大剂量地塞米松优化方案治疗ITP及双靶点联合干预的探索
|
摘要
研究背景
原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是一种免疫介导的以血小板减少为主要特征的自身免疫性疾病,是临床最常见的出血性疾病,约占出血性疾病的1/3。其临床特点是外周血中血小板数量减少,广泛皮肤、粘膜甚至内脏出血,严重者可引起致死性的颅内出血。近几年发现部分患者表现为乏力、倦怠、忧郁、精神压力大等,也是ITP患者临床表现之一,西方学者研究发现其生存质量低于癌症患者,严重影响了人们的身心健康。患者实验室检查表现为骨髓巨核细胞发育、成熟障碍；血小板生存时间缩短以及部分患者出现抗血小板自身抗体等。ITP发病机制除了与体液免疫抗体介导引起血小板破坏过多外,还与细胞免疫有关,特别是T细胞功能紊乱直接抑制巨核细胞产生血小板；另有研究巨核细胞本身凋亡异常也与ITP发病机制有关。
在过去近五十多年里,口服泼尼松(Prednisone, Pred)一直是本病的首选治疗,开始剂量1.0～1.5mg/kg·d,分次口服至少4周,约70%病例可获得疗效,患者血小板计数升高或回复正常后逐渐减量,到血小板数在安全水平以上时用最低量给予维持治疗,但只有30%左右的患者会长期持续缓解,而其余70%左右ITP患者在糖皮质激素逐渐减量或停药时复发。并且长期应用糖皮质激素过程中,几乎每位患者均出现不同程度的副反应,如Cushing症、高血压、糖尿病、骨质疏松、消化性溃疡、体液潴留、激素性精神病、免疫力低下造成严重感染等。值得注意的是几乎每位女性患者均出现库欣综合征,使之谈激素“色变”
因此,学者们在不断探索新的更为安全有效的治疗方案,为避免长期应用糖皮质激素造成各系统的并发症,有研究者尝试给予短周期大剂量地塞米松(high-dose dexamethasone, HD-DXM)冲击治疗ITP,即给予地塞米松40mg/d,分2次口服,连用4d,以后不再维持用药。尤其近年来,短周期大剂量地塞米松冲击作为初诊成人原发免疫性血小板减少症的一线治疗,其有效率高、安全性好、价格低廉等在国外有不少报道。然而,也有报道ITP患者给予单个疗程HD-DXM冲击治疗,尽管短期有效率高,副作用少,但停药后存在不同程度地复发,三个月后其复发率与传统泼尼松方案大致相同,而多个疗程HD-DXM冲击治疗,治疗周期长,患者依从性差,糖皮质激素副作用又会增加。到目前为止,就有关ITP患者HD-DXM冲击治疗,冲击几个疗程,间隔多长时间再次冲击或是否给予维持治疗尚没有统一的意见,应用短周期大剂量地塞米松冲击治疗ITP的研究在我国也比较少,本研究我们优化了HD-DXM治疗方案,采用连续2个周期大剂量地塞米治疗新诊断成人ITP患者,试图既能提高ITP患者疗效,又能降低远期复发率,且安全性好,患者能耐受。
目的
1)观察优化方案连续2个周期大剂量地塞米松冲击治疗成人新诊断原发免疫性血小板减少症(ITP)患者的近、远期疗效,并与传统常规剂量泼尼松治疗进行比较。
2)两种治疗方案安全性比较。方法
73例新诊断的ITP患者随机分为两组,地塞米松组37例,给予地塞米松40mg/d,分2次口服,连用4d。间隔7d后再重复一个周期,以后不再进行维持治疗；泼尼松治疗组36例,给予泼尼松1.0～1.5mg/kg-d分3次口服,连用4周后逐渐减量。治疗前有活动性出血的患者酌情给予输注血小板。观察二组间的近、远期疗效和安全性。治疗期间无效的病人,采用其它方案,包括rhTPO、脾切除、CsA、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。
治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上。另外,检测地塞米松组患者第一周期治疗结束后第一天血象(即冲击治疗第5天),检测血小板数。结果
近期疗效：治疗后第1、2周末地塞米松组有效率明显高于泼尼松组(67.6%比36.1%,78.4%比55.6%,P值均<0.05),治疗后第3周末有效率仍高于泼尼松组,但差异无统计学意义(86.5%比75.0%,P>0.05)。
远期疗效：随访3个月,除第1个月末地塞米松组复发率与泼尼松组差异无统计学意义(18.7%比22.2%,p>0.05)外,第2、3个月末地塞米松组复发率明显低于泼尼松组(21.9%比48.1%,34.4%比63.0%,P值均<0.05)。
地塞米松组冲击治疗(第一周期)第5天血小板数低于100×109者与高于100×109者比较,3月后其复发率明显升高(47.1%比15.0%,P值<0.05)。
不良反应：地塞米松组不良反应轻微,少数患者出现一过性高血压及高血糖,无1例并发感染及出现柯兴氏症。所有患者均能耐受,完成治疗方案。而泼尼松组32例出现不同程度柯兴氏症表现,2例病人继发口腔真菌感染,1例女性病人继发真菌性阴道炎,1例老年病人继发带状疱疹,经相应治疗病情控制,完成治疗方案。
结论
1)连续2个疗程大剂量地塞米松治疗ITP患者的近、远期疗效均优于常规剂量泼尼松；大剂量地塞米松治疗ITP较传统泼尼松治疗起效迅速,能短期内实现血小板快速上升。
2)地塞米松组冲击治疗(第一周期)第5天血小板数低于100±109/L的患者与高于100±109/L的患者比较,3月后复发率高,有利于ITP的分层治疗。
3)大剂量地塞米松治疗ITP均能耐受,安全性好,副作用少；而泼尼松治疗组副作用明显多于地塞米松组。
研究背景
原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是血液系统常见出血性疾病,主要由于自身免疫因素,导致血小板破坏过多或巨核细胞生成障碍,使患者血液中血小板数量减少,临床表现以出血为主。糖皮质激素是治疗初诊成人ITP的一线药物,对大部分ITP有效；而约1/3患者糖皮质激素治疗无效或治疗过程中复发,或需要较大剂量的糖皮质激素才能维持疗效从而引起明显的副作用。对这部分患者,目前尚无统一的治疗标准。国外部分学者认为,在所有治疗ITP的方案中,脾切除是获得持续完全反应最有效的手段引,故将经脾切除仍无反应的患者定义为难治性ITP。
难治性ITP定义目前尚无统一的标准,根据有关文献,具有下列之一者为难治性ITP：(1)标准剂量糖皮质激素(泼尼松1-2mg/kg/d)治疗4周,血小板计数仍<50×109/L,或者血小板恢复正常,但随激素减量血小板计数随之下降,或需泼尼松>30mg才能维持血小板数目稳定者；(2)脾切除(包括脾栓塞、脾化疗)后血小板计数仍≦50x109/L,或者血小板一度恢复正常又下降,需继续内科治疗者；(3)经糖皮质激素、脾切除、静脉注射免疫球蛋白、免疫抑制剂等多方面治疗无效,血小板计数≦30×109/L；(4)血小板计数≦20x109/L,尤以≦10×109/L有明显出血危及生命的重症患者。也有资料提出了比较完整的难治性ITP的诊断标准：(1)经糖皮质激素和脾切除治疗无效；(2)年龄10岁以上；(3)排除可能导致血小板减少的其他疾病；(4)血小板计数≦20×109/L；(5)ITP病程3个月以上；符合以上5项者为难治性ITP。2013年ITP国内专家共识(修订版),诊断难冶性ITP需满足以下3点：①脾切除后无效或者复发；②仍需要治疗以降低出血的风险；③除外了其它引起血小板减少的原因。由于脾切除对某些经糖皮质激素治疗无效的病人来说难以接受或者无法实施,所以难治性ITP可能还应该包括这部分患者。
对于难治性ITP的病人,可以选择脾切除治疗或者应用二线治疗药.脾切除是对糖皮质激素治疗耐药患者的首选,不过仍有1/3患者无效或复发。另外,部分患者由于年龄、基础疾病等因素而无脾切除手术适应症,还有部分患者不愿接受外科脾切除治疗。ITP治疗的二线药物包括免疫抑制剂(环孢素A, Cyclosporin A,CsA)、利妥昔单抗(rituximab, RTX)、促血小板生成素(thrombopietin,TPO)等。
利妥昔单抗是人鼠嵌合型单克隆抗CD20抗体,因其能够清除产生自身抗体的B淋巴细胞,且相对安全及较少引起骨髓抑制,现多用于治疗难冶性ITP。项系统性回顾表明利妥昔单抗的完全反应率(血小数>150×109/L)为44%,总体有效率(血小板>50×109/L)为62%,治疗反应从3周到6个月,且价格昂贵。环孢菌素是钙依赖磷酸酶抑制剂,抑制T淋巴细胞增殖,并能调节ITP患者体内失衡的T细胞亚群。其作用特点是作用于淋巴细胞增殖的早期,不抑制造血系统。起效较慢,视病情情况,可以选择环孢菌素。TPO可以增加巨核细胞的数量,刺激血小板增生,实验表明TPO一次注射可使造血功能正常患者的血小板增加约3倍。给药方法是皮下注射hTPO1.Oug/kg,1次/d,疗程14d,总有效率68%,但停药后血小板数量逐渐下降至基线。
免疫抑制剂及利妥昔单抗治疗起效时间长,TPO起效快但停药后血小板回落,患者不能获得长期缓解。因此寻找一种既能使难治性ITP患者血小板快速上升,又能获得长期缓解的治疗方案尤为迫切,我们应用rhTPO联合环孢素A双靶点针对ITP不同发病机制,干预难治性ITP。目的
观察重组人血小板生成素(recombinant human thrombopoietin,rhTPO)联合环孢素A(CsA)治疗难治性免疫性血小板减少症(R-ITP)的近期、远期疗效及安全性。方法
41例难治性ITP患者,随机分为观察组和对照组2组。观察组(21例)皮下注射rhTPO1ug(300U)/kg·d,疗程14d,同时口服环孢素A (CsA)3～4mg/kg·d,分2次,疗程3个月。对照组(20例)皮下注射rhTPO lug(300U)/kg·d,疗程14d后,停药观察。治疗期间无效或复发的病人,采用其它方案,包括脾切除、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。
治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上结果
近期疗效：第1、2周末观察组与对照组有效率分别为61.9%、55.5%(x2=0.17,P>0.05);90.5%、90.0%(x2=0.22, P>0.05),均无显著性差异。
远期疗效：治疗后第1月末观察组与对照组复发率分别为15.8%、44.4%(x2=3.62,P>0.05)无显著性差异。而第2、3个月末2组复发率分别为26.3%、61.1%(x2=5.90, P<0.05);31.6%、83.3%(x2=10.07, P<0.01),均有显著性差异。
对照组及观察者所有患者均能耐受治疗,治疗后患者2组白细胞计数、血红蛋白及血凝常规、尿常规、电解质、心电图均无明显异常变化。对照组有1例出现轻度头晕乏力,1例注射部位疼痛均自行缓解。观察组恶心腹胀1例,转氨酶轻度升高2例,经对症处理后消失,均未停用环孢素A。2组患者无一例因副作用而停药。结论
TPO联合环孢素A治疗难治性ITP,既能获得显著近期疗效,又能较长时间维持疗效。
对照组及观察者所有患者均能耐受治疗,副作用轻微。
Background
Primary immune thrombocytopenia (ITP) is an immune-mediated autoimmune disease, characterized by platelet destruction induced by auto antibodies directed against specific glycoproteins of platelet surface, impaired megakaryocyte maturation with reduced platelet production. Accumulating evidence from studies of platelet kinetics also points to the contribution of immune-mediated suppression of megakaryocyte and platelet development in many patients; megakaryocyte apoptosis and suppression of megakaryopoiesis in vitro by ITP plasma or T-cells.ITP is one of the most common clinical bleeding disorders, ITP occurs in approximately one-third of bleeding disorders., its clinical features include petechiae, ecchymoses, mucosa bleeding, menorrhagia,rare visceral hemorrage, even fatal intracranial bleeding. Some patients experience fatigues, apprehension of bleeding, withdraw from important professional activities, and a poor quality of life.
Conventional prednisone is the first-line therapy for ITP patients,1.0to1.5mg of prednisone per kilogram of body weight daily for four weeks, approximate70%of ITP patients can achieve response, and only30%of patient can receive sustaining remission. The long-term treatment of prednisone for ITP patients will cause severe side effects, such as Cushing syndrome, hyperglycemia, hypertention, peptic ulcer, infection and mental disorders. Unfortunately, tapering in prednisone dosage or discontinuation causes most ITP patients to relapse. So that it is necessary to develop effective and safe therapeutic regimen for ITP patients, which not only increase platelet count quickly but also achieve a long-term remission and patients could tolerate it.
In recent years, treatment of primary immune thrombocytopenia with a short of course of high-dose dexamethasone (HD-DXM) has achieved better therapeutic response. Now HD-DXM regimen has been recommended as the first-line therapy for patients with ITP by west doctors and experts. ITP patients were given a single course of HD-DXM pulse therapy, although the short-term efficacy was very high and less side effects, relapse rate also was high after three months, patients could not receive sustained remission. Multiple courses of HD-DXM pulse therapy were given, treatment cycle is long, patient compliance is poor, glucocorticoid effects will increase again. So far, for the HD pulse therapy, how long interval to administer or whether to give maintenance treatment, there is no unified opinion.
