1、溶血性贫血溶血性贫血Hemolytic AnemiaHemolytic Anemia华山医院血液科华山医院血液科陈勤奋陈勤奋HEMOLYTIC ANEMIAHEMOLYTIC ANEMIA(reduced reduced RBCRBC life span life span)vAnemia of increased destructionAnemia of increased destructionNormochromic,normochromic anemiaNormochromic,normochromic anemiaShortened RBC survivalShortened RBC
2、 survivalReticulocytosisReticulocytosis-Response to-Response to increased RBC destructionincreased RBC destructionIncreased indirect bilirubinIncreased indirect bilirubinIncreased LDHIncreased LDHMechanismsMechanisms and Causes and CausesvINTRACORPUSCULAR HEMOLYSISINTRACORPUSCULAR HEMOLYSISMembrane
3、AbnormalitiesMembrane AbnormalitiesMetabolic AbnormalitiesMetabolic AbnormalitiesHemoglobinopathiesHemoglobinopathiesvEXTRACORPUSCULAR HEMOLYSISEXTRACORPUSCULAR HEMOLYSISNonimmune Nonimmune ImmuneImmuneMembrane DefectsMembrane DefectsvMicroskeletalMicroskeletal defects defectsHereditary spherocytosi
4、sHereditary spherocytosisvIncreased sensitivity to complementIncreased sensitivity to complementParoxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuriaEnzymopathiesEnzymopathiesvGlucose 6-Phosphate DehydrogenaseGlucose 6-Phosphate Dehydrogenase DeficiencyDeficiencyvPyruvate KinasePyru
5、vate Kinase Deficiency DeficiencyHemoglobinopathiesHemoglobinopathiesvHemoglobinopathyHemoglobinopathyvThalassemiaThalassemiaExtracorpuscular HemolysisExtracorpuscular HemolysisNonimmuneNonimmunevInfectiousInfectiousvChemicalChemicalvThermalThermalvOsmoticOsmoticExtracorpuscular HemolysisExtracorpus
6、cular Hemolysis ImmuneImmunevAll require antigen-antibody reactionsAll require antigen-antibody reactionsvTypes of reactions dependent on:Types of reactions dependent on:Class of AntibodyClass of AntibodyNumber&Spacing of antigenic sites on cellNumber&Spacing of antigenic sites on cellAvailability o
7、f complementAvailability of complementEnvironmental TemperatureEnvironmental TemperatureFunctional status of reticuloendothelial systemFunctional status of reticuloendothelial systemvManifestationsManifestationsIntravascular hemolysisIntravascular hemolysisExtravascular hemolysisExtravascular hemoly
8、sisExtracorpuscular HemolysisExtracorpuscular Hemolysis ImmuneImmunevAntibodies combine with RBC,&eitherAntibodies combine with RBC,&either1.1.Activate complement cascade,&/orActivate complement cascade,&/or2.2.Opsonize RBC for immune systemOpsonize RBC for immune systemvIf 1,if all of complement ca
9、scade is If 1,if all of complement cascade is fixed to red cell,intravascular cell fixed to red cell,intravascular cell lysis occurslysis occursvIf 2,&/or if complement is only If 2,&/or if complement is only partially fixed,macrophages recognize partially fixed,macrophages recognize Fc receptor of
10、Ig&/or C3b of Fc receptor of Ig&/or C3b of complement&phagocytize RBC,causing complement&phagocytize RBC,causing extravascular RBC destructionextravascular RBC destructionClassificationClassificationvIntravascularIntravascularvE Extravascularxtravascularclinical featuresclinical featuresvchronicchro
11、nicpallorpallor 、jaundicejaundice 、splenomegalysplenomegalycholelithiasischolelithiasisaplasticaplastic crisis crisisvacuteacutealgoralgor、hyperpyrexiahyperpyrexia、sore waistsore waisthemoglobinuriahemoglobinuriajaundicejaundice、anaemiaanaemialaboratory examinationlaboratory examinationvIncreased RB
12、C destructionIncreased RBC destructionvE Erythroid hyperplasiarythroid hyperplasiadiagnosis diagnosis and and differential diagnosisdifferential diagnosisvhemolysishemolysis or not?or not?vtype of hemolysistype of hemolysisvanother anemia?another anemia?vanother jaundice another jaundice with anemia
13、?with anemia?vanother jaundice another jaundice without anemia?without anemia?TreatmentTreatmentvRemove the causes Remove the causes vImmunosupressiveImmunosupressive drug drugvW Washed RBC transfusionashed RBC transfusionvSplenectomySplenectomyvSymptomatic treatmentSymptomatic treatmentHereditary S
14、pherocytosisHereditary SpherocytosisvDefective or absent spectrin Defective or absent spectrin moleculemoleculevLeads to loss of RBC membrane,Leads to loss of RBC membrane,leading to spherocytosisleading to spherocytosisvDecreased deformability of cellDecreased deformability of cellvIncreased osmoti
