Thrombo-Inflammation in Preeclampsia and Pregnancy Induced Hypertension: Proteomics And Metabolomics Profiling of Platelets and Plasma Mediators

Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.

背景：血小板可能是子痫前期（preeclampsia, PE）血栓出血性并发症的关键介导因子，将炎症与血栓形成和内皮及血管功能障碍紧密关联。妊娠期高血压（gestational hypertension, GH）属于妊娠高血压并发症谱系，且是子痫前期的独立危险因素，但目前尚不明确可有效区分子痫前期与妊娠期高血压的生物标志物。
研究目的：旨在筛选可提示子痫前期的特异性血浆及血小板血栓炎症性生物标志物，实现子痫前期与妊娠期高血压的鉴别诊断。
研究方法：本研究采用多重免疫分析法，对子痫前期患者的血小板及血浆蛋白质组学、代谢组学数据进行系统性评估，并与非妊娠（non-pregnant, NP）、健康妊娠（healthy pregnant, PC）及妊娠期高血压受试者进行对照分析。
研究结果：相较于非妊娠及健康妊娠人群，子痫前期与妊娠期高血压患者的血小板中存在显著高表达的蛋白，同时血浆中存在富集的代谢物与蛋白。健康妊娠人群的促凝活性可能由纤维蛋白原驱动；α1-抗胰蛋白酶抑制剂ITIH2与ITIH3在妊娠高血压并发症（子痫前期与妊娠期高血压）患者体内显著富集；纤连蛋白与S100A8/9可能是子痫前期而非妊娠期高血压的主要促凝血激动剂。此外，子痫前期患者血小板中富含亮氨酸重复序列的蛋白27和42（leucine-rich repeat-containing protein 27 and 42, LRRC27/42）——容积调控性VRAC阴离子通道（volume-regulated VRAC anion channels）的亚基——表达显著上调，这可能与该病增强的葡萄糖敏感性及促血栓形成倾向密切相关。本研究的多重免疫分析法验证了既往研究结论：子痫前期患者血浆细胞因子水平升高，包括可直接激活血小板的基质细胞衍生因子-1α（stromal cell-derived factor 1α, SDF-1α）；同时还检测到i-309与CTACK细胞因子水平上升，本研究通过STRING蛋白质相互作用数据库分析探究了这两种细胞因子对血小板的调控作用。
研究结论：本研究筛选出可用于监测子痫前期发生与进展、并能有效鉴别子痫前期与妊娠期高血压的生物标志物。此外，通过蛋白质相互作用分析，本研究为血小板在子痫前期血栓炎症状态中的作用机制提出了全新假说。