplenomegalyFamilialoccurrenceInvariablebenefitfromsplenectomy2223PathobiologyofthemembranelesioninHSAbnormalitiesofthecytoskeletalproteinsleadtoverticaluncoupling,withvesicleformationandlossofpiecesofmembrane,leadingtoshapechangeandlossofelasticity.Defectisusuallyautosomaldominant.Somecasesaredoubleheterozygotesforarecessivegene.24WhydoessplenectomybenefitpatientswithHS?25ClassificationofHemolyticAnemiasIntracellularDefectsMembranedefectMetabolicdefectHemoglobinabnormality26An18yohealthyAfricanAmericanmalehadthesuddenonsetofnausea,fever,abdominalpainanddarkurineFourdayspreviouslyhehadtakenlargedosesofacetaminophenforaflu-likeillnessPEshowedscleralicterusHgb8g,Reticct12%HeinzBodyprep+Whenquestionedcarefully,herecalledsimilarsymptomsafteraurinarytractinfectiontreatedwithsulfamethoxazoleabout5yrsagoCase#227“Blister”cellswithacutehemolysisafteranoxidantstressinG6PDDeficiencyFromHoffbrand,PettitandMoss28HeinzBodyPreparation2930G6PDdeficiencyMostcommoninheritedRBCenzymedeficiencyAffectsover400millionpeopleworldwide.HighestgenefrequenciesfoundintropicalandsubtropicalcountrieswherethedeficiencyoffersprotectionagainstfalciparummalariaIsanexampleofbalancedpolymorphismDiscoveredin1956IndividualsdevelopingHAaftertheantimalarialdrugprimaquinehadlowlevelsofG6PDintheirbloodSubsequentlyasimilaritywasnotedbetweentheHAassociatedwithFavaBeaningestion.31G6PDDeficiencyIsx-linked–femalemosaicslesssymptomaticthanaffectedmalesMorethan450biochemicaland140molecularvariants-mostlypointmutationsClassI–severelydeficientduetoclusterofmutationsinexons10and11atNADPorG6PbindingsitesAssociatedwithchronicnon-spherocytichemolyticanemia-uncommonClassII–severelydeficient(1-10%residualactivity)associatedwithacutehemolysisinducedbyoxidativestressMediterraneanvariantwithsensitivitytofavabeans.Neonataljaundicewithdeficiencyinhepatocytes(kernicterus)andRBCs(hemolyticanemia)ClassIII–moderatelydeficient(10-60%residualactivity)African(A-variant).Accountsfor90%ofcasesPresentin10%ofAfricanAmericansDeficiencyonlyinolderRBC’sHemolysisistriggeredbyoxidantdrugsorsevereinfectionsDiagnosisismadebyG6PDassayafterthehemolyticevent

32HowdoesG6PDdeficiencycausehemolysis?33HexoseMonophosphateShunt34G6PDNADPHGSHHeinzBodiesRBCMembraneDamage35HeinzBodies36ClassificationofHemolyticAnemiasIntracellularDefectsMembranedefectMetabolicdefectHemoglobinabnormality37SickleCellAnemia

Over200,000birthsannuallyworldwideSicklecellanemiaiscausedbythepresenceofamutanthemoglobinthatformsrigidaggregateswheninthedeoxyform.38ThemutationinhemoglobinSHemoglobinScontainsavalineinsteadofaglutamicacidatposition6onthebetachain.DuetothereplacementofadeninebythymineInthedeoxyconfirmation,theBeta6valinebecomesburiedinahydrophobicpocketonanadjacentBetachain,joiningthetwomoleculestogetherThisstronginteractiondoesnotoccurwhenthemoleculeisintheoxyconfirmation39ThepolymerizationofdeoxyhemoglobinSWhentheSSredcellisplacedinanenvironmentwhereitlosesitsoxygen,clustersofdeoxyHgbSform,polymerize,andalignthemselvesinlongcable-likestructures.TherateofformationofthepolymersisexquisitelydependentonconcentrationofdeoxyHgbSintheredcell.40AnirreversiblysickledcellThesebundlesoffiberdeformthecellintoanirregularrodorcrescentresemblingasickle.Polymerformationisreversiblewithoxygenation,butthemembranedamageitcausesisirreversibleandthesickledcellisdestinedforearlydestruction.InhibitionoftheformationofthesebundlesthroughmanipulationofHgbSconcentrationhasbeenamajorfocusoftherapeuticeffortstopreventsickling.4142PathophysiologyofSickleCellAnemiaSicklecellanemiaisachronicinflammatorystate,punctuatedbyanacuteincreaseininflammationinvolvingparticipationbythefollowingelements.EndotheliumWhitebloodcellsPlateletsCoagulationfactorsOtherplasmaproteinsAdhesionmoleculesDerangementsinnitricoxidemetabolismTheseparticipatealongwithhemoglobinpolymerizationtocausechronicanemiapunctuatedby“crises”termedPainfulvasoocclusiveHemolyticAplasticSequestration43WilliamsHematologyMcGrawHill8thed,2010,pg71444DiagnosisofSickleCellAnemia

