成人原发免疫性血小板减少症诊治中国专家共识解读

.,成人原发免疫性血小板减少症诊治中国专家共识（2012修订版）解读,山东大学齐鲁医院侯明,.,提纲,概述诊断要点疾病分期治疗原则疗效判断,.,概述,获得性自身免疫性出血性疾病占出血性疾病1/3，老年人高发以皮肤黏膜出血为主患者可有明显乏力症状,.,AverageannualITPincidencebyagegroupandgender(n=1145),.,LifeQualityinChronicITPPatients,Healthy,GeneralPopulation,Cancer,Hypertension,Arthritis,ITP,ITP,Diabetes,Limo,CHF,McMillanetal.AmericanJournalofHematologyDOI10.1002/ajh/20992,.,临床表现,出血症状一般与血小板计数负相关部分重度血小板减少患者无出血症状或仅轻度出血老年患者出血发生率明显高于年轻患者注意：乏力与血栓形成,.,Estimatedannualrateofbleedingaccordingtoagegroup,.,ITP出血评分量表,王琳侯明.原发免疫性血小板减少症出血评分系统临床应用分析。中华血液学杂志。2012,.,发病机制,对自身抗原免疫耐受缺失血小板生成减少血小板破坏增多,.,OligoclonalexpansionsofGP-specificCD4+TcellsFogartyPF,etal.ClinAdvHematolOncol2003;1:365-71T-cellactivationinITPSempleetal.Blood1991;78:2619-25Sempleetal.Blood1996;87:4245-54LostofT-celltolerancetoselfantigeninITPPeng，etal.Blood2003；101：2721-26Zhang，etal.JThrombosisHaemostasis2007；6:15865DisturbedapoptosisofTcellsOlsson,etal.ThrombHaemost2005;93:139-44,LossofT-celltolerance,.,发病机制,对自身抗原免疫耐受缺失血小板生成减少血小板破坏增多,.,PlateletproductionissuboptimalinITPpatients,Autologous111In-plateletstudiesshowplateletproductionnormalin2/3patientsTPOlevelsnormalin75%ofITPpatients(relativeTPOdeficiency)AutoantibodiesinhibitbothMkgrowthandMkapoptosisTrail-mediatedmegakaryocytepara-apoptosisleadingtoinvitrodysmegakaryocytopoiesisandimpairedplateletproduction,.,ThrombopoietinlevelsinITPpatients,Houetal.BrJHaematol1998;101:420-4,.,Decreasedplateletproduction,Trail-mediatedmegakaryocytepara-apoptosisleadingtoinvitrodysmegakaryocytopoiesis,plasma,antibody,Removalofantibody,Thenumberofmegakaryocytes,Megakaryocyteapoptosis,AntibodiesinhibittheGenerationofmegakaryocytes,Yang,etal.Blood2010;116:4307-16,.,发病机制,对自身抗原免疫耐受缺失血小板生成减少血小板破坏增多,.,Increasedplateletdestruction,Autoantibody-mediatedplateletclearanceZucker-Franklin,etal.NEnglJMed1977;297:517-23CTL-mediatedplateletlysisOlsson,etal.NatMed2003;9:1123-27GPIbdesialyationleadingtoplateletapoptosisHeyuNi,etal.JCI.2013onpublished,.,Increasedplateletdestruction,Chow,etal.Blood2010;115:1247-53,GPIIIaknockoutmiceImmunizedwithplatelets,CD19(+)Splenocytes,CD8(+)Splenocytes,SCIDmice,Thrombo-cytopenia,Thrombo-cytopenia,MousemodelofITP,.,提纲,概述诊断要点疾病分期治疗原则疗效判断,.,诊断要点,血小板计数减少，形态无异常脾脏不大骨髓检查：巨核细胞增多/正常，成熟障碍排除继发性血小板减少药物相关性血小板减少病毒（HIV、HCV）相关性血小板减少继发于SLE、MPD的血小板减少,.,诊断要点,特殊实验室检查：血小板抗体检测（MAIPA法和流式微球法）检测抗原特异性自身抗体的特异性较高鉴别免疫性与非免疫性血小板减少血小板生成素（TPO）不作为常规检测有助于鉴别ITP与不典型AA或低增生性MDS,.,提纲,概述诊断要点疾病分期治疗原则疗效判断,.,疾病分期,新诊断ITP：确诊后3个月以内持续性ITP：确诊后312个月血小板持续减少慢性ITP：血小板减少持续超过12个月重症ITP：血小板10109/L，出血症状难治性ITP：脾切除无效或复发需治疗以降低出血危险除外其他原因,.,.,提纲,概述诊断要点疾病分期治疗原则疗效判断,.,治疗原则,治疗原则紧急治疗新诊断ITP的一线治疗成人ITP的二线治疗,.,治疗原则,随访观察：血小板30109/L，无出血表现，不从事增加出血危险的工作或活动增加出血风险的危险因素：年龄和患病时间血小板功能缺陷凝血因子缺陷未被控制的高血压外科手术或外伤感染必须服用抗凝药物,.,紧急治疗,重症ITP（血小板计数10109/L），活动性出血或需要急诊手术方案：血小板输注IVIg1.0g/(kgd)23天和/或甲基强的松龙(1.0g/d3天)其他方案重组人活化因子（rhFa）,.,新诊断ITP的一线治疗,短程肾上腺糖皮质激素：泼尼松剂量从1.0mg/(kgd)，稳定后剂量快速减少至最小维持量（15mg/d），不能维持考虑二线治疗HD-DXM，40mg/d4d，无效者半月后可重复静脉输注丙种球蛋白（IVIg）治疗,.,Antibodyspeciesonresponsetosteroid,*R=Response;*NR=Noresponse,ITPpatientswithanti-GPIbantibodiesarelessresponsivetosteroidtherapy,Zeng,etal.AmericanJournalofHematology2011,.,Overallresponserate：64.5%GPIb/IX(+)responserate：41.8%GPIb/IX(-)responserate：79.5%(-)(-)responserate：83.7%,Ourunpublisheddata,AntibodyspeciesonresponsetoIVIg,.,成人ITP的二线治疗,脾切除*：正规糖皮质激素治疗无效，病程迁延6个月以上强的松有效，维持量30mg/d糖皮质激素禁忌药物治疗利妥昔单抗#，TPO和TPO受体激动剂，硫唑嘌呤，环孢素A，达那唑，长春碱类,*GodeauB,etal.Blood.2008;112:999-1004.#GudbrandsdottirS,etal.Blood.2013,121:1976-81.SalehMN,etal.Blood.2013,121:537-45.,.,Zaja,etal.Haematologica2008;93:930-33Taube,etal.Haematologica2005;90:281-3,DecreasethedestructionofplateletRituximab(Standarddose),.,Long-termfollow-upanalysisafterrituximabsalvagetherapy,Zaja,F.,etal.(2012).AmJHematol87(9):886-889.,.,Longtermresponsetorituximab,Patel,V.L.,etal.(2012).Blood119(25):5989-5995.LiborCervinek,etal.IntJHematol.201287(9):886-889.,Estimatedevent-freesurvivalcurveswithstandarddoseorlowdose,.,PlateletResponseandRomiplostimDoseRemainedStableOverTime,Note:datapointswithn5notplotted,D.Kuteretal.ASH2010.,.,299adultITPpatientswereinvolved,87%ofpatientsachievedaPC50109/L;MedianPCincreasedtoPC50109/Lbyweek2andremainedconsistentlythrough164weeks;Theincidenceofanybleedingsymptomsdeclinedfrom56%atbaselineto16%and20%atweek52andweek104respectively.Salehetal.ASH2010，Abstract#67,Eltrombopag,.,不同措施治疗ITP的起效时间,BusselJB,ProvanD,KovalevaL,etal.Lancet.2009;373(9664):641-648.KuterDJ,BusselJB,LyonsRM,SenecalFM,etal.Lancet.2008;371(9610):395-403.WangSJ,YangRC,ZouP,etal.IntJHematol.2012;96(2):222-2228.ArnoldDM,DentaliF,CrowtherMA,MeyerRM,CookRJ,SigouinC,etalAnnInternMed.2007;146:25-33,.,联合治疗,地塞米松联合利妥昔单抗血小板生成素联合利妥昔单抗地塞米松联合血小板生成素,.,Dexamethasoneplusrituximab,Zaja,etal.Blood2010;115:2755-62,Dexamethasoneplusrituximabyieldshighersustainedresponseratesthandexamethasonemonotherapyinadultswithprimaryimmunethrombocytopenia,.,rhTPOplusRituximab,Rituximab,rhTPO,Decreaseplateletdestruction,Increaseplateletproduction,HighresponseratewithalongTTRandSR,HighresponseratewithashortTTR,andrelapsesoonafterwithdrawal,.,Open-label,non-randomized,non-placebo-controlled;rhTPO：300U/Kg/d，d1-14;Rituximab：375mg/m2,qw*4(d1,8,15,22);,RituximabcombinedrhTPOincorticosteroidnon-responsiveITP,rhTPOplusRituximab,*Unpublisheddata*Arnold,etal.AnnofInternMed2007;146:25-33#Wang,etal.ChinJThrombHaemost2010;15:149-53,.,EfficacyComparison,*OR:overallresponse;CR:completeresponse;R:response;,rhTPOplusRituximab,*Unpublisheddata*Arnold,etal.AnnofInternMed2007;146:25-33#Wang,etal.ChinJThrombHaemost2