特发性血小板减少性紫癜与骨髓增生异常综合征染色体核型分析
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摘要
[目的]:特发性血小板减少性紫癜(Idiopathic thrombocytopenic purpura,ITP),是以免疫介导的血小板破坏为特征的疾病,为临床异常出血最常见的病因;骨髓增生异常综合征(Myelodysplastic syndrome,MDS)是一组获得性造血干/祖细胞克隆性疾病,以无效造血、病态造血为特征;二者发病机制、病程及预后均有显著不同,然而发病初期都可表现为单纯的血小板减少,建立诊断均需用排除法,使鉴别十分困难。且近年来发现某些初诊为ITP的患者随着病情进展,检查后发现有遗传学上的异常,故有学者提出二者除临床表现相似外,可能有着共同的发病机制,本研究通过探讨老年ITP患者及MDS患者染色体核型异常以及异常位置,为理解ITP的发病机制并完善其与单纯血小板减少性MDS的鉴别诊断标准提供更进一步的信息,为难治性血小板减少(refractory thrombo cytopenia,RTC)的诊断提供一种新的思路。
[材料和方法]:采取病例-对照研究,收集汉族人群中33例中老年ITP患者,9例MDS患者及10例正常对照者的骨髓,均抽取3～5ml受试者骨髓于肝素抗凝的无菌小瓶中,同时采用直接法和24h培养法,核型分析采用R显带技术,在山东大学齐鲁医院血液学研究室完成。异常核型按1995年《人类细胞遗传学国际命名体制ISCN》描述。
[结果]:正常对照组均未发现染色体核型异常,33例ITP患者中有2例存在染色体核型异常,其中1例为(47,XY,+8),另1例为(46,XX,20q-);9例MDS患者共出现4例染色体核型异常,其中2例染色体核型异常分别为为(47,XX,+8),(47,XY,+8),另外1例染色体核型为(46,XX,20q-),1例为染色体核型为(46,XX,5q-)。
[结论]:ITP与MDS可能在临床表现和发病机制上存在重叠,ITP患者中出现染色体异常者应从ITP中分出来归入骨髓增生异常综合征。
Object Idiopathic thrombocytopenic purpura is an immune-mediated thrombocytopenic disease,which is the most common cause for abnormal bleeding. Myelodysplastic syndrome is an acquired clonal disease affecting both hemopoietic stem cell and progenitor cell,characterized by ineffective hematopoiesis and dyshaematopoiesis;They are distinctly different in pathogenesis,course of disease and prognosis.But both of them may first present as isolated thrombocytopenia, diagnosis established by exclusion,the overlapping clinical appearance make the differential diagnosis difficult.This research discuss the karyotypic abnormality in aged idiopathic thrombocytopenic purpura patients and myelodysplastic syndrome patients to augment the understanding of the pathogenesis of ITP and improve a new diagnostic method with refractory thrombocytopenia
Materials and Methods The research is a case-control study.We collected the bone marrow of 33 ITP patients,9 MDS patients and 10 normal controls in Han nationality,and obtained their bone marrow and put them in the pyxis with heparin, and then adopted direct method and culture method synchronously.Finally we get the karyotype analysis by R-banding.These were done in the Hemotology Lab.of Qilu Hospital.
Results No mutation was found in normal controls.In thirty-three ITP patients, One abnormity of chromosome was detected(47,XY,+8),One abnormity of chromosome was found in another patient(46,XX,20q-).Four abnormities were positive in MDS patients.Among them two had the abnormity of +8,one had 20q-, another had 5q-.
Conclusions ITP and MDS may be overlapping in clinical manifestations and pathogenesis,and the patients with karyotypic abnormality should be ruled out from ITP and classified into MDS again.
