复件ITP特异诊断与定向干预-侯明长春

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,特发性血小板减少性紫癜,特异性诊断与定向免疫干预,山东大学齐鲁医院血液科,侯 明,发病：约占成人出血性疾病,30%,儿童出血性疾病,60%,，,5,19/10,万人，女,:,男,1:1,。,诊断：排除性诊断，缺乏特异性。,治疗：非特异，有效率,60-70%,。,Idiopathic thrombocytopenic,purpura,(ITP),Harrington et al,J Lab,Clin,Med 38:1,1951,Zucker-Franklin D&,Karpatkin S,N Engl J Med 1977;297:517,Platelet,Phagocytosis,In RES,Platelet antibody,Platelet-associated,IgG,(,PAIg,):70s,Elevated in both immune and non-immune thrombocytopenia.,Non-specific.,特发性血小板减少性紫癜,精确诊断,GP-specific assays,Immunoblot,Immunoprecipitation,MACE,Immunobeads,MAIPA,MAIPA,原理,羊抗鼠,IgG,MoAb,-GP,GP,自身抗体,IgG,-GP,人抗鼠,IgG,酶标二抗,酶标二抗,ITP,抗原特异性诊断实验,单抗俘获血小板抗原法,MAIPA,(,MoAb,immobilization of platelet antigen assay),Kiefel,V.,Transfus,Med,1992;2:181-8,MAIPA,阳性与,ITP,诊断符合率达,92%,。,McMillan R,et al,.,Curr,Hematol,Rep,2005;4:160-5,能区分,免疫,与,非免疫性,血小板减少,MAIPA,vs,PAIgG,_,特异性,敏感性,_,PAIgG,20%90%,MAIPA,92%47-66%,_,McMillan R,et al,.,Curr,Hematol,Rep,2005;4:160-5,ITP,抗原特异性诊断,改良,MAIPA,:,祛除人抗鼠异种抗体,Hou,M,et al.,Eur,J,Haematol,2003;70:353-7,Hou,M,et al.,Thromb,Res,2003;110:1-5,直接,MAIPA,:,血小板洗脱液代替血浆,芦璐，侯明等。中华血液学杂志,2003,；,24,：,477-9,秦平，侯明等。,中华血液学杂志,2005,；,26;167-9,增加,MAIPA,抗原谱：,GPIIb/IIIa,GPIb,/IX,GPIa/IIa,，,GPIV,，,GPV,，,GPVI,张海燕，侯明等。中华血液学杂志,2004,；,25,：,509-10,MAIPA,的,改良,效果,_,敏感性增强,_,改良,MAIPA,3%,直接,MAIPA,10%,增加,MAIPA,抗原谱,10%,合计,23%,_,Hou,M,et al.,Eur,J,Haematol,2003;70:353-7,Hou,M,et al.,Thromb,Res 2003,；,110,：,1-5,芦璐，侯明等。中华血液学杂志,2003,；,24,：,477-9,张海燕，侯明等。中华血液学杂志,2004,；,25,：,509-10,秦平，侯明等。,中华血液学杂志,2005,；,26;167-9,MAIPA,的,改良,效果,_,特异性 敏感性,_,Indirct,MAIPA90%50%,Direct,MAIPA,95%73%,_,芦璐，侯明等。中华血液学杂志,2003,；,24,：,477-9,张海燕，侯明等。中华血液学杂志,2004,；,25,：,509-10,秦平，侯明等。,中华血液学杂志,2005,；,26;167-9,直接,MAIPA,直接,MAIPA,对,ITP,的诊断价值,结论,：直接,MAIPA,检测血小板膜糖蛋白特异性自身抗体对于鉴别免疫性与非免疫性血小板减少有重要意义,。,秦平，侯明，等。中华血液学杂志,2005,；,26,（,3,）；,167-169,指标,抗,GPb,/a,抗,GPb,抗,GPa,/a,抗,GPb,/a,和抗,GPb,抗,GPb,/a,、抗,GPb,和抗,GPa,/a,敏感性,特异性,阳性预测值,46.1%,98.2%,97.6%,34.8%,98.2%,96.6%,14.6%,98.2%,92.9%,65.0%,96.4%,96.7%,76.4%,96.4%,97.1%,流式微球技术,（,Cytometric,Bead Array,CBA,）,CBA,、,改良间接,MAIPA,对,ITP,的诊断价值比较,结论：,流式微球技术检测血小板特异性抗体，耗时短、重复性好，敏感性高，对提高,ITP,的实验诊断水平及指导临床治疗有重要价值。,刘欣光，侯明等。