23例获得性低巨核细胞性血小板减少性紫癜的临床分析
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摘要
目的：了解获得性低巨核细胞性血小板减少性紫癜(AATP)的临床特点、治疗及预后。探讨血小板生成素(TPO)、抗TPO自身抗体、抗c-Mpl自身抗体的临床意义和三者与外周血小板计数之间的关系。
方法：收集从2002年至2009年在汕头大学医学院第一附属医院诊断为获得性低巨核细胞性血小板减少性紫癜的病人,通过电话、面访或问卷的方式随访病人的临床症状、治疗情况及预后。应用酶联免疫吸附法(ELISA)检测8例AATP患者、10例ITP患者及10例健康对照血浆TPO水平,抗TPO自身抗体和抗c-Mpl自身抗体的吸光度,自动血细胞仪测定其血小板数。
结果：共收集病人资料28例,随访获得23例完整的病人资料。在23例病人中,10例治疗有效,1例因颅内出血死亡,2例转化为再生障碍性贫血,1例转化为骨髓增生异常综合征。女性治疗有效率(58.4%)高于男性(25%),但差异无统计学意义(P>0.05)。初诊时骨髓巨核细胞数缺如的患者治疗有效率(50%)低于骨髓巨核细胞数减少的(63.2%),但尚不能认为骨髓巨核细胞数可影响到治疗效果(P>0.05)。AATP组血浆TPO水平较ITP组及正常对照组升高,差异有统计学意义(P<0.05)。ITP组TPO水平略高于正常对照组,差异无统计学意义(P>0.05)。AATP组抗TPO自身抗体吸光度与正常对照组相近。AATP组抗c-Mpl自身抗体吸光度高于正常对照组,差异无统计学意义(P>0.05)。相关分析表明AATP组血浆TPO水平与血小板计数、抗TPO自身抗体、抗c-Mpl自身抗体均无相关性(P>0.05)。
结论：男性患者、巨核细胞缺如可能是AATP的高危因素,具有这些因素的患者对常规治疗反应差。AATP患者血浆TPO水平较ITP患者及健康人群升高,TPO水平的检测能较好地反映血小板减少的发病机制,对提高AATP的诊断水平及指导临床治疗有一定意义。完善抗c-Mpl自身抗体检测可能为诊断AATP提供证据。
Objective:To investigate the clinical features, therapy and prognosis of acquired amegakaryocytic thrombocytopenic purpura(AATP). To explore the clinical significance of thrombopoietin, anti-TPO antibody and anti-c-Mpl antibody, and their relationship with peripheral blood platelet counts.
Method:Clinical data of inpatient cases undergoing acquired amegakaryocytic thrombocytopenic purpura(AATP) between 2002 and 2009 were collected. Follow-up information on clinical symptoms, therapy effect and prognosis was collected through interview, telephone call and questionnaire. The level of plasma TPO, the optical density of anti-TPO antibody and anti-c-Mpl antibody, platelet counts in 8 patients with AATP,10 patients with ITP and 10 healthy controls were tested by enzyme-linked immunosorbent assay(ELISA) and automatic hemocytoanalyser.
Result:28 cases were collected. Follow-up was complete in 23 patients, among which,10 patients were cured,1 patient died of intracerebral hemorrhage,2 patients progressed to aplastic anemia(AA),1 patient progressed to myelodysplastic syndrome(MDS). The cure rate was higher in female than in male, but the difference was not statistically significant(P>0.05). The cure rate in the absence of bone marrow megakaryocyte group was lower than the reduction of bone marrow megakaryocyte group, but it didn't mean the bone marrow megakaryocyte counts could affect the therapy effect(P>0.05). The level of plasma TPO in AATP patients was higher than those in ITP patients and healthy controls, the difference was statistically significant (P<0.05). ITP patients also had higher level of plasma TPO compared with healthy controls, but the difference was not statistically significant(P>0.05). Optical density of anti-TPO antibody in AATP patients was closed to the healthy controls. Optical density of anti-c-Mpl antibody in AATP patients was higher than in healthy controls, but the difference was not statistically significant(P>0.05). The level of plasma TPO in AATP patients was not correlate with PLT counts、optical density of anti-TPO antibody and anti-c-Mpl antibody(P>0.05).
