ITP特异诊断与定向干预

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,特异诊断与定向干预,In 1951 Dr William Harrington infused himself with plasma from an ITP patient and developed severe but transient thrombocytopenia,Since then platelet destruction in ITP is believed to be mediated by platelet autoantibodies,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,特发性血小板减少性紫癜,(Idiopathic thrombocytopenic purpura,ITP,),发病：约占出血性疾病,30%,。女男,体征：皮肤粘膜出血、月经多、内脏颅内出血。,诊断：排除性,治疗：非特异，有效率,60-70%,ITP,诊断现状,临床排除性诊断,PAIgG,不能区分免疫与非免疫性血小板减少,Non-specific,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,Specific,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,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,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，等。中华血液学杂志,2003,；,24,：,477-9,秦平，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，等。中华血液学杂志,2004,；,25,：,509-10,建立,MAIPA,过筛实验：,血小板抗体免疫流式检测法（,PAICA,）,改良,MAIPA,的效果,_,敏感性增强,_,改良,MAIPA,3%,直接,MAIPA,10%,增加,MAIPA,抗原谱,10%,建立,MAIPA,过筛实验,10%,合计,33%,_,Hou M,et al.Eur J Haematol 2003;70:353-7,Hou M,et al.,Thromb Res 2003,；,110,：,1-5,芦璐，等。中华血液学杂志,2003,；,24,：,477-9,张海燕，等。中华血液学杂志,2004,；,25,：,509-10,秦平，等。中华血液学杂志,2005,；,26;167-9,改良,MAIPA,的效果,_,特异性 敏感性,_,Indirct MAIPA90%50%,Direct MAIPA,95%80%,(modified),_,芦璐，等。中华血液学杂志,2003,；,24,：,477-9,张海燕，等。中华血液学杂志,2004,；,25,：,509-10,秦平，等。中华血液学杂志,2005,；,26;167-9,ITP,治疗现状,一线治疗,:,糖皮质激素,二线治疗,:,脾切除,抢救,:,血小板输注、,IVIgs,、,rhTPO,、,FVIIa,Non-specific,难治性,ITP,的非常规治疗,FcrR-blocking Agents,：,IvIg,Anti,-D,MDX-33,Immunosuppresents:VCR,CTX,Anti-B cell:Rituxan,Anti-T cell:Campath-1h,ATG,MMF,HDDex,Anti-CD40L:Anti-CD154,B7-blocking Agents:CTLA4-Ig,CsA,Thrombopoietic Agents:TPO&its analogs,Individualization,ITP,主要发病机制,自身抗体致敏的血小板被单核巨噬细胞清除。,Cines DE.N ENGL J MED,2002;346:995-1008,HDDex,治疗,ITP,疗效肯定,。,Cheng Y.N ENGL J MED,2003;349:831-6,秦平，等。中华内科杂志,2005;44:293-6,封闭,FcR,减少血小板破坏。,Cooper N,et al.,Br J Haematol.2004;124:511-8,.,ITP,机制进展（,I,）,自身抗体致敏巨核细胞，导致巨核细胞成熟障碍，血小板生成减少。,McMillan R,et al.,Blood,2004;103:1364-9,HDDex,治疗,ITP,疗效肯定,。,Cheng Y.N ENGL J MED 2003;349:831-6,秦平，等。,中华内科杂志,2005;44:293-6,TPO,类似物治疗,ITP,显示初步疗效。,Bussel JB,et al.,Blood,2003;102:86a,赵永强，等。,中华内科杂志,2004;8:608-10,ITP,机制进展（,II,）,阻断共刺激信号诱导,T,细胞免疫耐受,.,体内疗效与其体外敏感性试验一致。,Peng J,et al.,Blood,2003;101:2721-6,人源化,CD154,单抗,I,期临床试验显效。,Kuwana M,et al.,Blood,2004;103:1229-36,ITP,机制进展（,III,）,细胞毒,T,细胞（,CTL,）和,NK,细胞直接杀伤血小板。,Olsson B,et al.,NAT MED,2003;9:1123-4,霉酚酸酯（,MMF,）下调血小板特异性,T,细胞水平,.,Hou M.Eur J Haematol,2003;70:353-7,ITP,机制进展（,IV,）,血小板抗原特异性,Th,细胞凋亡受阻。,Olsson B.,Thromb Haemost,2005;93:139-44,HDDex,治疗,ITP,疗效肯定,。,秦平，等。,中华内科杂志,2005;44:293-6,ITP,免疫机制判定实验,MAIPA,体液免疫机制,血小板破坏过多,Megakaryocyte proliferation assay,体液免疫机制,血小板生成减少,Autologous platelet lysis test,细胞免疫机制,直接杀伤血小板,Identification of platelet-reactive T cell,细胞免疫机制,免疫失耐受,In vitro Th apoptosis assay,细胞免疫机制,Th,细胞凋亡受阻,ITP,定向干预（,I,）,MAIPA,体液免疫机制,致敏血小板破坏过多,定向干预方案,:,Anti-CD20,MDX-33,ITP,定向干预（,II,）,Megakaryocyte proliferation assay,体液免疫机制,致敏巨核细胞增殖障碍，血小板生成减少。,定向干预方案：,Anti-CD20,rhTPO,类似物 或,rhIL-11,ITP,定向干预（,III,）,Autologous platelet lysis test,细胞免疫机制,CTL/NK,细胞直接杀伤血小板,定向干预方案：,MMF,Campath-1h,ATG/ALG,ANTI-CD3,ITP,定向干预（,IV,）,Tolerance-reinduction,细胞免疫机制,阻断共刺激信号，诱,导,T,、,B,细胞耐受。,定向干预方案：,CTLA-4Ig,Anti-CD154,CsA,ITP,定向干预（,V,）,Decreased Th cell apoptosis,细胞免疫机制,促进,Th,细胞凋亡,定向干预方案：,HDDex,护士站,百级层流室,层流室探视走廊,普通病房,流式细胞仪,细胞遗传室,止血血栓室,细胞培养室,