Thesicklingphenomenoncanbedemonstratedinvitrobyaddingareducingagenttowholeblood.ThediagnosisismadebydoingafunctionaltestforsicklingandbyrunningahemoglobinelectrophoresiswhichdemonstratesthepresenceoftheabnormalbandofhemoglobinSandtheabsenceofhemoglobinA. 45TreatmentofSickleCellAnemiaTransfusiontherapyisakeyinterventionindecreasingmorbidityandmortalitybyPreventionofneurologicandperioperativecomplicationsTreatmentofacutechestsyndromeTreatmentofacuteanemiaHydroxyureaistheonlytherapythathasbeenshowntobeefficacious46HydreaenhancessurvivalinSickleCellAnemiaVoskaridouetalBlood25Mar201047ClassificationofHemolyticAnemiasExtracellularDefectsFragmentationsyndromesAutoimmunehemolyticanemiaInfectionsHypersplenism48Case#3A60yowomancomplainedofincreasingfatigue,DOEandweaknessShehadhadanaorticball-valveprosthesisplaced20yrspreviouslyPErevealedscleralicterus,aspleentipandaloudmurmurofaorticinsufficiencywithsignsofcongestiveheartfailureHerHgbwas7gm.Reticct20%.49505152FragmentationsyndromesMacroangiopathicAorticvalvularhemolysisMicroangiopathicTTPDeficiencyofmetalloproteaseADAMTS-13withresultantverylargeVWFmultimerswhichinduceplateletaggregationandresultinmicrothrombiunderhighshearstressconditions53ClassificationofHemolyticAnemiaExtracellulardefectsFragmentationsyndromesAutoimmunehemolyticanemiaHypersplenismInfections54Case#4Apreviouslyhealthy35yowomandevelopedjointswelling/painandfatigueoveraperiodof2-3monthsPErevealedamalarrash,swellingofthehandsandwrists,scleralicterusandpalpablespleenHgb10gReticct15%DirectCoombstestpositive55TheCoombs’TestThedirectCoombs’testisthehallmarkofautoimmunehemolyticanemiaItdetectsthepresenceofantibodiesboundtotheredcellsurface565758AutoimmuneHemolyticAnemiaAutoantibodiesArecausedbyantibodyproductionbythebodyagainstitsownredcells.ArecharacterizedbyapositivedirectantiglobulintestknownastheCoombs’testAredividedintowarmandcoldtypes,dependingonwhethertheyreactmorestronglywithredcellsatbodytemperatureorinthecold59AutoimmuneHemolyticAnemiasWarmantibodytype–mostcommonDATpositiveforIgGSplenicdestruction(Splenomegaly)Steroidresponsive.SplenectomymaybenecessaryColdagglutinintypeDuetoIgMabs–bindtoRBCsbestat4CFixComplement.DATpositiveforC3BothintravascularandextravascularhemolysisoccurMaycauseacrocyanosis(Raynauds)Aremoredifficulttotreat606162Microagglutinatesinapatientwithcoldagglutininhemolyticanemia6364DruginducedimmunehemolysisAvarietyofdrugsproducepositiveCoombs’tests–sometimeswithoverthemolyticanemiaOver100drugshavebeenimplicatedAntimicrobialsaccountfor>40%Themostfrequentlyassociatedwithhemolysisarecefotetan,ceftriaxoneandpiperacillin.Hemolysisstopswithremovalofthedrug656