Complement and cytokine response in acute Thrombotic Thrombocytopenic Purpura

Complement dysregulation is key in the pathogenesis of atypical Haemolytic Uraemic Syndrome (aHUS), but no clear role for complement has been identified in Thrombotic Thrombocytopenic Purpura (TTP). We aimed to assess complement activation and cytokine response in acute antibody‐mediated TTP. Complement C3a and C5a and cytokines (interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor, interferon‐γ and IL‐17a) were measured in 20 acute TTP patients and 49 remission cases. Anti‐ADAMTS13 immunoglobulin G (IgG) subtypes were measured in acute patients in order to study the association with complement activation. In acute TTP, median C3a and C5a were significantly elevated compared to remission, C3a 63·9 ng/ml vs. 38·2 ng/ml (P < 0·001) and C5a 16·4 ng/ml vs. 9·29 ng/ml (P < 0·001), respectively. Median IL‐6 and IL‐10 levels were significantly higher in the acute vs. remission groups, IL‐6: 8 pg/ml vs. 2 pg/ml (P = 0·003), IL‐10: 6 pg/ml vs. 2 pg/ml (P < 0·001). C3a levels correlated with both anti‐ADAMTS13 IgG (r_s = 0·604, P = 0·017) and IL‐10 (r_s = 0·692, P = 0·006). No anti‐ADAMTS13 IgG subtype was associated with higher complement activation, but patients with the highest C3a levels had 3 or 4 IgG subtypes present. These results suggest complement anaphylatoxin levels are higher in acute TTP cases than in remission, and the complement response seen acutely may relate to anti‐ADAMTS13 IgG antibody and IL‐10 levels.     

Risk factors and clinical profile of thrombotic thrombocytopenic purpura in systemic lupus erythematosus patients. Is this a distinctive clinical entity in the thrombotic microangiopathy spectrum?: A case control study

Introduction

The association of thrombotic thrombocytopenic purpura (TTP) with systemic lupus erythematosus (SLE) is rare. It is associated with high morbidity and mortality. Information about risk factors and clinical outcomes is scant.

Material and Methods

A retrospective case-control study was performed in a referral center in Mexico City between 1994 and 2013. Patients were diagnosed with TTP if they fulfilled the following criteria: microangiopathic haemolytic anaemia, thrombocytopenia, high LDH levels, normal fibrinogen and negative Coombs’ test. Patients with SLE were diagnosed with ≥ 4 ACR criteria. We included three study groups: group A included patients with SLE-associated TTP (TTP/SLE; cases n = 22, TTP events n = 24); patients with non-autoimmune TTP (NA-TTP; cases n = 19, TTP events n = 22) were included in group B and patients with SLE without TTP (n = 48) in group C.

Results

After multivariate analysis, lymphopenia < 1000/mm3 [OR 19.84, p = 0.037], high SLEDAI score three months prior to hospitalisation [OR 1.54, p = 0.028], Hg < 7 g/dL [OR 6.81, p = 0.026], low levels of indirect bilirubin [OR 0.51, p = 0.007], and less severe thrombocytopenia [OR 0.98, p = 0.009] were associated with TTP in SLE patients. Patients with TTP/SLE received increased cumulative steroid dose vs. NA-TTP (p = 0.006) and a higher number of immunosuppressive drugs (p = 0.015). Patients with TTP/SLE had higher survival than NA-TTP (p = 0.033); however, patients hospitalised for TTP/SLE had a higher risk of death than lupus patients hospitalised for other causes

Conclusions

Lymphopenia is an independent risk factor for TTP/SLE. It is likely that patients with TTP/SLE present with less evident clinical features, so the level of suspicion must be higher to avoid delay in treatment.     

FCGR2A rs1801274 polymorphism is associated with risk of childhood-onset idiopathic (immune) thrombocytopenic purpura: Evidence from a meta-analysis

Introduction

Previous studies have evaluated the association between FCGR2A H131R (rs1801274) polymorphism and idiopathic (immune) thrombocytopenic purpura (ITP), but results remain inconsistent. This meta-analysis was conducted to clarify these controversies.

Methods

Literatures on PubMed/ Medline, Embase and CENTRAL databases up to September 2013 were searched by two investigators. The distributions of alleles and genotypes between cases and controls were compared by using odds ratios (ORs) and 95% confidence intervals (95% CIs). Fixed or Random-effects models were used when appropriate.

