Anticoagulation targeting membrane-bound anionic phospholipids improves outcomes of traumatic brain injury in mice
Anticoagulation targeting membrane-bound anionic phospholipids improves outcomes of traumatic brain injury in mice
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针对膜结合阴离子磷脂的抗凝可改善小鼠创伤性脑损伤的结果
DOI：
10.1182/blood.2021011310
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发表时间：
2021-12-23
期刊：
影响因子：
20.3
通讯作者：
Dong, Jing-fei
中科院分区：
文献类型：
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作者：
Dong, Xinlong;Liu, Wei;Dong, Jing-fei
严重创伤性脑损伤常导致急性全身性高凝状态，并迅速发展为消耗性凝血障碍。我们最近证实，脑损伤诱发的凝血病(TBI-IC)是由脑源性细胞外小泡(BDEV)启动和传播的，并由内皮细胞和血小板的细胞外小泡(EV)传播。在这里，我们介绍了一项研究的结果，该研究旨在测试一项假设，即以表达阴离子磷脂的EVS为靶点的抗凝可以预防TBI-IC并改善遭受严重TBI的小鼠的预后。我们结合体外实验评估了一种融合蛋白(ANV-6L15)在改善小鼠脑外伤模型预后方面的效果。ANV-6L15将与磷脂酰丝氨酸(PS)结合的膜联蛋白V(ANV)与多肽抗凝剂结合在一起，以优先靶向外源性凝血。我们发现ANV-6L15在1.9atm液压冲击伤小鼠中减少了70.2%的颅内血肿，改善了神经功能，减少了56.8%的死亡率。它通过防止血管渗漏、组织水肿和脑损伤引起的高凝状态来保护脑损伤小鼠。我们进一步表明，外源性张力酶复合体形成在循环EVS的表面，其中BDEV上的水平最高。磷脂分析检测到BDEV上PS的水平最高，而来自内皮细胞和血小板的EV(分别为79.1、15.2和3.5 NM/mg蛋白质)。这些发现表明，TBI-IC是创伤诱导的高凝状态的结果，可以通过靶向来自脑和其他细胞的EV的阴离子磷脂表达膜来治疗。
Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI in mouse models combined with in vitro experiments. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V (ANV) with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. The phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared with EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.