Conclusions:Male patients、absence of bone marrow megakaryocyte could be the risk factors of AATP. These patients failed to have a response of routine therapy. The level of plasma TPO in AATP patients was higher than those in ITP patients and healthy controls. The level of TPO could reflect the pathogenesis of thrombocytopenia. It could be able to improve the diagnosis of AATP and guide clinical therapy. The expression of anti-c-Mpl antibody may have a major role in the diagnosis of AATP.
方法：收集从2002年至2009年在汕头大学医学院第一附属医院诊断为获得性低巨核细胞性血小板减少性紫癜的病人,通过电话、面访或问卷的方式随访病人的临床症状、治疗情况及预后。应用酶联免疫吸附法(ELISA)检测8例AATP患者、10例ITP患者及10例健康对照血浆TPO水平,抗TPO自身抗体和抗c-Mpl自身抗体的吸光度,自动血细胞仪测定其血小板数。
结果：共收集病人资料28例,随访获得23例完整的病人资料。在23例病人中,10例治疗有效,1例因颅内出血死亡,2例转化为再生障碍性贫血,1例转化为骨髓增生异常综合征。女性治疗有效率(58.4%)高于男性(25%),但差异无统计学意义(P>0.05)。初诊时骨髓巨核细胞数缺如的患者治疗有效率(50%)低于骨髓巨核细胞数减少的(63.2%),但尚不能认为骨髓巨核细胞数可影响到治疗效果(P>0.05)。AATP组血浆TPO水平较ITP组及正常对照组升高,差异有统计学意义(P<0.05)。ITP组TPO水平略高于正常对照组,差异无统计学意义(P>0.05)。AATP组抗TPO自身抗体吸光度与正常对照组相近。AATP组抗c-Mpl自身抗体吸光度高于正常对照组,差异无统计学意义(P>0.05)。相关分析表明AATP组血浆TPO水平与血小板计数、抗TPO自身抗体、抗c-Mpl自身抗体均无相关性(P>0.05)。
结论：男性患者、巨核细胞缺如可能是AATP的高危因素,具有这些因素的患者对常规治疗反应差。AATP患者血浆TPO水平较ITP患者及健康人群升高,TPO水平的检测能较好地反映血小板减少的发病机制,对提高AATP的诊断水平及指导临床治疗有一定意义。完善抗c-Mpl自身抗体检测可能为诊断AATP提供证据。
Objective:To investigate the clinical features, therapy and prognosis of acquired amegakaryocytic thrombocytopenic purpura(AATP). To explore the clinical significance of thrombopoietin, anti-TPO antibody and anti-c-Mpl antibody, and their relationship with peripheral blood platelet counts.
Method:Clinical data of inpatient cases undergoing acquired amegakaryocytic thrombocytopenic purpura(AATP) between 2002 and 2009 were collected. Follow-up information on clinical symptoms, therapy effect and prognosis was collected through interview, telephone call and questionnaire. The level of plasma TPO, the optical density of anti-TPO antibody and anti-c-Mpl antibody, platelet counts in 8 patients with AATP,10 patients with ITP and 10 healthy controls were tested by enzyme-linked immunosorbent assay(ELISA) and automatic hemocytoanalyser.
Result:28 cases were collected. Follow-up was complete in 23 patients, among which,10 patients were cured,1 patient died of intracerebral hemorrhage,2 patients progressed to aplastic anemia(AA),1 patient progressed to myelodysplastic syndrome(MDS). The cure rate was higher in female than in male, but the difference was not statistically significant(P>0.05). The cure rate in the absence of bone marrow megakaryocyte group was lower than the reduction of bone marrow megakaryocyte group, but it didn't mean the bone marrow megakaryocyte counts could affect the therapy effect(P>0.05). The level of plasma TPO in AATP patients was higher than those in ITP patients and healthy controls, the difference was statistically significant (P<0.05). ITP patients also had higher level of plasma TPO compared with healthy controls, but the difference was not statistically significant(P>0.05). Optical density of anti-TPO antibody in AATP patients was closed to the healthy controls. Optical density of anti-c-Mpl antibody in AATP patients was higher than in healthy controls, but the difference was not statistically significant(P>0.05). The level of plasma TPO in AATP patients was not correlate with PLT counts、optical density of anti-TPO antibody and anti-c-Mpl antibody(P>0.05).
Conclusions:Male patients、absence of bone marrow megakaryocyte could be the risk factors of AATP. These patients failed to have a response of routine therapy. The level of plasma TPO in AATP patients was higher than those in ITP patients and healthy controls. The level of TPO could reflect the pathogenesis of thrombocytopenia. It could be able to improve the diagnosis of AATP and guide clinical therapy. The expression of anti-c-Mpl antibody may have a major role in the diagnosis of AATP.
