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1、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,Average annual ITP incidence by age group and gender(n=1145),Life Quality in Chronic ITP Patients,Healthy,General Population,Cancer,Hypertension,Arthritis,ITP,ITP,Diabetes,Limo,CHF,
2、McMillan et al.American Journal of Hematology DOI 10.1002/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,Estimated annual rate of bleeding according to age group,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,Oligoclonal expansio
3、ns of GP-specific CD4+T cells Fogarty PF,et al.Clin Adv Hematol Oncol 2003;1:365-71T-cell activation in ITPSemple et al.Blood 1991;78:2619-25Semple et al.Blood 1996;87:4245-54Lost of T-cell tolerance to self antigen in ITPPeng，et al.Blood 2003；101：2721-26 Zhang，et al.J Thrombosis Haemostasis 2007；6:
4、15865Disturbed apoptosis of T cellsOlsson,et al.Thromb Haemost 2005;93:139-44,Loss of T-cell tolerance,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,Platelet production is suboptimal in ITP patients,Autologous 111In-platelet studies show platelet production normal in 2/3 patientsTPO levels normal in 75%of ITP pati
5、ents(relative TPO deficiency)Autoantibodies inhibit both Mk growth and Mk apoptosisTrail-mediated megakaryocyte para-apoptosis leading to in vitro dysmegakaryocytopoiesis and impaired platelet production,Thrombopoietin levels in ITP patients,Hou et al.Br J Haematol 1998;101:420-4,Decreased platelet
6、production,Trail-mediated megakaryocyte para-apoptosis leading to in vitro dysmegakaryocytopoiesis,plasma,antibody,Removal of antibody,The number of megakaryocytes,Megakaryocyte apoptosis,Antibodies inhibit the Generation of megakaryocytes,Yang,et al.Blood 2010;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
7、破坏增多,Increased platelet destruction,Autoantibody-mediated platelet clearance Zucker-Franklin,et al.N Engl J Med 1977;297:517-23CTL-mediated platelet lysisOlsson,et al.Nat Med 2003;9:1123-27GPIb desialyation leading to platelet apoptosis Heyu Ni,et al.JCI.2013 on published,Increased platelet destruct
8、ion,Chow,et al.Blood 2010;115:1247-53,GPIIIa knockout miceImmunized with platelets,CD19(+)Splenocytes,CD8(+)Splenocytes,SCID mice,Thrombo-cytopenia,Thrombo-cytopenia,Mouse model of ITP,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
9、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
10、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IVIg1.0 g/(kgd)23天和/或甲基强的松龙(1.0 g/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
11、，无效者半月后可重复静脉输注丙种球蛋白（IVIg）治疗,Antibody species on response to steroid,*R=Response;*NR=No response,ITP patients with anti-GPIb antibodies are less responsive to steroid therapy,Zeng,et al.American Journal of Hematology 2011,Overall response rate：64.5%GP Ib/IX(+)response rate：41.8%GP Ib/IX(-)response ra
12、te：79.5%(-)(-)response rate：83.7%,Our unpublished data,Antibody species on response to IVIg,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,*Godeau B,et al.Blood.2008;112:999-1004.#Gudbrandsdottir S,et al.Blood.2013,121:1976-81.Saleh MN,et al.Blo
13、od.2013,121:537-45.,Zaja,et al.Haematologica 2008;93:930-33Taube,et al.Haematologica 2005;90:281-3,Decrease the destruction of plateletRituximab(Standard dose),Long-term follow-up analysis after rituximab salvage therapy,Zaja,F.,et al.(2012).Am J Hematol 87(9):886-889.,Long term response to rituxima
14、b,Patel,V.L.,et al.(2012).Blood 119(25):5989-5995.Libor Cervinek,et al.Int J Hematol.2012 87(9):886-889.,Estimated event-free survival curves with standard dose or low dose,Platelet Response and Romiplostim Dose Remained Stable Over Time,Note:data points with n 5 not plotted,D.Kuter et al.ASH 2010.,
15、299 adult ITP patients were involved,87%of patients achieved a PC50109/L;Median PC increased to PC50109/L by week 2 and remained consistently through 164 weeks;The incidence of any bleeding symptoms declined from 56%at baseline to 16%and 20%at week 52 and week 104 respectively.Saleh et al.ASH2010，Ab
16、stract#67,Eltrombopag,不同措施治疗ITP的起效时间,Bussel JB,Provan D,Kovaleva L,et al.Lancet.2009;373(9664):641-648.Kuter DJ,Bussel JB,Lyons RM,Senecal FM,et al.Lancet.2008;371(9610):395-403.Wang SJ,Yang RC,Zou P,et al.Int J Hematol.2012;96(2):222-2228.Arnold DM,Dentali F,Crowther MA,Meyer RM,Cook RJ,Sigouin C,e
17、t alAnn Intern Med.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,Dexamethasone plus rituximab,Zaja,et al.Blood 2010;115:2755-62,Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia,rhTPO plus Ritu
18、ximab,Rituximab,rhTPO,Decrease platelet destruction,Increase platelet production,High response rate with a long TTR and SR,High response rate with a short TTR,and relapse soon after withdrawal,Open-label,non-randomized,non-placebo-controlled;rhTPO：300U/Kg/d，d1-14;Rituximab：375 mg/m2,qw*4(d1,8,15,22)
19、;,Rituximab combined rhTPO in corticosteroid non-responsive ITP,rhTPO plus Rituximab,*Unpublished data*Arnold,et al.Ann of Intern Med 2007;146:25-33#Wang,et al.Chin J Thromb Haemost 2010;15:149-53,Efficacy Comparison,*OR:overall response;CR:complete response;R:response;,rhTPO plus Rituximab,*Unpubli
20、shed data*Arnold,et al.Ann of Intern Med 2007;146:25-33#Wang,et al.Chin J Thromb Haemost 2010;15:149-53 115:2755-62,HD-Dex plus rhTPO,作用机制互补,协同作用？,长期缓解？,James B.Bussel et al.Blood,2012 120:960-969,Treatment strategy,提纲,概述诊断要点疾病的分期治疗原则疗效判断,疗效判断,完全反应（CR）：治疗后血小板100109/L且无出血 有效（R）：治疗后血小板30109/L且比基础血小板增加2倍，且无出血无效（NR）：治疗后血小板30109/L或比基础血小板增加不到2倍，或有出血 在定义CR或R时，应至少检测2次，其间至少间隔7天,谢谢！,
