Platelets cause microvascular occlusion and delayed neurological deficits after subarachnoid hemorrhage in mice.

Abstract

After subarachnoid hemorrhage (SAH), some patients develop delayed neurological deficits (DND). Microthrombi are considered a contributing factor to DND, but clinical trials of antiplatelets had mixed results. Existing research suggests that platelets play a role in the etiology of DND, but no comprehensive study has tested causality between platelets and DND after SAH. Here we hypothesize that after SAH, platelet activation promotes microthrombi formation, occlusion of the brain microvasculature and contributes to DND, and that inhibiting platelet aggregation is a therapeutic strategy. Mice experiencing SAH were administered various interventions. The animals were subjected to stimulation of platelets, platelet depletion, or antiplatelet drugs and then underwent daily neurological assessment until day 7 before euthanasia for brain microthrombi counting. In parallel, platelets isolated from blood of patients with aneurysmal SAH were tested with antiplatelets to determine how they effected platelet activation. In mice, SAH caused increased levels of platelet-activating factors and more cerebrovascular microthrombi, which correlated with DND. Exogenous platelet activation caused worse outcomes and DND, whereas platelet depletion reduced microthrombi, leading to improved outcomes and a lower incidence of DND. Selected antiplatelet drugs improved outcomes on days 1 and 2 (sex-specific benefits were observed) and one antagonist reduced DND incidence. In platelets from human patients with SAH, antagonism can also prevent platelet activation. After SAH, platelets lead to brain microthrombi and DND, suggesting that platelets are a therapeutic target. Platelet depletion and antagonism can prevent microthrombi and DND in mice. This study serves as a preclinical proof-of-concept that platelets may represent a therapeutic target for SAH.