Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19.
Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19.
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DOI：
10.3389/fimmu.2022.834988
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发表时间：
2022
影响因子：
7.3
通讯作者：
Wherry EJ
中科院分区：
文献类型：
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作者：
Apostolidis SA;Sarkar A;Giannini HM;Goel RR;Mathew D;Suzuki A;Baxter AE;Greenplate AR;Alanio C;Abdel-Hakeem M;Oldridge DA;Giles JR;Wu JE;Chen Z;Huang YJ;Belman J;Pattekar A;Manne S;Kuthuru O;Dougherty J;Weiderhold B;Weisman AR;Ittner CAG;Gouma S;Dunbar D;Frank I;Huang AC;Vella LA;UPenn COVID Processing Unit;Reilly JP;Hensley SE;Rauova L;Zhao L;Meyer NJ;Poncz M;Abrams CS;Wherry EJ
新冠肺炎患者的临床表现多种多样。在感染SARS-CoV-2的患者中，血栓栓子事件是导致发病率和死亡率的重要原因。严重的新冠肺炎与过度炎症和既往心血管疾病有关。血小板是炎症反应的重要介质和感受器，直接受到心血管应激源的影响。在这份报告中，我们发现重症住院新冠肺炎患者的血小板表现出更高的基础活化水平，通过P-选择素表面表达来衡量，并且在体外刺激时功能储备较差。为了更详细地研究这个问题，我们开发了一种方法来评估新冠肺炎患者的血浆激活健康捐赠者的血小板的能力。血小板活化是新冠肺炎患者血浆的共同特征，并与包括肾和肝损伤在内的临床结果的关键指标以及APACHEIII评分相关。此外，我们发现铁蛋白是与血小板过度激活相关的关键临床标记物。对于随后发生住院血栓形成事件的患者，新冠肺炎血浆介导的对对照血小板的影响最高。对新冠肺炎患者血浆的蛋白质组学分析确定了炎症和心血管疾病的关键介质，这些介质与体外血小板激活呈正相关。从机制上讲，用抗体中和、清除γ或Syk抑制剂福斯塔替尼阻断血小板上Fc Ig G RIIA-Syk和C5a-C5aR通路的信号通路，可以逆转由新冠肺炎血浆驱动的这种过度活动，并防止在内皮微流室条件下的血小板聚集。这些数据确定了这些潜在的可操作通路对于新冠肺炎患者的血小板激活和/或血管并发症和临床结果至关重要。总之，我们揭示了新冠肺炎中血小板介导的免疫血栓形成的关键作用，并确定了介导这一作用的不同的、临床相关的、有针对性的信号通路。
Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect.