《红细胞与贫血》PPT课件

基础血液学红细胞与贫血Erythrocyte带3阴离子运转蛋白（高丰度跨膜糖蛋白，转运Cl-水通道蛋白KCC1,氯化物-阳离子协同转运蛋白家族KCl协同转运系统NKCC2,Na-K-Cl协同转运蛋白基底侧分子形式SK,smallconductancepotassiumchannel.小电导钾通道,2.CellMembrane,MembraneFunctionmembraneantigenicityandimmunologicfunction,Bloodgroupantigensareassociatedwiththeredcellmembraneandareeitherintegraltoitsstructureorareadsorbedontoitfromtheplasma.Theyaremadeofproteinsorcarbohydrates.senescentcellantigen,SCA（老化抗原）,2.CellMembrane,ANTIGENSONRBCMEMBRANE,MembraneFunctionmembraneantigenicityandimmunologicfunction,2.CellMembrane,MembraneFunctionreceptors,hormonereceptors：insulin，glucagonNeurotransmitterreceptors：noradrenalineVirusreceptors：flu.receptorothers：TfR，EPOreceptor,2.CellMembrane,2.CellMembrane(disease),HereditarySpherocytosis,Elliptocytosis（遗传性球形红细胞增多症，椭圆形红细胞增多症）,abnormalspectringenereducedspectrinsynthesisordysfunctionalspectrinspherocytesorelliptocytes,遗传性球形红细胞增多症是一种以外周血涂片成熟红细胞呈球形、网织红细胞增多和脾脏肿大为特征的先天性溶血性贫血。红细胞在通过脾脏微循环时，由于细胞膜丢失和膜面积缩小而呈球形样改变并伴有变形可塑性降低。失去变形能力的红细胞在脾脏被破坏最终导致贫血。,HereditarySpherocytosis,Elliptocytosis（遗传性球形红细胞增多症，椭圆形红细胞增多症）,遗传性球形红细胞增多症病理生理学。HS主要缺陷为细胞膜丢失，膜面积减少，表面积减少，导致细胞球形变，变形能力减弱。,2.CellMembrane(disease),theprocessofspherocytosisinhereditaryspherocytosis,HereditarySpherocytosis,Elliptocytosis,2.CellMembrane(disease),TheCongenitalDyserythropoieticAnemias（CDA）先天性红细胞生成异常性贫血,先天性红细胞生成异常性贫血（CDA）是指一类罕见的，以红系无效造血，多核红细胞和组织内铁蓄积为特征的遗传性难治性贫血。可分为、型。,先天性红细胞生成异常性贫血（CDA）型中带3蛋白-N-乙酰乳糖聚糖链合成不足，而鞘磷脂表现为过度糖基化。,2.CellMembrane(disease),Lipids,PSexposure磷脂酰丝氨酸外翻,磷脂酰丝氨酸外翻可启动凝血活化途径PSexposuretotriggerthrombosis,磷脂酰丝氨酸外翻可被巨噬细胞识别并吞噬PSexposuretoberecognizedandphagocytizedbymacrophage,2.CellMembrane(disease),Alterationinlipidcompositioncanproducetargetcellsoracanthocytes.,靶形红细胞,棘形红细胞,Lipids,2.CellMembrane(disease),3.CellMetabolism,metabolicchangesinerythropoiesis,3.CellMetabolism,3.CellMetabolism,HAEMOGLOBIN血红蛋白,Haemoglobin,MW68,000Da96%oftheredbloodcellsdryweight65%ofhaemoglobinsynthesisoccursduringthenucleatedstagesofRBCmaturationand35%occursduringthereticulocytestage,HAEMOGLOBINStructure,3.CellMetabolism,HAEMOGLOBINFunction,3.CellMetabolism,IronatomineachhemecanbindtooneO2moleculeEachHbmoleculecantransportfourO2HemoglobinbindsreversiblywithoxygenO2loadinginthelungsProducesoxyhemoglobin（氧合血红蛋白）(rubyred)O2unloadinginthetissuesProducesdeoxyhemoglobin（脱氧血红蛋白）orreducedhemoglobin(darkred)CO2loadinginthetissuesProducescarbaminohemoglobin（氨基甲酰血红蛋白）(carries20%ofCO2intheblood),HAEMOGLOBINGlobin（珠蛋白）,3.CellMetabolism,HemoglobinGenesandGeneProducts、,Mehta,A.B.,andA.V.Hoffbrand.2000.Haematologyataglance,BlackwellScience,Malden,Mass.,3.CellMetabolism,HemoglobinGenesandGeneProducts,HAEMOGLOBINGlobin（珠蛋白）,EmbryonichaemoglobinsincludeGower1,Gower2andHbPortland.HbFisthepredominanthaemoglobinoffetallife(65-95%).AdultshaveonlytraceamountsofHbF(95%)andHbA2(2.5-3.5%)arethemainadulthaemoglobins.,3.CellMetabolism,SixHbvariantsarenormallyformed.,HAEMOGLOBINGlobin（珠蛋白）,3.CellMetabolism,Hemincanacceleratethesynthesis珠蛋白的合成受血红素调节,HRI，Heme-regulatedeIF2kinase；eIF，eukaryoteInitiationfactor；eIF-2B，eIF-2BGDP-GTPexchangefactor,HAEMOGLOBINGlobin（珠蛋白）,HAEMOGLOBINHEME（血红素）,3.CellMetabolism,HAEMOGLOBINHEME（血红素）,3.CellMetabolism,HEMEconsistsoffourpyrrolerings（吡咯环）withacentralironatomlinkedtothefournitrogenatoms.Theironatomhastwofurtherbindingsites,oneofwhichisboundtoaglobinhistidineresidueandtheotherbindsreversiblytooxygen.,3.CellMetabolism,HAEMOGLOBINHEME（血红素）,血红素合成的限速酶：ALAsynthase，aminolevulinicacid合酶(-氨基-酮基戊酸合酶)辅酶：磷酸吡哆醛（VitB6）,3.CellMetabolism,RegulationofALASynthase（ALA合酶的调节）Levelofenzymesynthesis（ALA合酶的表达水平）Enzymesynthesis,aswellasitstransporttothemitochondria,isinhibitedbyelevatedlevelsofhemeandhemin(theFe3+oxidationproductofheme)（过量的血红素高铁血红素抑制酶合成）Enzymesynthesisisupregulatedbyalargenumberofdrugsincludingbarbiturates,steroids(e.g.testosterone)andsomeoralcontraceptives.（巴比妥类药物，类固醇，睾丸素，口服避孕药）Levelofenzymeactivity（ALA合酶的酶活性）Heme（血红素）andhemin（高铁血红素）inhibitALAsynthaseactivityRequirespyridoxalphosphate(VitaminB6，磷酸吡哆醛)asacoenzyme,HAEMOGLOBINHEME（血红素）,3.CellMetabolism(disease),PORPHYRIAS卟啉症,卟啉病是由于血红素生物合成途径中酶缺陷导致反应过程中间代谢产物过量生成与蓄积，并引发神经系统症状和（或）关照性皮肤症状等疾患,血红素生物合成途径中各种酶与中间代谢产物，以及与酶缺乏相对应的卟啉病类型。,Chronicinfectionsandinflammatorydisorderscausechronicanaemiaasaresultof;1.slightlyshortenedredbloodcelllifespan2.sequestrationofironininflammatorycellscalledmacrophagesBothproceduresresultinadecreaseintheamountofironavailabletomakeredbloodcells.,3.CellMetabolism(disease),HEMOGLOBINOPATHY血红蛋白病,血红蛋白病是全球最常见的遗传性红细胞疾病。是指珠蛋白生成障碍贫血（珠蛋白合成不足）和异常血红蛋白病（珠蛋白一级结构中氨基酸突变），以地中海贫血和镰状细胞综合征为主。可导致中度到重度贫血。,3.CellMetabolism(disease),地中海贫血以一条或多条珠蛋白链合成缺陷的遗传性疾病。包括和-地中海贫血。由于珠蛋白链合成的不平衡，导致无效红细胞生成，溶血和不同程度的贫血。,HEMOGLOBINOPATHY-Thalassemias（地中海贫血）,3.CellMetabolism(disease),HEMOGLOBINOPATHY-Thalassemias（地中海贫血）,地中海贫血，过多的链形成4分子（HBH）（可溶）,-地中海贫血，过多的链（不可溶）致红细胞损伤，造成重度贫血。