[材料和方法]:采取病例-对照研究,收集汉族人群中33例中老年ITP患者,9例MDS患者及10例正常对照者的骨髓,均抽取3～5ml受试者骨髓于肝素抗凝的无菌小瓶中,同时采用直接法和24h培养法,核型分析采用R显带技术,在山东大学齐鲁医院血液学研究室完成。异常核型按1995年《人类细胞遗传学国际命名体制ISCN》描述。
[结果]:正常对照组均未发现染色体核型异常,33例ITP患者中有2例存在染色体核型异常,其中1例为(47,XY,+8),另1例为(46,XX,20q-);9例MDS患者共出现4例染色体核型异常,其中2例染色体核型异常分别为为(47,XX,+8),(47,XY,+8),另外1例染色体核型为(46,XX,20q-),1例为染色体核型为(46,XX,5q-)。
[结论]:ITP与MDS可能在临床表现和发病机制上存在重叠,ITP患者中出现染色体异常者应从ITP中分出来归入骨髓增生异常综合征。
Object Idiopathic thrombocytopenic purpura is an immune-mediated thrombocytopenic disease,which is the most common cause for abnormal bleeding. Myelodysplastic syndrome is an acquired clonal disease affecting both hemopoietic stem cell and progenitor cell,characterized by ineffective hematopoiesis and dyshaematopoiesis;They are distinctly different in pathogenesis,course of disease and prognosis.But both of them may first present as isolated thrombocytopenia, diagnosis established by exclusion,the overlapping clinical appearance make the differential diagnosis difficult.This research discuss the karyotypic abnormality in aged idiopathic thrombocytopenic purpura patients and myelodysplastic syndrome patients to augment the understanding of the pathogenesis of ITP and improve a new diagnostic method with refractory thrombocytopenia
Materials and Methods The research is a case-control study.We collected the bone marrow of 33 ITP patients,9 MDS patients and 10 normal controls in Han nationality,and obtained their bone marrow and put them in the pyxis with heparin, and then adopted direct method and culture method synchronously.Finally we get the karyotype analysis by R-banding.These were done in the Hemotology Lab.of Qilu Hospital.
Results No mutation was found in normal controls.In thirty-three ITP patients, One abnormity of chromosome was detected(47,XY,+8),One abnormity of chromosome was found in another patient(46,XX,20q-).Four abnormities were positive in MDS patients.Among them two had the abnormity of +8,one had 20q-, another had 5q-.
Conclusions ITP and MDS may be overlapping in clinical manifestations and pathogenesis,and the patients with karyotypic abnormality should be ruled out from ITP and classified into MDS again.
引文
[1]侯明,秦平.欧美国家特发性血小板减少性紫癜诊治意见介绍.中华血液学杂志,2005;26:191-192
[2]Douglas B.Cines and Robert McMillan.Management of adult idiopathic thrombocytopenic purpura.Annu.Rev.Med.2005;56:425-42
[3]王吉耀,廖二元,胡品津.内科学.人民卫生出版社,2001;P802-805
[4]崔平江,蔡力力.单纯血小板减少为首发症状的MDS.军队进修学院学报,2004;25:355-356
[5]Menke DM,Colon-Otero G,Cockerill KJ,etal.Refractory thrombocytopenia:A myelodysplastic syndrome that may mimic immune thrombocytopenic purpura[J].Am J Clin Pathol,1992;98:502-510
[6]Duun DE,Tanawattanacharoen P,Boccuni P,Nagakura S,Green SW,Kirby MR,etal.Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.Ann Int Med,1999;131:401-8
[7]James N.George.Idiopathic thrombocytopenic purpura and myelodysplastic syndrome:distinct entities or overlapping syndromes? Leukemia Research,2002;789-790
[8]Hisamaru Hirai.Molecular Mechanisms of Myelodysplastic Syndrome.Jpn J Clin Oncol,2003;33:153-160
[9]cobs A.Gene mutations in myelodysplasia,leukemia Res,1992;16:47-50
[10]Padua RA,Guinn BA.RAS,FMS and p53 mutations and poor clinical outcome in myelodysplasias:a 10-year follow-up.Leukemia,1998;12:887-92
[11]、de Souza Fernandez T,Menezes de Souza J,Macedo Silva ML,etal.Leuk Res,1998;22:125-34
[12]Fenaux P,Preudhomme C.Molecular abnormalities and clonality in myelodysplastic syndromes.Pathol Biol(Paris),1997;45:556-60
[13]Ridge SA,Worwood M,Oscier D,etal.FMS mutations in myelodysplastic,leukemic,and normal subjects.Proc Natl Acad Sci U S A,1990;87:1377-80
[14]梅长林,李兆申等.内科学教程.人民卫生出版社,2003;P1114
[15]Imbach P,Kuhne T,Signer E.Historical aspects and present knowledge of idiopathic thrombocytopenic purpura.Br J Haematol,2000;119:894-900.
[16]McMillan R,Wang L,Tomer A,Nichol J,Pistollo J.Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP.Blood,2004;103:1364-9.
[17]Olsson B,Andersson PO,Jemas M,etal.T-cell mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med,2003;9:1123-1124
[18]Van-der Harst D,de Jong D,Limpens J,etal.Clonal B-cell population in patients with idiopathic thrombocytopenic purpura.Blood,1990;76:2321-2326
[19]Christie DJ,Sauro SC,Fairbanks KD,etal.Detection of clonal platelet antibodies in immunologically-mediated thrombocytopenias:association with circulating clonal/oligoclonal B cells.Br J Haematol,1993;85:277-284
[20]侯明,石艳,彭军等.慢性特发性血小板减少性紫癜自身抗体克隆性分析.Chin J Intern Med,2004;43:87-89
[21]Hou M,Stockelberg D,Kutti J,etal.Fab-mediated binding of glycoprotein Ⅰb/Ⅸand Ⅱb/Ⅲa specific antibodies in chronic idiopathic thrombocytopenic purpura.Br J Haematol,1995;91:944-50
[22]侯明,彭军.特发性血小板减少性紫癜的克隆性研究.Journal of Experimental Hematology,2004;12:538-541
[1] Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349: 831-6.
[2] Kojouri K, Vesely SK, Terrell DR, et al. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic literature review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004; 104:2623-34.
[3] Vesely SK, Perdue JJ, Rizvi MA, et al. Management of adult patients with idiopathic thrombocytopenic purpura after failure of splenectomy. A systematic review. Ann Int Med 2004; 140:112-20.
[4] Cooper N, Stasi R, Cunningham-Randies S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune hrombocytopenia purpura[J]. British J Haematol. 2004,125(5):232-239.
[5] Kuwana M, Nomura S, Fujimura, et al. Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet specific autoimmune response in patients with autoimmune thrombocytopenic purpura. Blood. 2004; 103:1229-1236.
[6] Salama A, Kiefel V, Amberg R, et al. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies [anti-Rh(D)]. Blut, 1984,49(1):29-35.
[7] Salama A, Kiefel V, Mueller Eckhardt C. Effect of IgG anti-Rho(D) in adult patientswith chornic autoimmune thrombocytopenia. Am J Hematol, 1986,22(3):241-250.
[8] Bussel JB, Graziano JN, Kimberly RP, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy , toxicity, and mechanism of effect. Blood, 1991, 77 (9):1884-1893.
[9] Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood, 1997,89(8):2689-2700.
[10] Gaines AR. Acute onset hemoglobinuria and sequelae following Rh(D) immune globulin intra- venous administration in immune thrombocytopenic purpura patients. Blood,2000,95(8):2523-2529.
[11]American Society of Hematology 42nd annual meeting,San Francisco,California,USA.December 1-5,2000.Abstracts Part 1 of 2.Blood,2000,96(11 Pt 1):249a.
[12]Proctor SJ,Jackson G,Carey P,et al.Improvement of platelet counts in steroid-unresponsive idiopathic immune thrombocytopenic purpura after short-course therapy with recombinant α-2a interferon.Blood,1989,74(6):1894-1897.
[13]Dubbeld P,Hillen HF,Schouten HC.Interferon treatment of refractory idiopathic thrombocytopenic purpura.Eur J Haematol,1994,52(4):233-235.
[14]Hudson JG,Yates P,et al.Further concern over use of α-inerferon in immune thrombocytopenic purpura.Br J Haematol,1992,82(3):630.
[15]Emilia G,Messora C,Longo G,et al.Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders.Br J Haematol,1996,93(2):341-344.
[16].Kappers-klune MC,Vantveer MB.Cyclosporin A for the treatment of patientswith chronic idiopathic thrombocytopenic purpura refractory to cortiscosteroids or splenetomy.Br J Heamotol,2001;114:121-125.
[17]Moskowitz IP,Gaynon PS,Shahidi NT,et al.Low-dose cyclosporin A therapy in children with refractory immune thrombocytopenic purpura.J Pediatr Hematol Oncol,1999,21(1):77-79.
[18]Pratt G,Kennedy B,SmithG,et al.Cyclosporin neurotocicity after chemotherapy:case had features of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome.BMJ,1999,319(7201):54.
[19]洪少杰,唐小玲等.霉酚酸酯治疗难治性特发性血小板减少性紫癜16例疗效观察.中国实用内科杂志,2005,25(6):531-532.
[20]Fibich C,Rohrberg R,Sommer H,et al.Long-term follow-up of a phase Ⅰ-Πstudy of mycophenolatemofetil(MMF)in refractory Evans syndrome.Blood,2001,98(2):442a.
[21]Nomura S,Kazuo D,Tomomitsu H,et al.Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura.Blood.2002,100(3):728-730.
[22]Cohen RJ,Dennis LH,Conrad ME.Anticoagulant therapy in chronic idiopathic thrombocytopenic purpura.Blood,1968,31(2):647-652.
[23]沈志祥,李军民,王振义等.Fraxiparin对巨核细胞—血小板系统刺激增生作用的研究.中华血液学杂志,1994,15(9):455-457.