15、c fragilityIncreased osmotic fragilityvExtravascular hemolysis in spleenExtravascular hemolysis in spleenHereditary SpherocytosisHereditary SpherocytosisvPathophysiologyPathophysiology-RBC-RBC membrane protein membrane protein defects(spectrin deficiency)resulting defects(spectrin deficiency)resulti
16、ng cytoskeleton instabilitycytoskeleton instabilityvFamilly historyFamilly historyvClinical featuresClinical featuressplenomegalysplenomegalyHereditary SpherocytosisHereditary SpherocytosisvLaboratory featuresLaboratory features -hemolytic anemia -hemolytic anemia -blood smear-microspherocytes -bloo
17、d smear-microspherocytes -abnormal osmotic fragility test -abnormal osmotic fragility test -positive autohemolysis test -positive autohemolysis test -prevention of increased -prevention of increased autohemolysis by including autohemolysis by including glucose inglucose in incubation medium incubati
18、on medium vTreatmentTreatment-splenectomysplenectomyHereditary SpherocytosisHereditary SpherocytosisHereditary SpherocytosisHereditary Spherocytosis Osmotic FragilityOsmotic Fragility0204060801000.30.40.50.6NaCl(%of normal saline)%HemolysisNormalHSParoxysmal Nocturnal HemoglobinuriaParoxysmal Noctur
19、nal Hemoglobinuria (PNH)(PNH)PNH is an acquired chronic hemolytic PNH is an acquired chronic hemolytic anemia which arises from a somatic anemia which arises from a somatic mutation in a hematopoietic stem cell.mutation in a hematopoietic stem cell.Most hematopoitic cell lines may be Most hematopoit
20、ic cell lines may be affected by the intrinsic membrane defect.affected by the intrinsic membrane defect.This defect renders the red cells highly This defect renders the red cells highly susceptible to complement mediated lysis susceptible to complement mediated lysis resulting in the characteristic
21、 hemolysisresulting in the characteristic hemolysis.Paroxysmal Nocturnal HemoglobinuriaParoxysmal Nocturnal Hemoglobinuria (PNH)(PNH)vPathogenesisPathogenesis -an acquired clonal disease,arising from a -an acquired clonal disease,arising from a somatic mutation in a single abnormal stem cellsomatic
22、mutation in a single abnormal stem cell -glycosyl-phosphatidyl-inositol(GPI)anchor -glycosyl-phosphatidyl-inositol(GPI)anchor abnormalityabnormality -deficiency of the GPI anchored membrane -deficiency of the GPI anchored membrane proteins(CD55 and CD59)proteins(CD55 and CD59)-red cells are more sen
23、sitive to the lytic -red cells are more sensitive to the lytic effect of complement effect of complement -intravascular hemolysis -intravascular hemolysisurine aliquot of PNHurine aliquot of PNHclinical manifestationclinical manifestationvpancytopeniapancytopeniavpassage of dark brown urine in the p
24、assage of dark brown urine in the morningmorningvvenous thrombosis(Budd-Chiarivenous thrombosis(Budd-Chiari Syndrome)Syndrome)Laboratory featuresLaboratory featuresvPancytopeniaPancytopeniavC Chronic urinary iron losshronic urinary iron lossvS Serum iron concentration decreasederum iron concentratio
25、n decreasedvHemoglobinuriaHemoglobinuriavHemosiderinuriaHemosiderinuriavP Positive Hams test(acid hemolysis test)ositive Hams test(acid hemolysis test),sugar-water testsugar-water testvS Specific immunophenotype ofpecific immunophenotype of blood cells blood cells(CD59,(CD59,CD55)CD55)AttentionAtten
26、tionvAA-PNH syndromeAA-PNH syndromeAAPNHAAPNHPNHAAPNHAAPNH with AAPNH with AAAA AA with PNHwith PNHTreatmentTreatmentvavoid causesavoid causesvwashed RBC transfusionwashed RBC transfusionviron therapyiron therapyvallogenic bone marrow allogenic bone marrow transplantationtransplantationG-6-PD Defici
27、encyG-6-PD Deficiencyvacute hemolytic anemiaacute hemolytic anemiavcongenital nonspherocyticcongenital nonspherocytic hemolytic anemiahemolytic anemiavneonatal hyperbilirubinemianeonatal hyperbilirubinemia （kernicteruskernicterus）vfavismfavism00.20.40.60.81020406080100120RBC Age(Days)G6PD Activity(%
28、)Normal(GdB)Black Variant(GdA-)Mediterranean(Gd Med)Level needed for protection vs ordinary oxidative stressAutoimmune HemolysisAutoimmune HemolysisvDue to formation of autoantibodies that Due to formation of autoantibodies that attack patients own RBCsattack patients own RBCsvType characterized by
