免疫性血小板减少性紫癜分型施治的基础与临床研究进展

免疫性血小板减少性紫癜（ITP）的发病涉及血小板免疫性破坏增多和骨髓巨核细胞产生血小板过少两个方面。经典的ITP治疗只涉及抑制血小板免疫破坏的一个方面，即采用免疫抑制剂如糖皮质激素、免疫球蛋白和抗-D抗体（针对Rh系统D抗原的抗体），也有采用长春新碱或抗人CD20单克隆抗体清除B淋巴细胞，以及环孢菌素等免疫抑制剂等。对难治性病例还要进行脾脏切除手术。虽然免疫抑制治疗方案对大多数患者治疗有效，但30％以上的ITP患者会复发，且这类治疗不良反应较多，脾脏切除还会导致机体免疫力下降，容易出现感染等并发症。临床需要更加安全有效的治疗方法。重组人血小板生成素（TPO）由于自身抗体而继发严重的血小板，目前已退出ITP的治疗。最近。欧洲批准了2个血小板受体激活剂AMG531和Eltrombopag，通过促进巨核细胞分化和血小板生成来治疗ITP。国内采用泛细胞保护剂为主的联合方案治疗难治／复发性ITP也取得了良好的效果。总之，根据ITP患者不同的发病机理进行个体化治疗是未来ITP基础与临床的研究方向。本文就ITP的发病机理和临床治疗作一综述．并对ITP分型施治的可能性进行了初步的探讨。     

原发免疫性血小板减少症患者抗可提取性核抗原抗体分析

目的 探讨原发免疫性血小板减少症(ITP)患者抗可提取性核抗原(ENA)抗体分布状况.方法采用免疫印迹法检测76例ITP患者和30例健康者抗ENA抗体.结果 76例ITP患者抗ENA抗体总阳性率23.68%,30例健康者均为阴性,二者阳性率差异有统计学意义(P＜0.05).结论 抗ENA抗体检测有利于判断ITP患者由于伴发或有可能发展至SLE或其他自身免疫性疾病,对探讨 ITP与SLE、自身免疫性疾病之间相互联系及ITP发病机制有重要有意义.     

脾动脉栓塞治疗原发性血小板减少性紫癜的护理体会

原发性血小板减少性紫癜(ITP)是一种原因未明的出血性疾病。其特点为血循环中存在一种抗血小板抗体,致使血小板破坏过多,血小板计数低下,引起紫癜,发病原理与免疫有关。脾脏是人体重要的最大的外周免疫器官,是产生血小板抗体的主要器官,又是破坏血小板的重要场所。ITP患者睥脏产生的血小板抗体增多,脾池坛多,脾血小板扣留率58％。以往在治疗ITP患者时除用药物治疗外部分患者药物无效时可行脾脏切除,使血小板抗体的滴度下降,成功率为70％,此手术危险性较大。今年我们用脾栓塞法成功地治疗1例ITP患者,现介绍如下。     

免疫性血小板减少症中血小板生成与清除研究进展

免疫性血小板减少症(immune thrombocytopenia,ITP)是机体对血小板抗原免疫失耐受,从而导致血小板生成受抑和破坏过度的一种获得性自身免疫性疾病,主要临床特征是血小板计数降低。血小板数量的维持与血小板生成和清除两方面机制有关。ITP中抗血小板自身抗体、CD8⁺ T细胞等多种免疫因素抑制血小板生成或介导血小板破坏,最终导致血小板数量减少。该文将对血小板生成与清除机制及其在ITP中的作用进行综述。     

血小板特异性抗体与ITP发病、临床特点、治疗及预后效果的关系

免疫性血小板减少症（immune thrombocytopenia,ITP）是一种自身免疫性出血性疾病。目前认为血小板自身抗体的形成是本病主要的发病机制之一,其一线治疗中激素和丙种球蛋白均主要通过抑制自身抗体产生、封闭网状内皮系统FC受体等作用以减少血小板的破坏,但有部分患者对一线治疗无效,病程迁延,预后不良,最终进展为慢性/难治性ITP（chronic/refractory ITP,C/RITP）。研究发现,血小板膜糖蛋白GPIIb/IIIa和GPIbα是本病最常见的抗原靶位,而一线治疗对具有抗GPIbα的ITP患者疗效欠佳。进一步研究发现抗GPIIb/IIIa抗体与抗GPIbα抗体导致血小板破坏的途径不尽相同：前者主要为依赖FC途径,而后者主要通过FC非依赖性途径清除血小板。以上研究结果提示早期发现ITP血小板抗体类型对于治疗和预后该疾病起关键作用。本文主要对ITP特异性血小板抗体与疾病的发生、临床特点、治疗及预后的关系进行综述。     

