溶血性贫血的介绍

第六篇血液系统疾病第六章溶血性贫血弋矶山医院血液内科黄东平溶血性贫血（HA）概述定义临床分类临床表现发病机制与实验室检查诊断和鉴别诊断治疗一、定义溶血是一组由于后天或先天的各种原因使红细胞遭破坏寿命缩短的过程。HA系指红细胞破坏超过骨髓造血代偿功能而发生的一种贫血。如溶血发生而骨髓能代偿时，临床无贫血，称为溶血性疾病。二、临床分类红细胞自身异常所致的HA红细胞外部异常所致的HA

（一）红细胞自身异常所致的HA红细胞膜异常遗传性红细胞酶的缺乏遗传性珠蛋白生成障碍血红素异常

红细胞膜异常遗传性红细胞膜缺陷遗传性球形红细胞增多症、遗传性椭圆形红细胞增多症、遗传性棘性细胞增多症、遗传性口形细胞增多症获得性血细胞膜糖化肌醇磷酯（GPI）锚链膜蛋白异常，如PNH遗传性红细胞酶的缺乏戊糖磷酸途径酶缺陷如G6PD缺乏症等无氧糖酵解途径缺陷如丙酮酸激酶缺乏症等核苷代谢酶系、氧化还原酶系等缺陷等遗传性珠蛋白生成障碍珠蛋白肽链结构异常不稳定血红蛋白病、血红蛋白病S、D、E等珠蛋白肽链数量异常—地中海贫血血红素异常先天性红细胞卟啉代谢异常如红细胞生成性血卟啉病，原卟啉型、尿卟啉型和粪卟啉型铅中毒可影响血红素的合成发生HA（二）红细胞外部异常所致的HA免疫性HA血管性生物因素理化因素免疫性HA自身免疫性HA温抗体型或冷抗体型（冷凝集型、D-L抗体型）；原发性或继发性（SLE、病毒或药物等0同种免疫性HA如血型不合的输血反应、新生儿HA血管性微血管病性HA如（TTP/HUS）、DIC、败血症等瓣膜病：钙化性主动脉瓣狭窄、人工心瓣膜和血管炎等血管壁受到反复挤压：行军性血红蛋白尿生物因素、理化因素蛇毒、疟疾和黑热病等大面积烧伤、血浆中渗透压改变和化学因素如苯肼、亚硝酸盐等中毒，可引起获得性高铁血红蛋白血症而溶血（三）临床表现急性溶血：起病急，突然寒战、高热、头痛、四肢酸痛等，面色苍白、血红蛋白尿和黄疸。严重者周围循环衰竭和急性肾衰竭慢性溶血：起病慢，常有贫血、黄疸和肝脾肿大三个特征胆石症、肝功能损害严重溶血时骨髓腔扩大，X线骨皮质变薄、骨骼变形（四）发病机制和临床表现红细胞破坏和血红蛋白降解红系代偿性增生红细胞具有缺陷或寿命缩短红细胞破坏和血红蛋白降解血管内溶血游离Hb升高（>40mg/L）结合珠蛋白降低（<0.5g/L），溶血停止3-4天后恢复正常尿常规:隐血阳性，尿蛋白阳性而红细胞阴性Rous试验慢性溶血时常阳性红细胞破坏和血红蛋白降解血管外溶血血清游离胆红素升高尿常规：尿胆原增多，呈强阳性，胆红素阴性24小时粪胆原和尿胆原增多血管外溶血的一种特殊形式无效性红细胞生成原位溶血红系代偿性增生骨髓红系代偿性增生，粒红比值减低或倒置RC升高外周血涂片可见有核红细胞，严重溶血还可见幼粒细胞部分红细胞可见和碎片，如Howell-Jolly小体和Cabot环红细胞具有缺陷或寿命缩短通过有关的实验室检查用放射性核素51Cr标记红细胞测定红细胞寿命，HA寿命一般小于15天（五）诊断和鉴别诊断诊断病史有急慢性溶血的临床表现要确定血管内还是血管外溶血Coombs试验鉴别诊断贫血伴网织红升高如失血性、缺铁性和巨幼细胞贫血的恢复早期急性黄疸性肝炎肌红蛋白尿先天性胆红素代谢缺陷如家族性非溶血性黄疸（Gilbert综合症）幼红幼粒细胞贫血伴轻度RC增多如骨髓转移癌等自身免疫性溶血性贫血概述：是一种获得性溶血性贫血，由于免疫功能紊乱产生自身红细胞抗体，与红细胞表面抗原结合，或激活补体使红细胞加速破坏而致溶血性贫血。占溶血性疾病约1/3，国内仅次于PNH,占溶血性疾病患者第二位，女性多于男性，以青壮年为多，AIHA分温抗体型和冷抗体型，温抗体型占80%。温抗体型AIHA抗体为IgG或C3，少数为IgM，370C时最活跃为不完全抗体，吸附与红细胞表面，致敏的红细胞易被巨噬细胞所破坏，可形成球形红细胞IgG和C3抗体同时存在时溶血最重一、病因原发性或特发性即原因不明的占45%继发性或症状性有：①淋巴增殖性疾病如慢淋、淋巴瘤、骨髓瘤等②风湿病：SLE、类风湿关节炎和溃疡性结肠炎等③慢性炎症：慢性肝病、溃结④非淋巴系肿瘤：卵巢囊肿、肝癌等⑤药物：青霉素类、奎尼丁、甲基多巴、头孢菌素和福达拉宾等二、临床表现急性型多发生于儿童伴病毒感染，偶见成人，起病急，常有寒战、高热、腰背酸痛、呕吐，严重时可伴休克、昏迷多数温抗体型AIHA起病缓慢，成人多见，无性别差别。虚弱、头昏为常见症状体征：皮肤黏膜苍白、黄疸；轻度脾肿大（50%），质硬，中度肝肿大（30%）三、实验室检查血象：正细胞正色素性贫血，网织红细胞增高，少数可达50%，可见较多的球形红细胞和幼红细胞，红细胞大小不等，粒细胞基本正常，急性溶血阶段白细胞可增高，血小板多正常，10~20%合并免疫性血小板减少，称Evans综合症。骨髓象：增生活跃，少数发生再障危象，骨髓增生不良，网织红极度减少，但片尾部可见巨大的早幼红细胞三、实验室检查Coombs试验阳性分直接和间接试验，是温抗体型AIHA最重要和最具诊断意义的指标免疫学检查部分患者血清球蛋白增高，抗核抗体阳性，补体降低，淋巴转化率降低，ASO阳性，ESR增快，RF阳性胆红素升高，以间接胆红素为主，尿粪胆原排出增多，红细胞脆性增加