29、ability of Type characterized by ability of autoantibodies to fix complement&site autoantibodies to fix complement&site of RBC destructionof RBC destructionvOften associated with either Often associated with either lymphoproliferative disease or collagen lymphoproliferative disease or collagen vascu
30、lar diseasevascular diseaseAutoimmune Hemolytic AnemiaAutoimmune Hemolytic Anemiavwarm-reactive warm-reactive antibodiesantibodiesprimaryprimarysecondarysecondaryvcoldcold-reactive-reactive antibodiesantibodiescold agglutinin cold agglutinin syndromesyndromeparoxysmal cold paroxysmal cold hemoglubin
31、uriahemoglubinuriaAutoimmune hematolysisAutoimmune hematolysisWarm TypeWarm TypevIgG+C3IgG+C3vIgGIgGvC3C3Autoimmune hematolysisAutoimmune hematolysis Warm TypeWarm TypevUsually IgG antibodiesUsually IgG antibodiesvFix complement only to level of C3,if at allFix complement only to level of C3,if at a
32、llvImmunoglobulin binding occurs at all tempsImmunoglobulin binding occurs at all tempsvFc receptors/C3b recognized by macrophagesFc receptors/C3b recognized by macrophagesvHemolysis primarily extravascularHemolysis primarily extravascularv70%associated with other illnesses70%associated with other i
33、llnessesvResponsive to steroids/splenectomyResponsive to steroids/splenectomyClinical manifestationClinical manifestationvanemiaanemia、jaundicejaundice、splenohepatomegaliasplenohepatomegaliavITP+AIHA=Evens syndromeITP+AIHA=Evens syndromeLaboratory examinationLaboratory examinationvBloodBlood：anemiaa
34、nemia；RetRet；e erythroblastsrythroblasts,anisopoikilocytosisanisopoikilocytosisvBone marrowBone marrow：e evCoombs TestCoombs TestCoombs Test-DirectCoombs Test-DirectvLooks for immunoglobulin&/or complement of Looks for immunoglobulin&/or complement of surface of red blood cell(normally neither surfa
35、ce of red blood cell(normally neither found on RBC surface)found on RBC surface)vCoombs reagent-combination of anti-human Coombs reagent-combination of anti-human immunoglobulin&anti-human complementimmunoglobulin&anti-human complementvMixed with patients red cells;if Mixed with patients red cells;i
36、f immunoglobulin or complement are on surface,immunoglobulin or complement are on surface,Coombs reagent will link cells together and Coombs reagent will link cells together and cause agglutination of RBCscause agglutination of RBCsCoombs Test-IndirectCoombs Test-IndirectvLooks for anti-red blood ce
37、ll Looks for anti-red blood cell antibodies in the patients serum,antibodies in the patients serum,using a panel of red cells with known using a panel of red cells with known surface antigenssurface antigensvCombine patients serum with cells Combine patients serum with cells from a panel of RBCs wit
38、h known from a panel of RBCs with known antigensantigensvAdd Coombs reagent to this mixtureAdd Coombs reagent to this mixturevIf anti-RBC antigens are in serum,If anti-RBC antigens are in serum,agglutination occursagglutination occursDiagnosisDiagnosisTreatmentTreatmentvSteroidsSteroidsvSplenectomyS
39、plenectomyvI Immunosupressive agents mmunosupressive agents vT TransfusionransfusionAutoimmune hematolysisAutoimmune hematolysis Cold TypeCold TypevMost commonly IgM mediatedMost commonly IgM mediatedvAntibodies bind best at 30Antibodies bind best at 30 or lower or lowervFix entire complement cascad
40、eFix entire complement cascadevLeads to formation of membrane attack Leads to formation of membrane attack complex,which leads to RBC lysis in complex,which leads to RBC lysis in vasculaturevasculaturevTypically only complement found on cellsTypically only complement found on cellsv90%associated wit
41、h other illnesses90%associated with other illnessesvPoorly responsive to steroids,splenectomy;Poorly responsive to steroids,splenectomy;responsive to plasmapheresisresponsive to plasmapheresisHemolytic anemiaHemolytic anemiaSummarySummaryvMyriad causes of increased RBC Myriad causes of increased RBC
42、 destructiondestructionvMarrow function usually normalMarrow function usually normalvOften requires extra folic acid to Often requires extra folic acid to maintain hematopoiesismaintain hematopoiesisvAnything that turns off the bone Anything that turns off the bone marrow can result in acute,life-marrow can result in acute,life-threatening anemiathreatening anemia
