The Role of Platelets in Remote Organ Injury and Infection After Stroke

Strokes are a leading cause of death globally, and the leading cause of preventable disability in the United States. The current clinical management of ischemic strokes is removing the occlusion to allow for reperfusion. However, the subsequent reperfusion can lead to increased tissue death and further pathologies such as remote organ injury (ROI) and infection. During the post-acute state of recovery, stroke victims most commonly die due to stroke-associated infection, predominantly pneumonia. Platelets get activated after ischemic stroke and can then circulate throughout the body, but whether platelets affect ROI after stroke has not been studied. Following transient Middle Cerebral Artery Occlusion (tMCAO) with 1h of ischemia, we found that stroke significantly increased platelet adhesion and P-selectin expression, suggesting that stroke/reperfusion increases platelet activity. To specifically investigate the role of platelets in ROI after stroke, we depleted platelets from mice 1 day after tMCAO, as cerebral infarct size does not increase after 1 day. Excitingly, platelet depletion significantly improved survival of mice after stroke, compared to vehicle-treated mice, along with preventing damage to the intestinal villi, attenuating intestinal epithelial and vascular permeability, and dramatically reducing bacteria in the liver, spleen, and the bronchoalveolar lavage fluid (BALF) after stroke. After rectally instilling Ampicillin-resistant, green fluorescent protein expressing E. coli into sham and stroke mice, we found that platelet depletion dramatically reduced bacterial translocation across all observed tissues. Lastly, we used DC101 (a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist) and various antiplatelet therapies, including aspirin and clopidogrel, to decrease platelet mediated ROI and infection after stroke. Promisingly, all of these treatments decreased the number of bacteria in the BALF of post-stroke mice, compared to vehicle treated mice. Thus, our studies show, for the first time, that platelets promote ROI and infection after stroke and, very excitingly, targeting platelet activity may be a promising therapeutic target to help in the recovery of stroke patients