成年人原发免疫性血小板减少症的二线治疗方案选择

原发免疫性血小板减少症(ITP)为以血小板数目减少为特征的自身免疫性疾病.近年来,成年人ITP在发病机制、诊断、治疗等方面均获得重大进展,尤其是利妥昔单抗、血小板生成素(TPO)及血小板生成素受体激动剂(TPORA)在临床成年人ITP治疗中的广泛应用,使成年人ITP二线治疗方案的选择不再局限于脾切除术.笔者主要探讨成年人ITP患者二线治疗方案的选择,为采取一线治疗方案治疗失败的ITP患者提供个体化治疗方案.     

促血小板生成制剂治疗慢性难治性特发性血小板减少性紫癜的发展概况

特发性血小板减少性紫癜(idiopathic thrombocytopenic purpura,ITP),是一种自身抗体介导的血小板过度破坏引起的出血性疾病,因此,抑制血小板破坏成为治疗的主要手段.同样,对慢性难治性ITP的传统治疗方法,是用免疫抑制剂(如激素、环孢素)、免疫调节剂(球蛋白制剂、单克隆自身抗体)和去除破坏部位(切脾、脾放疗)等针对血小板破坏进行治疗的.近些年,随着对ITP发病机制的进一步研究,发现除血小板破坏外,血小板生成不足在ITP的发病中也起了重要作用[1].因此,作为慢性难治性ITP治疗的补充手段--促血小板生成制剂也一直足研究的热点,现对促血小板生成制剂的发展概况综述如下.     

腹腔镜脾切除术治疗ITP患者的围手术期护理

原发性血小板减少性紫癜(ITP)是一种获得性器官特异性的自身免疫性疾病,是由于人体内产生抗血小板自身抗体导致单核-巨噬细胞系统破坏血小板过多从而导致血小板减少[1].脾切除术是治疗ITP的主要手段之一,腹腔镜下脾脏切除(LS)术相对于传统的脾切除术具有创伤小、切口美观、术后疼痛轻、平均住院时间缩短等优点.苏北人民医院微创外科2006年2月～2008年7月为20例ITP患者成功地实施了腹腔镜下脾脏切除术.经过精心细致的护理,患者均痊愈出院,现将护理体会报告如下.     

环孢素A联合硫唑嘌呤治疗对糖皮质激素或脾切除无效的免疫性血小板减少症

特发性血小板减少性紫癜（ITP）是一种获得性自身免疫性疾病,也称为免疫性血小板减少症,以抗体介导的血小板破坏增多而致血小板减少为其特点。T淋巴细胞在ITP发病中起重要作用,可直接或间接调节B淋巴细胞产生血小板自身抗体。大约25%-30%成人ITP患者对一线治疗方案（包括类固醇皮质激素、脾切除）无效,这部分患者10年死亡率10%-20%,归因于出血和治疗毒副作用。所以,对这部分ITP患者寻找高效而低毒性的免疫抑制治疗具有重要意义。本文旨在探讨环孢素A（CsA）联合硫唑嘌呤治疗ITP的疗效。     

氨磷汀联合中剂量丙种球蛋白治疗12例难治性特发性血小板减少性紫癜患者近期疗效观察

特发性血小板减少性紫癜(ITP),是机体产生抗血小板抗体和血小板破坏增多的自身免疫性出血性疾病。有70%患者可获得缓解,约有9%的ITP成为难治性免疫性血小板减少性紫癜(RITP),对后者的治疗目前仍是临床非常棘手的问题[1]。我们尝试应用氨磷汀联合中剂量丙种球蛋白治疗12例RITP患     

