Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Blood. 2021 Mar 11;137(10):1406-1415. doi: 10.1182/blood.2020007155.
Thrombosis and its associated complications are a major cause of morbidity and mortality worldwide. Microvesicles (MVs), a class of extracellular vesicles, are increasingly recognized as mediators of coagulation and biomarkers of thrombotic risk. Thus, identifying factors targeting MV-driven coagulation may help in the development of novel antithrombotic treatments. We have previously identified a subset of circulating MVs that is characterized by the presence of oxidation-specific epitopes and bound by natural immunoglobulin M (IgM) antibodies targeting these structures. This study investigated whether natural IgM antibodies, which are known to have important anti-inflammatory housekeeping functions, inhibit the procoagulatory properties of MVs. We found that the extent of plasma coagulation is inversely associated with the levels of both free and MV-bound endogenous IgM. Moreover, the oxidation epitope-specific natural IgM antibody LR04, which recognizes malondialdehyde adducts, reduced MV-dependent plasmatic coagulation and whole blood clotting without affecting thrombocyte aggregation. Intravenous injection of LR04 protected mice from MV-induced pulmonary thrombosis. Of note, LR04 competed the binding of coagulation factor X/Xa to MVs, providing a mechanistic explanation for its anticoagulatory effect. Thus, our data identify natural IgM antibodies as hitherto unknown modulators of MV-induced coagulation in vitro and in vivo and their prognostic and therapeutic potential in the management of thrombosis.
血栓及其相关并发症是全球发病率和死亡率的主要原因。微泡（MVs），一类细胞外囊泡，越来越被认为是凝血的介质和血栓风险的生物标志物。因此，确定针对 MV 驱动的凝血的因素可能有助于开发新型抗血栓治疗方法。我们之前已经鉴定出一组循环 MVs，其特征在于存在氧化特异性表位，并与针对这些结构的天然免疫球蛋白 M（IgM）抗体结合。本研究调查了天然 IgM 抗体是否抑制 MVs 的促凝特性，天然 IgM 抗体已知具有重要的抗炎管家功能。我们发现，血浆凝固的程度与游离和 MV 结合的内源性 IgM 的水平呈负相关。此外，氧化表位特异性天然 IgM 抗体 LR04 识别丙二醛加合物，可减少 MV 依赖性血浆凝固和全血凝结，而不影响血小板聚集。LR04 的静脉注射可保护小鼠免受 MV 诱导的肺血栓形成。值得注意的是，LR04 竞争凝血因子 X/Xa 与 MVs 的结合，为其抗凝作用提供了机制解释。因此，我们的数据确定天然 IgM 抗体是体外和体内 MV 诱导的凝血的未知调节剂，以及它们在血栓管理中的预后和治疗潜力。