The study of this regimen is rare in our country. In our present study, we optimize the regimen, by administering2cycles'high-dose dexamethasone as initial therapy in primary thrombocytopenia and compare with conventional prednisone therapy.
Objective:
To investigate the efficacy and safety of a schedule of2cycles' high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP), and compare with conventional dose prednisone therapy.
Method:
A total of73newly diagnosed ITP patients were divided into2groups randomly. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then failed to maintain. In the remaining36patients (Prednisone group), prednisone was administered orally at1.0～1.5mg·kg-1·d-1for4weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.
Results:
For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.
Conclusion
1)HD-DXM possesses an advantage over traditional dose prednisone therapy in efficacy and reduces the recurrence rate. High-dose dexamethasone therapy could result in rapider response than prednisone treatment.
2) A platelet count of less than100×109/L on day5was associated with a high risk of relapse.
3)HD-DXM is well tolerated and safety.
Objective:
To investigate the efficacy and safety of a schedule of2cycles of high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP),and compare with conventional dose prednisone therapy.
Methods:
A total of73patients with newly diagnosed ITP were randomly divided into2groups. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then the patients discontinued treatment. In the remaining36patients (prednisone group), prednisone was administered orally at1.0～1.5mg mg·kg-1·d-1for4consecutive weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.
Results:
For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.
Conclusion
(1)HD-DXM possesses an advantage over traditional prednisone therapy in efficacy and reduces the recurrence rate; high-dose dexamethasone pulse could result in rapider response than prednisone.
(2) A platelet count of less than100×109/L on day5in patient (Dexamethasone group) was associated with a high risk of relapse at the end of third month of follow-up.
(3) HD-DXM is well tolerated and safety.
Background
Primary immune thrombocytopenia (ITP), one of the most common bleeding disorders, is an acquired immune-mediated autoimmune disease. The pathogenic mechanism of ITP is complex, and both accelerated platelet destruction in the reticuloendothelial system and impaired megakaryocyte maturation with reduced platelet production have been proven to contribute to thrombocytopenia.1,2The incidence is nearly30new cases per1million per year. Depending on the severity of the thrombocytopenia, the most common manifestations of ITP range from easy bruising and petechiae, to epistaxis and gingival bleeding and, more rarely, anal, gastrointestinal, or intracranial bleeding.
Glucocorticoids are the standard first-line therapy for ITP and most patients achieve a durable response. However, approximately one third of the patients with ITP fail to response to glucocorticoid therapy. These patients often need high doses of glucocorticoids to maintain the therapeutic effects, and these usually cause significant adverse effects. Splenectomy or second-line therapies such as immunosuppressive agents, Rituximab, and recombinant human thrombopoietin (rhTPO) can be chosen for patientswith glucocorticoid treatment failure. Treatments with immunosuppressive agents or Rituximab often require a long treatment course to achieve satisfactory responses.4,5Patients can achieve a rapid response with rhTPO treatment but usually the response is not sustained once the regime was withdrawn, making it difficult to achieve a long-term remission for ITP patients. It has become increasingly important to develop effective therapeutic regimens, which not only increase the number of platelets quickly but also achieve a long-term remission for ITP. In the present study, the efficacy of rhTPO combined with cyclosporin A(CsA) for the treatment of refractory ITP was investigated, and results showed that the short-term and long-term responses in the combination treatment group was better than that in the rhTPO control group. This suggests that combined use of rhTPO and CsA might be an effective alternate regimen for the management of refractory ITP patients. Objective
The management of patients with refractory immune thrombocytopenia is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in combination with cyclosporin A (CsA) for the management of refractory ITP patients.
Methods
Forty-one refractory ITP patients were randomly divided into an observation group and control group. In the observation group, twenty-one patients received subcutaneous injection of rhTPO at a dose of lug/kg (300U/kg) once daily up to day14. Simultaneously they also received oral CsA at a dose of1.5-2mg/kg twice daily for three months. In the control group, rhTPO alone was administered subcutaneously at1ug/kg once daily in the other twenty ITP patients for14consecutive days and then the treatment was withdrawn. If treatment failure occurred or patients relapsed during therapy, other treatment regimens, including splenectomy, Rituximab, or combined application of immunosuppressive therapy, could be chosen.
Results
There was no significant difference in the response rate at the end of the first week after treatment initiation between the observation group and the control group (61.9%vs.55.5%, x2=0.17, P>0.05), neither was there at the end of the second week(90.5%vs.90.0%, x2=0.22,P>0.05).However, the relapse rate in the observation group was significantly lower than that in control group at the end of the first (15.8%vs.44.4%, x2=3.62, P<0.05), second (26.3%vs.61.1%, x2=5.90, P<0.05) and the third month(31.6%vs.83.3%, x2=10.07, P<0.01). In addition, rhTPO plus CsA were well tolerated and adverse events recorded were mild.
Conclusion
Combination therapy with rhTPO and CsA was effective in the management of refractory ITP patients, with a relatively short time to response and low recurrence rate, it might be considered as a potential second-line treatment regimen for ITP.
原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是一种免疫介导的以血小板减少为主要特征的自身免疫性疾病,是临床最常见的出血性疾病,约占出血性疾病的1/3。其临床特点是外周血中血小板数量减少,广泛皮肤、粘膜甚至内脏出血,严重者可引起致死性的颅内出血。近几年发现部分患者表现为乏力、倦怠、忧郁、精神压力大等,也是ITP患者临床表现之一,西方学者研究发现其生存质量低于癌症患者,严重影响了人们的身心健康。患者实验室检查表现为骨髓巨核细胞发育、成熟障碍；血小板生存时间缩短以及部分患者出现抗血小板自身抗体等。ITP发病机制除了与体液免疫抗体介导引起血小板破坏过多外,还与细胞免疫有关,特别是T细胞功能紊乱直接抑制巨核细胞产生血小板；另有研究巨核细胞本身凋亡异常也与ITP发病机制有关。
在过去近五十多年里,口服泼尼松(Prednisone, Pred)一直是本病的首选治疗,开始剂量1.0～1.5mg/kg·d,分次口服至少4周,约70%病例可获得疗效,患者血小板计数升高或回复正常后逐渐减量,到血小板数在安全水平以上时用最低量给予维持治疗,但只有30%左右的患者会长期持续缓解,而其余70%左右ITP患者在糖皮质激素逐渐减量或停药时复发。并且长期应用糖皮质激素过程中,几乎每位患者均出现不同程度的副反应,如Cushing症、高血压、糖尿病、骨质疏松、消化性溃疡、体液潴留、激素性精神病、免疫力低下造成严重感染等。值得注意的是几乎每位女性患者均出现库欣综合征,使之谈激素“色变”
因此,学者们在不断探索新的更为安全有效的治疗方案,为避免长期应用糖皮质激素造成各系统的并发症,有研究者尝试给予短周期大剂量地塞米松(high-dose dexamethasone, HD-DXM)冲击治疗ITP,即给予地塞米松40mg/d,分2次口服,连用4d,以后不再维持用药。尤其近年来,短周期大剂量地塞米松冲击作为初诊成人原发免疫性血小板减少症的一线治疗,其有效率高、安全性好、价格低廉等在国外有不少报道。然而,也有报道ITP患者给予单个疗程HD-DXM冲击治疗,尽管短期有效率高,副作用少,但停药后存在不同程度地复发,三个月后其复发率与传统泼尼松方案大致相同,而多个疗程HD-DXM冲击治疗,治疗周期长,患者依从性差,糖皮质激素副作用又会增加。到目前为止,就有关ITP患者HD-DXM冲击治疗,冲击几个疗程,间隔多长时间再次冲击或是否给予维持治疗尚没有统一的意见,应用短周期大剂量地塞米松冲击治疗ITP的研究在我国也比较少,本研究我们优化了HD-DXM治疗方案,采用连续2个周期大剂量地塞米治疗新诊断成人ITP患者,试图既能提高ITP患者疗效,又能降低远期复发率,且安全性好,患者能耐受。
目的
1)观察优化方案连续2个周期大剂量地塞米松冲击治疗成人新诊断原发免疫性血小板减少症(ITP)患者的近、远期疗效,并与传统常规剂量泼尼松治疗进行比较。
2)两种治疗方案安全性比较。方法
73例新诊断的ITP患者随机分为两组,地塞米松组37例,给予地塞米松40mg/d,分2次口服,连用4d。间隔7d后再重复一个周期,以后不再进行维持治疗；泼尼松治疗组36例,给予泼尼松1.0～1.5mg/kg-d分3次口服,连用4周后逐渐减量。治疗前有活动性出血的患者酌情给予输注血小板。观察二组间的近、远期疗效和安全性。治疗期间无效的病人,采用其它方案,包括rhTPO、脾切除、CsA、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。
治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上。另外,检测地塞米松组患者第一周期治疗结束后第一天血象(即冲击治疗第5天),检测血小板数。结果
近期疗效：治疗后第1、2周末地塞米松组有效率明显高于泼尼松组(67.6%比36.1%,78.4%比55.6%,P值均<0.05),治疗后第3周末有效率仍高于泼尼松组,但差异无统计学意义(86.5%比75.0%,P>0.05)。
远期疗效：随访3个月,除第1个月末地塞米松组复发率与泼尼松组差异无统计学意义(18.7%比22.2%,p>0.05)外,第2、3个月末地塞米松组复发率明显低于泼尼松组(21.9%比48.1%,34.4%比63.0%,P值均<0.05)。
地塞米松组冲击治疗(第一周期)第5天血小板数低于100×109者与高于100×109者比较,3月后其复发率明显升高(47.1%比15.0%,P值<0.05)。
不良反应：地塞米松组不良反应轻微,少数患者出现一过性高血压及高血糖,无1例并发感染及出现柯兴氏症。所有患者均能耐受,完成治疗方案。而泼尼松组32例出现不同程度柯兴氏症表现,2例病人继发口腔真菌感染,1例女性病人继发真菌性阴道炎,1例老年病人继发带状疱疹,经相应治疗病情控制,完成治疗方案。
结论
1)连续2个疗程大剂量地塞米松治疗ITP患者的近、远期疗效均优于常规剂量泼尼松；大剂量地塞米松治疗ITP较传统泼尼松治疗起效迅速,能短期内实现血小板快速上升。
2)地塞米松组冲击治疗(第一周期)第5天血小板数低于100±109/L的患者与高于100±109/L的患者比较,3月后复发率高,有利于ITP的分层治疗。
3)大剂量地塞米松治疗ITP均能耐受,安全性好,副作用少；而泼尼松治疗组副作用明显多于地塞米松组。
研究背景
原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是血液系统常见出血性疾病,主要由于自身免疫因素,导致血小板破坏过多或巨核细胞生成障碍,使患者血液中血小板数量减少,临床表现以出血为主。糖皮质激素是治疗初诊成人ITP的一线药物,对大部分ITP有效；而约1/3患者糖皮质激素治疗无效或治疗过程中复发,或需要较大剂量的糖皮质激素才能维持疗效从而引起明显的副作用。对这部分患者,目前尚无统一的治疗标准。国外部分学者认为,在所有治疗ITP的方案中,脾切除是获得持续完全反应最有效的手段引,故将经脾切除仍无反应的患者定义为难治性ITP。
难治性ITP定义目前尚无统一的标准,根据有关文献,具有下列之一者为难治性ITP：(1)标准剂量糖皮质激素(泼尼松1-2mg/kg/d)治疗4周,血小板计数仍<50×109/L,或者血小板恢复正常,但随激素减量血小板计数随之下降,或需泼尼松>30mg才能维持血小板数目稳定者；(2)脾切除(包括脾栓塞、脾化疗)后血小板计数仍≦50x109/L,或者血小板一度恢复正常又下降,需继续内科治疗者；(3)经糖皮质激素、脾切除、静脉注射免疫球蛋白、免疫抑制剂等多方面治疗无效,血小板计数≦30×109/L；(4)血小板计数≦20x109/L,尤以≦10×109/L有明显出血危及生命的重症患者。也有资料提出了比较完整的难治性ITP的诊断标准：(1)经糖皮质激素和脾切除治疗无效；(2)年龄10岁以上；(3)排除可能导致血小板减少的其他疾病；(4)血小板计数≦20×109/L；(5)ITP病程3个月以上；符合以上5项者为难治性ITP。2013年ITP国内专家共识(修订版),诊断难冶性ITP需满足以下3点：①脾切除后无效或者复发；②仍需要治疗以降低出血的风险；③除外了其它引起血小板减少的原因。由于脾切除对某些经糖皮质激素治疗无效的病人来说难以接受或者无法实施,所以难治性ITP可能还应该包括这部分患者。
对于难治性ITP的病人,可以选择脾切除治疗或者应用二线治疗药.脾切除是对糖皮质激素治疗耐药患者的首选,不过仍有1/3患者无效或复发。另外,部分患者由于年龄、基础疾病等因素而无脾切除手术适应症,还有部分患者不愿接受外科脾切除治疗。ITP治疗的二线药物包括免疫抑制剂(环孢素A, Cyclosporin A,CsA)、利妥昔单抗(rituximab, RTX)、促血小板生成素(thrombopietin,TPO)等。
利妥昔单抗是人鼠嵌合型单克隆抗CD20抗体,因其能够清除产生自身抗体的B淋巴细胞,且相对安全及较少引起骨髓抑制,现多用于治疗难冶性ITP。项系统性回顾表明利妥昔单抗的完全反应率(血小数>150×109/L)为44%,总体有效率(血小板>50×109/L)为62%,治疗反应从3周到6个月,且价格昂贵。环孢菌素是钙依赖磷酸酶抑制剂,抑制T淋巴细胞增殖,并能调节ITP患者体内失衡的T细胞亚群。其作用特点是作用于淋巴细胞增殖的早期,不抑制造血系统。起效较慢,视病情情况,可以选择环孢菌素。TPO可以增加巨核细胞的数量,刺激血小板增生,实验表明TPO一次注射可使造血功能正常患者的血小板增加约3倍。给药方法是皮下注射hTPO1.Oug/kg,1次/d,疗程14d,总有效率68%,但停药后血小板数量逐渐下降至基线。
免疫抑制剂及利妥昔单抗治疗起效时间长,TPO起效快但停药后血小板回落,患者不能获得长期缓解。因此寻找一种既能使难治性ITP患者血小板快速上升,又能获得长期缓解的治疗方案尤为迫切,我们应用rhTPO联合环孢素A双靶点针对ITP不同发病机制,干预难治性ITP。目的
观察重组人血小板生成素(recombinant human thrombopoietin,rhTPO)联合环孢素A(CsA)治疗难治性免疫性血小板减少症(R-ITP)的近期、远期疗效及安全性。方法
41例难治性ITP患者,随机分为观察组和对照组2组。观察组(21例)皮下注射rhTPO1ug(300U)/kg·d,疗程14d,同时口服环孢素A (CsA)3～4mg/kg·d,分2次,疗程3个月。对照组(20例)皮下注射rhTPO lug(300U)/kg·d,疗程14d后,停药观察。治疗期间无效或复发的病人,采用其它方案,包括脾切除、利妥昔单抗、长春新碱、联合应用免疫抑制剂等治疗。
治疗后每周和随访过程中查血象监测血小板数,用药过程中监测血压、血糖、水平变化,治疗前后检测患者肝肾功、空腹血糖、尿常规等。随访观察3月以上结果
近期疗效：第1、2周末观察组与对照组有效率分别为61.9%、55.5%(x2=0.17,P>0.05);90.5%、90.0%(x2=0.22, P>0.05),均无显著性差异。
远期疗效：治疗后第1月末观察组与对照组复发率分别为15.8%、44.4%(x2=3.62,P>0.05)无显著性差异。而第2、3个月末2组复发率分别为26.3%、61.1%(x2=5.90, P<0.05);31.6%、83.3%(x2=10.07, P<0.01),均有显著性差异。
对照组及观察者所有患者均能耐受治疗,治疗后患者2组白细胞计数、血红蛋白及血凝常规、尿常规、电解质、心电图均无明显异常变化。对照组有1例出现轻度头晕乏力,1例注射部位疼痛均自行缓解。观察组恶心腹胀1例,转氨酶轻度升高2例,经对症处理后消失,均未停用环孢素A。2组患者无一例因副作用而停药。结论
TPO联合环孢素A治疗难治性ITP,既能获得显著近期疗效,又能较长时间维持疗效。
对照组及观察者所有患者均能耐受治疗,副作用轻微。
Background
