Management of patients with refractory immune thrombocytopenic purpura

In immune thrombocytopenic purpura (ITP), thrombocytopenia is a result of both increased platelet destruction and insufficient platelet production. In adults, the course is commonly chronic, but most patients never experience serious bleeding even with severe thrombocytopenia. In case series of consecutive adult patients identified at the time of diagnosis, the frequency of death from bleeding is low, < 1%. The goal of treatment is only to prevent bleeding, not to correct the platelet count to normal. All current treatments are designed to diminish the increased platelet destruction, either by immunosuppression or splenectomy. The frequency of death from complications of treatment is similar to the frequency of death from bleeding. Perhaps because of increasing recognition of both the infrequent occurrence of serious bleeding and the risks of immunosuppressive treatment and splenectomy, data from case series across the past 30 years suggest a trend toward less therapy and fewer splenectomies among patients with ITP. However treatment is necessary for patients with severe and symptomatic thrombocytopenia. Splenectomy remains the most effective treatment for ITP, with two-thirds of patients achieving durable complete remissions. Immunosuppressive agents, including rituximab and combinations of agents, may be less effective than splenectomy in achieving complete remissions and the remissions may also be less durable. New agents for patients with ITP are currently in development that enhance platelet production, rather than diminish platelet destruction. In preliminary reports, these agents have been effective in maintaining safe platelet counts in patients with chronic ITP that was refractory to splenectomy and other treatments.     

Coexistence of thrombotic thrombocytopenic purpura and immune thrombocytopenic purpura in an Asian woman: a case report

A 33-year-old Chinese woman with a history of immune thrombocytopenic purpura presented with heavy menstrual bleeding. She was found to have thrombocytopenia, plasma ADAMTS13 activity of 0%, and positivity for the plasma ADAMTS13 inhibitor. She was diagnosed with the coexistence of thrombotic thrombocytopenic purpura and immune thrombocytopenic purpura. The patient was treated by plasmapheresis, a glucocorticoid, and rituximab. Her platelet level returned to normal, and she was discharged 28 days after admission. The number of plasmapheresis sessions and the timing of rituximab administration may be the key aspects of management of patients with thrombotic thrombocytopenic purpura who have underlying immune dysfunction caused by diseases such as immune thrombocytopenic purpura.     

Prospective evaluation of the immunobead assay for the diagnosis of adult chronic immune thrombocytopenic purpura (ITP)

Summary.  Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by antibody-induced platelet destruction. To better define the role of antigen-specific assays in adult chronic ITP, we prospectively measured platelet-associated autoantibody against either glycoprotein (GP) IIb/IIIa or GPIb/IX in 282 patients with chronic ITP and 289 patients with thrombocytopenia of other causes. We divided chronic ITP into four subgroups: presplenectomy, mild (platelet count >30 000 µL⁻¹ requiring no therapy), presplenectomy, severe (platelet count <30 000 µL⁻¹ requiring therapy but not splenectomy), postsplenectomy, remission (postsplenectomy partial or complete remission without further therapy) and postsplenectomy refractory (required therapy after splenectomy failure). Positive results: total ITP group, 55.4%; presplenectomy, mild, 31.1%; presplenectomy, severe, 42.6%; postsplenectomy, remission, 50.0%; and postsplenectomy, refractory, 87.8%. In addition, the degree of positivity increased with the severity of the patient's disease. The assay had a minimum specificity of 84.4% if clinical factors, consistent with immune thrombocytopenia, were not considered in patients with thrombocytopenia associated with other diseases. However, if clinical factors consistent with immune thrombocytopenia were considered and only patients with questionable immune thrombocytopenia and patients 'lost to follow-up' were included in the false-positive group the specificity was 93.1%. We conclude that the presence of immune thrombocytopenia is highly probable if the immunobead assay is positive and that antigen-specific assays are diagnostically useful in adult chronic ITP.     