[24]沈志祥,李军民,王振义等.肝素治疗慢性.特发性血小板减少性紫癜的初步疗效观察.中华血液学杂志,1995,16(4):196-197.
[25]American Society of Hematology 41st annual meeting.New Orleans,Louisiana,USA.December 3-7,1999.Abstracts.Part 1 of 2.Blood,1999,94(10 Pt 1):646a.
[26]张芬琴,李秀松,沈志祥等.复方环磷酰胺片治疗ITP的疗效.上海第二医科大学学报,2000,20(5):466-467.
[27]季林祥,杨德光,SE玫等.西艾克治疗特发性血小板减少性紫癜疗效观察.中华血液学杂志,1995,16(3):142.
[28]郑玉荣,罗桂霞.脾照射术治疗原发性血小板减少性紫19例.中国煤炭工业医学杂志,2004,7(10):986-987.
[2]Douglas B.Cines and Robert McMillan.Management of adult idiopathic thrombocytopenic purpura.Annu.Rev.Med.2005;56:425-42
[3]王吉耀,廖二元,胡品津.内科学.人民卫生出版社,2001;P802-805
[4]崔平江,蔡力力.单纯血小板减少为首发症状的MDS.军队进修学院学报,2004;25:355-356
[5]Menke DM,Colon-Otero G,Cockerill KJ,etal.Refractory thrombocytopenia:A myelodysplastic syndrome that may mimic immune thrombocytopenic purpura[J].Am J Clin Pathol,1992;98:502-510
[6]Duun DE,Tanawattanacharoen P,Boccuni P,Nagakura S,Green SW,Kirby MR,etal.Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.Ann Int Med,1999;131:401-8
[7]James N.George.Idiopathic thrombocytopenic purpura and myelodysplastic syndrome:distinct entities or overlapping syndromes? Leukemia Research,2002;789-790
[8]Hisamaru Hirai.Molecular Mechanisms of Myelodysplastic Syndrome.Jpn J Clin Oncol,2003;33:153-160
[9]cobs A.Gene mutations in myelodysplasia,leukemia Res,1992;16:47-50
[10]Padua RA,Guinn BA.RAS,FMS and p53 mutations and poor clinical outcome in myelodysplasias:a 10-year follow-up.Leukemia,1998;12:887-92
[11]、de Souza Fernandez T,Menezes de Souza J,Macedo Silva ML,etal.Leuk Res,1998;22:125-34
[12]Fenaux P,Preudhomme C.Molecular abnormalities and clonality in myelodysplastic syndromes.Pathol Biol(Paris),1997;45:556-60
[13]Ridge SA,Worwood M,Oscier D,etal.FMS mutations in myelodysplastic,leukemic,and normal subjects.Proc Natl Acad Sci U S A,1990;87:1377-80
[14]梅长林,李兆申等.内科学教程.人民卫生出版社,2003;P1114
[15]Imbach P,Kuhne T,Signer E.Historical aspects and present knowledge of idiopathic thrombocytopenic purpura.Br J Haematol,2000;119:894-900.
[16]McMillan R,Wang L,Tomer A,Nichol J,Pistollo J.Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP.Blood,2004;103:1364-9.
[17]Olsson B,Andersson PO,Jemas M,etal.T-cell mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med,2003;9:1123-1124
[18]Van-der Harst D,de Jong D,Limpens J,etal.Clonal B-cell population in patients with idiopathic thrombocytopenic purpura.Blood,1990;76:2321-2326
[19]Christie DJ,Sauro SC,Fairbanks KD,etal.Detection of clonal platelet antibodies in immunologically-mediated thrombocytopenias:association with circulating clonal/oligoclonal B cells.Br J Haematol,1993;85:277-284
[20]侯明,石艳,彭军等.慢性特发性血小板减少性紫癜自身抗体克隆性分析.Chin J Intern Med,2004;43:87-89
[21]Hou M,Stockelberg D,Kutti J,etal.Fab-mediated binding of glycoprotein Ⅰb/Ⅸand Ⅱb/Ⅲa specific antibodies in chronic idiopathic thrombocytopenic purpura.Br J Haematol,1995;91:944-50
[22]侯明,彭军.特发性血小板减少性紫癜的克隆性研究.Journal of Experimental Hematology,2004;12:538-541
[1] Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349: 831-6.
[2] Kojouri K, Vesely SK, Terrell DR, et al. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic literature review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood 2004; 104:2623-34.
[3] Vesely SK, Perdue JJ, Rizvi MA, et al. Management of adult patients with idiopathic thrombocytopenic purpura after failure of splenectomy. A systematic review. Ann Int Med 2004; 140:112-20.