Primary immune thrombocytopenia (ITP) is an immune-mediated autoimmune disease, characterized by platelet destruction induced by auto antibodies directed against specific glycoproteins of platelet surface, impaired megakaryocyte maturation with reduced platelet production. Accumulating evidence from studies of platelet kinetics also points to the contribution of immune-mediated suppression of megakaryocyte and platelet development in many patients; megakaryocyte apoptosis and suppression of megakaryopoiesis in vitro by ITP plasma or T-cells.ITP is one of the most common clinical bleeding disorders, ITP occurs in approximately one-third of bleeding disorders., its clinical features include petechiae, ecchymoses, mucosa bleeding, menorrhagia,rare visceral hemorrage, even fatal intracranial bleeding. Some patients experience fatigues, apprehension of bleeding, withdraw from important professional activities, and a poor quality of life.
Conventional prednisone is the first-line therapy for ITP patients,1.0to1.5mg of prednisone per kilogram of body weight daily for four weeks, approximate70%of ITP patients can achieve response, and only30%of patient can receive sustaining remission. The long-term treatment of prednisone for ITP patients will cause severe side effects, such as Cushing syndrome, hyperglycemia, hypertention, peptic ulcer, infection and mental disorders. Unfortunately, tapering in prednisone dosage or discontinuation causes most ITP patients to relapse. So that it is necessary to develop effective and safe therapeutic regimen for ITP patients, which not only increase platelet count quickly but also achieve a long-term remission and patients could tolerate it.
In recent years, treatment of primary immune thrombocytopenia with a short of course of high-dose dexamethasone (HD-DXM) has achieved better therapeutic response. Now HD-DXM regimen has been recommended as the first-line therapy for patients with ITP by west doctors and experts. ITP patients were given a single course of HD-DXM pulse therapy, although the short-term efficacy was very high and less side effects, relapse rate also was high after three months, patients could not receive sustained remission. Multiple courses of HD-DXM pulse therapy were given, treatment cycle is long, patient compliance is poor, glucocorticoid effects will increase again. So far, for the HD pulse therapy, how long interval to administer or whether to give maintenance treatment, there is no unified opinion.
The study of this regimen is rare in our country. In our present study, we optimize the regimen, by administering2cycles'high-dose dexamethasone as initial therapy in primary thrombocytopenia and compare with conventional prednisone therapy.
Objective:
To investigate the efficacy and safety of a schedule of2cycles' high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP), and compare with conventional dose prednisone therapy.
Method:
A total of73newly diagnosed ITP patients were divided into2groups randomly. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then failed to maintain. In the remaining36patients (Prednisone group), prednisone was administered orally at1.0～1.5mg·kg-1·d-1for4weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.
Results:
For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.
Conclusion
1)HD-DXM possesses an advantage over traditional dose prednisone therapy in efficacy and reduces the recurrence rate. High-dose dexamethasone therapy could result in rapider response than prednisone treatment.
2) A platelet count of less than100×109/L on day5was associated with a high risk of relapse.
3)HD-DXM is well tolerated and safety.
Objective:
To investigate the efficacy and safety of a schedule of2cycles of high-dose dexamethasone (HD-DXM) as an initial therapy in adults immune thrombocytopenia (ITP),and compare with conventional dose prednisone therapy.
Methods:
A total of73patients with newly diagnosed ITP were randomly divided into2groups. In37patients (Dexamethasone group), oral HD-DXM was administered at40mg/d for4consecutive days, repeated one week later, and then the patients discontinued treatment. In the remaining36patients (prednisone group), prednisone was administered orally at1.0～1.5mg mg·kg-1·d-1for4consecutive weeks, and then gradually tapered. If treatment failure occurred during therapy, other treatment regimens, including splenectomy, Rituximab, CsA, or combined application of immunosuppressive therapy, could be chosen.
Results:
For short-term efficacy, at the end of1st and second week after treatment, the response rate in Dexamethasone group was significantly higher than that in Prednisone group (67.7%vs.36.1%, P<0.05;78.4%vs.55.6%P<0.05), while at the end of the third week, there was no significant difference between two groups (86.5%vs75.0%, P>0.05), though the response rate in Dexamethasone group remained higher. For long-term effect, at the end of2nd and3rd months of follow-up, the relapse rate in Dexamethasone group was significantly lower than that in Prednisone group (21.9%vs.48.1%, P<0.05,34.4%vs.63.0%, P<0.05),while at the end of1st month of follow-up, there was no significant difference ((18.7%vs.22.2%, P>0.05). In HD-DXM group, the relapse rate in patients whose platelet count was less than100×109/L on day5was significantly higher than those more than100×109/L at the end of third month of follow-up (47.1%vs15.0%, P<0.05). In addition, it is well tolerated and no complications such as severe infection or Cushing syndrome were complained in Dexamethasone group. And in prednisone group, most patients presented Cushing syndrome, some patients complicated with infection.
Conclusion
(1)HD-DXM possesses an advantage over traditional prednisone therapy in efficacy and reduces the recurrence rate; high-dose dexamethasone pulse could result in rapider response than prednisone.
(2) A platelet count of less than100×109/L on day5in patient (Dexamethasone group) was associated with a high risk of relapse at the end of third month of follow-up.
(3) HD-DXM is well tolerated and safety.
Background
Primary immune thrombocytopenia (ITP), one of the most common bleeding disorders, is an acquired immune-mediated autoimmune disease. The pathogenic mechanism of ITP is complex, and both accelerated platelet destruction in the reticuloendothelial system and impaired megakaryocyte maturation with reduced platelet production have been proven to contribute to thrombocytopenia.1,2The incidence is nearly30new cases per1million per year. Depending on the severity of the thrombocytopenia, the most common manifestations of ITP range from easy bruising and petechiae, to epistaxis and gingival bleeding and, more rarely, anal, gastrointestinal, or intracranial bleeding.
Glucocorticoids are the standard first-line therapy for ITP and most patients achieve a durable response. However, approximately one third of the patients with ITP fail to response to glucocorticoid therapy. These patients often need high doses of glucocorticoids to maintain the therapeutic effects, and these usually cause significant adverse effects. Splenectomy or second-line therapies such as immunosuppressive agents, Rituximab, and recombinant human thrombopoietin (rhTPO) can be chosen for patientswith glucocorticoid treatment failure. Treatments with immunosuppressive agents or Rituximab often require a long treatment course to achieve satisfactory responses.4,5Patients can achieve a rapid response with rhTPO treatment but usually the response is not sustained once the regime was withdrawn, making it difficult to achieve a long-term remission for ITP patients. It has become increasingly important to develop effective therapeutic regimens, which not only increase the number of platelets quickly but also achieve a long-term remission for ITP. In the present study, the efficacy of rhTPO combined with cyclosporin A(CsA) for the treatment of refractory ITP was investigated, and results showed that the short-term and long-term responses in the combination treatment group was better than that in the rhTPO control group. This suggests that combined use of rhTPO and CsA might be an effective alternate regimen for the management of refractory ITP patients. Objective
The management of patients with refractory immune thrombocytopenia is challenging, as there is no standard treatment option. The aim of this study was to investigate the efficacy of recombinant human thrombopoietin (rhTPO) in combination with cyclosporin A (CsA) for the management of refractory ITP patients.
Methods
Forty-one refractory ITP patients were randomly divided into an observation group and control group. In the observation group, twenty-one patients received subcutaneous injection of rhTPO at a dose of lug/kg (300U/kg) once daily up to day14. Simultaneously they also received oral CsA at a dose of1.5-2mg/kg twice daily for three months. In the control group, rhTPO alone was administered subcutaneously at1ug/kg once daily in the other twenty ITP patients for14consecutive days and then the treatment was withdrawn. If treatment failure occurred or patients relapsed during therapy, other treatment regimens, including splenectomy, Rituximab, or combined application of immunosuppressive therapy, could be chosen.
Results
There was no significant difference in the response rate at the end of the first week after treatment initiation between the observation group and the control group (61.9%vs.55.5%, x2=0.17, P>0.05), neither was there at the end of the second week(90.5%vs.90.0%, x2=0.22,P>0.05).However, the relapse rate in the observation group was significantly lower than that in control group at the end of the first (15.8%vs.44.4%, x2=3.62, P<0.05), second (26.3%vs.61.1%, x2=5.90, P<0.05) and the third month(31.6%vs.83.3%, x2=10.07, P<0.01). In addition, rhTPO plus CsA were well tolerated and adverse events recorded were mild.
Conclusion
Combination therapy with rhTPO and CsA was effective in the management of refractory ITP patients, with a relatively short time to response and low recurrence rate, it might be considered as a potential second-line treatment regimen for ITP.
引文
1. Johnsen J. Pathogenesis in immune thrombocytopenia:new insights. Hematology Am Soc Hematol Educ Program 2012; 2012:306-312.
2. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working group. Blood,2009,113: 2386-2393.
3. Provan D, Stasi R, Newland AC, et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood, 2010,115:168-186.
4. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults,children and in pregnancy. Br J Haenmtol, 2003.120:574-596.
5. Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-Dose dexamethasone. N Engl J Med,2003, 349:831-836.
6. Zhu XJ, Shi Y, Sun JZ, et al. High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol,2009,29:603-610.
7.张之南,沈悌等.血液病诊断及疗效标准(第3版).北京：科学出版2007：172-174
8.侯明,中华医学会血液分会血栓与止血组.成人原发免疫性血小板减少症诊治的中国专家共识.中华血液学杂志,2012,33(11)：975-977
9. Ling Y, Cao X, Yu Z, et al. Circulating dendritic cell subsets and CD4+Fox3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone. Eur J Hematol,2007,79:310-316.
10. Gao C,Chu X, Shi Y, et al. Correction of Thl-dominant cytokine profiles by high-dose dexamethasone in patients with high-dose dexamethasone in patients with chronic idiopathic thrombocytopenia purpura. J Clin Immunol,2007,27: 557-562.
