Salet Dorien M, Bekkering Siroon, Middeldorp Saskia, van den Hoogen Lucas L
Department of Vascular Medicine, Amsterdam UMC, Amsterdam, The Netherlands.
Department of Internal Medicine & Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands.
J Thromb Haemost. 2023 Apr;21(4):744-757. doi: 10.1016/j.jtha.2022.12.002. Epub 2022 Dec 22.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications. APS is a paradigmatic thromboinflammatory disease. Thromboinflammation is a pathophysiological mechanism coupling inflammation and thrombosis, which contributes to the pathophysiology of cardiovascular disease. APS can serve as a model to unravel mechanisms of thromboinflammation and the relationship between innate immune cells and thrombosis. Monocytes are activated by aPL into a proinflammatory and procoagulant phenotype, producing proinflammatory cytokines such as tumor necrosis factor α, interleukin 6, as well as tissue factor. Important cellular signaling pathways involved are the NF-κB-pathway, mammalian target of rapamycin (mTOR) signaling, and the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome. All of these may serve as future therapeutic targets. Neutrophils produce neutrophil extracellular traps in response to aPL, and this leads to thrombosis. Thrombosis in APS also stems from increased interaction of neutrophils with endothelial cells through P-selectin glycoprotein ligand-1. NETosis can be targeted not only with several experimental therapeutics, such as DNase, but also through the redirection of current therapies such as defibrotide and the antiplatelet agent dipyridamole. Activation of platelets by aPL leads to a procoagulant phenotype. Platelet-leukocyte interactions are increased, possibly mediated by increased levels of soluble P-selectin and soluble CD40-ligand. Platelet-directed future treatment options involve the inhibition of several platelet receptors activated by aPL, as well as mTOR inhibition. This review discusses mechanisms underlying thromboinflammation in APS that present targetable therapeutic options, some of which may be generalizable to other thromboinflammatory diseases.
抗磷脂综合征（APS）是一种全身性自身免疫性疾病，抗磷脂抗体（aPL）的持续存在会导致血栓形成和产科并发症。APS是一种典型的血栓炎症性疾病。血栓炎症是一种将炎症和血栓形成联系起来的病理生理机制，它参与了心血管疾病的病理生理过程。APS可作为一个模型来揭示血栓炎症的机制以及先天免疫细胞与血栓形成之间的关系。单核细胞被aPL激活后转变为促炎和促凝表型，产生肿瘤坏死因子α、白细胞介素6等促炎细胞因子以及组织因子。涉及的重要细胞信号通路包括核因子κB通路、雷帕霉素靶蛋白（mTOR）信号通路以及含NOD样受体蛋白3（NLRP3）炎症小体。所有这些都可能成为未来的治疗靶点。中性粒细胞在aPL作用下产生中性粒细胞胞外陷阱，进而导致血栓形成。APS中的血栓形成还源于中性粒细胞通过P选择素糖蛋白配体-1与内皮细胞的相互作用增加。不仅几种实验性治疗药物（如脱氧核糖核酸酶）可针对中性粒细胞胞外诱捕作用，而且目前的治疗药物（如去纤苷和抗血小板药物双嘧达莫）的重新定向使用也可针对此作用。aPL激活血小板会导致促凝表型。血小板与白细胞之间的相互作用增加，这可能是由可溶性P选择素和可溶性CD40配体水平升高介导的。针对血小板的未来治疗选择包括抑制几种被aPL激活的血小板受体以及抑制mTOR。本综述讨论了APS中血栓炎症的潜在机制，这些机制提供了可靶向的治疗选择，其中一些可能适用于其他血栓炎症性疾病。
