肝素诱导的血小板减少症

肝素诱导的血小板减少症演示文稿第一页，共四十一页。（优选）肝素诱导的血小板减少症第二页，共四十一页。Epidemiologythechanceofsignificantexposuretoheparinexceeds50%inhospitalizedpatientsacutecoronarysyndrome(UA/MI)pulmonaryembolismdeepvenousthrombosisandprophylaxisatrialfibrillation/strokeheparinizedpulmonarywedgecathetersPCIIABPSemiThrombHemost1999;25Suppl1:57-60第三页，共四十一页。U.S.EstimatedCausesofAccidentalDeaths〈100040,00090,000Deathsperyear第四页，共四十一页。MedicationErrors–HospitalAudit%REFERENCE第五页，共四十一页。血小板减少症（HIT/HITS）

美国每年有1200万人因肢体或肺部血栓、心脏病或血管成型术而接受肝素治疗36万人发生HIT12万人出现血栓并发症（静脉、动脉）3.6万人死亡

第六页，共四十一页。Heparin-inducedThrombocytopeniaHeparin-inducedthrombocytopenia(HIT),anantibody-mediatedsyndrome,isassociatedwithsignificantmorbidityandmortalityconsideredararityinthepastunrecognizedbymanycliniciansdiagnosescanbedifficulttoconfirmuntilrecentlytherewasnotherapeuticoptionsotherthandiscontinuationofheparin第七页，共四十一页。EpidemiologythrombocytopeniaisoneofthemostcommonlaboratoryabnormalitiesfoundamonghospitalizedpatientsserologicallyprovenHIToccursin1.5%to3%ofpatientswithheparinexposureNEnglJMed1995;332:1330-5第八页，共四十一页。CascadeofeventsleadingtoformationofHITantibodiesandprothromboticcomponents第九页，共四十一页。BleedingandClottingthemostfearedconsequenceinthesepatientswithalowplateletcountisnotbleedingbutclottingpresentwithmucocutaneousbleeding,rangingfrompetechiaeandecchymosestolife-threateninggastrointestinalandintracranialhemorrhage

第十页，共四十一页。Thrombosisthrombosisismostlyvenousnotarterialmayresultinbilateraldeepvenousthrombosisofthelegspulmonaryembolismvenousgangreneoffingers,toes,penis,ornipplesmyocardialinfarction,strokemesentericarterialthrombosislimbischemiaandamputationCirculation1999;100:587-93

AmJMed1996;101:502-7

ThrombHaemost1993;70:554-61第十一页，共四十一页。OtherClinicalFeaturesSkinlesionsatheparininjectionsiteSkinnecrosisAcuteplateletactivationAcuteinflammatoryreactions(fever,chills,etc.)第十二页，共四十一页。SkinNecrosisUsedwithpermissionfromWarkentinTE.BrJHaematol.1996;92:494–497.第十三页，共四十一页。VenousLimbGangrene

UsedwithpermissionfromWarkentinTE,ElavathilLJ,HaywardCPM,JohnstonMA,RussettJI,KeltonJG.AnnInternMed.1997;127:804–812.第十四页，共四十一页。MorbidityandMortalityHIT-associatedmortalityishigh(about18%)5%ofaffectedpatientsrequirelimbamputationOvertbleedingorbruisingisrareevenwithseverethrombocytopeniaAppropriatemanagementcanlimitmorbidityandmortality第十五页，共四十一页。HITSyndromeTypeInonimmunologicmechanisms(milddirectplateletactivationbyheparin)associatedwithanearly(within4days)andusuallymilddecreaseinplateletcount(rarely<100x109/L)typicallyrecoverswithin3daysdespitecontinueduseofheparinnotassociatedwithanymajorclinicalsequelaeoccursprimarilywithhighdoseivheparin第十六页，共四十一页。HITSyndromeTypeIIinducedbyimmunologicmechanismssubstantialfallinplateletcount(>50%)countinthe50,000-80,000/mmrangetypicalonsetof4-14daysoccurswithanydosebyanyroutepotentialfordevelopmentoflife-threateningthromboemboliccomplicationsrarelycausesbleeding第十七页，共四十一页。RisksforHITTypeIintravenoushigh-doseheparinTypeIIvarieswithdoseofheparinunfractionatedheparin>LMWHbovine>porcinesurgical>medicalpatients第十八页，共四十一页。DiagnosisofHITabsenceofanotherclearcauseforthrombocytopeniathetimingofthrombocytopeniathedegreeofthrombocytopeniaadverseclinicalevents(mostoftenthrombocytpenia)positivelaboratorytestsforHITantibodies第十九页，共四十一页。Pathogenesisof

Drug-inducedthrombocytopeniaCertaindrugs(quinine,quinidine,sulfaantibiotics)linknon-covalentlytoplateletmembraneglycoproteinsveryrarely,IgGantibodiesareproducedthatrecognizethesedrug-glycoproteincomplexesmacrophagesremovethecomplexescausingseverethrombocytopenia第二十页，共四十一页。ComparisonofHITandother

Drug-InducedThrombocytopenia

HIT

Quinine/SulfaFrequency ~1/100 ~1/10,000Onset 5-8days 7daysPlateletcount 20-150x109/L <20x109/LSequelae Thrombosis BleedingLaboratory Immunoassay Platelet- (heparin/PF4) associatedIgG