11. Lim HW,Hillsamer P, Banham AH, et al. Cutting edge:direct suppression of B cells by CD4+CD25+regulatory T cells [J]. J Immunol,2005,175(7):4180-4183
12. Olsson B,Andersson PO, Jemas M,et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathathic thrombocytopenic purpura [J]. Nat Med,2003, 9(9):1123-1124
13. Zhao Ch, Li Xf, Zhang F. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies[J]. Haematologica,2008,93(9):1428-1430
14. Du WT, Zhao HF, Xu JH, et al. The role of T-cell immunoglobulin and mucin-domain-containing molecule-3 polymorphisms in idiopathic thrombocytopenic purpura [J]. Human Immunology,2009,70(6):398-402.
15. Shan NN, Zhu XJ, Wang Q, et al. High-dose dexamethasone regulates interleukin-18 binding protein in idiopathic thrombocytopenic purpura. Haematologica,2009,94:1603-1607.
16. Gu D S, Che Z P, Zhao H F. Thl(CXCL10)and Th2(CCL2)chemokine expression in patients with immune thrombocytopenia[J]. Human Immunology,2010,71(6): 586-591.
17.Ren H, Zhao H, Wang T, et al. Lepin enhances in vito secretion of IgG antiplatet an-bodies by splenocytes and peripheral blood mononuclear cells from patients with chronic idiopathic thrombocytopenic purpura [J]. Clinical Immunology,2006, 120(2):205-211
18. Bertrand Godeau,Marc Michel. Treatment of chronic immune thrombocytopenic purpura in adult [J]. Ann hematol,2010,89(Suppll):s55
19. Waleed Ghanima, Bertrand Godeau, Douglas B. How I treat immune thrombocytopenia:the choice between splenectomy or a medical therapy as a second-line treatment [J].Blood 2012,120:960-969
20. Sarpatwari A, Provan D, Erqou S, Sobnack R,David Tai FW, Newland AC. Autologous 111 Inlabelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy:a report from the United Kingdom ITP Registry. Br J Haematol.2010; 151(5):477-487.
21.秦平,陈峰,张春青,等.大剂量地塞米松治疗慢性特发性血小板减少性紫癜的疗效观察.中华内科杂志,2005,44：451-452.
22.李玉峰,刘定胜,丁帮和,等.短周期大剂量地塞米松治疗特发性血小板减少性紫癜的疗效分析.中华内科杂志,2009,48：734-736.
23. Borst F, Keuning JJ, van Hulsteijin H, et al. High-dose dexamethasone as first-and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol,2004,83:764-768.
24. Mazzuccoi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:a GIMEMA experience. Blood,2007,109: 1401-1407.
25. Hedlund-Treutiger I. Henter JI,Elinder G Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol,2003,25(2):139-144.
26. Cines DB, McMillan R.Management of adult idiopathic thrombocytopenic purpura. Almu Rev Med,2005,56:425-442
27. Chu XX, Huang BH, Zhang XL, et al. Dexamethasone inhibits immunoreactivity of dendritic cells in patients with chronic idiopathic thrombocytopenic purpura. Blood Coagul Fibrinolysis,2010,21:564-567.
28. Wang T, Zhao H, Ren H, et al. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 2005; 90:914-923.
29. Liu B, Zhao H, Poon Ma. Abnormality of CD4 CD 25 regulatory T ceils in idiopathic t thrombocytopenia purpura[J]. European J of Haematology,2007, 78(2):139-143.
30. Li S, Wang L, Zhao C, et al. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol,2007,139: 605-611.
31. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; 93:139-144.
32. Zhang F, Chu X, Wang L, et al. Cell mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura[J]. Eur Haematol 2006,76(5): 427-431.
1. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working group. Blood,2009,113: 2386-2393.
2. Provan D, Stasi R, Newland AC, et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood, 2010,115:168-186.
3. Johnsen J. Pathogenesis in immune thrombocytopenia:new insights. Hematology Am Soc Hematol Educ Program 2012; 2012:306-312.
4. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haenmtol, 2003.120:574-596.
5. Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-Dose dexamethasone. N Engl J Med,2003, 349:831-836.
6. Zhu XJ, Shi Y, Sun JZ, et al. High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol,2009,29:603-610.
7. Cines DB, Liebman HA. The Immune Thrombocytopenia Syndrome:A Disorder of Diverse Pathogenesis and Clinical Presentation [J]. Hematol Oncol Clin North Am,2009,23(6):1151-1161
8. Marieke Schoonen W, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol.2009; 145:235-244.
9. Ling Y, Cao X, Yu Z, et al. Circulating dendritic cell subsets and CD4 +Fox3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone. Eur J Hematol,2007,79:310-316.
10. Gao C, Chu X, Shi Y, et al. Correction of Thl-dominant cytokine profiles by high-dose dexamethasone in patients with high-dose dexamethasone in patients with chronic idiopathic thrombocytopenia purpura. J Clin Immunol,2007,27: 557-562.
11. Shan NN, Zhu XJ, Wang Q, et al. High-dose dexamethasone regulates interleukin-18 binding protein in idiopathic thrombocytopenic purpura. Haematologica,2009,94:1603-1607.
12. Gu DS, Cen ZP, Zhao HF. Thl(CXCL10)and Th2(CCL2)chemokine expression in patients with immune thrombocytopenia[J]. Human Immunology,2010,71(6): 586-591.
13. Zhao Ch, Li Xf, Zhang F. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies[J]. Haematologica,2008,93(9):1428-1430.
14. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
15. Bertrand Godeau, Marc Michel. Treatment of chronic immune thrombocytopenic purpura in adult [J]. Ann hematol,2010,89(Suppll):s55-57
16. Chow L, Aslam R, Speck ER, et a. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood 2010; 115:1247-1253.
17. Waleed Ghanima, Bertrand Godeau, Douglas B. How I treat immune thrombocytopenia:the choice between splenectomy or a medical therapy as a second-line treatment [J].Blood 2012,120:960-969
18. Sarpatwari A, Provan D, Erqou S, Sobnack R,David Tai FW, Newland AC. Autologous 111 Inlabelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy:a report from the United Kingdom ITP Registry. Br J Amatol.2010; 151(5):477-487.
19. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
20. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187-188.
21. Borst F, Kenning JJ, van Hulsteijin H, et al. High-dose dexamethasone as first-and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol,2004,83:764-768.
22. Mazzuccoi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:a GIMEMA experience. Blood,2007,109: 1401-1407.
23. Cines DB, McMillan R.Management of adult idiopathic thrombocytopenic purpura. Almu Rev Med,2005,56:425-442
24. Chu XX, Huang BH, Zhang XL, et al. Dexamethasone inhibits immunoreactivity of dendritic cells in patients with chronic idiopathic thrombocytopenic purpura. Blood Coagul Fibrinolysis,2010,21:564-567.
25. Wang T, Zhao H, Ren H, et al. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 2005; 90:914-923.
26. Liu B, Zhao H, Poon Ma. Abnormality of CD4 CD 25 regulatory T ceils in idiopathic t hrombocytopenie purpura[J]. European J of Haematology,2007, 78(2):139-143.
27. Li S, Wang L, Zhao C, et al. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol,2007,139: 605-611.
28. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; 93:139-144.
29. Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura[J]. Eur Haematol 2006,76(5): 427-431.
30. Hedlund-Treutiger I. Henter JI,Elinder G Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol,2003,25(2):139-144.
1. Johnsen J.Pathogenesis in immune thrombocytopenia:new insights.Hematology Am Soc Hematol Educ Program 2012; 2012:306-312.
2. Sakakura M,Wada H,Tawara I,et al.Reduced CD4+CD25+ T cells in patients withidiopathic thrombocytopenic purpura.Thromb Res 2007;120:187-193.
3. Zhang X-L,Peng J,Sun J-Z,et al.De novo induction of platelet-specific CD4+CD25+regulatory T cells from CD4+CD25-cells in patients with idiopathic thrombocytopenic purpura.Blood 2009; 113:2568-2577.
4. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children, report from an international working group. Blood 2009; 113:2386-2393.
5. Provan D, Stasi R,Newland AC,et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168-186.
6. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
7. George JN. Management of patients with refractory immune thrombocytopenic purpura [J]. Thromb Haemost.2006,4:1664-161670
8. Bertrand Godeau, M arc M ichel. Treatm ent of chronic immune thrombocytopenic purpura in adults[J]. Ann Hematol,2010,89(Suppll):S55-58
9.中华医学会血液分会成人原发免疫性血小板减少症诊治中国专家共识(修订版)[J].血栓与止血学组中华血液学杂志,2011,32(3)：218-220
10. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004; 125:232-239.
11.Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001;114:121-125.
12.赵永强,王庆余,翟明,等.重组人血小板生成素治疗慢性难治性特发性血小板减少性紫癜的多中心临床试验[J].中华内科杂志,2004,43(8)：608-610.
13. Liu XG, Peng J, Hou M. Restoration of T cell tolerance in primary ITP. J Hematol Oncol 2012; 5 Suppl 1:A5.
14. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost2005;93:139-144.
15. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
16. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med 2003;9:1123-1124.
17.Zaja F, Baccarani M, Mazza P, Bocchia M, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia.Blood2010; 115:2755-2762.
18. Kuter DJ, Begley CG. Recombinant human thrombopoietin:Basic biology and evaluation of clinical studies. Blood 2002; 100:3457-3469.
19.Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
20.Wang S, Yang R, Zou P, et al. A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia. Int J Hematol 2012;96:222-228.
21.Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 2002; 114:433-437.
22.Peng J, Liu C, Liu D, Ren C, et al. Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura.Blood 2003;101:2721-2726.
1. Johnsen J.Pathogenesis in immune thrombocytopenia:new insights.Hematology Am Soc Hematol Educ Program 2012;2012:306-312.
2. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children, report from an international working group. Blood 2009; 113:2386-2393.
3. Segal JB, Powe NR.Prevalence of immune thrombocytopenia:analyses of administrative data.J Thromb Haemost 2006;4:2377-2383.
4. Provan D, Stasi R,Newland AC,et al.International consensus report on the investigation and management of primary immune thrombocytopenia.Blood2010; 115:168-186.
5. Neunert C, Lim W, Crowther M, et al.The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190-4207.
6. Zhao YQ, Wang QY, Zhai M, et al. A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura. ZhonghuaNeiKeZaZhi 2004; 43:608-610.
7. Liu XG, Peng J, Hou M. Restoration of T cell tolerance in primary ITP. J Hematol Oncol 2012;5(Suppl 1):A5.
8. Panitsas FP, Theodoropoulou M, Kouraklis A, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response.Blood 2004; 103:2645-2647.
9. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost2005;93:139-144.
10. Liu B, Zhao H, Poon MC, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura.Eur J Haematol 2007;78:139-143.
11. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med2003;9:1123-1124.
12. Hou M, Andersson PO, Stockelberg D, et al. Plasma thrombopoietin levels in thrombocytopenic states:implication for a regulatory role of bone marrow megakaryocytes.Br J Haematol 1998; 10:420-424.
13.Zaja F, Baccarani M, Mazza P, Bocchia M, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia.Blood2010; 115:2755-2762.
14. Guo L, Dong XY, Li J, et al. Recombinant Human Thrombopoietin (rh-TPO) in Combination with Rituximab As a Novel Therapy in Refractory Primary Immune Thrombocytopenia (ITP). ASH Annual Meeting Abstracts 2011 118:2223.
15. Wang S, Yang R, Zou P, et al. A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia. Int J Hematol 2012;96:222-228.
16. Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 2002;114:433-437.
17. Peng J, Liu C, Liu D, Ren C, et al. Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura.Blood 2003; 101:2721-2726.
18. Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001;114:121-125.
19. Emilia G, Luppi M, Morselli M, Forghieri F, et al. A possible role for low-dose cyclosporine in refractory immune thrombocytopenic purpura. Haematologica2008;93:1113-1115.
1. Italiano JE Jr, Lecine P Shivdasani RA,Hartwig JH.Blood platelet are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol 1999; 147:1299-1312.
2. Italiano JE Jr, Patel-Hett S,Hartwig JH.Mechanics of proplatelet elaboration. J Thromb Haemost 2007;5(Suppl 1):18-23.
3. Pang L,Weiss MJ,Poncz M.Megakaryocyte biology and related disorders J Clin Invest 2005;115:3332-3338.
4. Kaushansky K.The molecular mechanisms that control thrombopoiesis.J Clin Invest 2005; 115:3339-3347.
5. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura:A randomized, double-blind, placebo-controlled trial. Lancet 2009; 373:641-648.
6. Weyrich AS,Denis MM,Schwertz H,et al.mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets. Blood 2007;109:1975-1983.
7. Italiano JE Jr, Hartwig JH.Megakaryocyte development and platelet formation.In: Platelet,2nd ed.A.D.Michelson,ed.Elsevier,San Diego 23-44,2007.
8. Italiano JE Jr,RA Shivdasani. Megakaryocytes and beyond:The birth of platelets.J Thromb Haemost 2003; 1:1174-1182.
9. Foulks JM,Marathe GK,Michetti N,et al.PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids.Blood 113: 6699-6706,2009.
10. Denis MM,Tolley ND,Bunting M,et al.Escaping the nuclear confines: Signal-dependent pre-mRNA splicing in anucleate platelets.Cell 2005;122: 379-391.