,3.CellMetabolism(disease),HEMOGLOBINOPATHY-Thalassemias（地中海贫血）,3.CellMetabolism(disease),HEMOGLOBINOPATHY-Sicklecellanemia(镰状细胞贫血),3.CellMetabolism(disease),镰状细胞综合征是-珠蛋白链第6位氨基酸谷氨酸被缬氨酸所替代，导致血红蛋白分子脱氧时变得不可溶，形成HBS多聚体，改变了红细胞的正常结构，使红细胞呈僵硬，并由双凹圆盘状变为镰刀形。这类红细胞变形能力差，易破损溶血，导致血管阻塞、组织缺氧、损伤、坏死。,GeneticsofSickleCellAnemia,HEMOGLOBINOPATHY-Sicklecellanemia(镰状细胞贫血),3.CellMetabolism(disease),HemoglobinElectrophoresis,/hemoglobin-myoglobin.html,Relativeproteincharge,Start(samplesappliedhere),Anode(+),Cathode(-),HEMOGLOBINOPATHY-Sicklecellanemia,3.CellMetabolism(disease),HEMOGLOBINOPATHY-Sicklecellanemia,3.CellMetabolism(disease),Schemasummarizingthepathophysiologyofsicklecellanemia.K+,potassium;NO,nitricoxide;PS,phosphatidylserine;RBC,redbloodcell;ROS,reactiveoxygenspecies;TF,tissuefactor;WBC,whitebloodcell;XO,xanthineoxidase.,HEMOGLOBINOPATHY-Sicklecellanemia,3.CellMetabolism(disease),metabolicchangesinerythropoiesis,3.CellMetabolism,3.CellMetabolism,Glycometabolism,Matureredcellsnomitochondrialapparatusforoxidativemetabolism-Redcellsdeliveroxygen,notconsumeitLimitedGlucoseasasourceofenergyGlycolysisgeneratesATPand2,3-bisphosphoglycerate（2,3-二膦酸甘油酸，2,3-DPG）ThepentosephosphatepathwayproducesNADPHGlutathionesynthesis(谷胱甘肽合成)theantioxidantdefensesystem,Energyrequiredfor:MaintenanceofcationpumpsMaintenanceofRBCintegrityanddeformabilityReduceoxidantsinthesystemMaintenanceofHBinreducedstateMaintenanceofreducedsulfhydrylgroupsinHBandotherproteins,3.CellMetabolism,Glycometabolism,KeyMetabolicPathwaysfortheErythrocyte,GlycolysisorEmbden-Meyerhofpathway（糖酵解，恩-迈氏途径）Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路）HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路）Methemoglobinreductasepathway（高铁血红蛋白还原酶途径）,3.CellMetabolism,KeyMetabolicPathwaysfortheErythrocyte,GlycolysisorEmbden-Meyerhofpathway糖酵解（恩-迈氏途径）,3.CellMetabolism,KeyMetabolicPathwaysfortheErythrocyte,GlycolysisorEmbden-Meyerhofpathway（糖酵解，恩-迈氏途径）Generates90-95%ofenergyneededbyRBCsGlucoseismetabolizedandgeneratestwomoleculesofATP(energy).FunctionsinthemaintenanceofRBCshape,flexibilityandthecationpumps,3.CellMetabolism,KeyMetabolicPathwaysfortheErythrocyte,Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路）,3.CellMetabolism,1,3-二膦酸甘油酸,二膦酸甘油酸变位酶,3膦酸甘油酸,2，3-二膦酸甘油酸,