51Cr标记红细胞寿命缩短四、诊断临床表现实验室检查诊断依据⑴近4个月内无输血史或特殊药物服用史，Coombs阳性结合临床表现和实验室检查可确诊⑵如Coombs阴性，但临床表现较符合，肾上腺皮质激素或脾切术有效，除外其他溶血性贫血特别是遗传性球形红细胞增多症等可诊断抗人球蛋白试验阴性的AIHA原发性多为女性，年龄不限。临床表现除溶血和贫血外无特殊症状，半数有脾肿大，1/3有黄疸和肝大，继发性常伴有原发病的临床表现。实验室检查贫血程度不一，有时很严重，可爆发急性溶血危象，外周血可见多数球形红细胞及数量不等的幼红细胞，偶见吞噬红细胞现象，网织红细胞增多骨髓幼红细胞增生象，偶见红系轻度巨幼变再障危象时，RC极度减少，骨髓呈再生障碍，外周血象全血细胞减少Coombs阳性，主要为抗IgG和抗补体C3型，偶有抗IgA型，间接试验可阳性或阴性五、治疗糖皮质激素脾切除免疫制剂贫血较重者应输洗涤红细胞继发性应积极寻找病因，治疗原发病冷抗体型AIHA冷凝集素综合症阵发性冷性血红蛋白尿冷抗体为D-L（IgG）抗体，多继发病毒和梅毒感染，常遇冷发作血红蛋白尿，伴发热、腹痛、腰背酸、恶心呕吐等，反复发作者可有脾大、黄疸，含铁血黄素尿等ANEMIASOFEFFECTIVEERYTHROPOIESISCLS843ADVANCEDCLINICALHEMATOLOGYRaymondL.Olesinski©2001UniversityofKentuckyAnemiasofEffectiveErythropoiesis:ModuleObjectivesAttheendofthismoduleyoushouldbeabletoDefinehemolyticanemia(HA)ExplainthemeaningofIntravascularhemolysisExtravascularhemolysisAnemiasofEffectiveErythropoiesis:ModuleObjectivesDescribewhatperipheralbloodfindingsareconsistentwithaHAListwhatlaboratoryfindingsareassociatedwithspecificHAsAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesAnemiasofEffectiveErythropoiesis:ModuleObjectivesClassification