11. Weyrich AS,Schwertz HL,Kraiss W,Zimmerman GA.Protein synthesis by platelets:Historical and new perspectives.J Thromb Haemost 2009;7:241-246.
12. Schwertz H,Tolley ND,Foulks JM,et al.Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.J Exp Med 203: 2433-2440,2006.
13. Schwertz HS,Koster WH,Kahr N,et al.Anucleate platelets generate progeny.Blood 2010;115:3801-3809.
14. Behnke O,Forer A.From megakaryocytes to platelets:Platelet morphogenesis takes place in the bloodstream.Eur J Haematol Suppl 1998;61:3-23.
15. Junt T,Schulze H,Chen Z,et al.Dynamic visualization of thrombopoiesis within bone marrow.Science 2007;317:1767-1770.11:546-554.
16. Walker LS, Abbas AK.peripheral T Cell tolerance.Nat Rev Immunol 2002;2:11-19.
17. Semple JW,Freedman J.Increased antiplatelet Y helper lymphocyte reactivity in patients with autoimmune thrombocytopenia.Blood 1991;78:2619-2625.
18. Ware RE,Howard TA.Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura.Blood 1993;82:2137-2142.
19. Semple JW,Milev Y,Cosgrave D,et al.Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura:Relationship to platelet phenotype and antiplatelet T-cell reactivity.Blood 1996;87:4245-4254.
20. Shimomura T,Fujimura K,et al.Oligoclonal accumulation of Tcells in peripheral blood from patients with idiopathic thrombocytopenic purpura.Br J Haematol1996;95:732-737.
21. Shenoy S,Mohanakumar T,et al.Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias.Clin Immunol 2001;99:266-275.
22. Yoshimura C,Nomura S,Nagahama M,et al.Plasma-soluble Fas(APO-l,CD95)and soluble Fas ligand in immune thrombocytopenic purpura.Eur J Haematol 2000;64:219-224.
23.Kuwana M,Kaburaki J,Ikeda YAutoreactive T cells to platelet GPⅡb-Ⅲa in immune thrombocytopenic purpura:Role in production of anti-platelet autoantibody.J Clin Invest1998;102:1393-1402.
24. Kuwana M,Kaburaki J,Kitasato H,et al.Immunodominant epitopes on glycoprotein Ⅱb-Ⅲa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura.Blood 2001;98:130-139.
25. Olsson B,Andersson PO,Jernas M,et al.T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med 2003;9:1123-1124.
26. Coopamah MD,Garvey MB,Freedman J,et al.Cellular immune mechanisms in autoimmune thrombocytopenic purpura:An update.Transfus Med Rev 2003;17:69-80.
27. Sakakura M,Wada H,Tawara I,et al.Reduced CD4+CD25+ T cells in patients withidiopathic thrombocytopenic purpura.Thromb Res 2007; 120:187-193.
28. Ling Y,Cao X,Yu Z,Ruan C.Circulating dendritic cells subsets and CD4+FOXP3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome.Eur J Haematol 2007;79:310-316.
29. Liu B,Zhao H,Poon M-C,et al.Abnormality of CD4(+)CD25(+)regulatory T cells in idiopathic thrombocytopenic purpura.Eur J Haematol 2007;78:139-143.
30. Olsson et al.Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1.Blood 2008; 112:1078-1084.
31. Yu J,Heck S,Patel V,et al.Defective circulating CD25 regulatory Tcells in patients with chronic immune thrombocytopenic purpura.Blood 2008; 112:1325-1328.
32. Stasi R,Cooper N,Del Poeta G,et al.Analysis of regulatory T-cell changrs in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab.Blood 2008;112:1147-1150.
33. Zhang X-L,Peng J,Sun J-Z,et al.De novo induction of platelet-specific CD4+CD25+regulatory T cells from CD4+CD25-cells in patients with idiopathic thrombocytopenic purpura.Blood 2009; 113:2568-2577.
34. Kessel A,Ammuri H,Peri R,et al.Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function J Immunol 2007;179:5571-5575.
35. Ephrem A,Chamat S,Miquel C,et al.Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin:A critical factor in controlling experimental autoimmune encephalomyelitis.Blood 2008;111:715-722.
36. Bao W,Bussel JB,Heck S,et al.Improved regulatory T cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agent.Blood 2010 Aug 5.[Epub ahead of print].
37. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:Report from an international working group. Blood 2009; 113: 2386-2393.
38. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168-186.
39. Marieke Schoonen W, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol 2009; 145:235-244.
40. Abrahamson PE, Hall SA, Feudjo-Tepie M, et al. The incidence of idiopathic thrombocytopenic purpura among adults:A population-based study and literature review. Eur J Haematol 2009; 83:83-89.
41. Rischewski JR, Imbach P, Paulussen M, Kuhne T. Idiopathic thrombocytopenic purpura (ITP):Is there a genetic predisposition? Pediatr Blood Cancer 2006; 47: 678-680..
42. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood 2009; 113:6511-6521.
43. Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood 2005; 106:572-576.
44. Zhang W, Nardi MA, Borkowsky W, et al. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 2009; 113:4086-4093.
45. Takahashi T, Yujiri T, Shinohara K, et al. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura. Br J Haematol 2004; 124:91-96.
46. Sullivan PS, Hanson DL, Chu SY, et al. Surveillance for thrombocytopenia in persons infected with HIV:Results from the multistate Adult and Adolescent Spectrum of Disease Project. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:374-379.
47. Sloand EM, Klein HG, Banks SM, et al. Epidemiology of thrombocytopenia in HIV infection. Eur J Haematol 1992; 48:168-172.
48. Nardi M, Tomlinson S, Greco MA, Karpatkin S. Complement-independent, peroxideinduced antibody lysis of platelets in HIV-1-related immune thrombocytopenia. Cell 2001; 106:551-561.
49. Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: Clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol 2005; 129:818-824.
50. Chiao EY, Engels EA, Kramer JR, et al. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection. Arch Intern Med 2009; 169:357-363.
51. Iga D, Tomimatsu M, Endo H, et al. Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon-alpha therapy: Possible etiology of HCVassociated immune thrombocytopenia. Eur J Haematol 2005; 75:417-423.
52. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura:A systematic review. Blood 2009; 113:1231-1240.
53. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 2002; 100:1388-1398.
54. Zhu XJ, Shi Y, Peng J, et al. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood 2009; 114:5362-5367.
55. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPⅡb-Ⅲa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102:1393-1402.
56. Sukati H, Watson HG, Urbaniak SJ, Barker RN. Mapping helper T-cell epitopes on platelet membrane glycoprotein Ⅲa in chronic autoimmune thrombocytopenic purpura. Blood 2007; 109:4528-4538.
57. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
58. Zaja F, Baccaranti M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010; 115:2755-2762.
59. Cooper N, Woloski BM, Fodero EM, et al. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy? Blood 2002; 99:1922-1927.
60. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004; 104:956-960.
61.Berchtold P, Muller D, Beardsley D, et al. International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies. Br J Haematol 1997; 96:477-483.
62. Akiyama M, Kashiwagi H, Todo K, et al. Presence of platelet-associated anti-glycoprotein (GP)VI autoantibodies and restoration of GPVI expression in patients with GPVI deficiency. J Thromb Haemost 2009; 7:1373-1383.
63. Stoll D, Cines DB, Aster RH, Murphy S. Platelet kinetics in patients with idiopathic thromobcytopenic purpura and moderate thrombocytopenia. Blood 1985;65:584-588.
64. Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 1992; 327:1779-1784.
65. McMillan R, Wang L, Tomer A, et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103:1364-1369.
66. Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood 2008; 112:1078-1084.
67. Houwerzijl EJ, Blom NR, van der Want JJL, et al. Ultrastructural study shows morphological features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2003; 103:500-506.
68. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura:A randomised, double-blind, placebo-controlled trial. Lancet 2009; 373:641-648.
69. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
70. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009; 113: 2161-2171.
71. Chow L, Aslam R, Speck ER, et a. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood 2010; 115:1247-1253.
72. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000; 160:1630-1638.
73. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346:995-1008.
74. Imbach P, Barandun S, d'Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; i: 1228-1231.
75. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004; 125:232-239.
76. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients:A report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113:4834-4840.
77. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
78. Cheng Y, Wong RS, Soo Yo, et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349:831-836.
79. Mazzucconi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HDDXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:A GIMEMA experience. Blood 2007; 109: 1401-1407.
80. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura-results of a prospective multicenter phase 2 study. Blood 2008; 112:999-1004.
81. Stasi R. Rituximab in autoimmune hematologic diseases:Not just a matter of B cells. Semin Hematol 2010 47:170-179.
82. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
83. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187-188.
84. Kinuya K, Matano S, Nakashima H, Taki S. Scintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia. Ann Nucl Med 2003; 17:161-164.
85. Bussel JB, Kaufinann CP, Ware RE, Woloski BM. Do the acute platelet responses of patients with immune thrombocytopenic purpura (ITP) to IV anti-D and to IV gammaglobulin predict response to subsequent splenectomy? Am J Hematol 2001; 67:27-33.
86. Sarpatwari A, Bennett D, Logie JW, et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica 2010; 95:1167-1175.
87. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. British Journal of Haematology 2003; 120:574-596.
88. Mazzucconi NG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HDDXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura. A GIMEMA experience. Blood 2007; 109: 1401-1407.
89. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE):A 6-month, randomised, phase 3 study. Lancet 2011; 377:393-402.
90. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403
91. Kuter DJ, Begley CG. Recombinant human thrombopoietin:Basic biology and evaluation of clinical studies. Blood 2002; 100:3457-3469.
92. Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
93. Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
94. Schuster MW, Beveridge R, Frei-Lahr D, et al. The effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet recovery in breast cancer patients undergoing autologous bone marrow transplantation. Exp Hematol 2002; 30:1044-1050.
95. Harker LA, Carter RA, Marzec UM, et al. Correction of thrombocytopenia and ineffective platelet production in patients infected with human immunodeficiency virus (HIV) by PEG-rHuMGDF therapy (). Blood 1998; 92:707a.
96. Nomura S, Dan K, Hotta T, et al. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood 2002; 100:728-730.
97. Kuter DJ, Goodnough LT, Romo J, et al. Thrombopoietin therapy increases platelet yields in healthy platelet donors. Blood 2001; 98:1339-1345.
98. Frederickson S, Renshaw MW, Lin B, et al. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci USA 2006; 103:14307-14312.
99. Orita T, Tsunoda H, Yabuta N, et al. A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor. Blood 2005; 105:562-566.
100. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237-2247.
101. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
102. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357:2227-2236.
103. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol 2010; 28:437-444.
104. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98:952-957.
105. Mahevas M, Le Page L, Salle V, et al. Efficiency of rituximab in the treatment of autoimmune thrombocytopenic purpura associated with common variable immunodeficiency. Am J Hematol.2006; 81:645-646.
106. Patel V, Mihatov N, Cooper N, et al. Long term follow-up of patients with immune thrombocytopenic purpura (ITP) whose initial response to rituximab lasted a minimum of 1 year. Blood (ASH Annual Meeting s), Nov 2006; 108:479.
107. Zaja F, Vianelli N, Volpetti S, et al. Low-dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol 85:329-334,2010.
108. Provan D, Butler T, Evangelista ML, et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica 2007;92:1695-1698.
109. Saleh MN, Liebman H, Bernstein ZP, et al. Subcutaneous injections of low-dose anti-CD20 veltuzumab for treatment of relapsed immune thrombocytopenia (ITP). Blood (ASH Annual Meeting s), Nov 2009; 114:1322.
110. Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum 2008; 58:2993-2999.
111. Lund FE, Randall TD. Effector and regulatory B cells:Modulators of CD4+ T cell immunity. Nature Rev Immunol 2010; 10:236-247.
112. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab:A Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009; 10:816-824.
113. Zhang W, Nardi MA, Borkowsky W, et al. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 2009; 17:4086-4093.
114. Nieswandt B, Bergmeier W, Rackebrandt K, et al. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood 2000; 96:2520-2527.
115. Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response to intravenous immunoglobulin G in the treatment of patients with immune thrombocytopenia. Haematologica 2007; 92: 283-284.
116. Albert H, Collin M, Dudziak D, et al. In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci USA 2008; 105:15005-15009.
117. McMillan R. Antiplatelet antibodies in chronic immune thrombocytopenia and their role in platelet destruction and defective platelet production. Hematol Oncol Clin North Am 2009; 23:1163-1175. Review.
118. Nakar CT, Bussel JB.3G8 and GMA161, Anti Fc[gamma]RIII Inhibitory Monoclonal Antibodies in the Treatment of Chronic Refractory ITP. (Summary of 2 Pilot Studies). Blood 2009; 114:949. Abstract 2404.
119. Cooper N, Heddle NM, Haas M, et al. Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: Modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms. Br J Haematol 2004; 124:511-518.
120. Boruchov DM, Gururangan S, Driscoll MC, Bussel JB. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 2007; 110:3526-3531.
121. Amigorena S. Fc gamma receptors and cross-presentation in dendritic cells. J Exp Med 2002; 195:F1-3.
122. Bergtold A, Desai D, Gavhane A, Clynes R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005; 23: 503-514.
123. Podolanczuk A, Lazarus AH, Crow AR, et al. Of mice and men:An open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 2009; 3154-3160.
