肝素诱导的血小板减少症.ppt

肝素诱导的血小板减少症史旭波首都医科大学同仁医院,XIa,XIIa,IXa,VIIa-III,组织因子途径抑制物,抗凝血酶,IIa,纤维蛋白原,纤维蛋白,蛋白C，蛋白S系统,Xa,VIIIa,Va,内源性凝血系统,外源性凝血系统,凝血与抗凝系统,Epidemiology,thechanceofsignificantexposuretoheparinexceeds50%inhospitalizedpatientsacutecoronarysyndrome(UA/MI)pulmonaryembolismdeepvenousthrombosisandprophylaxisatrialfibrillation/strokeheparinizedpulmonarywedgecathetersPCIIABP,SemiThrombHemost2019;25Suppl1:57-60,U.S.EstimatedCausesofAccidentalDeaths,1000,40,000,90,000,Deathsperyear,MedicationErrorsHospitalAudit,%,REFERENCE,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,Heparin-inducedThrombocytopenia,Heparin-inducedthrombocytopenia(HIT),anantibody-mediatedsyndrome,isassociatedwithsignificantmorbidityandmortalityconsideredararityinthepastunrecognizedbymanycliniciansdiagnosescanbedifficulttoconfirmuntilrecentlytherewasnotherapeuticoptionsotherthandiscontinuationofheparin,Epidemiology,thrombocytopeniaisoneofthemostcommonlaboratoryabnormalitiesfoundamonghospitalizedpatientsserologicallyprovenHIToccursin1.5%to3%ofpatientswithheparinexposure,NEnglJMed2019;332:1330-5,CascadeofeventsleadingtoformationofHITantibodiesandprothromboticcomponents,thrombosite,BleedingandClotting,themostfearedconsequenceinthesepatientswithalowplateletcountisnotbleedingbutclottingpresentwithmucocutaneousbleeding,rangingfrompetechiaeandecchymosestolife-threateninggastrointestinalandintracranialhemorrhage,Thrombosis,thrombosisismostlyvenousnotarterialmayresultinbilateraldeepvenousthrombosisofthelegspulmonaryembolismvenousgangreneoffingers,toes,penis,ornipplesmyocardialinfarction,strokemesentericarterialthrombosislimbischemiaandamputation,Circulation2019;100:587-93AmJMed2019;101:502-7ThrombHaemost1993;70:554-61,OtherClinicalFeatures,SkinlesionsatheparininjectionsiteSkinnecrosisAcuteplateletactivationAcuteinflammatoryreactions(fever,chills,etc.),SkinNecrosis,UsedwithpermissionfromWarkentinTE.BrJHaematol.2019;92:494497.,VenousLimbGangrene,UsedwithpermissionfromWarkentinTE,ElavathilLJ,HaywardCPM,JohnstonMA,RussettJI,KeltonJG.AnnInternMed.2019;127:804812.,MorbidityandMortality,HIT-associatedmortalityishigh(about18%)5%ofaffectedpatientsrequirelimbamputationOvertbleedingorbruisingisrareevenwithseverethrombocytopeniaAppropriatemanagementcanlimitmorbidityandmortality,HITSyndrome,TypeInonimmunologicmechanisms(milddirectplateletactivationbyheparin)associatedwithanearly(within4days)andusuallymilddecreaseinplateletcount(rarely50%)countinthe50,000-80,000/mmrangetypicalonsetof4-14daysoccurswithanydosebyanyroutepotentialfordevelopmentoflife-threateningthromboemboliccomplicationsrarelycausesbleeding,RisksforHIT,TypeIintravenoushigh-doseheparinTypeIIvarieswithdoseofheparinunfractionatedheparinLMWHbovineporcinesurgicalmedicalpatients,DiagnosisofHIT,absenceofanotherclearcauseforthrombocytopeniathetimingofthrombocytopeniathedegreeofthrombocytopeniaadverseclinicalevents(mostoftenthrombocytpenia)positivelaboratorytestsforHITantibodies,PathogenesisofDrug-inducedthrombocytopenia,Certaindrugs(quinine,quinidine,sulfaantibiotics)linknon-covalentlytoplateletmembraneglycoproteinsveryrarely,IgGantibodiesareproducedthatrecognizethesedrug-glycoproteincomplexesmacrophagesremovethecomplexescausingseverethrombocytopenia,ComparisonofHITandotherDrug-InducedThrombocytopenia,HITQuinine/SulfaFrequency1/1001/10,000Onset5-8days7daysPlateletcount20-150 