血小板特异性抗体对特发性血小板减少性紫癜诊断价值的研究

目的:检测特发性血小板减少性紫癜及非免疫性血小板减少症患者抗血小板特异性抗体与血小板相关抗体,评价其在特发性血小板减少性紫癜中的诊断价值。方法:用流式细胞仪检测血小板相关抗体PAIgG,PAIgA,PAIgM;用改良单克隆抗体特异性俘获血小板抗原技术检测抗血小板膜糖蛋白(GPⅡb/Ⅲa,GPⅠb/Ⅸ)特异性自身抗体。结果:血小板相关抗体在特发性血小板减少性紫癜组敏感度为80%,在非免疫性血小板减少症组为63.3%。改良单克隆抗体特异性俘获血小板抗原法检测抗GPⅡb/Ⅲa和GPⅠb/Ⅸ抗体,在特发性血小板减少性紫癜组中的敏感度分别为53.3%和30%;在非免疫性血小板减少症组中除1例GPⅠb/Ⅸ阳性外,其余均为阴性;2组检出率比较差异有统计学意义(P<0.05)。结论:血小板相关抗体敏感度较高,但特异度较低;抗血小板特异性抗体敏感度虽较低,但特异性较高,可鉴别特发性血小板减少性紫癜和非免疫性血小板减少症。可作为特发性血小板减少性紫癜的特异性诊断指标。     

The association between idiopathic thrombocytopenic purpura and cardiovascular disease: a retrospective cohort study

Essentials

• We estimated the cardiovascular risk of patients with idiopathic thrombocytopenic purpura (ITP).
• The risk of cardiovascular disease was 38% higher in ITP patients compared with controls.
• Among the ITP patients, splenectomy was associated with higher cardiovascular disease.
• Clinicians should consider cardiovascular risk when managing ITP patients.

Summary

Background

Idiopathic thrombocytopenic purpura (ITP) is classically characterized by a transient or persistent decrease of platelet count. Mortality is higher in the ITP population than the general population, with a possible association with increased cardiovascular disease (CVD).

Objectives

The objective was to assess the strength of the association between ITP and CVD, with a secondary aim to assess the impact of splenectomy on CVD.

Methods

A population‐based retrospective, open cohort study using clinical codes was performed using data from 6591 patients with ITP and 24 275 randomly matched controls (up to 1:4 ratio matched by age, sex, body mass index and smoking status). The main outcome was the risk of CVD, which included ischemic heart disease, stroke, trans‐ischemic attack and heart failure. Adjusted incidence rate ratios were calculated using Poisson regression.

Results

During a median 6‐year observation period there was a CVD diagnosis recorded in 392 (5.9%) ITP patients and 1114 (4.5%) control patients. There was an increased risk of developing CVD in the ITP cohort (incidence rate ratio [IRR], 1.38; 95% confidence interval [CI], 1.23–1.55), which remained robust even after a sensitivity analysis only including incident cases of ITP. Findings suggested that patients who had undergone splenectomy were at even further increased risk of developing CVD when compared with the ITP population who had not undergone splenectomy (adjusted IRR, 1.69; 95% CI, 1.22–2.34).

Conclusion

There is an increased risk of developing CVD in patients with ITP and even further increased risk for those patients with ITP who underwent splenectomy.

     

Decreased plasma cytokines are associated with low platelet counts in aplastic anemia and immune thrombocytopenic purpura

Summary. Background: We previously found plasma levels of CD40 ligand (CD40L), chemokine (C‐X‐C motif) ligand 5 (CXCL5), chemokine (C‐C motif) ligand 5 (CCL5) and epidermal growth factor (EGF) to be low in aplastic anemia (AA) patients and to be correlated with platelet count. Objectives: To study the association of CD40L, CXCL5, CCL5 and EGF with platelets. Methods: We measured cytokines in the plasma of immune thrombocytopenic purpura (ITP) and AA patients using the Luminex assay and confirmed the results in a mouse model and in vitro experiments. Results: Both ITP and AA showed similarly low levels of CD40L, CXCL5, CCL5 and EGF, compared with healthy controls. In ITP, levels of these proteins were significantly greater in patients with higher platelet counts than in those with lower platelet counts. In a murine thrombocytopenia model, levels of CD40L, CXCL5, CCL5 and EGF decreased with platelet count after immune‐mediated destruction, while the cytokine levels increased when the platelet count recovered. In vitro, concentrations of these cytokines in the supernatants of platelet suspensions were proportional to platelet numbers, and levels in sera prepared by simple blood coagulation were equivalent to those in platelet‐rich plasma‐converted sera. mRNA expression for CXCL5, CCL5 and EGF was higher in platelets than in megakaryocytes, peripheral blood mononuclear cells, granulocytes and non‐megakaryocytic bone marrow cells. Conclusions: Plasma CD40L, CXCL5, CCL5 and EGF are mainly platelet‐derived, suggesting a role of platelets in immune responses and inflammation. Measurement of CD40L, CXCL5, CCL5 and EGF in human blood allowed testable inferences concerning physiology and pathophysiology in quantitative platelet disorders.     