引文
[1]. Hirsh EH, Vogler WR, McDonald TP, et al. Acquired hypomegakaryocytic thrombocytopenic purpura occurrence in a patient with absent thrombopoietic stimulating factor. Arch Intern Med,1980 May,140(5):721-3.
[2].张之南.血液病诊断及疗效标准,3版.北京科学出版社,2008.
[3]. Hoffman R.获得性单纯无巨核细胞性血小板减少性紫癜.国外医学输血及血液学分册,1993,16(1)：19.
[4].陆廷伟,等.纯巨核细胞再生障碍21例的临床与诊断.临床血液学杂志,1997,10(2)：70.
[5].邢明礼,等.38例获得性低巨核细胞性血小板减少性紫斑临床分析.中华血液学会第三届血细胞学术会议论文汇编,1991,642.
[6].徐克惠主编.血液病基础与临床.北京：人民卫生出版社,1992,389.
[7].何晓彤,唐世超,尤宁,等.关于AA TP诊断问题的商榷.中级医刊,1993,28：16.
[8].李涛.先锋Ⅳ致获得性低巨核细胞血小板减少性紫癜1例.科学之友,2008,04：152.
[9]. Kuwana M, Okazaki Y, Kajihara M, et al. Autoantibody to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus:relationship to thrombocytopenia with megakaryocytic hypoplasia. Arthritis Rheum,2002,Aug,46(8):2148-59.
[10]. Katsumata Y, Suzuki T, Kuwana M, et al. Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis. Arthritis Rheum,2003 Jun,48(6):1647-51.
[11]. G Lugassy. Non-Hodgkin's lymphoma presenting with amegakaryocytic thrombocytopenic purpura. Ann Hematol,1996,73(1):41-42.
[12]. King JA, Elkhalifa MY, Latour LF, et al. Rapid progression of acquired amegakaryocytic thrombocytopenia to aplastic anemia. South Med J,1997 January 1,90(1):91.
[13]. Zafar T, Yasin F, Anwar M,et al. Acquired amegakaryocytic thrombocytopenic purpura (AATP):a hospital based study. J Pak Med Assoc,1999 May,49(5):114-7.
[14]. Ergas D, Tsimanis A, Shtalrid M, et al. T-gamma large granular lymphocyte leukemia associated with amegakaryocytic thrombocytopenic purpura, Sjogren's syndrome, and polyglandular autoimmune syndrome type Ⅱ, with subsequent development of pure red cell aplasia. Am J Hematol,2002,69:132-134.
[15]. Dominic W, Lai a, Thomas P, et al. Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia. Leukemia Research,2008,32:823-827.
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[1]. Hirsh EH, Vogler WR, McDonald TP, et al. Acquired hypomegakaryocytic thrombocytopenic purpura:Occurrence in a patient with absent thrombopoietic stimulating factor. Arch Intern Med,1980 May,140(5):721-3.
[2].张之南.血液病诊断及疗效标准[M].北京科学技术出版社,1998,279.
[3].Hoffman R.获得性单纯无巨核细胞性血小板减少性紫癜.国外医学输血及血液学分册,1993,16(1)：19.
[4].陆廷伟.纯巨核细胞再生障碍21例的临床与诊断.临床血液学杂志,1997,10(2)：70.
[5].邢明礼.38例获得性低巨核细胞性血小板减少性紫斑临床分析.中华血液学会第三届血细胞学术会议论文汇编,1991,642。
[6].徐克惠主编.血液病基础与临床.北京人民卫生出版社,1992,389.
[7].何晓彤,唐世超,尤宁,等.关于AA TP诊断问题的商榷.中级医刊,1993,28：16.
[8].李涛.先锋Ⅳ致获得性低巨核细胞血小板减少性紫癜1例.科学之友,2008,04：152.
[9]. Kuwana M, Okazaki Y, Kajihara M, et al. Autoantibody to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus:relationship to thrombocytopenia with megakaryocytic hypoplasia. Arthritis Rheum,2002 Aug,46(8):2148-59.
[10]. Katsumata Y, Suzuki T, Kuwana M, et al. Anti-c-Mpl (thrombopoietin receptor) autoantibody-induced amegakaryocytic thrombocytopenia in a patient with systemic sclerosis. Arthritis Rheum,2003 Jun,48(6):1647-51.