124. McMillan R, Wang L, Tomer A, et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103:1364-1369.
125. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103:500-506.
126. Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 1991; 78: 2619-2625.
127. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102:1393-1402.
128. Sakakura M, Wada H, Tawara I, et al. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb Res 2007; 120:187-193.
129. Ling Y, Cao X, Yu Z, Ruan C. Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. Eur J Haematol 2007; 79:310-316.
130. Yu J, Heck S, Patel V, et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood 2008; 112: 1325-1328.
131. Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76:427-431.
132. Zhao C, Li X, Zhang F, et al. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 2008; 93:1428-1430.
133. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:Report from an international working group. Blood 2009; 113: 2386-2393.
134. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
135. Stasi R, Del Poeta G, Stipa E, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007; 110:2924-2930.
136. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995-1008.
137. Li X., Hou M. Emerging drugs for idiopathic thrombocytopenic purpura in adults. Expert Opin Emerging Drugs 2008; 13:237-254.
138. Kaveri SV, Lacroix-Desmazes S, Bayry J. The Antiinflammatory IgG. N Engl J Med 2008; 359:307-309.
139. Provan D, Butler T, Evangelista ML, et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica 2007; 92:1695-1698.
140. Goldenberg DM, Rossi EA, Stein R, et al. Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood 2009; 113:1062-1070.
141. Zhang XL, Peng J, Sun JZ, et al. Modulation of immune response with cytotoxic Tlymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura. J Thromb Haemost 2008; 6: 158-165.
142. George JN, Terrell DR. Novel thrombopoietic agents:A new era for the management of patients with thrombocytopenia. Haematologica 2008; 93: 1445-1449.
143. Dziewanowska ZE, Kapil PR, Zhang JK et al. Clinical characterization of a novel oral thrombopoietin mimetic LGD-4665 in healthy volunteers demonstrate safe and sustained increases in platelet counts with flexible dosing choices for phase II trials. Blood 2008; 112, Abs 3406.
144. Nogami W, Yoshida H, Koizumi K, et al. The effect of a novel, small non-pepitdyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis. Haematologica 2008; 93:1495-1498.
145. Peeters K, Loyen S, Van Kerckhoven S, et al. Thrombopoietic effect of VPAC1 inhibition during megakaryopoiesis. Br J Haematol 2010; 151:54-61.
146. Kuwana M, Nomura S, Fujimura K, et al. Effect of a single injection of humanised anti-CD 154 monoclonal antobody on the platelet specific autoimmune response in patients with ITP. Blood 2004; 103:1229-1236.
147. Roopenian DC, Akilesh S. FcRn:The neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715-725.
148. Deng R, Balthasar JP. Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia. J Pharm Sci 2007; 96: 1625-1637.
149. Roopenian DC,Akilesh S.FcRn:The neonatal Fc receptor comes of age.Nat RevImmunol 2007;7:715-725.
2. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working group. Blood,2009,113: 2386-2393.
3. Provan D, Stasi R, Newland AC, et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood, 2010,115:168-186.
4. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults,children and in pregnancy. Br J Haenmtol, 2003.120:574-596.
5. Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-Dose dexamethasone. N Engl J Med,2003, 349:831-836.
6. Zhu XJ, Shi Y, Sun JZ, et al. High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol,2009,29:603-610.
7.张之南,沈悌等.血液病诊断及疗效标准(第3版).北京：科学出版2007：172-174
8.侯明,中华医学会血液分会血栓与止血组.成人原发免疫性血小板减少症诊治的中国专家共识.中华血液学杂志,2012,33(11)：975-977
9. Ling Y, Cao X, Yu Z, et al. Circulating dendritic cell subsets and CD4+Fox3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone. Eur J Hematol,2007,79:310-316.
10. Gao C,Chu X, Shi Y, et al. Correction of Thl-dominant cytokine profiles by high-dose dexamethasone in patients with high-dose dexamethasone in patients with chronic idiopathic thrombocytopenia purpura. J Clin Immunol,2007,27: 557-562.
11. Lim HW,Hillsamer P, Banham AH, et al. Cutting edge:direct suppression of B cells by CD4+CD25+regulatory T cells [J]. J Immunol,2005,175(7):4180-4183
12. Olsson B,Andersson PO, Jemas M,et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathathic thrombocytopenic purpura [J]. Nat Med,2003, 9(9):1123-1124
13. Zhao Ch, Li Xf, Zhang F. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies[J]. Haematologica,2008,93(9):1428-1430
14. Du WT, Zhao HF, Xu JH, et al. The role of T-cell immunoglobulin and mucin-domain-containing molecule-3 polymorphisms in idiopathic thrombocytopenic purpura [J]. Human Immunology,2009,70(6):398-402.
15. Shan NN, Zhu XJ, Wang Q, et al. High-dose dexamethasone regulates interleukin-18 binding protein in idiopathic thrombocytopenic purpura. Haematologica,2009,94:1603-1607.
16. Gu D S, Che Z P, Zhao H F. Thl(CXCL10)and Th2(CCL2)chemokine expression in patients with immune thrombocytopenia[J]. Human Immunology,2010,71(6): 586-591.
17.Ren H, Zhao H, Wang T, et al. Lepin enhances in vito secretion of IgG antiplatet an-bodies by splenocytes and peripheral blood mononuclear cells from patients with chronic idiopathic thrombocytopenic purpura [J]. Clinical Immunology,2006, 120(2):205-211
18. Bertrand Godeau,Marc Michel. Treatment of chronic immune thrombocytopenic purpura in adult [J]. Ann hematol,2010,89(Suppll):s55
19. Waleed Ghanima, Bertrand Godeau, Douglas B. How I treat immune thrombocytopenia:the choice between splenectomy or a medical therapy as a second-line treatment [J].Blood 2012,120:960-969
20. Sarpatwari A, Provan D, Erqou S, Sobnack R,David Tai FW, Newland AC. Autologous 111 Inlabelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy:a report from the United Kingdom ITP Registry. Br J Haematol.2010; 151(5):477-487.
21.秦平,陈峰,张春青,等.大剂量地塞米松治疗慢性特发性血小板减少性紫癜的疗效观察.中华内科杂志,2005,44：451-452.
22.李玉峰,刘定胜,丁帮和,等.短周期大剂量地塞米松治疗特发性血小板减少性紫癜的疗效分析.中华内科杂志,2009,48：734-736.
23. Borst F, Keuning JJ, van Hulsteijin H, et al. High-dose dexamethasone as first-and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol,2004,83:764-768.
24. Mazzuccoi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:a GIMEMA experience. Blood,2007,109: 1401-1407.
25. Hedlund-Treutiger I. Henter JI,Elinder G Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol,2003,25(2):139-144.
26. Cines DB, McMillan R.Management of adult idiopathic thrombocytopenic purpura. Almu Rev Med,2005,56:425-442
27. Chu XX, Huang BH, Zhang XL, et al. Dexamethasone inhibits immunoreactivity of dendritic cells in patients with chronic idiopathic thrombocytopenic purpura. Blood Coagul Fibrinolysis,2010,21:564-567.
28. Wang T, Zhao H, Ren H, et al. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 2005; 90:914-923.
29. Liu B, Zhao H, Poon Ma. Abnormality of CD4 CD 25 regulatory T ceils in idiopathic t thrombocytopenia purpura[J]. European J of Haematology,2007, 78(2):139-143.
30. Li S, Wang L, Zhao C, et al. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol,2007,139: 605-611.
31. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; 93:139-144.
32. Zhang F, Chu X, Wang L, et al. Cell mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura[J]. Eur Haematol 2006,76(5): 427-431.
1. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:report from an international working group. Blood,2009,113: 2386-2393.
2. Provan D, Stasi R, Newland AC, et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood, 2010,115:168-186.
3. Johnsen J. Pathogenesis in immune thrombocytopenia:new insights. Hematology Am Soc Hematol Educ Program 2012; 2012:306-312.
4. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haenmtol, 2003.120:574-596.
5. Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-Dose dexamethasone. N Engl J Med,2003, 349:831-836.
6. Zhu XJ, Shi Y, Sun JZ, et al. High-dose dexamethasone inhibits BAFF expression in patients with immune thrombocytopenia. J Clin Immunol,2009,29:603-610.
7. Cines DB, Liebman HA. The Immune Thrombocytopenia Syndrome:A Disorder of Diverse Pathogenesis and Clinical Presentation [J]. Hematol Oncol Clin North Am,2009,23(6):1151-1161
8. Marieke Schoonen W, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol.2009; 145:235-244.
9. Ling Y, Cao X, Yu Z, et al. Circulating dendritic cell subsets and CD4 +Fox3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasone. Eur J Hematol,2007,79:310-316.
10. Gao C, Chu X, Shi Y, et al. Correction of Thl-dominant cytokine profiles by high-dose dexamethasone in patients with high-dose dexamethasone in patients with chronic idiopathic thrombocytopenia purpura. J Clin Immunol,2007,27: 557-562.
11. Shan NN, Zhu XJ, Wang Q, et al. High-dose dexamethasone regulates interleukin-18 binding protein in idiopathic thrombocytopenic purpura. Haematologica,2009,94:1603-1607.
12. Gu DS, Cen ZP, Zhao HF. Thl(CXCL10)and Th2(CCL2)chemokine expression in patients with immune thrombocytopenia[J]. Human Immunology,2010,71(6): 586-591.
13. Zhao Ch, Li Xf, Zhang F. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies[J]. Haematologica,2008,93(9):1428-1430.
14. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
15. Bertrand Godeau, Marc Michel. Treatment of chronic immune thrombocytopenic purpura in adult [J]. Ann hematol,2010,89(Suppll):s55-57
16. Chow L, Aslam R, Speck ER, et a. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood 2010; 115:1247-1253.
17. Waleed Ghanima, Bertrand Godeau, Douglas B. How I treat immune thrombocytopenia:the choice between splenectomy or a medical therapy as a second-line treatment [J].Blood 2012,120:960-969
18. Sarpatwari A, Provan D, Erqou S, Sobnack R,David Tai FW, Newland AC. Autologous 111 Inlabelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy:a report from the United Kingdom ITP Registry. Br J Amatol.2010; 151(5):477-487.
19. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
20. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187-188.
21. Borst F, Kenning JJ, van Hulsteijin H, et al. High-dose dexamethasone as first-and second-line treatment of idiopathic thrombocytopenic purpura in adults. Ann Hematol,2004,83:764-768.
22. Mazzuccoi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:a GIMEMA experience. Blood,2007,109: 1401-1407.
23. Cines DB, McMillan R.Management of adult idiopathic thrombocytopenic purpura. Almu Rev Med,2005,56:425-442
24. Chu XX, Huang BH, Zhang XL, et al. Dexamethasone inhibits immunoreactivity of dendritic cells in patients with chronic idiopathic thrombocytopenic purpura. Blood Coagul Fibrinolysis,2010,21:564-567.
25. Wang T, Zhao H, Ren H, et al. Type 1 and type 2 T-cell profiles in idiopathic thrombocytopenic purpura. Haematologica 2005; 90:914-923.
26. Liu B, Zhao H, Poon Ma. Abnormality of CD4 CD 25 regulatory T ceils in idiopathic t hrombocytopenie purpura[J]. European J of Haematology,2007, 78(2):139-143.
27. Li S, Wang L, Zhao C, et al. CD8+ T cells suppress autologous megakaryocyte apoptosis in idiopathic thrombocytopenic purpura. Br J Haematol,2007,139: 605-611.
28. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost 2005; 93:139-144.
29. Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura[J]. Eur Haematol 2006,76(5): 427-431.
30. Hedlund-Treutiger I. Henter JI,Elinder G Randomized study of IVIg and high-dose dexamethasone therapy for children with chronic idiopathic thrombocytopenic purpura. J Pediatr Hematol Oncol,2003,25(2):139-144.
1. Johnsen J.Pathogenesis in immune thrombocytopenia:new insights.Hematology Am Soc Hematol Educ Program 2012; 2012:306-312.
2. Sakakura M,Wada H,Tawara I,et al.Reduced CD4+CD25+ T cells in patients withidiopathic thrombocytopenic purpura.Thromb Res 2007;120:187-193.
3. Zhang X-L,Peng J,Sun J-Z,et al.De novo induction of platelet-specific CD4+CD25+regulatory T cells from CD4+CD25-cells in patients with idiopathic thrombocytopenic purpura.Blood 2009; 113:2568-2577.
4. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children, report from an international working group. Blood 2009; 113:2386-2393.
5. Provan D, Stasi R,Newland AC,et al.International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168-186.
6. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
7. George JN. Management of patients with refractory immune thrombocytopenic purpura [J]. Thromb Haemost.2006,4:1664-161670
8. Bertrand Godeau, M arc M ichel. Treatm ent of chronic immune thrombocytopenic purpura in adults[J]. Ann Hematol,2010,89(Suppll):S55-58
9.中华医学会血液分会成人原发免疫性血小板减少症诊治中国专家共识(修订版)[J].血栓与止血学组中华血液学杂志,2011,32(3)：218-220
10. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004; 125:232-239.
11.Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001;114:121-125.