原发免疫性血小板减少症的规范化诊治

原发免疫性血小板减少症(primary immune thrombocytopenia, ITP)是一种获得性免疫介导的血小板减少性疾病,其发病机制为免疫失耐受导致的血小板破坏过多及巨核细胞产生血小板不足。临床表现主要为血小板减少性的出血及疲劳等症状。ITP的诊断无特异性指标,需排除其他的血小板减少性疾病。治疗目的为维持血小板在安全水平,预防出血,并提高患者生活质量。治疗指征为血小板≤30×10⁹/L和(或)有出血表现,对于老年患者、重体力劳动者、有高血压等出血风险较高的合并症患者以及需抗血小板、抗凝治疗患者等,可适当放宽治疗指征。一线治疗为糖皮质激素及静脉注射人免疫球蛋白;二线治疗包括促血小板生成药物、利妥昔单抗及脾切除等治疗;对于难治性ITP患者,可考虑维A酸等三线治疗。     

Management of adult idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is defined as isolated thrombocytopenia without a clinically apparent cause. It is categorized as acute, chronic, and refractory. Its clinical presentation ranges from acute to insidious and the bleeding may vary from minimal to severe. The target platelet count with therapy is more than 30,000/microL in sedentary individuals. Since studies regarding therapies for ITP have been mostly uncontrolled case series, the treatment recommendations are largely derived from expert opinion. This review paper summarizes the data on available therapies for adult acute and chronic/refractory ITP. The therapies include splenectomy, steroids, intravenous immunoglobulin, anti-Rh(D), monoclonal antibodies, danazol, chemotherapy, plasma exchange, and others.     

Development of thrombopoietin receptor agonists for clinical use

Summary.  Thrombopoietin (TPO) is an essential hematopoietic cytokine for megakaryopoiesis. In 2002, we demonstrated that pegylated-recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increased platelet counts in patients with chronic immune thrombocytopenic purpura (ITP) in a Phase I/II clinical trial. After the cessation of clinical trials of PEG-rHuMGDF because of severe thrombocytopenia or pancytopenia due to the development of the neutralizing antibody cross-reacting with endogenous TPO, second generation non-immunogenic TPO receptor agonists have been developed. A small molecule eltrombopag and Romiplostim were approved for clinical use by FDA in 2008 to treat patients with chronic ITP who are refractory to the prior therapy. Although the efficacy of both TPO receptor agonists is convincing for the refractory ITP, further investigation is necessary to assess the potential long-term side effects and clinical applications of these therapies for other thrombocytopenic conditions.     

应用促血小板生成剂治疗儿童免疫性血小板减少症的研究进展

免疫性血小板减少症(ITP)是一种常见的获得性出血性疾病。传统观点认为,其发病机制为血小板相关抗体介导的血小板破坏增多,治疗靶点在于抑制抗体产生和阻断血小板在网状内皮系统破坏,但在部分ITP患者无效,逐渐演变成慢性/难治性ITP(C/RITP)。对于儿童C/RITP患者来说,一线治疗效果不佳,二线药物疗效不肯定且副作用明显,因而亟需一种安全有效的二线药物。近期发现,ITP发病机制中还存在血小板生成障碍,促血小板生成药物血小板生成素(TPO)和血小板生成素受体激动剂(TRA)逐步被研发和使用。国内rhTPO已通过成人C/RITPⅢ期临床试验,TRA代表药物Romiplostim和Eltrombopag也均已完成成人CITP治疗Ⅲ期临床试验,目前两项关于Romiplostim治疗儿童CITP的临床试验也证实了该类药物在儿科应用的有效性及安全性,且由于使用方便,更适宜在儿科应用。今后,促血小板生成药物的维持治疗将成为其主要的治疗方式之一。本文就促血小板生成剂的研发及其在儿科临床应用前景进行综述。     

Autoimmune thrombocytopenia

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder in which platelets coated with mainly antibodies against platelet GPIIb/IIIa and GPIb/IX are destroyed in the spleen. Recent evidence suggests that platelets are also destroyed by cytotoxic T cells. The diagnosis is made by exclusion for other causes of thrombocytopenia. As routine blood counts are becoming more available, many mild cases of ITP (platelets >30 x 10(9) L(-1)) are being diagnosed and they usually do not require treatment. In patients with platelet counts persistently <30 x 10(9) L(-1), treatment with corticosteroids, and/or intravenous immunoglobulin (IVIG) or anti-D may be required. The primary goal of treatment is to maintain the platelet count at a safe level with minimal side effects. After 3-6 months, if spontaneous remission has not occurred and if the side effects are significant, splenectomy is recommended. This is the single most effective treatment of ITP. The refractory patients who fails splenectomy and subsequently first- and second-line therapies, is a management dilemma. Therapeutic options are limited, available treatments potentially toxic and the chances of sustained response low. Observation with no active treatment is a reasonable option. With the increased availability of the thrombopoietic agents in the future, there may be a good prospect of keeping the platelet counts of these refractory patients at a safe long-term level with one of these drugs.     