中华血液学杂志,2008,；,29,（,3,）：,方法 敏感性 特异性 阳性预测值,流式微球技术,71.43%94.28%95.24%,改良间接,MAIPA,51.79%94.28%93.55%,ITP,精确诊断,一线治疗,排除性诊断：病史、体格检查、血细胞计数和涂片检查、骨髓细胞学检查,改良直接,MAIPA,MAPIA,过筛试验,流式或全血小板,ELISA,确诊,诊断仍不能确定 或一线治疗失败,特发性血小板减少性紫癜,定向干预,Standard therapy,First-line:Oral,glucocorticoids,Second-line:,Splenectomy,RR60,70%,Chronic refractory ITP,35%of patients fail to respond to first-line treatment and,splenectomy,or require unacceptably high doses of corticosteroids to maintain a safe platelet count.,Bearsley,D.,ASH Education Book,2006;,397-401,.,BSH.,Br J,Haematol,2003;120:574-596,Alternative therapy,HD,IVIg,anti-D,VCR/VDS,Azathioprine,CTX,MMF,CSA,Rituximab,rhTPO,缺少循证医学支持,作用靶点局限,不良反应明显,价格高昂,Management of ITP,Alternative therapy,(individualization),:,Age of patient,Severity of presentation,Platelet count,Primary refractory or relapsed,Length of time prior to relapse,特发性血小板减少性紫癜,(Idiopathic thrombocytopenic,purpura,ITP,),Pathogenesis,Loss of self-tolerance,Autoantibody-mediated platelet,destruction,CTL-mediated platelet,lysis,Apoptosis defect of,megakaryocyte,ITP,免疫机制及其判定,免疫失耐受,共刺激信号体外阻断实验,自身抗体介导的血小板破坏,直接,MAIPA,直接杀伤血小板,Autologous,platelet,lysis,test,巨核细胞凋亡异常,Megakaryocyte,proliferation assay,ITP,机制判定及定向免疫干预,（,I,）,共刺激信号阻断剂体内疗效与其体外敏感性试验一致，故可通过,外敏感性试验来预测,CsA,等共刺激信号阻断剂对难治性,ITP,的疗效。,Peng,J,Hou,M,et al.,Blood,2003;101:2721-6,CsA,、,CD154,单抗、,CTLA4-Ig,通过阻断共刺激信号，诱导,血小板抗原特异性,T,细胞免疫无能,。,Zhang XL,Hou,M,et al.,J,Thromb,Haemost,2008;6:158-65,Kuwana M,et al.,Blood,.2004;103:1229-36,Nomura S,et al.,Autoimmunity,.2003;36:317-9,ITP,机制判定及定向免疫干预（,II,）,改良直接,MAIPA,血小板自身抗体的定性和定量判定实验，可为大剂量激素、,CD20,单抗治疗,ITP,提供依据。,HDDex,、,HDDex+T1,、,Rituximab,治疗,ITP,疗效肯定,。,Guo,CS,Hou,M,et al.,J,Clin,Immunol,2007;27:557-62,王文、周郁红、侯明等。,中华内科杂志,2008,；,47,；,274-6,Arnold DM,et al.,Ann Intern Med,2007;146:25-33,Garcia-Chavez J,et al.,Ann,Haematol,2007;86:871-7,Provan D,et al.,Haematologica,2007;92:1695-8,ITP,机制判定及定向免疫干预,（,III,）,CTL,血小板杀伤实验提供,细胞毒,T,细胞（,CTL,）和,NK,细胞杀伤自身血小板的证据,是,MMF,、抗,CD3,单抗、,ATG/ALG,应用于,ITP,的依据。,Olsson B,et al.,Nat Med,2003;9:1123-4,Zhang F,Hou,M,et al.,Eur,J,Haematol,2006;76;153-9,Zhao CH,Hou,M,et,al.,Haematologica,2008 in press,霉酚酸酯（,MMF,）,通过抑制,T,细胞增殖，下调血小板特异性,T,细胞水平,.,Hou,M.,Eur,J,Haematol,2003;70:353-7,ITP,机制判定及定向免疫干预（,IV,）,巨核细胞增殖判定实验：,ITP,患者巨核细胞成熟障碍或凋亡受抑。,McMillan R,et a1.,Blood.,2004;103:1364-9,Chang M,，,et al.,Blood.,2003;102:887-95,Li SG,Hou M,et al.,Br J,Haematol,.,2007;139:605-11,rhTPO,、,AMG531,、,Eltrombopag,治疗,ITP,显示初步疗效。,赵永强，等。,中华内科杂志,2004,；,43,：,608-10,Kuter,DJ,Lancet,2008;371:395403,Bussel JB,N Engl J Med,2007;357:2237-47,ITP,机制判定,ITP,发病机制,自身抗体介导的血小板破坏,CTL,直接杀伤血小板,免疫失耐受,巨核细胞凋亡异常,改良直接,MAIPA,FITC-,annexin,V,标记血小板技术,共刺激信号阻断剂体外敏感试验,巨核细胞培养,大剂量激素、,CD20,单抗等,霉酚酸酯,（,MMF,）、抗,CD3,单抗、,ATG,、,ALG,等,CTLA-4Ig,、,CsA,、抗,CD154,单抗等,血小板生成素,(,rhTPO,),及其小分子模拟肽等,