Plateletpheresis for postsplenectomy rebound thrombocytosis in a patient with chronic immune thrombocytopenic purpura on romiplostim

Immune thrombocytopenic purpura (ITP) is an autoimmune disease in which IgG‐coated platelets are removed from circulation by the spleen, and platelet production is impaired due to increased thrombopoietin (TPO) clearance. Romiplostim, a novel TPO‐mimetic agent, is approved for patients with ITP that are unresponsive to traditional treatments. However, there is little experience when using this drug before splenectomy. We describe herein the case of a young female with chronic ITP who was treated with romiplostim, underwent splenectomy shortly thereafter, and required plateletpheresis for postoperative rebound thrombocytosis with concomitant neurologic symptoms. J. Clin. Apheresis 28:321–324, 2013. © 2013 Wiley Periodicals, Inc.     

Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura

Summary. The apparently spontaneous development of autoantibodies to ADAMTS13 in previously healthy individuals is a major cause of thrombotic thrombocytopenic purpura (TTP). Epitope mapping studies have shown that in most patients antibodies directed towards the spacer domain of ADAMTS13 are present. A single antigenic surface comprising Arg⁶⁶⁰, Tyr⁶⁶¹ and Tyr⁶⁶⁵ that contributes to the productive binding of ADAMTS13 to unfolded von Willebrand factor is targeted by anti‐spacer domain antibodies. Antibodies directed to the carboxyl‐terminal CUB1–2 and TSP2–8 domains have also been observed in the plasma of patients with acquired TTP. As yet it has not been established whether this class of antibodies modulates ADAMTS13 activity. Inspection of the primary sequence of human monoclonal anti‐ADAMTS13 antibodies suggests that the variable heavy chain germline gene segment VH1–69 is frequently incorporated. We suggest a model in which ‘shape complementarity’ between the spacer domain and residues encoded by the VH1–69 gene segment explain the preferential use of this variable heavy chain gene segment. Finally, a model is presented for the development of anti‐ADAMTS13 antibodies in previously healthy individuals that incorporates the recent identification of HLA DRB1*11 as a risk factor for acquired TTP.     

External validation of the PLASMIC score: a clinical prediction tool for thrombotic thrombocytopenic purpura diagnosis and treatment

Essentials

• Severe ADAMTS‐13 deficiency is key to thrombotic thrombocytopenic purpura (TTP) diagnosis.
• PLASMIC score predicts ADAMTS‐13 deficiency in suspected TTP with high discrimination.
• PLASMIC score is more generalizable with fewer missing data than alternative clinical scores.
• PLASMIC score identifies a subgroup of patients lacking significant response to plasma exchange.

Summary

Background

The PLASMIC score was recently published to distinguish patients with severe ADAMTS‐13 deficiency from those without for early identification of thrombotic thrombocytopenia purpura (TTP).

Objective

We performed an independent external validation of the PLASMIC score for clinical prediction of severe ADAMTS‐13 deficiency.

Patients/Methods

We studied an independent cohort of 112 consecutive hospitalized patients with suspected thrombotic microangiopathy and appropriate ADAMTS‐13 testing (including 21 patients with TTP diagnosis).

Results

The PLASMIC score model predicted severe ADAMTS‐13 deficiency with a c statistic of 0.94 (0.88–0.98). When dichotomized at high (score 6–7) vs. low‐intermediate risk (score 0–5), the model predicted severe ADAMTS‐13 deficiency with positive predictive value of 72%, negative predictive value of 98%, sensitivity of 90% and specificity of 92%. In the low‐intermediate risk group (score 0–5) there was no significant improvement in overall survival associated with plasma exchange.

Conclusions

The PLASMIC score model had excellent applicability, discrimination and calibration for predicting severe ADAMTS‐13 deficiency. The clinical algorithm allowed identification of a subgroup of patients who lacked a significant response to empiric treatment.     