第二十一页，共四十一页。UnusualClinicalEventsSuspiciousforHITmildtomoderatethrombocytopenia,ofteninconjunctionwiththrombosisadrenalhemorrhagicinfarction(causedbyadrenalveinthrombosis)warfarin-inducedvenouslimbgangrenefever,chills,beginning5to30minutesafteranIVheparinbolusheparin-inducedskinlesionsassociatedwithHITantibodies,evenintheabsenceofthrombocytopania

第二十二页，共四十一页。OtherClinicalFeatures

SuspiciousforHITarapiddropinplateletsmayalsobeindicativeofHIT,particularlyifthepatientsreceivedheparinwithintheprevious3monthsafallinplateletcountof>50%thatbeginsafter5daysofheparintherapy,butwiththeplateletcount>150x109/L,shouldalsoraisethesuspicionofHIT

第二十三页，共四十一页。CommonLaboratoryTestsforHITTest Advantages DisadvantagesPAA Rapidandsimple Lowsensitivity-notsuitablefor testingmultiplesamplesSRA Sensitivity>90% Washedplatelet(technically demanding),needsradiolabeled material14CHIPA Rapid,sensitivity>90%WashedplateletsELISA Highsensitivity, Highcost,lowerspecificityfor clinicallysignificantHIT ThrombHaemost1998;79:1-7plateletaggregationassay(PAA)serotoninreleaseassay(SRA)heparininducedplateletactivation(HIPA)第二十四页，共四十一页。FunctionalAssayPlateletaggregationassay(PAA)performedbymanylaboratoriesincubateplatelet-richplasmafromnormaldonorswithpatientplasmaandheparinlimitedbypoorsensitivityandspecificitybecauseheparincanactivateplateletsundertheseconditions,evenintheabsenceofHITantibodies第二十五页，共四十一页。AntigenAssayAntibodiesagainstheparin/PF4complexes(themajorantigenofHIT)aremeasuredbycolorimetricabsorbanceTwoELISAhavebeendevelopedStagoGTIlimitedbyhighcost第二十六页，共四十一页。ManagementofHITriskforthrombosisishighinHIT,preventionofthrombosisisthegoalofinterventionhepariniscontraindicatedinpatientswithHITdiscontinuationofheparin-allsourcesofheparinmustbeeliminatedmostpatientswillrequiretreatmentwithanalternateanticoagulantforinitialclinicalproblemHITinducedthrombosis第二十七页，共四十一页。HIT处理措施

药物 可用

禁用

评价

华法令

x warfarinintheabsenceofananticoagulant

canprecipitatevenouslimbgangrene

补充血小板

x infusingplateletsmerely“addsfueltothefire”

静脉滤器

x

oftenresultsindevastatingcaval,pelvic,and

lowerlegvenousthrombosis

低分子肝素

x lowmolecularweightheparinusuallycross-

reactwithunfractionatedheparinafterHITor

HITTS(HITthrombosissyndrome)hasoccurred

水蛭素/阿加曲班

x Bewarerenalinsufficiency,antibodyformation

血浆置换

x removesmicro-particlesformedfromplatelet

activation;notastandardindication

阿司匹林

xcaninhibitplateletactivationbyHIT

氯吡格雷

xantibodies

Gp2b/3a受体

x

阻滞剂第二十八页，共四十一页。StepstoPreventHITporcineheparinpreferredoverbovineheparinLMWHpreferredoverunfractionatedheapirnoralanticoagulationshouldbestartedasearlyaspossibletoreducethedurationofheparinexposureintravenousadaptersshouldnotbeflushwithheparinmonitoringserialplatecountsfordevelopingthrombocytopenia第二十九页，共四十一页。第七次ACCP抗栓和溶栓会议

肝素诱导的血小板减少症防治指南

第三十页，共四十一页。HIT监测—血小板计数接受治疗剂量UFH患者，建议隔日血小板计数，直到第14天或直至停用UFH(2C级)100天内接受过UFH治疗的患者或既往是否使用过UFH的病史不详者，再次开始使用UFH或LMWH时，建议先进行血小板计数，随后在肝素治疗后的24小时以内再次血小板计数(2C级)第三十一页，共四十一页。HIT监测—血小板计数

静脉UFH注射后30min内出现发热、寒战、呼吸困难、或其他不常见的症状体征，建议立即进行血小板计数，并与先前的计数值进行比较(1C级)

第三十二页，共四十一页。HIT监测—血小板计数

HIT发生率不高患者（0.1-1%）下列患者建议术后4-14天，至少隔2-3天进行血小板计数（或直到停用UFH）(2C级)

内科/产科患者预防性使用UFH术后患者预防性使用LMWHUFH冲洗穿刺导管或内科/产科患者使用过UFH后接受LMWH治疗第三十三页，共四十一页。HIT监测—血小板计数

HIT发生率很低患者（<0.1%）仅接受LMWH治疗的内科/产科患者或仅在血管内介入治疗中使用UFH的患者（HIT危险<0.1%），建议临床医师不常规使用血小板监测(2C级)

第三十四页，共四十一页。HIT监测—血小板计数

HIT抗体筛查