x109/L50%thatbeginsafter5daysofheparintherapy,butwiththeplateletcount150 x109/L,shouldalsoraisethesuspicionofHIT,CommonLaboratoryTestsforHIT,TestAdvantagesDisadvantagesPAARapidandsimpleLowsensitivity-notsuitablefortestingmultiplesamplesSRASensitivity90%Washedplatelet(technicallydemanding),needsradiolabeledmaterial14CHIPARapid,sensitivity90%WashedplateletsELISAHighsensitivity,Highcost,lowerspecificityforclinicallysignificantHIT,ThrombHaemost2019;79:1-7,plateletaggregationassay(PAA)serotoninreleaseassay(SRA)heparininducedplateletactivation(HIPA),FunctionalAssay,Plateletaggregationassay(PAA)performedbymanylaboratoriesincubateplatelet-richplasmafromnormaldonorswithpatientplasmaandheparinlimitedbypoorsensitivityandspecificitybecauseheparincanactivateplateletsundertheseconditions,evenintheabsenceofHITantibodies,AntigenAssay,Antibodiesagainstheparin/PF4complexes(themajorantigenofHIT)aremeasuredbycolorimetricabsorbanceTwoELISAhavebeendevelopedStagoGTIlimitedbyhighcost,ManagementofHIT,riskforthrombosisishighinHIT,preventionofthrombosisisthegoalofinterventionhepariniscontraindicatedinpatientswithHITdiscontinuationofheparin-allsourcesofheparinmustbeeliminatedmostpatientswillrequiretreatmentwithanalternateanticoagulantforinitialclinicalproblemHITinducedthrombosis,HIT处理措施,药物可用禁用评价华法令xwarfarinintheabsenceofananticoagulantcanprecipitatevenouslimbgangrene补充血小板xinfusingplateletsmerely“addsfueltothefire”静脉滤器xoftenresultsindevastatingcaval,pelvic,andlowerlegvenousthrombosis低分子肝素xlowmolecularweightheparinusuallycross-reactwithunfractionatedheparinafterHITorHITTS(HITthrombosissyndrome)hasoccurred水蛭素/阿加曲班xBewarerenalinsufficiency,antibodyformation血浆置换xremovesmicro-particlesformedfromplateletactivation;notastandardindication阿司匹林xcaninhibitplateletactivationbyHIT氯吡格雷xantibodiesGp2b/3a受体x阻滞剂,StepstoPreventHIT,porcineheparinpreferredoverbovineheparinLMWHpreferredoverunfractionatedheapirnoralanticoagulationshouldbestartedasearlyaspossibletoreducethedurationofheparinexposureintravenousadaptersshouldnotbeflushwithheparinmonitoringserialplatecountsfordevelopingthrombocytopenia,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,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),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),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,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),HIT监测血小板计数,HIT抗体筛查使用肝素的患者，如果无血小板减少症、血栓形成、肝素诱发的皮肤改变或其他HIT相关的情况，不建议常规监测HIT抗体(1C级),HIT治疗,非肝素类抗凝药物治疗HIT高度怀疑（或确诊）HIT，无论是否合并血栓栓塞，建议选用另外一种非肝素抗凝剂，如来匹卢定（1C级），阿加曲班（1C级），比伐卢定（2C级），或达那肝素（1B级）,而不是继续使用UFH或LMWH，也不建议不使用抗凝剂（有或无下腔静脉滤器）。,HIT治疗,非肝素类抗凝药物治疗HIT高度怀疑（或确诊）HIT，无论是否有下肢DVT的临床证据，建议常规下肢静脉超声以明确是否存在DVT（IC级）,HIT治疗,VKAs高度怀疑或确诊HIT的患者建议不使用维生素K拮抗剂（香豆素），直至血小板计数明显恢复（如至少100109/L，最好150109/L）VKA仅用于替换抗凝剂时的重叠期（最少重叠5天），起始剂量小，替换使用的抗凝剂直到血小板计数恢复至稳定状态时，或至少最近2天的INR达到靶治疗目标范围内才能停用（IC级）,HIT治疗,VKAs使用VKAs的患者在诊断为HIT后，建议使用维生素K逆转VKA抗凝疗效（2C级）,HIT治疗,LMWH治疗HIT高度怀疑HIT的患者，无论是否合并血栓形成，建议不使用LMWH（IC+级）高度怀疑或确诊HIT的患者，如无活动性出血，不建议预防性输注血小板（2C级）,HIT治