Cobalamin deficiency presenting with thrombotic microangiopathy (TMA) features: A systematic review

Introduction

Cobalamin deficiency may result in hematologic characteristics similar to thrombotic microangiopathy (TMA). To facilitate diagnosis, we reviewed reported cases of acquired cobalamin deficiency presenting with TMA features (c.def-TMA).

Treatment with short-term,high-dose cyclosporin A in children with refractory chronic idiopathic thrombocytopenic purpura

We report on 14 children (seven boys, seven girls) with chronic idiopathic thrombocytopenic purpura (ITP) refractory to multiple treatments, who were given a short-term therapy (range between 6 and 10 weeks) with high doses of cyclosporin A (CyA) (median, 10 mg/kg/d). Six patients experienced adverse events and one developed severe systemic mycosis during therapy. A complete response (CR) was observed in four patients and a partial response (PR) in three patients. Only the four CR patients, who were all girls, had a sustained response. These data suggest that CyA may be effective in some children with chronic symptomatic ITP.     

Ten years of prophylactic treatment with fresh-frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease

We report the results of 10 years of prophylactic fresh-frozen plasma (FFP) infusion therapy in a 14-year-old girl with chronic relapsing thrombotic thrombocytopenic purpura (TTP), in whom a severe congenital von Willebrand factor (VWF)-cleaving protease deficiency has been documented. Severe haemolytic crises triggered by infections were prevented and her present renal and neurological functions have been preserved. Sequential measurements of protease activity and platelet count after FFP infusion led us to conclude tentatively that 5% may be sufficient to degrade very large and adhesive VWF multimers.     

CD4^＋CD25^＋调节性T细胞在特发性血小板减少性紫癜患者中的变化及意义

目的:通过检测特发性血小板减少性紫癜(ITP)患者治疗前后外周血CD4 CD25 调节性T细胞(regulatory T cell,Treg)的比例及变化规律,探讨Treg细胞在ITP发病中的可能作用。方法:采集30例急、慢性ITP患者治疗前、后和20例正常对照者的外周血标本,流式细胞仪检测Treg细胞的比例及变化,并评价其与血小板计数的相关性。结果:30例ITP患者治疗前Treg细胞的比例为(1.59±0.86)%,明显低于正常对照组(3.87±1.73)%(P<0.01),治疗后其比例显著升高,为(2.51±1.17)%,明显高于治疗前(P<0.01),但仍低于正常对照组(P<0.01);Treg细胞在治疗显效和良效组显著高于进步和无效组(P<0.01),进步组与无效组比较差异无统计学意义(P>0.05);此外治疗前后Treg细胞比例与血小板计数呈显著正相关(P<0.05)。结论:ITP患者外周血Treg细胞比例降低,但随免疫抑制治疗的疗效逐渐升高,提示CD4 CD25 调节性T细胞可能参与了ITP的发病机制。     

Plasma-soluble Fas (APO-1, CD95) and soluble Fas ligand in immune thrombocytopenic purpura

We investigated the levels of various cytokines and soluble factors in ITP patients, in order to determine the influence of these factors on the pathogenesis of ITP. We found increases in IL-2, IL-6, IFN-gamma, and M-CSF levels in ITP patients compared with those in healthy individuals. On lymphocyte phenotype analysis, we found no clear difference in total T cell population (CD2+ CD19- cells) or cytotoxic T cell frequency (CD8+ CD11b- cells) between these two groups. The frequency of helper/inducer T cells (CD4+ CD8- cells) was decreased in ITP patients. There was a significant increase in activated T cells (CD3+ HLA-DR+ cells) in ITP patients. Furthermore, frequencies of NK cells of potent activity (CD16+ CD56+ cells) were significantly elevated in ITP patients. Seventeen of the 54 ITP patients (31.5%) had elevated levels of sFas, and 11 of the 54 patients (20.4%) of sFasL. In addition, a significant increase of sFasL was observed in sFas-positive ITP patients, and in these patients the sFasL level was correlated with that of sFas (r = 0.687, p < 0.01). We found significant increases in IL-2 and sIL-2R levels in sFas-positive ITP patients. For other factors examined, however, there were no differences in level between sFas-positive and -negative ITP patients. Percentages of activated T cells (CD3+ and HLA-DR+ cells) and NK cells (CD16+ and CD56+ cells) were significantly higher in sFas-positive ITP patients than in sFas-negative ITP patients. These findings suggests that the pathogenesis of ITP includes alteration of the Fas/FasL pathway.     

The Role of Autoreactive T-cells in the Pathogenesis of Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by antiplatelet autoantibodies. The major target of these autoantibodies is a platelet membrane glycoprotein, GPIIb-IIIa, which is a receptor for fibrinogen and other ligands. We recently identified CD4+ T-cells autoreactive to GPIIb-IIIa in ITP patients. These T-cells are considered pathogenic because they help B-cells produce antibodies that bind to normal platelet surfaces. GPIIb-IIIa-reactive T-cells respond to chemically reduced and tryptic peptides of GPIIb-IIIa but not to native GPIIb-IIIa, indicating that the epitopes they recognize are "cryptic" determinants generated at a subthreshold level by the processing of native GPIIb-IIIa under normal circumstances. Although GPIIb-IIIa-reactive T-cells are also detected in healthy individuals, they are activated in vivo only in ITP patients. Activation of GPIIb-IIIa-specific T-cells and the subsequent production of pathogenic anti-GPIIb-IIIa antibodies can be induced by functional antigen-presenting cells in the spleen that present cryptic GPIIb-IIIa peptides to these T-cells. The pathogenic process of ITP can be explained as a continuous loop in which B-cells produce antiplatelet autoantibodies, splenic macrophages phagocytose antibody-coated platelets and present GPIIb-IIIa-derived cryptic peptides, and GPIIb-IIIa-reactive CD4+ T-cells exert their helper activity. Further studies examining the mechanisms that induce the processing and presentation of cryptic peptides derived from the platelet antigen at disease onset will clarify how the pathogenic autoantibody response in ITP is initiated.     