Results

10 studies involving 553 patients and 1088 controls were available for this study, including 7 studies of Caucasian descendents, 2 studies of Asian descendents, and 1 study contained diverse ethnicity. In this studied overall population, we didn’t found any significant association between the FCGR H131R polymorphism and the risk of ITP for all genetic models. But in the subgroup analysis, a significant association between FCGR H131R polymorphism and ITP susceptibility was observed in Caucasian population of childhood-onset group for H vs. R (OR = 1.246, 95% CI 1.021-1.522, p = 0.031), HH vs. HR + RR (OR = 1.562, 95% CI 1.145-2.129, p = 0.005), HH vs. HR (OR = 1.598, 95% CI 1.146-2.228, p = 0.006), HH vs. RR (OR = 1.484, 95% CI 1.005-2.191, p = 0.047). No significantly between-study heterogeneity was observed for all genotype models in Caucasian childhood-onset ITP subtype analysis. However, this association was not stable after sensitivity analysis.

Conclusion

Our present meta-analysis indicated that FCGR H131R polymorphism might not be associated with risk of ITP in overall population. However, in Caucasian childhood-onset subgroup, there might be an association between FCGR2A H131R polymorphism and ITP risk, which is not robust and should be explained with caution.     

Prise en charge du purpura thrombopénique immunologique en France avant la mise à disposition des agonistes du récepteur à la thrombopoïétine

Purpose

Adult immune thrombocytopenia (ITP) is an auto-immune disease with most often a chronic course for which a consensual therapeutic strategy is missing. The objective of this study was to describe treatment practices in adult ITP in France before the era of thrombopoietin receptor (TpoR) agonists.

Methods

A retrospective observational study was conducted in eight hospitals in France. All eligible patients were at least 18 years of age and were seen for a chronic ITP between January 2004 and March 2006 in one of the participating centers. Data were collected retrospectively from clinical charts. ITP treatment from disease onset was analyzed for every patient according to the time of diagnosis.

Results

The study included 122 patients (73% of women) with a mean age of 52.6 years. Patients in whom ITP had been diagnosed less than 4 years earlier (n = 71) received on average 2.9 treatment lines. Corticosteroids possibly combined with intravenous immunoglobulins were most often used as a first-line. From the second line, up to 12 different regimens were identified. As a third line, rituximab and splenectomy were the most common therapeutic procedures. The number of splenectomy tended to decrease over time.

Conclusion

This analysis reflects the great heterogeneity into the management of chronic ITP. Whether such heterogeneity has declined after national guidelines have been produced remains to be assessed as well as the place of the newly develop TpoR agonists.     

Purpura thrombotique thrombocytopénique et autres syndromes de microangiopathie thrombotique au cours de l’infection par le virus de l’immunodéficience humaine

Human immunodeficiency virus (HIV) infection represents a risk factor for thrombotic microangiopathy. HIV-associated thrombotic microangiopathies encompass two entities with distinct pathophysiology, clinical presentation, treatment and prognosis. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus is typically characterized by a sudden onset in a patient with a moderate immune deficiency and a few events of opportunistic diseases, and a profound acquired deficiency in the von Willebrand factor cleaving protease ADAMTS13. This diagnosis requires a well-codified management including daily therapeutic plasma exchanges, a highly active antiretroviral therapy and eventually immunomodulatory drugs. The prognosis is good with a response rate and an overall survival comparable to that of HIV-negative thrombotic thrombocytopenic purpura. On the opposite, HIV-associated thrombotic microangiopathy with a progressive onset that occurs in profoundly immunocompromised patients with past history of multiple opportunistic diseases usually have a detectable ADAMTS13 activity and a worse prognosis. Usual treatment is poorly efficient. Forthcoming studies should assess the role of immunomodulatory drugs such as rituximab in the setting of HIV-associated thrombotic microangiopathy, and identify possible risk factors associated with the occurrence of these diseases.     

Évolution d’une thrombopénie chronique idiopathique en cours de grossesse (62 grossesses)

Purpose

The aim of this study was to assess the platelet count outcome during a pregnancy occurring in a series of 62 women followed for a chronic idiopathic thrombocytopenia.

Methods

We studied the medical files of women who had a previous history of chronic idiopathic thrombocytopenia persistently below 150 G/L for at least 1 year, and who became pregnant over a 14-year period.