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路）,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,http:/www.mfi.ku.dk/PPaulev/chapter8/images/8-3.jpg,Rapaport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路）,KeyMetabolicPathwaysfortheErythrocyte,Rapoport-LueberingShunt（2,3-DPG支路，2，3二膦酸甘油酸支路）AllowstheRBCtoregulateoxygentransportduringconditionsofhypoxiaoracid-baseimbalance.Permitstheaccumulationof2,3-DPGwhichisessentialformaintainingnormaloxygentension,regulatinghemoglobinaffinity,3.CellMetabolism,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路）,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路）,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路）,KeyMetabolicPathwaysfortheErythrocyte,Metabolizes5-10%ofglucose.NADPHisendproductProtectstheRBCfromoxidativeinjury.Ifthepathwayisdeficient,intracellularoxidantscantbeneutralized,andthenglobindenaturesandprecipitates.TheprecipitatesarereferredtoasHeinzbodies.Mostcommondefectisdeficiencyoftheenzymeglucose-6-phosphatedehydrogenase(G-6PD，葡萄糖-6-磷酸脱氢酶).,3.CellMetabolism,HexoseMonophosphateShunt（磷酸戊糖途径，磷酸己糖支路）,Inredcells,thereisaMetHbreductase(高铁血红蛋白还原酶)whichcanuseNADHtoregenerateHb,KeyMetabolicPathwaysfortheErythrocyte,Methemoglobinreductasepathway（高铁血红蛋白还原酶途径）,3.CellMetabolism,KeyMetabolicPathwaysfortheErythrocyte,Maintainsironintheferrous(Fe+)state.Intheabsenceoftheenzyme(methemoglobinreductase),methemoglobinaccumulatesanditcannotcarryoxygen.,3.CellMetabolism,Methemoglobinreductasepathway（高铁血红蛋白还原酶途径）,KeyMetabolicPathwaysfortheErythrocyte,3.CellMetabolism,3.CellMetabolism(Disease),DisordersofRedCellsResultingfromEnzymeAbnormalities酶异常导致的红细胞疾病,Glucose-6-phosphatedehydrogenase(G6PD)deficiency6-磷酸葡萄糖脱氢酶缺乏是最常见的红细胞酶缺陷，溶血发作只有在感染或应用“氧化性”药物，以及某些进食蚕豆等应激时才发生。临床上最严重的并发症是新生儿黄疸。,DisordersofRedCellsResultingfromEnzymeAbnormalities,3.CellMetabolism(Disease),DisordersofRedCellsResultingfromEnzymeAbnormalities,Pyruvatekinasedeficiency丙酮酸激酶缺陷是引起非球形红细胞溶血性贫血的常见原因。,3.CellMetabolism(Disease),3.CellMetabolism,ironmetabolism,铁分布,ironmetabolism,3.CellMetabolism,铁的出入平衡,ironmetabolism,3.CellMetabolism,人体铁循环铁在一个几乎完全封闭的系统内紧密保存。,3.CellMetabolism,ironmetabolism,铁的吸收,肠绒毛细胞从肠道摄入铁并转运到血浆DMT-1，二价金属离子运转蛋白Ferritin，铁蛋白Ferroportin，膜铁运转蛋白Hephaestin，膜铁转运辅助蛋白,ironmetabolism,3.CellMetabolism(disease),DisordersofIronMetabolism铁代谢异常,铁缺乏和缺铁性贫血是常见的营养性和血液学疾病。铁缺乏是体内铁含量低于正常的一种状态。