Altered platelet proteome in lupus anticoagulant (LA)-positive patients-protein disulfide isomerase and NETosis as new players in LA-related thrombosis.,Experimental & Molecular Medicine

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Altered platelet proteome in lupus anticoagulant (LA)-positive patients-protein disulfide isomerase and NETosis as new players in LA-related thrombosis.
Experimental & Molecular Medicine ( IF 9.5 ) Pub Date : 2020-01-20 , DOI: 10.1038/s12276-019-0358-4
Lena Hell ₁ , Kristina Lurger ₁ , Lisa-Marie Mauracher ₁ , Ella Grilz ₁ , Christina Maria Reumiller ₂ , Georg Johannes Schmidt ₃ , Huriye Ercan ₁ , Silvia Koder ₁ , Alice Assinger ₂ , José Basilio ₂ , Johanna Gebhart ₁ , Cihan Ay ₁ , Ingrid Pabinger ₁ , Maria Zellner ₂

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Patients with antiphospholipid syndrome (APS) are at high risk of developing venous and arterial thromboembolism (TE). The role of platelets in the pathogenesis of these prothrombotic conditions is not yet fully understood. The aim of this study was to gain mechanistic insights into the role of platelets in APS by comparing the platelet proteome between lupus anticoagulant (LA)-positive patients with (LA+ TE+) and without a history of TE (LA+ TE-) and healthy controls. The platelet proteome of 47 patients with LA, 31 with a history of TE and 16 without thrombotic history, and 47 healthy controls was analyzed by two-dimensional differential in-gel electrophoresis and mass spectrometry to identify disease-related proteins. Afterward, selected LA-related platelet proteins were validated by western blot and ELISA. Alterations of 25 proteins were observed between the study groups. STRING pathway analysis showed that LA-related protein profiles were involved in platelet activation, aggregation, and degranulation. For example, protein disulfide isomerase family members, enzymes that promote thrombosis, were upregulated in platelets and plasma of LA+ TE+ patients. Leukocyte elastase inhibitor (SERPINB1), an antagonist of neutrophil extracellular trap (NET) formation, was decreased in platelets of LA+ TE+ patients compared to healthy controls. Additionally, citrullinated histone H3, a NET-specific marker, was increased in plasma of LA+ TE+ patients. These findings suggest that decreased platelet SERPINB1 levels favor prothrombotic NETosis, especially in LA+ TE+ patients. Our findings reveal protein abundance changes connected to altered platelet function in LA-positive patients, thus suggesting a pathogenic role of platelets in thrombotic complications in APS.

中文翻译：

狼疮抗凝物 (LA) 阳性患者的血小板蛋白质组改变——蛋白质二硫键异构酶和 NETosis 作为 LA 相关血栓形成的新参与者。

抗磷脂综合征 (APS) 患者发生静脉和动脉血栓栓塞 (TE) 的风险很高。血小板在这些促血栓条件的发病机制中的作用尚未完全了解。本研究的目的是通过比较具有 (LA+ TE+) 和无 TE 病史 (LA+ TE-) 的狼疮抗凝物 (LA) 阳性患者与健康对照之间的血小板蛋白质组，从而深入了解血小板在 APS 中的作用. 通过二维微分凝胶电泳和质谱分析 47 名 LA 患者、31 名有 TE 病史和 16 名无血栓病史的患者以及 47 名健康对照者的血小板蛋白质组，以确定与疾病相关的蛋白质。之后，选定的 LA 相关血小板蛋白通过蛋白质印迹和 ELISA 进行验证。在研究组之间观察到 25 种蛋白质的改变。STRING 通路分析表明，LA 相关蛋白谱参与血小板活化、聚集和脱颗粒。例如，蛋白质二硫键异构酶家族成员，促进血栓形成的酶，在 LA+ TE+ 患者的血小板和血浆中被上调。与健康对照组相比，白细胞弹性蛋白酶抑制剂 (SERPINB1) 是中性粒细胞胞外陷阱 (NET) 形成的拮抗剂，在 LA+ TE+ 患者的血小板中有所减少。此外，瓜氨酸化组蛋白 H3（一种 NET 特异性标记物）在 LA+ TE+ 患者的血浆中增加。这些发现表明，血小板 SERPINB1 水平降低有利于促血栓形成 NETosis，尤其是在 LA+ TE+ 患者中。

更新日期：2020-01-21

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