Stoll Guido, Nieswandt Bernhard, Schuhmann Michael K
Institute of Experimental Biomedicine I, University Hospital Wurzburg, Josef-Schneider-Str. 2, 97080, Wurzburg, Germany.
Rudolf Virchow Center, Center for Integrative and Translational Biomaging, University of Wurzburg, Josef-Schneider-Str. 2, 97080, Wurzburg, Germany.
Neurol Res Pract. 2024 Nov 25;6(1):57. doi: 10.1186/s42466-024-00355-y.
Despite high recanalization rates of > 90% after endovascular thrombectomy (EVT) clinical outcome in around 50% of treated acute ischemic stroke (AIS) patients is still poor. Novel treatments augmenting the beneficial effects of recanalization are eagerly awaited, but this requires mechanistic insights to explain and overcome futile recanalization.
At least two mechanisms contribute to futile recanalization after cerebral large vessel occlusions (LVO): (i) the no reflow phenomenon as evidenced by randomly distributed areas without return of blood flow despite reperfusion of large cerebral arteries, and (ii) ischemia/reperfusion (I/R) injury, the paradoxically harmful aspect of blood flow return in transiently ischemic organs. There is accumulating evidence from experimental stroke models that platelets and leukocytes interact and partly obstruct the microvasculature under LVO, and that platelet-driven inflammation (designated thrombo-inflammation) extends into the reperfusion phase and causes I/R injury. Blocking of platelet glycoprotein receptors (GP) Ib and GPVI ameliorated inflammation and I/R injury providing novel therapeutic options. Recently, MRI studies confirmed a significant, up to 40% infarct expansion after recanalization in AIS thereby proofing the existance of I/R injury in the human brain. Moreover, analysis of minute samples of ischemic arterial blood aspirated directly from the pial cerebral collateral circulation under LVO during the routine EVT procedure confirmed platelet activation and platelet-driven leukocyte accumulation in AIS and, thus, the principal transferability of pathophysiological stroke mechanisms from rodents to man. Two recently published clinical phase 1b/2a trials targeted (thrombo-) inflammation in AIS: The ACTIMIS trial targeting platelet GPVI by glenzocimab provided encouraging safety signals in AIS similar to the ApTOLL trial targeting toll-like receptor 4, a central receptor guiding stroke-induced innate immunity. However, both studies were not powered to show clinical efficacy.
The fact that the significance of I/R injury in AIS has recently been formally established and given the decisive role of platelet-leukocytes interactions herein, new avenues for adjunct stroke treatments emerge. Adjusted study designs to increase the probability of success are of outmost importance and we look forward from what can be learned from the so far unpublished, presumbably negative ACTISAFE and MOST trials.
尽管血管内血栓切除术（EVT）后再通率高达90%以上，但约50%接受治疗的急性缺血性卒中（AIS）患者的临床结局仍然较差。人们急切期待能增强再通有益效果的新治疗方法，但这需要深入的机制研究来解释和克服无效再通。
脑大动脉闭塞（LVO）后无效再通至少有两种机制：（i）无复流现象，表现为尽管大脑大动脉再灌注，但仍有随机分布的无血流回流区域；（ii）缺血/再灌注（I/R）损伤，即短暂缺血器官中血流恢复带来的矛盾性有害方面。来自实验性卒中模型的证据越来越多，表明在LVO情况下血小板和白细胞相互作用并部分阻塞微血管，且血小板驱动的炎症（称为血栓炎症）会持续到再灌注阶段并导致I/R损伤。阻断血小板糖蛋白受体（GP）Ib和GPVI可减轻炎症和I/R损伤，提供了新的治疗选择。最近，MRI研究证实AIS患者再通后梗死灶显著扩大，扩大率高达40%，从而证明人脑存在I/R损伤。此外，在常规EVT手术期间，对LVO情况下直接从软脑膜脑侧支循环抽吸的缺血动脉血微量样本进行分析，证实了AIS患者中血小板活化和血小板驱动的白细胞聚集，因此，病理生理卒中机制从啮齿动物到人类具有主要的可转移性。最近发表的两项1b/2a期临床试验针对AIS中的（血栓）炎症：通过glenzo cimab靶向血小板GPVI的ACTIMIS试验在AIS中提供了令人鼓舞的安全信号，类似于靶向Toll样受体4的ApTOLL试验，Toll样受体4是指导卒中诱导的固有免疫的核心受体。然而，两项研究均未设定显示临床疗效的效力。
最近正式确立了I/R损伤在AIS中的重要性，且鉴于血小板 - 白细胞相互作用在此过程中的决定性作用，出现了辅助性卒中治疗的新途径。调整研究设计以提高成功概率至关重要，我们期待从未发表的、可能为阴性的ACTISAFE和MOST试验中能学到什么。