High-dose intravenous IgG for chronic idiopathic thrombocytopenic purpura in adults

Summary Sixteen adult patients of mean age 48 years with chronic ITP were studied for platelet response to high-dose (0.4 g/kg body weight per day for five consecutive days) intravenous polyvalent intact IgG in the absence of any concurrent treatment. The platelet count returned to normal values in nine patients, a partial response (rise in the platelet count between 50 and 150 ×10⁹/l) was observed in three cases. One patient refractory to any other treatment went into a sustained remission. In the other responsive patients the response was only transient. Among seven splenectomised patients only three responded to IgG infusions versus nine in the non-splenectomised group. The length of ITP history appeared as a more critical factor for the response to IgG than previous splenectomy.     

老年特发性血小板减少性紫癜患者的临床观察

目的 总结老年特发性血小板减少性紫癜(ITP)患者的发病特点、治疗及临床转归.方法 回顾分析1992-2007年我院住院治疗的老年ITP患者的临床资料,并与同期住院的非老年患者的临床资料进行对照.结果 老年患者(老年组)43例,男性16例,女性27例;随访时间1个月～15年,存活35例.43例患者中,7例血小板持续(30～50)×109/L,出血不显著,未予以治疗;36例首选泼尼松治疗,敏感型25例(69.4%),以完全反应或部分反应健康存活;脾切除或栓塞4例,3例血小板恢复正常;对于泼尼松治疗不敏感者分别使用免疫抑制剂,其中硫唑嘌呤21例,环孢A23例,长春新碱3例及环磷酰胺9例,硫唑嘌呤、环孢A疗效优于长春新碱及环磷酰胺.进展为难治性ITP5例,难治率为13.9%;进展为未定性单克隆免疫球蛋白增多症(MGUS)和淋巴瘤各1例.死亡8例,死于外伤感染引发的心肺功能衰竭4例,肿瘤3例,脑出血1例.结论 老年ITP患者临床表现不典型,致命性出血的风险低,对免疫抑制剂的反应与非老年组近似,治疗宜个体化.     

Investigation of megakaryocyte apoptosis in children with acute and chronic idiopathic thrombocytopenic purpura

OBJECTIVE: Although the platelet destruction shows a primary role in the thrombocytopenia of idiopathic thrombocytopenic purpura (ITP), it has been demonstrated that impaired platelet production may also contribute to the severity of thrombocytopenia in ITP. The present study examined megakaryocyte apoptosis in bone marrow aspirates of children with acute and chronic ITP and investigated the role of megakaryocyte apoptosis in ITP pathophysiology. METHODS: Thirteen children diagnosed with acute ITP and eight children diagnosed with chronic ITP comprised the study group. Ten children, who were hospitalized for scoliosis operation but healthy otherwise, comprised the control group. In all children, megakaryocytes were isolated from the same amount of bone marrow aspirate samples using MACS CD61 MicroBeads (Miltenyl Biotec, Auburn, CA, USA). Megakaryocyte apoptosis was studied with transferase-mediated d-UTP-bitin nick end-labeling method. RESULTS: Isolated megakaryocyte counts did not differ significantly between acute ITP, chronic ITP and control groups. The percentage of apoptotic megakaryocytes did not differ significantly between acute ITP group and control group and between chronic ITP group and control group. The percentage of apoptotic megakaryocytes in patients with chronic ITP was significantly lower than the patients with acute ITP. There was no correlation between the percentage of apoptotic megakaryocytes and platelet counts of the cases. CONCLUSIONS: Increased megakaryocytic apoptosis does not play a role in the pathogenesis of dysmegakaryopoiesis and impaired platelet production in children with ITP. Decreased megakaryocyte apoptosis in cases with chronic ITP may be due to suppression of megakaryocyte maturation, as the terminal phase of the megakaryocyte lifespan is characterized by the onset of apoptosis.     

抗CD20抗体治疗慢性特发性血小板减少性紫癜机制的研究

目的:通过抗CD20抗体(Rituximab,商品名:美罗华)与慢性特发性血小板减少性紫癜(cITP)骨髓体外培养,了解cITP患者B细胞的活化与凋亡的状况。方法:选择cITP患者30 例,对照组缺铁性贫血患者10例,进行骨髓体外培养,于培养前、培养3 d、培养6 d、培养9 d,检测B细胞相关分子(CD19、CD20、CD23)和透射电镜观测淋巴细胞凋亡状态。结果:cITP患者骨髓CD20、CD23分子表达显著高于对照组CD20、CD23分子表达(P<0.01)。加抗CD20抗体和加半量抗CD20抗体培养前后B细胞相关分子(CD19、CD20、CD23)检测结果差异有统计学意义(P<0.01)。加抗CD20抗体组透射电镜观测有淋巴细胞凋亡。结论:抗CD20 抗体能靶向性地与表达CD20抗原的B细胞结合,通过抗体抗原反应,诱导B细胞加速凋亡。