12.赵永强,王庆余,翟明,等.重组人血小板生成素治疗慢性难治性特发性血小板减少性紫癜的多中心临床试验[J].中华内科杂志,2004,43(8)：608-610.
13. Liu XG, Peng J, Hou M. Restoration of T cell tolerance in primary ITP. J Hematol Oncol 2012; 5 Suppl 1:A5.
14. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost2005;93:139-144.
15. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
16. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med 2003;9:1123-1124.
17.Zaja F, Baccarani M, Mazza P, Bocchia M, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia.Blood2010; 115:2755-2762.
18. Kuter DJ, Begley CG. Recombinant human thrombopoietin:Basic biology and evaluation of clinical studies. Blood 2002; 100:3457-3469.
19.Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
20.Wang S, Yang R, Zou P, et al. A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia. Int J Hematol 2012;96:222-228.
21.Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 2002; 114:433-437.
22.Peng J, Liu C, Liu D, Ren C, et al. Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura.Blood 2003;101:2721-2726.
1. Johnsen J.Pathogenesis in immune thrombocytopenia:new insights.Hematology Am Soc Hematol Educ Program 2012;2012:306-312.
2. Rodeghiero F,Stasi R,Gernsheimer T,et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children, report from an international working group. Blood 2009; 113:2386-2393.
3. Segal JB, Powe NR.Prevalence of immune thrombocytopenia:analyses of administrative data.J Thromb Haemost 2006;4:2377-2383.
4. Provan D, Stasi R,Newland AC,et al.International consensus report on the investigation and management of primary immune thrombocytopenia.Blood2010; 115:168-186.
5. Neunert C, Lim W, Crowther M, et al.The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190-4207.
6. Zhao YQ, Wang QY, Zhai M, et al. A multi-center clinical trial of recombinant human thrombopoietin in chronic refractory idiopathic thrombocytopenic purpura. ZhonghuaNeiKeZaZhi 2004; 43:608-610.
7. Liu XG, Peng J, Hou M. Restoration of T cell tolerance in primary ITP. J Hematol Oncol 2012;5(Suppl 1):A5.
8. Panitsas FP, Theodoropoulou M, Kouraklis A, et al. Adult chronic idiopathic thrombocytopenic purpura (ITP) is the manifestation of a type-1 polarized immune response.Blood 2004; 103:2645-2647.
9. Olsson B, Andersson PO, Jacobsson S, et al. Disturbed apoptosis of T-cells in patients with active idiopathic thrombocytopenic purpura. Thromb Haemost2005;93:139-144.
10. Liu B, Zhao H, Poon MC, et al. Abnormality of CD4(+)CD25(+) regulatory T cells in idiopathic thrombocytopenic purpura.Eur J Haematol 2007;78:139-143.
11. Olsson B, Andersson PO, Jernas M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med2003;9:1123-1124.
12. Hou M, Andersson PO, Stockelberg D, et al. Plasma thrombopoietin levels in thrombocytopenic states:implication for a regulatory role of bone marrow megakaryocytes.Br J Haematol 1998; 10:420-424.
13.Zaja F, Baccarani M, Mazza P, Bocchia M, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia.Blood2010; 115:2755-2762.
14. Guo L, Dong XY, Li J, et al. Recombinant Human Thrombopoietin (rh-TPO) in Combination with Rituximab As a Novel Therapy in Refractory Primary Immune Thrombocytopenia (ITP). ASH Annual Meeting Abstracts 2011 118:2223.
15. Wang S, Yang R, Zou P, et al. A multicenter randomized controlled trial of recombinant human thrombopoietin treatment in patients with primary immune thrombocytopenia. Int J Hematol 2012;96:222-228.
16. Borel JF. History of the discovery of cyclosporin and of its early pharmacological development. Wien Klin Wochenschr 2002;114:433-437.
17. Peng J, Liu C, Liu D, Ren C, et al. Effects of B7-blocking agent and/or CsA on induction of platelet-specific T-cell anergy in chronic autoimmune thrombocytopenic purpura.Blood 2003; 101:2721-2726.
18. Kappers-Klunne MC, van't Veer MB. Cyclosporin A for the treatment of patients with chronic idiopathic thrombocytopenic purpura refractory to corticosteroids or splenectomy. Br J Haematol 2001;114:121-125.
19. Emilia G, Luppi M, Morselli M, Forghieri F, et al. A possible role for low-dose cyclosporine in refractory immune thrombocytopenic purpura. Haematologica2008;93:1113-1115.
1. Italiano JE Jr, Lecine P Shivdasani RA,Hartwig JH.Blood platelet are assembled principally at the ends of proplatelet processes produced by differentiated megakaryocytes. J Cell Biol 1999; 147:1299-1312.
2. Italiano JE Jr, Patel-Hett S,Hartwig JH.Mechanics of proplatelet elaboration. J Thromb Haemost 2007;5(Suppl 1):18-23.
3. Pang L,Weiss MJ,Poncz M.Megakaryocyte biology and related disorders J Clin Invest 2005;115:3332-3338.
4. Kaushansky K.The molecular mechanisms that control thrombopoiesis.J Clin Invest 2005; 115:3339-3347.
5. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura:A randomized, double-blind, placebo-controlled trial. Lancet 2009; 373:641-648.
6. Weyrich AS,Denis MM,Schwertz H,et al.mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets. Blood 2007;109:1975-1983.
7. Italiano JE Jr, Hartwig JH.Megakaryocyte development and platelet formation.In: Platelet,2nd ed.A.D.Michelson,ed.Elsevier,San Diego 23-44,2007.
8. Italiano JE Jr,RA Shivdasani. Megakaryocytes and beyond:The birth of platelets.J Thromb Haemost 2003; 1:1174-1182.
9. Foulks JM,Marathe GK,Michetti N,et al.PAF-acetylhydrolase expressed during megakaryocyte differentiation inactivates PAF-like lipids.Blood 113: 6699-6706,2009.
10. Denis MM,Tolley ND,Bunting M,et al.Escaping the nuclear confines: Signal-dependent pre-mRNA splicing in anucleate platelets.Cell 2005;122: 379-391.
11. Weyrich AS,Schwertz HL,Kraiss W,Zimmerman GA.Protein synthesis by platelets:Historical and new perspectives.J Thromb Haemost 2009;7:241-246.
12. Schwertz H,Tolley ND,Foulks JM,et al.Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets.J Exp Med 203: 2433-2440,2006.
13. Schwertz HS,Koster WH,Kahr N,et al.Anucleate platelets generate progeny.Blood 2010;115:3801-3809.
14. Behnke O,Forer A.From megakaryocytes to platelets:Platelet morphogenesis takes place in the bloodstream.Eur J Haematol Suppl 1998;61:3-23.
15. Junt T,Schulze H,Chen Z,et al.Dynamic visualization of thrombopoiesis within bone marrow.Science 2007;317:1767-1770.11:546-554.
16. Walker LS, Abbas AK.peripheral T Cell tolerance.Nat Rev Immunol 2002;2:11-19.
17. Semple JW,Freedman J.Increased antiplatelet Y helper lymphocyte reactivity in patients with autoimmune thrombocytopenia.Blood 1991;78:2619-2625.
18. Ware RE,Howard TA.Phenotypic and clonal analysis of T lymphocytes in childhood immune thrombocytopenic purpura.Blood 1993;82:2137-2142.
19. Semple JW,Milev Y,Cosgrave D,et al.Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura:Relationship to platelet phenotype and antiplatelet T-cell reactivity.Blood 1996;87:4245-4254.
20. Shimomura T,Fujimura K,et al.Oligoclonal accumulation of Tcells in peripheral blood from patients with idiopathic thrombocytopenic purpura.Br J Haematol1996;95:732-737.
21. Shenoy S,Mohanakumar T,et al.Defective apoptosis in lymphocytes and the role of IL-2 in autoimmune hematologic cytopenias.Clin Immunol 2001;99:266-275.
22. Yoshimura C,Nomura S,Nagahama M,et al.Plasma-soluble Fas(APO-l,CD95)and soluble Fas ligand in immune thrombocytopenic purpura.Eur J Haematol 2000;64:219-224.
23.Kuwana M,Kaburaki J,Ikeda YAutoreactive T cells to platelet GPⅡb-Ⅲa in immune thrombocytopenic purpura:Role in production of anti-platelet autoantibody.J Clin Invest1998;102:1393-1402.
24. Kuwana M,Kaburaki J,Kitasato H,et al.Immunodominant epitopes on glycoprotein Ⅱb-Ⅲa recognized by autoreactive T cells in patients with immune thrombocytopenic purpura.Blood 2001;98:130-139.
25. Olsson B,Andersson PO,Jernas M,et al.T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.Nat Med 2003;9:1123-1124.
26. Coopamah MD,Garvey MB,Freedman J,et al.Cellular immune mechanisms in autoimmune thrombocytopenic purpura:An update.Transfus Med Rev 2003;17:69-80.
27. Sakakura M,Wada H,Tawara I,et al.Reduced CD4+CD25+ T cells in patients withidiopathic thrombocytopenic purpura.Thromb Res 2007; 120:187-193.
28. Ling Y,Cao X,Yu Z,Ruan C.Circulating dendritic cells subsets and CD4+FOXP3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome.Eur J Haematol 2007;79:310-316.
29. Liu B,Zhao H,Poon M-C,et al.Abnormality of CD4(+)CD25(+)regulatory T cells in idiopathic thrombocytopenic purpura.Eur J Haematol 2007;78:139-143.
30. Olsson et al.Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1.Blood 2008; 112:1078-1084.
31. Yu J,Heck S,Patel V,et al.Defective circulating CD25 regulatory Tcells in patients with chronic immune thrombocytopenic purpura.Blood 2008; 112:1325-1328.
32. Stasi R,Cooper N,Del Poeta G,et al.Analysis of regulatory T-cell changrs in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab.Blood 2008;112:1147-1150.
33. Zhang X-L,Peng J,Sun J-Z,et al.De novo induction of platelet-specific CD4+CD25+regulatory T cells from CD4+CD25-cells in patients with idiopathic thrombocytopenic purpura.Blood 2009; 113:2568-2577.
34. Kessel A,Ammuri H,Peri R,et al.Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function J Immunol 2007;179:5571-5575.
35. Ephrem A,Chamat S,Miquel C,et al.Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin:A critical factor in controlling experimental autoimmune encephalomyelitis.Blood 2008;111:715-722.
36. Bao W,Bussel JB,Heck S,et al.Improved regulatory T cell activity in patients with chronic immune thrombocytopenia treated with thrombopoietic agent.Blood 2010 Aug 5.[Epub ahead of print].
37. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:Report from an international working group. Blood 2009; 113: 2386-2393.
38. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2010; 115:168-186.
39. Marieke Schoonen W, Kucera G, Coalson J, et al. Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database. Br J Haematol 2009; 145:235-244.
40. Abrahamson PE, Hall SA, Feudjo-Tepie M, et al. The incidence of idiopathic thrombocytopenic purpura among adults:A population-based study and literature review. Eur J Haematol 2009; 83:83-89.
41. Rischewski JR, Imbach P, Paulussen M, Kuhne T. Idiopathic thrombocytopenic purpura (ITP):Is there a genetic predisposition? Pediatr Blood Cancer 2006; 47: 678-680..
42. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: Pathogenic and clinical diversity. Blood 2009; 113:6511-6521.
43. Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood 2005; 106:572-576.
44. Zhang W, Nardi MA, Borkowsky W, et al. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 2009; 113:4086-4093.
45. Takahashi T, Yujiri T, Shinohara K, et al. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura. Br J Haematol 2004; 124:91-96.
46. Sullivan PS, Hanson DL, Chu SY, et al. Surveillance for thrombocytopenia in persons infected with HIV:Results from the multistate Adult and Adolescent Spectrum of Disease Project. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:374-379.
47. Sloand EM, Klein HG, Banks SM, et al. Epidemiology of thrombocytopenia in HIV infection. Eur J Haematol 1992; 48:168-172.
48. Nardi M, Tomlinson S, Greco MA, Karpatkin S. Complement-independent, peroxideinduced antibody lysis of platelets in HIV-1-related immune thrombocytopenia. Cell 2001; 106:551-561.
49. Rajan SK, Espina BM, Liebman HA. Hepatitis C virus-related thrombocytopenia: Clinical and laboratory characteristics compared with chronic immune thrombocytopenic purpura. Br J Haematol 2005; 129:818-824.
50. Chiao EY, Engels EA, Kramer JR, et al. Risk of immune thrombocytopenic purpura and autoimmune hemolytic anemia among 120 908 US veterans with hepatitis C virus infection. Arch Intern Med 2009; 169:357-363.
51. Iga D, Tomimatsu M, Endo H, et al. Improvement of thrombocytopenia with disappearance of HCV RNA in patients treated by interferon-alpha therapy: Possible etiology of HCVassociated immune thrombocytopenia. Eur J Haematol 2005; 75:417-423.
52. Stasi R, Sarpatwari A, Segal JB, et al. Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura:A systematic review. Blood 2009; 113:1231-1240.
53. Roark JH, Bussel JB, Cines DB, Siegel DL. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 2002; 100:1388-1398.
54. Zhu XJ, Shi Y, Peng J, et al. The effects of BAFF and BAFF-R-Fc fusion protein in immune thrombocytopenia. Blood 2009; 114:5362-5367.
55. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPⅡb-Ⅲa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102:1393-1402.
56. Sukati H, Watson HG, Urbaniak SJ, Barker RN. Mapping helper T-cell epitopes on platelet membrane glycoprotein Ⅲa in chronic autoimmune thrombocytopenic purpura. Blood 2007; 109:4528-4538.
57. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
58. Zaja F, Baccaranti M, Mazza P, et al. Dexamethasone plus rituximab yields higher sustained response rates than dexamethasone monotherapy in adults with primary immune thrombocytopenia. Blood 2010; 115:2755-2762.
59. Cooper N, Woloski BM, Fodero EM, et al. Does treatment with intermittent infusions of intravenous anti-D allow a proportion of adults with recently diagnosed immune thrombocytopenic purpura to avoid splenectomy? Blood 2002; 99:1922-1927.
60. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 2004; 104:956-960.
61.Berchtold P, Muller D, Beardsley D, et al. International study to compare antigen-specific methods used for the measurement of antiplatelet autoantibodies. Br J Haematol 1997; 96:477-483.
62. Akiyama M, Kashiwagi H, Todo K, et al. Presence of platelet-associated anti-glycoprotein (GP)VI autoantibodies and restoration of GPVI expression in patients with GPVI deficiency. J Thromb Haemost 2009; 7:1373-1383.
63. Stoll D, Cines DB, Aster RH, Murphy S. Platelet kinetics in patients with idiopathic thromobcytopenic purpura and moderate thrombocytopenia. Blood 1985;65:584-588.
64. Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 1992; 327:1779-1784.
65. McMillan R, Wang L, Tomer A, et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103:1364-1369.
66. Olsson B, Ridell B, Carlsson L, et al. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood 2008; 112:1078-1084.
67. Houwerzijl EJ, Blom NR, van der Want JJL, et al. Ultrastructural study shows morphological features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2003; 103:500-506.
68. Bussel JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura:A randomised, double-blind, placebo-controlled trial. Lancet 2009; 373:641-648.
69. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
70. Bussel JB, Kuter DJ, Pullarkat V, et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood 2009; 113: 2161-2171.
71. Chow L, Aslam R, Speck ER, et a. A murine model of severe immune thrombocytopenia is induced by antibody- and CD8+ T cell-mediated responses that are differentially sensitive to therapy. Blood 2010; 115:1247-1253.
72. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med 2000; 160:1630-1638.
73. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002; 346:995-1008.
74. Imbach P, Barandun S, d'Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; i: 1228-1231.
75. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol 2004; 125:232-239.
76. Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients:A report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113:4834-4840.
77. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
78. Cheng Y, Wong RS, Soo Yo, et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med 2003; 349:831-836.
79. Mazzucconi MG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HDDXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura:A GIMEMA experience. Blood 2007; 109: 1401-1407.
80. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura-results of a prospective multicenter phase 2 study. Blood 2008; 112:999-1004.
81. Stasi R. Rituximab in autoimmune hematologic diseases:Not just a matter of B cells. Semin Hematol 2010 47:170-179.
82. Vianelli N, Galli M, de Vivo A. Efficacy and safety of splenectomy in immune thrombocytopenic purpura:Long-term results of 402 cases. Haematologica 2005; 90:72-77.
83. Schilling RF. Estimating the risk for sepsis after splenectomy in hereditary spherocytosis. Ann Intern Med 1995; 122:187-188.
84. Kinuya K, Matano S, Nakashima H, Taki S. Scintigraphic prediction of therapeutic outcomes of splenectomy in patients with thrombocytopenia. Ann Nucl Med 2003; 17:161-164.
85. Bussel JB, Kaufinann CP, Ware RE, Woloski BM. Do the acute platelet responses of patients with immune thrombocytopenic purpura (ITP) to IV anti-D and to IV gammaglobulin predict response to subsequent splenectomy? Am J Hematol 2001; 67:27-33.
86. Sarpatwari A, Bennett D, Logie JW, et al. Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database. Haematologica 2010; 95:1167-1175.
87. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. British Journal of Haematology 2003; 120:574-596.
88. Mazzucconi NG, Fazi P, Bernasconi S, et al. Therapy with high-dose dexamethasone (HDDXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura. A GIMEMA experience. Blood 2007; 109: 1401-1407.
89. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocytopenia (RAISE):A 6-month, randomised, phase 3 study. Lancet 2011; 377:393-402.
90. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403
91. Kuter DJ, Begley CG. Recombinant human thrombopoietin:Basic biology and evaluation of clinical studies. Blood 2002; 100:3457-3469.
92. Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
93. Vadhan-Raj S, Verschraegen, CF, Bueso-Ramos C, et al. Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer. Ann Intern Med 2000; 132:364-368.
94. Schuster MW, Beveridge R, Frei-Lahr D, et al. The effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on platelet recovery in breast cancer patients undergoing autologous bone marrow transplantation. Exp Hematol 2002; 30:1044-1050.
95. Harker LA, Carter RA, Marzec UM, et al. Correction of thrombocytopenia and ineffective platelet production in patients infected with human immunodeficiency virus (HIV) by PEG-rHuMGDF therapy (). Blood 1998; 92:707a.
96. Nomura S, Dan K, Hotta T, et al. Effects of pegylated recombinant human megakaryocyte growth and development factor in patients with idiopathic thrombocytopenic purpura. Blood 2002; 100:728-730.
97. Kuter DJ, Goodnough LT, Romo J, et al. Thrombopoietin therapy increases platelet yields in healthy platelet donors. Blood 2001; 98:1339-1345.
98. Frederickson S, Renshaw MW, Lin B, et al. A rationally designed agonist antibody fragment that functionally mimics thrombopoietin. Proc Natl Acad Sci USA 2006; 103:14307-14312.
99. Orita T, Tsunoda H, Yabuta N, et al. A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor. Blood 2005; 105:562-566.
100. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med 2007; 357: 2237-2247.
101. Kuter DJ, Bussel JB, Lyons RM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura:A double-blind randomised controlled trial. Lancet 2008; 371:395-403.
102. McHutchison JG, Dusheiko G, Shiffman ML, et al. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357:2227-2236.
103. Kantarjian H, Fenaux P, Sekeres MA, et al. Safety and efficacy of romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol 2010; 28:437-444.
104. Stasi R, Pagano A, Stipa E, Amadori S. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98:952-957.
105. Mahevas M, Le Page L, Salle V, et al. Efficiency of rituximab in the treatment of autoimmune thrombocytopenic purpura associated with common variable immunodeficiency. Am J Hematol.2006; 81:645-646.
106. Patel V, Mihatov N, Cooper N, et al. Long term follow-up of patients with immune thrombocytopenic purpura (ITP) whose initial response to rituximab lasted a minimum of 1 year. Blood (ASH Annual Meeting s), Nov 2006; 108:479.
107. Zaja F, Vianelli N, Volpetti S, et al. Low-dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol 85:329-334,2010.
108. Provan D, Butler T, Evangelista ML, et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica 2007;92:1695-1698.
109. Saleh MN, Liebman H, Bernstein ZP, et al. Subcutaneous injections of low-dose anti-CD20 veltuzumab for treatment of relapsed immune thrombocytopenia (ITP). Blood (ASH Annual Meeting s), Nov 2009; 114:1322.
110. Dass S, Rawstron AC, Vital EM, et al. Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis. Arthritis Rheum 2008; 58:2993-2999.
111. Lund FE, Randall TD. Effector and regulatory B cells:Modulators of CD4+ T cell immunity. Nature Rev Immunol 2010; 10:236-247.
112. Carson KR, Focosi D, Major EO, et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab:A Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 2009; 10:816-824.
113. Zhang W, Nardi MA, Borkowsky W, et al. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 2009; 17:4086-4093.
114. Nieswandt B, Bergmeier W, Rackebrandt K, et al. Identification of critical antigen-specific mechanisms in the development of immune thrombocytopenic purpura in mice. Blood 2000; 96:2520-2527.
115. Go RS, Johnston KL, Bruden KC. The association between platelet autoantibody specificity and response to intravenous immunoglobulin G in the treatment of patients with immune thrombocytopenia. Haematologica 2007; 92: 283-284.
116. Albert H, Collin M, Dudziak D, et al. In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner. Proc Natl Acad Sci USA 2008; 105:15005-15009.
117. McMillan R. Antiplatelet antibodies in chronic immune thrombocytopenia and their role in platelet destruction and defective platelet production. Hematol Oncol Clin North Am 2009; 23:1163-1175. Review.
118. Nakar CT, Bussel JB.3G8 and GMA161, Anti Fc[gamma]RIII Inhibitory Monoclonal Antibodies in the Treatment of Chronic Refractory ITP. (Summary of 2 Pilot Studies). Blood 2009; 114:949. Abstract 2404.
119. Cooper N, Heddle NM, Haas M, et al. Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: Modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms. Br J Haematol 2004; 124:511-518.
120. Boruchov DM, Gururangan S, Driscoll MC, Bussel JB. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood 2007; 110:3526-3531.
121. Amigorena S. Fc gamma receptors and cross-presentation in dendritic cells. J Exp Med 2002; 195:F1-3.
122. Bergtold A, Desai D, Gavhane A, Clynes R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 2005; 23: 503-514.
123. Podolanczuk A, Lazarus AH, Crow AR, et al. Of mice and men:An open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk. Blood 2009; 3154-3160.
124. McMillan R, Wang L, Tomer A, et al. Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP. Blood 2004; 103:1364-1369.
125. Houwerzijl EJ, Blom NR, van der Want JJ, et al. Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura. Blood 2004; 103:500-506.
126. Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 1991; 78: 2619-2625.
127. Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102:1393-1402.
128. Sakakura M, Wada H, Tawara I, et al. Reduced Cd4+Cd25+ T cells in patients with idiopathic thrombocytopenic purpura. Thromb Res 2007; 120:187-193.
129. Ling Y, Cao X, Yu Z, Ruan C. Circulating dendritic cells subsets and CD4+Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. Eur J Haematol 2007; 79:310-316.
130. Yu J, Heck S, Patel V, et al. Defective circulating CD25 regulatory T cells in patients with chronic immune thrombocytopenic purpura. Blood 2008; 112: 1325-1328.
131. Zhang F, Chu X, Wang L, et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76:427-431.
132. Zhao C, Li X, Zhang F, et al. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 2008; 93:1428-1430.
133. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children:Report from an international working group. Blood 2009; 113: 2386-2393.
134. Stasi R, Cooper N, Del Poeta G, et al. Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. Blood 2008; 112:1147-1150.
135. Stasi R, Del Poeta G, Stipa E, et al. Response to B-cell depleting therapy with rituximab reverts the abnormalities of T cell subsets in patients with idiopathic thrombocytopenic purpura. Blood 2007; 110:2924-2930.
136. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med 2002;346:995-1008.
137. Li X., Hou M. Emerging drugs for idiopathic thrombocytopenic purpura in adults. Expert Opin Emerging Drugs 2008; 13:237-254.
138. Kaveri SV, Lacroix-Desmazes S, Bayry J. The Antiinflammatory IgG. N Engl J Med 2008; 359:307-309.
139. Provan D, Butler T, Evangelista ML, et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica 2007; 92:1695-1698.
140. Goldenberg DM, Rossi EA, Stein R, et al. Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. Blood 2009; 113:1062-1070.
141. Zhang XL, Peng J, Sun JZ, et al. Modulation of immune response with cytotoxic Tlymphocyte-associated antigen 4 immunoglobulin-induced anergic T cells in chronic idiopathic thrombocytopenic purpura. J Thromb Haemost 2008; 6: 158-165.
142. George JN, Terrell DR. Novel thrombopoietic agents:A new era for the management of patients with thrombocytopenia. Haematologica 2008; 93: 1445-1449.
143. Dziewanowska ZE, Kapil PR, Zhang JK et al. Clinical characterization of a novel oral thrombopoietin mimetic LGD-4665 in healthy volunteers demonstrate safe and sustained increases in platelet counts with flexible dosing choices for phase II trials. Blood 2008; 112, Abs 3406.
144. Nogami W, Yoshida H, Koizumi K, et al. The effect of a novel, small non-pepitdyl molecule butyzamide on human thrombopoietin receptor and megakaryopoiesis. Haematologica 2008; 93:1495-1498.
145. Peeters K, Loyen S, Van Kerckhoven S, et al. Thrombopoietic effect of VPAC1 inhibition during megakaryopoiesis. Br J Haematol 2010; 151:54-61.
146. Kuwana M, Nomura S, Fujimura K, et al. Effect of a single injection of humanised anti-CD 154 monoclonal antobody on the platelet specific autoimmune response in patients with ITP. Blood 2004; 103:1229-1236.
147. Roopenian DC, Akilesh S. FcRn:The neonatal Fc receptor comes of age. Nat Rev Immunol 2007; 7:715-725.
148. Deng R, Balthasar JP. Pharmacokinetic/pharmacodynamic modeling of IVIG effects in a murine model of immune thrombocytopenia. J Pharm Sci 2007; 96: 1625-1637.
149. Roopenian DC,Akilesh S.FcRn:The neonatal Fc receptor comes of age.Nat RevImmunol 2007;7:715-725.