Majd B Protty, Victoria J Tyrrell, Keith Allen-Redpath, Shin Soyama, Ali A Hajeyah, Daniela Costa, Anirban Choudhury, Rito Mitra, Amal Sharman, Parveen Yaqoob, P Vince Jenkins, Zaheer Yousef, Peter W Collins, Valerie B O'Donnell
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Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples.</p><p><strong>Methods: </strong>Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics.</p><p><strong>Results: </strong>External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients.</p><p><strong>Conclusions: </strong>The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. Targeting EV formation/clearance and developing strategies to prevent the aPL surface of EV interacting with coagulation factors represents a novel antithrombotic target in ASCVD.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335086/pdf/","citationCount":"0","resultStr":"{\"title\":\"Thrombin Generation Is Associated With Extracellular Vesicle and Leukocyte Lipid Membranes in Atherosclerotic Cardiovascular Disease.\",\"authors\":\"Majd B Protty, Victoria J Tyrrell, Keith Allen-Redpath, Shin Soyama, Ali A Hajeyah, Daniela Costa, Anirban Choudhury, Rito Mitra, Amal Sharman, Parveen Yaqoob, P Vince Jenkins, Zaheer Yousef, Peter W Collins, Valerie B O'Donnell\",\"doi\":\"10.1161/ATVBAHA.124.320902\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Clotting, leading to thrombosis, requires interactions of coagulation factors with the membrane aminophospholipids (aPLs) phosphatidylserine and phosphatidylethanolamine. Atherosclerotic cardiovascular disease (ASCVD) is associated with elevated thrombotic risk, which is not fully preventable using current therapies. Currently, the contribution of aPL to thrombotic risk in ASCVD is not known. Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples.</p><p><strong>Methods: </strong>Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics.</p><p><strong>Results: </strong>External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients.</p><p><strong>Conclusions: </strong>The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. 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引用次数: 0
摘要
背景:凝血导致血栓形成,需要凝血因子与膜磷脂(aPL)磷脂酰丝氨酸和磷脂酰乙醇胺相互作用。动脉粥样硬化性心血管疾病(ASCVD)与血栓风险升高有关,目前的疗法无法完全预防这种疾病。目前,aPL 对 ASCVD 中血栓形成风险的贡献尚不清楚。在此,我们将描述不同严重程度的 ASCVD 患者循环膜中 aPL 的组成,以及患者样本中外部 aPL 对血浆凝血酶生成的贡献:使用纯化因子测定法测量急性冠状动脉综合征(24例)、稳定型冠状动脉疾病(18例)和阳性危险因素(23例)患者的血小板、白细胞和细胞外囊泡(EV)的凝血酶生成情况,并与健康对照组(24例)进行比较:结果:在EV、血小板和白细胞上检测到面向外部的aPL,细胞活化后aPL显著升高。与健康对照组相比,急性冠状动脉综合征患者的EV表面凝血酶生成量更高,同时循环中的EV数量也有所增加。凝血酶生成与外化的EV磷脂酰丝氨酸、血浆EV计数和EV膜总表面积有明显的相关性。相比之下,白细胞和血小板的aPL水平和凝血酶生成不受疾病影响,尽管患者的循环白细胞计数更高:EV的aPL膜支持ASCVD患者血浆中凝血酶生成水平的升高。结论:EV的aPL膜支持ASCVD患者血浆中凝血酶生成水平的升高,白细胞也可能起作用,但血小板膜似乎不起作用。以 EV 的形成/清除为靶点,制定策略防止 EV 的 aPL 表面与凝血因子相互作用,是 ASCVD 的新型抗血栓靶点。
Thrombin Generation Is Associated With Extracellular Vesicle and Leukocyte Lipid Membranes in Atherosclerotic Cardiovascular Disease.
Background: Clotting, leading to thrombosis, requires interactions of coagulation factors with the membrane aminophospholipids (aPLs) phosphatidylserine and phosphatidylethanolamine. Atherosclerotic cardiovascular disease (ASCVD) is associated with elevated thrombotic risk, which is not fully preventable using current therapies. Currently, the contribution of aPL to thrombotic risk in ASCVD is not known. Here, the aPL composition of circulating membranes in ASCVD of varying severity will be characterized along with the contribution of external facing aPL to plasma thrombin generation in patient samples.
Methods: Thrombin generation was measured using a purified factor assay on platelet, leukocyte, and extracellular vesicles (EVs) from patients with acute coronary syndrome (n=24), stable coronary artery disease (n=18), and positive risk factor (n=23) and compared with healthy controls (n=24). aPL composition of resting/activated platelet and leukocytes and EV membranes was determined using lipidomics.
Results: External facing aPLs were detected on EVs, platelets, and leukocytes, elevating significantly following cell activation. Thrombin generation was higher on the surface of EVs from patients with acute coronary syndrome than healthy controls, along with increased circulating EV counts. Thrombin generation correlated significantly with externalized EV phosphatidylserine, plasma EV counts, and total EV membrane surface area. In contrast, aPL levels and thrombin generation from leukocytes and platelets were not impacted by disease, although circulating leukocyte counts were higher in patients.
Conclusions: The aPL membrane of EV supports an elevated level of thrombin generation in patient plasma in ASCVD. Leukocytes may also play a role although the platelet membrane did not seem to contribute. Targeting EV formation/clearance and developing strategies to prevent the aPL surface of EV interacting with coagulation factors represents a novel antithrombotic target in ASCVD.
期刊介绍:
The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA).
The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.