HemolyticAnemiaInheritedvs.acquiredIntrinsicvs.extrinsicdefectMCV/RDWAcutevs.chronicSitesofHemolysis

HemolyticAnemiaExtravascular(SeeFigure16.1)Destructionoccursinreticuloendothelialsystem(mostlythespleen)HemoglobinreleasedtomacrophagesSenescentRBCCullingPittingSitesofHemolysisIntravascular(SeeFigure16.2)DestructionoccurswithinthebloodvesselsHemoglobinisreleasedtotheplasmaSitesofHemolysisFactorsleadingtointravascularhemolysisComplementcoatingArtificialsurfacesMicroangiopathicprocessesInfectionSitesofHemolysisFactorsleadingtointravascularhemolysis,continuedBurnsLiver/kidneydiseaseChemicalsPhysicaltraumaCatabolismSeefigure16-1PrimaryLaboratoryInvestigationHemogramfindingswillvarydependingonthespecifictypeofanemiaThemostimportantfindingisanincreasedreticulocytecountthatcontributestoanRPI>3PrimaryLaboratoryInvestigationTheincreasedreticulocytecountisusuallyaccompaniedbyperipheralsmearRBCpolychromasiaMorphologyPathophysiologyClinicalRelevanceRedBloodCellMorphology

Inter-relationshipTriadMorphologyinHAMorphologyspecifictothetypeofHAmaybepresent,e.g.,spherocytes,elliptocytesandstomatocytesSecondaryLaboratoryInvestigationDecisionsaboutwhatprocedurestouseforsecondary,orfollow-up,investigationarebasedonthefindingsofthehemogramandmorphologySecondaryLaboratoryInvestigationChemistryBilirubin:IncreasedunconjugatedbilirubinisindicativeofhemolysisSecondaryLaboratoryInvestigationChemistry,continuedHaptoglobinCarriesfreeplasmaglobinDecreasedlevelsareindicativeofhemolysisMaybeincreasedininflammationmaskinghemolysisSecondaryLaboratoryInvestigationChemistry,continuedIncreasedfreeplasmahemoglobinIncreasedlacticdehydrogenaseUrinalysisHemoglobinuriaormethemoglobinuriaHemosiderinuriaUrobilinogenSurveyofHAbyTypeHereditaryAcquiredHereditaryHAMembraneabnormalitiesEnzymopathiesPlasmaconstituentabnormalitiesRBCMembraneStructure++PlasmaIntegral

ProteinsPeripheralProteinsLipidBi-Layer——LipidBi-LayerRBCCytoplasmMembraneAbnormalitiesSpherocytosisElliptocytosisPyropoikilocytosisStomatocytosisMembraneAbnormalitiesSeefigure17-1ExcessmembranecholesterolRBCinclusionsSenescentRBCComplementcoatedRBCAntibodycoatedRBCRigidRBCSpleen:EffectsonRBCsHereditarySpherocytosisHereditarySpherocytosisSeefigures17-2and3SpherocyteMorphology&PathophysiologyLacksareaofcentralpallorAdditionalcausesImmunologicreactionPhysicaltraumaUsually<6.5mdiameterMicrospherocytes:<4mdiameterHereditaryElliptocytosisDefect:Unknown;spectrindefects?PathophysiologyIncreasedNa+efflux

