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 Platelet antibody Platelet-associated IgG (PAIg) : 70’s 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 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 MAIPA 90% 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 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):ITP 精确诊断特发性血小板减少性紫癜 定向干预 Standard therapy First-line: Oral glucocorticoids Second-line: Splenectomy RR 60~70% 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 CTL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+Tα1 、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: 395–403 Bussel JB, N Engl J Med 2007; 357:2237-47 ITP 机制判定In 1951 Dr William Harrington infused himself with plasma from an ITP patient and developed severe but transient thrombocytopenia. Since then it has
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