Results

Sixty-two pregnancies (including 41 in women suffering from an immune thrombocytopenic purpura according to updated definition criteria) which occurred in 50 women, were analysed. At the beginning of the pregnancy, platelet count was above 150 G/L in 16% of the cases and lower than 50 G/L in 8%. Platelets decreased by more than 25% for 55% of the pregnancies, remained stable during pregnancy in 33% and improved in 12%. Platelet count remained above 50 G/L in 70% of the pregnancies and higher than 100 G/L in 27%. Mean nadir was 84 G/L at 31 weeks of gestation. A treatment was started in 40% of pregnancies, among them 64% of the cases during the last month only in order to allow locoregional anaesthesia at delivery. Platelet count was below 150 G/L at delivery in 82% of the women (116 ± 56 G/L). No bleeding occurred in 83% of the pregnancies. Neonatal mean platelet count was 225 ± 87 G/L, thrombocytopenia occurred in 17% of the babies (platelet count below 150 G/L), without any serious bleeding.

Conclusion

Pregnancy worsens chronic idiopathic thrombocytopenia outcome in half of the cases, most of the time without any haemorrhagic complications.     

1例氯吡格雷引起TTP并发支架内血栓患者的用药分析

1例急性心肌梗死PCI术后抗血小板双联治疗的患者发生血栓性血小板紫癜（TTP）,住院过程中发生亚急性支架内血栓。临床药师分析认为,与双联抗血小板的治疗方案相关,建议调整用药方案,最终选择阿司匹林与替格瑞洛联合抗血小板治疗,取得良好效果。     

细胞因子变化是否与IgA血管炎患儿肾损害相关？

背景IgA血管炎（IgAV）的长期预后取决于肾脏损伤的程度,有关IgAV肾损害发病机制的研究发现细胞因子在介导、驱动肾脏的损伤过程中发挥了重要作用。目的通过研究IgAV及肾损害患儿血清细胞因子水平变化,探讨细胞因子在IgAV肾损害过程中的意义和价值。方法选取2018年1月至2020年6月于中国医科大学附属盛京医院小儿肾脏内科住院的IgAV患儿194例作为研究对象,根据有无肾脏损害分为IgAV肾损害组（n=97）,IgAV组（n=97）,选取同时期本院儿童保健科进行体检的健康儿童60例为对照组。收集受试儿童及患儿细胞因子〔白介素（IL）-2、IL-4、IL-6、IL-10、IL-17、干扰素γ（IFN-γ）及肿瘤坏死因子α（TNF-α）〕以及患儿淋巴细胞绝对计数、免疫球蛋白A、免疫球蛋白E。采用多因素Logistic回归分析探讨IgAV肾损害的影响因素,绘制细胞因子对IgAV肾损害诊断价值的受试者工作特征（ROC）曲线。结果lgAV组IL-2水平高于lgAV肾损害组、对照组,且lgAV肾损害组IL-2水平高于对照组（P<0.05）;lgAV肾损害组IL-17水平高于lgAV组、对照组,lgAV组IL-17水平高于对照组（P<0.05）;lgAV组IL-6、IL-10和TNF-α水平高于lgAV肾损害组和对照组（P<0.05）;lgAV肾损害组和对照组IFN-γ水平高于lgAV组（P<0.05）。多因素Logistic回归分析结果显示,IL-2、IL-17、IFN-γ、TNF-α是IgAV肾损害发生的影响因素（P<0.05）。IL-2预测IgAV肾损害的ROC曲线下面积（AUC）为0.589,灵敏度为38.0%,特异度为47.0%;IL-17预测IgAV肾损害的AUC为0.621,灵敏度为47.4%,特异度为77.3%;IFN-γ预测IgAV肾损害的AUC为0.688,灵敏度为75.0%,特异度为55.7%;TNF-α预测IgAV肾损害的AUC为0.614,灵敏度为42.0%,特异度为37.0%;IL-17和IFN-γ联合预测IgAV肾损害的AUC为0.710,灵敏度为71.1%,特异度为66.0%。结论细胞因子IL-17、IFN-γ与IgAV肾损害的发生密切相关,早期检测两者水平并动态监测其变化,可对肾脏受累的早期发现及调整治疗方案起到预警作用。