Emerging strategies to treat chronic immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is a fairly common hematological disorder and is a minor disease for many affected patients; most are in good health, and many can tolerate low platelet counts without the need for treatment. For the majority of patients who do undergo treatment, first-line therapies, including corticosteroids, are effective in increasing platelet counts, although long-term use can be associated with adverse effects. Second-line therapies, such as immunosuppressants, have been largely untested in controlled studies of ITP patients. Like first-line therapies, splenectomy is effective for many patients; however, it is frequently avoided by physicians who prefer the use of alternative drug therapies due to concerns about safety risks and is often declined by patients reluctant to undergo surgery. Thus, approaches to avoid or defer the use of splenectomy have been actively pursued. An anti-CD20 antibody, rituximab, can limit the production of autoantibodies, but reactivated viral infections have been reported with its use. Agents that directly stimulate platelet production, such as thrombopoietin (TPO) receptor-binding agents, have shown promise in clinical trials of ITP patients as well as in hepatitis C virus-infected individuals with thrombocytopenia. Two TPO receptor agonists in advanced clinical development--eltrombopag and AMG 531--are discussed here. Both eltrombopag and AMG 531 appear to be effective in raising platelet counts and both have been well tolerated in clinical trials to date. However, potential safety issues with thrombopoietic growth factors include thrombocytosis, rebound thrombocytopenia, and increased bone marrow fibrosis. Further testing will determine which safety issues--if any--are of clinical concern.     

The future expected therapeutic approaches for ITP patients

Idiopathic thrombocytopenic purpura(ITP) is autoimmune disorder characterized by production of anti-platelet autoantibodies. The first recommended therapy is an administration of corticosteroid. For the patients refractory to steroid, splenectomy is recommended. In a portion of patients these standard therapies are not effective, therefore, effective new therapies are looked for. In this paper following new therapeutic approaches are presented; 1) eradication of Helicobacter pylori, 2) administration of thrombopoietin, 3) administration of anti-CD40L monoclonal antibodies, 4) administration of anti-CD20 monoclonal antibodies, 5) splenic irradiation. These treatment options are now tried in a small group of refractory patients except for eradication of pylori. We hope these new therapeutics will be introduced in clinical practice in near future.     

Refractory immune thrombocytopenia. Successful treatment with repeated cyclosporine A: two case reports

Treatment of chronic, severe refractory immune thrombocytopenia after splenectomy is difficult. Only less data exist on clinical use of cyclosporine A (CyA) in the management of refractory ITP. In this report, we describe two cases in which standard immunosuppressive therapy, other immunosuppression including cyclosporine A or splenectomy had no therapeutic effect. Even after splenectomy, recommended procedures were inefficient and critical thrombocytes count persisted. After repeated administration of cyclosporine A which had been ineffective prior to splenectomy; however, both patients achieved long‐term complete remission of the ITP. Side effects of CyA were moderate. The presented cases have confirmed the potential therapeutic effect of CyA in refractory post‐SE ITP.     

The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes

Thrombocytopenia can be seen in a variety of disease states, including immune mediated thrombocytopenic purpura (ITP) and myelodysplastic syndromes (MDS). The most concerning complication is the development of hemorrhagic complications that may contribute to patient morbidity and mortality. The ligand thrombopoeitin (TPO) and its interaction with its receptor (c-mpl) are important in platelet production. Thrombopoietic agonists can help in the management of thrombocytopenia related to these conditions. Amgen Megakaryopoiesis Protein 531 (AMG-531) (Romiplostim) is a recombinant TPO with a peptide fragment that shares no sequence homology with endogenous TPO, preventing the production of neutralizing antibodies. Recent studies have shown that it is effective in raising platelet counts, and is well tolerated in ITP and MDS patients. In this review, we discuss thrombopoiesis regulation by TPO; the chemistry, pharmacokinetics and pharmacodynamics of AMG-531 in animals and humans; the pathophysiological mechanisms leading to thrombocytopenia in ITP and MDS; and clinical trials demonstrating its efficacy in treating thrombocytopenia.