网织血小板检测对特发性血小板减少性紫癜的诊断价值

目的探讨网织血小板对特发性血小板减少性紫癜（ITP）的诊断价值。方法选择35例ITP患者作为ITP组,60例健康者作为对照组。治疗前将ITP组患者按血小板计数（PLT）分为2组,PLT〉30×109/L组（n=20）及PLT〈30×109/L组（n=15）。以泼尼松或地塞米松治疗,总疗程为6个月。治疗后根据患者病情是否缓解,分为缓解组及未缓解组。采用Sysmex XE-5000全自动血细胞分析仪检测网织血小板百分比及其绝对值。结果 PLT〉30×109/L组及PLT〈30×109/L组患者的网织血小板百分比明显高于对照组（P〈0.01）,而这两组患者的网织血小板绝对值低于对照组（P〈0.05）。缓解组患者网织血小板百分比及其绝对值与对照组的差异无统计学意义（P〉0.05）,未缓解组患者网织血小板百分比显著高于对照组（P〈0.01）。结论网织血小板的检测对于ITP的诊断、疗效判定具有重要意义。     

Thrombotic thrombocytopenic purpura: a hematological emergency

Background

Thrombotic thrombocytopenic purpura is a hematological emergency and diagnostic challenge. The critical determinant of outcome is timely diagnosis and treatment.

Objectives

Describe the pathophysiology, presentation, diagnosis, and treatment of thrombotic thrombocytopenic purpura.

Discussion

Thrombotic thrombocytopenic purpura has a varied presentation and a tendency to mimic several disorders. However, it may be at least provisionally diagnosed in the patient with thrombocytopenia and microangiopathic hemolytic anemia without alternate cause. The mainstay of treatment is immediate plasma exchange to be repeated until platelet count is stabilized. Adjuvant therapies include corticosteroids, rituximab, and cyclosporine.

Conclusion

It is essential for the emergency physician to be aware of thrombotic thrombocytopenic purpura’s range of presentations, diagnostic criteria, and treatment.     

选择性脾切除治疗儿童特发性血小板减少性紫癜

目的总结脾切除对内科治疗无效或反复复发的儿童特发性血小板减少性紫癜（ITP）的治疗效果。方法对1996年1月至2006年12月36例儿童特发性血小板减少性紫癜行选择性脾切除术的疗效和术后早期并发症的临床资料作回顾性分析。结果所有患儿在转入外科前均在内科接受正规治疗。32例（88．89％）患儿脾切除后效果明显，4例（11．11％）部分显效，全组无重大并发症。结论选择性脾切除是治疗儿童特发性血小板减少性紫癜的一种安全和有效的治疗手段。     

免疫性血小板减少性紫癜动物模型的研究进展

免疫性血小板减少性紫癜（immune thrombocytopenic purpura,ITP）是一种较为常见的自身免疫病,其临床试验多建立于临床药物的应用,而非亚临床研究,有可能因为意外并发症被迫中止,因此建立理想的动物模型有助于加深对ITP发病机制和用药机理的理解.本综述回顾了ITP模型的发展过程,总结了被动型和主动型造模方法在ITP研究中的应用,尤其是转基因小鼠可更好模拟人类疾病病理状态,有利于进一步探讨新的诊断和治疗方法.     

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis

A 20 year old woman, admitted with acute pancreatitis, subsequently developed microangiopathic haemolytic anaemia, thrombocytopenia and mild neurological compromise. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made, and she was treated with plasma exchange leading to complete resolution of this condition. TTP is a rare multisystem disorder which may be life threatening if not treated promptly. The increasing recognition of acute pancreatitis as a potential aetiological factor offers new insights into the pathogenesis, diagnosis and treatment of TTP.     

网织血小板和血小板相关抗体在特发性血小板减少性紫癜鉴别诊断中的作用比较

本研究旨在探讨网织血小板和血小板相关抗体在特发性血小板减少性紫癜(ITP)鉴别诊断中的作用。用Sysmex XE-5000全自动血细胞分析仪对34例ITP患者、36例非ITP患者及411例正常人静脉血进行检测,获得未成熟血小板比例(immature platelets fraction,IPF)数据,同时利用酶联免疫法测定血小板相关抗体含量,并对二者结果进行统计学分析。结果表明,ITP患者的IPF值明显高于疾病对照组和正常对照组,差异显著(p均<0.05)。对于ITP诊断的意义,IPF的阳性率明显高于疾病对照组,差异显著(p<0.05);PAIgG的阳性率与疾病对照组比较,无显著性差异(p>0.05)。IPF的灵敏度、特异度、阴性预测值均高于PAIgG,仅阳性预测值略低于PAIgG。IPF的ROC曲线下面积大于PAIgG的ROC曲线下面积。结论IPF和PAIgG对于ITP的鉴别诊断均有一定的临床意义,IPF的诊断价值优于PAIgG。     

血小板生成素与慢性特发性血小板减少性紫癜的相关研究

目的探讨慢性特发性血小板减少性紫癜(CITP)患者Tpo水平及其与网织血小板(RP)、血小板计数(BPC)、骨髓巨核细胞及其成熟度的关系,以及Tpo水平在治疗中的预测作用.方法夹心酶联免疫吸附试验测定血清Tpo水平;噻唑橙染色,流式细胞仪检测RP;骨髓巨核细胞双重荧光染色后,多光子激光扫描共聚焦显微镜检测成熟度.结果22名正常对照和33例CITP患者血清Tpo水平分别为(204.05±65.70)ng/L和(345.46±222.23)ng/L(P>0.05);23例再生障碍性贫血(AA)及10例急性髓细胞白血病(AML)Tpo水平分别为(1427.62±468.84)ng/L和(596.09±462.95)ng/L,均较对照组显著升高(P<0.05);CITP组RP比例明显增高,AA组及AML组网织血小板绝对计数(RPC)明显降低;CITP患者糖皮质激素治疗无效组的Tpo水平高于有效及对照组(P<0.05).结论CITP组Tpo水平较对照组无明显升高.Tpo水平与RPC、RP比例相结合可反映骨髓血小板生成情况,鉴别血小板减少原因.Tpo水平与巨核细胞成熟度无相关性.血清Tpo水平可作为预测CITP患者对治疗反应的指标之一.     

Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura

Summary.  Background:  Immune thrombocytopenic purpura (ITP) is an autoimmune disease primarily caused by IgG anti-platelet autoantibodies. Activation of autoreactive CD4⁺ T cells upon recognition of cryptic GPIIb/IIIa peptides presented by antigen-presenting cells (APCs) is a critical step for triggering and maintaining the pathogenic anti-platelet autoantibody response. Objectives:  We investigated which APCs carry the cryptic peptides of GPIIb/IIIa that activate autoreactive CD4⁺ T cells in ITP patients. Methods:  GPIIb/IIIa-reactive T-cell lines generated from ITP patients were cultured with autologous freshly isolated splenic macrophages, B cells or dendritic cells. To further investigate how the macrophages presented the antigenic GPIIb/IIIa peptides, we prepared macrophages from the peripheral blood monocytes of the same patients during remission. Results:  Macrophages induced the proliferation of GPIIb/IIIa-reactive T-cell lines without an exogenous antigen, but B cells and dendritic cells required GPIIb/IIIa peptides to stimulate the T cells. Macrophages derived from peripheral blood during remission required an exogenous antigen to induce the GPIIb/IIIa-reactive T-cell line response, but could elicit a response without added antigen if they were preincubated with platelets from ITP patients with platelet-associated anti-GPIIb/IIIa antibodies or healthy platelets pretreated with ITP platelet eluates. The T-cell response was inhibited by anti-FcγRI antibody. Finally, cultured macrophages that captured opsonized platelets promoted anti-GPIIb/IIIa antibody production in mixed cultures of autologous GPIIb/IIIa-reactive T-cell lines and B cells. Conclusions:  Splenic macrophages that take up opsonized platelets via FcγRI are major APCs for cryptic GPIIb/IIIa peptides, and are central to the maintenance of anti-platelet autoantibody production in ITP patients.     

特发性血小板减少性紫癜患者免疫状态分析

目的 探讨特发性血小板减少性紫癜(ITP)患者免疫状态的异常改变.方法 以52例ITP确诊患者为观察组,其中慢性ITP(CITP)组27例、急性ITP(AITP)组25例;以52例体检健康者为对照组.检测各组受试对象外周血T淋巴细胞亚群、血清免疫球蛋白及补体、红细胞免疫功能,并对结果 进行统计学分析.结果 观察组CD3+、CD4+、CD4+/CD8+、红细胞C3b受体花环检出率均低于对照组,CD8+、IgA、IgG、IgM、C3、C4、免疫复合物花环检出率高于对照组(P＜0.05);CITP组变化幅度大于AITP组(P＜0.05).结论 ITP患者免疫状态呈异常状态,且与疾病严重程度等有较大的相关性.