Hemoglobinbipolarization;Cholesterolpolarization

RBCrigidity

DestructioninspleenEllipto/OvalocyteClinicalRelevanceHereditaryellipto-orovalocytosis(>25%ofallRBCs)Macro-ovalocytesseeninmegaloblasticanemiasNon-specificfindinginothertypesofanemia(<25%ofallRBCs)HereditaryElliptocytosisHereditaryElliptocytosisSlidesnotshown.SeeFigure8-7,p.91,ClinicalHematologyHereditaryPyropoikilocytosisHereditaryPyropoikilocytosisSlidesnotshown.SeeFigure8-15,p.95,ClinicalHematologyHereditaryStomatocytosisDefect:UnknownPathophysiology:IncreasedinfluxofRBCH2ORBCrigidityDestructioninspleenStomatocyteMorphology&PathophysiologySlit-likeareaofcentralpallorHereditaryStomatocytosisEnzymopathies

HemolyticAnemiaPyruvatekinasedeficiencyGlucose-6-phosphatedehydrogenasedeficiencyEnzymopathies

HemolyticAnemiaSeefigure17-5Enzymopathies

HemolyticAnemiaBiteCells

Morphology&PathophysiologyCrateredRBCCratersformedbyremovalofHeinzbodies

formedfromunstablehemoglobinEnzymopathies

HemolyticAnemiaSlidesnotshown.SeeFigure17-6,p.262,ClinicalHematologyEnzymopathies

HemolyticAnemiaPlasmaConstituentAbnormalitiesAbetalipoproteinemia:AKAhereditaryacanthocytosisLecithin-CholesterolAcyltransferaseDeficiency:NumeroustargetcellsTargetCell(Codocyte)PathophysiologyIncreasedcholesterolorphospholipidon

RBCmembraneIncreasedsurfacearea:volumePre-crystallinestateofhemoglobinCTargetCell(Codocyte)Slidesnotshown.SeeFigure8-11,p.92,ClinicalHematologyEchinocyteMorphology>30short,bluntprojectionsevenlydistributedoverthecellsurfaceA.K.A.burrcell,crenatedRBC&seaurchincellWetmountcomparisonAcanthocyteMorphology5-12thornlikespiculesunevenlydistributedoverthecellsurfaceProjectionsmaybeclubshapedordrumstickshaped(spurcells)AcquiredHemolyticAnemiaExtracorpusculardefectsAbnormalbloodvesselstructureMechanicalinjuryMiscellaneousIntracorpusculardefectsImmuneprocessesExtracorpuscularDefectsMicroangiopathichemolyticanemiaDisseminatedintravascularcoagulation(DIC)Hemolyticuremicsyndrome(HUS)Thromboticthrombocytopenicpurpura(TTP)DirectionofbloodflowFibrinSchistocyte

MicroangiopathicTraumaSchistocyte

MicroangiopathicTraumaSlidesnotshown.SeeFigure8-12,p.94,ClinicalHematologyIntracorpuscular-PNHMajordefect-ComplementsensitiveRBCsinacidifiedplasmaenvironmentPathophysiology-ExtravascularlysisofaffectedRBCoccurringduringtheeveninghoursleadingtoachronichemolyticanemiaIntracorpuscular-PNHModuleObjectives:

BloodLossAnemiaModuleObjectives:

BloodLossAnemiaLaboratoryFindings

BloodLossAnemiaAcutebloodlossanemiaNochangeinCBCparametersinfirstfewhours3-4hoursHb/HctPossible

WBCcountPossible

LaboratoryFindings

BloodLossAnemiaAcutebloodlossanemia,continued12-24hoursHb/Hct

reflectingdegreeofbloodlossProbableleukocytosisPossiblethrombocytosisLaboratoryFindings

BloodLossAnemiaAcutebloodlossanemia,continued3-5daysPossible

MCVPossible

reticulocytecountPossible

RPI(>3)LaboratoryFindings

BloodLossAnemiaSeeTable20-2LaboratoryFindings

BloodLossAnemiaFindingsandcourseinchronicbloodlossanemiaaresimilartoirondeficiencyanemiaLaboratoryFindings

Blood