铁缺乏的原因：慢性失血饮食中铁摄入不足（婴幼儿铁缺乏）妊娠和哺乳（铁转移至胎儿和婴儿的红系造血）铁吸收不良血管内溶血伴血红蛋白尿铁向非造血组织转移遗传因素铁减少储存铁减少血清铁浓度和转铁蛋白饱和度降低缺铁性贫血,DisordersofIronMetabolism铁代谢异常,成人缺铁性贫血红细胞指标。虚线为平均血红蛋白浓度（MCHC）的下限值。静脉血红蛋白浓度和MCHC之间的相关性（50%）。,成人缺铁性贫血红细胞指标。静脉血红蛋白浓度和平均红细胞体积（MCV）之间的相关性（70%）。对于缺铁状态改变，MCV比MCHC更敏感。,50%,70%,3.CellMetabolism(disease),DisordersofIronMetabolism铁代谢异常,凹甲，手指甲的成嵴、变薄和勺状凹陷。,3.CellMetabolism(disease),DisordersofIronMetabolism铁代谢异常,血涂片A正常血涂片形态正常正细胞色素性红细胞B轻度铁缺乏少量中心淡然区扩大的红细胞，少量呈卵圆或椭圆形C重度铁缺乏显著低色素的细胞明显增加且小细胞更多见,3.CellMetabolism(disease),3.CellMetabolism,NucleotideMetabolism（核苷酸代谢DNA合成）,PathwaysofdeoxynucleosideandDNAsynthesis脱氧核苷酸和DNA合成途径,胸腺嘧啶,叶酸的活性形式四氢叶酸作为一碳单位的载体参与DNA合成,3.CellMetabolism,NucleotideMetabolism,高半胱氨酸,胸腺嘧啶核苷酸合酶,亚甲基四氢叶酸,甲基四氢叶酸,二氢叶酸还原酶,叶酸,folicacid(叶酸)vitaminB12,钴胺素),蝶呤啶,对氨基苯甲酸,谷氨酸,人体不能合成叶酸，必须由食物供给。主要在绿色蔬菜、香蕉等水果。,VitB12只存在于动物食品中。,3.CellMetabolism,NucleotideMetabolism,内因子,叶酸，钴胺素和巨幼红细胞贫血FOLATE,COBALAMIN,ANDMEGALOBLASTICANEMIAS,deficiencyofvitaminB12orfolicacidanemiaorpancytopeniacausedbyimpairedDNAsynthesisaffectsallmarrowelements,血涂片恶性贫血卵圆形大红细胞，并有异形细胞,骨髓片恶性贫血幼红细胞体积变大及核质发育不平衡,3.CellMetabolism(disease),FateandDestructionofErythrocytes,4.CellAging,MacrophagesengulfdyingRBCsinthespleenOldRBCsbecomefragile,andHbbeginstodegeneratehemebilirubinsecretedinbilebyliverironrecycledglobulinaminoacids,Lifespan:100120dayscellularfunctionabilitytodeformincapillariesriskofrupture,Bilirubinindirect:unconjugated,notwatersolubleformedduringinitialdestructionbindswithalbuminfortransporttoliverdirect:conjugated,watersolubleformedinliverandexcretedinbile,5.RBCDiseases,PolycythemiaexcessofRBCsthatincreasebloodviscosityPolycythemiaverabonemarrowcancerSecondarypolycythemiawhenlessO2isavailable(highaltitude)orwhenEPOproductionincreasesBlooddoping,5.RBCDiseases,AnemiabloodhasabnormallylowO2-carryingcapacityasymptomofapathologicprocess(notaspecificdisease)BloodO2levelscannotsupportnormalmetabolismAccompaniedbyfatigue,paleness,shortnessofbreath,andchills,5.RBCDiseases,Anemia,physiologicdefinition:decreaseinoxygencarryingcapacityandthusoxygenavailabilitytotissuesisalabtermthatindicateslowRBCcountdecreasedhemoglobindecreasedhematocrit,LaboratoryDiagnosis,WHOsHemoglobinthresholdsusedtodefineanemia(1g/dL=0.6206mmol/L),5.RBCDiseases,Anemia,AnemiaScale（Hbleveling/L）,gradescale1(mild)91g/Llowerlimitofnormal2(moderate)61g/L90g/L3(severe)31g/L60g/L4(life-threatening)30g/L,5.RBCDiseases,A