[4] Cooper N, Stasi R, Cunningham-Randies S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune hrombocytopenia purpura[J]. British J Haematol. 2004,125(5):232-239.
[5] Kuwana M, Nomura S, Fujimura, et al. Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet specific autoimmune response in patients with autoimmune thrombocytopenic purpura. Blood. 2004; 103:1229-1236.
[6] Salama A, Kiefel V, Amberg R, et al. Treatment of autoimmune thrombocytopenic purpura with rhesus antibodies [anti-Rh(D)]. Blut, 1984,49(1):29-35.
[7] Salama A, Kiefel V, Mueller Eckhardt C. Effect of IgG anti-Rho(D) in adult patientswith chornic autoimmune thrombocytopenia. Am J Hematol, 1986,22(3):241-250.
[8] Bussel JB, Graziano JN, Kimberly RP, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy , toxicity, and mechanism of effect. Blood, 1991, 77 (9):1884-1893.
[9] Scaradavou A, Woo B, Woloski BM, et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood, 1997,89(8):2689-2700.
[10] Gaines AR. Acute onset hemoglobinuria and sequelae following Rh(D) immune globulin intra- venous administration in immune thrombocytopenic purpura patients. Blood,2000,95(8):2523-2529.
[11]American Society of Hematology 42nd annual meeting,San Francisco,California,USA.December 1-5,2000.Abstracts Part 1 of 2.Blood,2000,96(11 Pt 1):249a.
[12]Proctor SJ,Jackson G,Carey P,et al.Improvement of platelet counts in steroid-unresponsive idiopathic immune thrombocytopenic purpura after short-course therapy with recombinant α-2a interferon.Blood,1989,74(6):1894-1897.
[13]Dubbeld P,Hillen HF,Schouten HC.Interferon treatment of refractory idiopathic thrombocytopenic purpura.Eur J Haematol,1994,52(4):233-235.
[14]Hudson JG,Yates P,et al.Further concern over use of α-inerferon in immune thrombocytopenic purpura.Br J Haematol,1992,82(3):630.
[15]Emilia G,Messora C,Longo G,et al.Long-term salvage treatment by cyclosporin in refractory autoimmune haematological disorders.Br J Haematol,1996,93(2):341-344.
[16].Kappers-klune MC,Vantveer MB.Cyclosporin A for the treatment of patientswith chronic idiopathic thrombocytopenic purpura refractory to cortiscosteroids or splenetomy.Br J Heamotol,2001;114:121-125.
[17]Moskowitz IP,Gaynon PS,Shahidi NT,et al.Low-dose cyclosporin A therapy in children with refractory immune thrombocytopenic purpura.J Pediatr Hematol Oncol,1999,21(1):77-79.
[18]Pratt G,Kennedy B,SmithG,et al.Cyclosporin neurotocicity after chemotherapy:case had features of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome.BMJ,1999,319(7201):54.
[19]洪少杰,唐小玲等.霉酚酸酯治疗难治性特发性血小板减少性紫癜16例疗效观察.中国实用内科杂志,2005,25(6):531-532.
[20]Fibich C,Rohrberg R,Sommer H,et al.Long-term follow-up of a phase Ⅰ-Πstudy of mycophenolatemofetil(MMF)in refractory Evans syndrome.Blood,2001,98(2):442a.
[21]Nomura S,Kazuo D,Tomomitsu H,et al.Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura.Blood.2002,100(3):728-730.
[22]Cohen RJ,Dennis LH,Conrad ME.Anticoagulant therapy in chronic idiopathic thrombocytopenic purpura.Blood,1968,31(2):647-652.
[23]沈志祥,李军民,王振义等.Fraxiparin对巨核细胞—血小板系统刺激增生作用的研究.中华血液学杂志,1994,15(9):455-457.
[24]沈志祥,李军民,王振义等.肝素治疗慢性.特发性血小板减少性紫癜的初步疗效观察.中华血液学杂志,1995,16(4):196-197.
[25]American Society of Hematology 41st annual meeting.New Orleans,Louisiana,USA.December 3-7,1999.Abstracts.Part 1 of 2.Blood,1999,94(10 Pt 1):646a.
[26]张芬琴,李秀松,沈志祥等.复方环磷酰胺片治疗ITP的疗效.上海第二医科大学学报,2000,20(5):466-467.
[27]季林祥,杨德光,SE玫等.西艾克治疗特发性血小板减少性紫癜疗效观察.中华血液学杂志,1995,16(3):142.
[28]郑玉荣,罗桂霞.脾照射术治疗原发性血小板减少性紫19例.中国煤炭工业医学杂志,2004,7(10):986-987.