Circulating membrane aminophospholipids contribute to thrombotic risk in rheumatoid arthritis.

IF 5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Daniela O Costa, Majd B Protty, Victoria J Tyrrell, Ali A Hajeyah, Beth Morgan, Ben Mead, Martin Giera, Peter W Collins, P Vince Jenkins, Ernest Choy, Simon A Jones, Valerie B O'Donnell
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Abstract

Patients with rheumatoid arthritis (RA) are at elevated risk of thrombotic events, yet the underlying mechanisms remain unknown. The contribution of the procoagulant membrane-surface provided by aminophospholipids (aPL) in driving thrombotic risk in RA has not been investigated. Specifically, the type of aPL exposed on circulating blood cell membranes in patients is not characterized, nor is their ability to support thrombin generation known. Here, lipidomics was used to characterize the external-facing and total levels of aPL molecular species in RA, specifically phosphatidylserine (PS) and phosphatidylethanolamine (PE) on extracellular vesicles (EVs), platelets, and white blood cells (WBC). The ability of the cells and EVs to support thrombin generation from patients and healthy controls (HC) was compared using an in vitro prothrombinase assay. RA patient plasma had significantly higher levels of thrombin-antithrombin (TAT) and D-dimers, indicating increased thrombotic activity in vivo. Higher EV and platelet counts were seen in RA, but WBC counts were not elevated. EVs from RA patients supported higher levels of thrombin generation compared to HC, while for platelets and WBC, thrombin generation was similar for both groups. EVs from RA patients also showed elevated external-facing PS molecular species, with total aPL also increased. For platelets and WBC, total and external-facing aPL levels were similar. TATs significantly correlated with EV particle counts, indicating that their circulating numbers are directly related to coagulation in vivo. Overall, our data suggest that elevated plasma EV levels in RA are a major source of pro-coagulant membranes, contributing to thrombotic risk in RA.

循环膜氨基磷脂有助于类风湿关节炎的血栓形成风险。
类风湿性关节炎(RA)患者发生血栓事件的风险较高,但其潜在机制尚不清楚。由氨基磷脂(aPL)提供的促凝膜表面在驱动RA血栓形成风险中的作用尚未被研究。具体来说,暴露在患者循环细胞膜上的aPL的类型没有特征,也不知道它们支持凝血酶生成的能力。在这里,脂质组学被用来表征类风湿关节炎中aPL分子种类的外表面和总水平,特别是磷脂酰丝氨酸(PS)和磷脂酰乙醇胺(PE)在细胞外囊泡(ev)、血小板和白细胞(WBC)上的水平。使用体外凝血酶原测定法比较细胞和ev支持患者和健康对照(HC)凝血酶生成的能力。RA患者血浆中凝血酶-抗凝血酶(TAT)和d -二聚体水平明显升高,表明体内血栓活性增加。RA患者有较高的EV和血小板计数,但白细胞计数未升高。与HC相比,RA患者的EVs支持更高水平的凝血酶生成,而对于血小板和白细胞,两组的凝血酶生成相似。RA患者的ev也显示外面向PS分子种类升高,总aPL也增加。对于血小板和白细胞,总和外表面aPL水平相似。TATs与EV颗粒计数显著相关,表明其循环数量与体内凝血直接相关。总的来说,我们的数据表明,RA患者血浆EV水平升高是促凝膜的主要来源,有助于RA患者的血栓形成风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Lipid Research
Journal of Lipid Research 生物-生化与分子生物学
CiteScore
11.10
自引率
4.60%
发文量
146
审稿时长
41 days
期刊介绍: The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.
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