[11]. Hoffman R, Bruno E, Elwell J, et al. Acquired amegakaryocytic thrombocytopenic purpura: a syndrome of diverse etiologies. Blood,1982,60:1173-1178.
[12].陆德炎,陈义平,丁润生,等.获得性单纯无巨核细胞性血小板减少性紫癜发病机制的研究.中华血液学杂志,1999,22(3)：124-126.
[13]. M Podolak-Dawidziak. Acquired amegakaryocytic thrombocytopenic purpura (AATP):a study of autologous megakaryocyte progenitors and the effect of patients plasma on normal marrow megakaryocyte colony formation. Folia Haematol Int Mag Klin Morphol Blutforsch, 1990 January 1,117(2):347-51.
[14].李军民,沈志祥,王振义,等.成人慢性血小板减少性紫癜患者骨髓巨核细胞的研究.中华血液学杂志,1994,15：251.
[15]. G Lugassy. Non-Hodgkin's lymphoma presenting with amegakaryocytic thrombocytopenic purpura. Ann Hematol,1996,73(1):41-42.
[16]. King JA, Elkhalifa MY, Latour LF, et al. Rapid progression of acquired amegakaryocytic thrombocytopenia to aplastic anemia. South Med J,1997 January,90(1):91.
[17]. Zafar T, Yasin F, Anwar M, et al. Acquired amegakaryocytic thrombocytopenic purpura (AATP):a hospital based study. J Pak Med Assoc,1999 May,49(5):114-7.
[18]. Ergas D, Tsimanis A, et al. T-gamma large granular lymphocyte leukemia associated with amegakaryocytic thrombocytopenic purpura, Sjogren's syndrome, and polyglandular autoimmune syndrome type II, with subsequent development of pure red cell aplasia. Am J Hematol,2002,69:132-134.
[19]. Dominic W, Lai a, Thomas P, et al. Acquired amegakaryocytic thrombocytopenia and pure red cell aplasia associated with an occult large granular lymphocyte leukemia. Leukemia Research,2008,32:823-827.
[20]. Parker RI, Siegel RS, Ratajczak MZ, et al. Deficient in vitro megakaryocytopoiesis and decreased in vivo platelet turnover in children and young adults with chronic thrombocytopenia. J Pediatr Hematol Oncol,1998 May-Jun,20(3):196-201.
[21]. Basser RL, Rasko JE, Clarke K, et al. Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood,1997 May 1, 89(9):3118-28.
[22]. Kuter DJ. New thrombopoietic growth factors. Clin Lymphoma,2009,9 Suppl 3:S347-56.
[23]. Newland A. Thrombopoietin receptor agonists in the treatment of thrombocytopenia. Curr Opin Hematol,2009 Sep,16(5):357-64.
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[27]. Debili N, Wendling F, Katz A, et al. The Mpl ligand or thromopoietin or megakaryoeyte growth and differentiative facor has both direct proliferative and differentiative activities on human megaryocyte progenitors. Blood,1995,86:2516-2525.
[28]. Kaushansky K, Broudy VC, Lin NL, et al. Thrombopoietin, the Mpl ligand, is essential for full megakaeyocyte development. Proc Natl Acad Sei USA,1995,92:3234-3238.
[29]. Mignotte V, Vigon I, Boucher de Crevecoeur E, et al. Structure and transcription of the human c-mpl gene (MPL). Genomics,1994 Mar 1,20(1):5-12.
[30]. Tomoaki Kuwaki, Tetsuya Hagiwara, Chizuru Yuki, et al. Quantitative analysis of thrombopoietin receptors on human megakaryocytes. FEBS Lett,1998 May 1,427(1):46-50.
[31]. Saur SJ, Sangkhae V, Geddis AE, et al. Ubiquitination and degradation of the thrombopoietin receptor c-Mpl. Blood,2010 Feb 11,115(6):1254-63.
[32]. Gurney AL, Wong SC, Henzel WJ. Distinct regions of c-mpl cytoplasmic domain recoupled to the JAK-STAT signal transduction pathway and SHC phosphorylation[J]. Proc Natl Acad Sci USA,1995,92:5292.
[33]. Li J, Xia Y, Kuter D. Interaction of thrombopoietin with the platelet c-mpl receptor in plasma:binding, internalization, stability and pharmacodynamics. Br J Haematol,1999, 106:345-356.
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