Preventing Microthrombi Formation Improves Function After Subarachnoid Hemorrhage in Mice

Abstract

Abstract INTRODUCTION Aneurysmal subarachnoid hemorrhage (aSAH) is a debilitating disease affecting around 30 000 people per year in the United States, with a mortality estimated as high as 67%. Morbidity resulting from SAH is also extensive and includes delayed cerebral ischemia (DCI). However, the mechanism by which delayed neurological deficits develop is still poorly understood. To date, the importance of microthrombosis in SAH has been underappreciated, with few studies reporting on its occurrence and no studies probing the mechanism of microthrombi formation. We hypothesize that platelet activity results in microthrombi formation and contributes to delayed neurological deficits. We aim to address the knowledge gap in regard to the role of platelet activity and microthrombosis in DCI. METHODS For all experiments, adult male mice 4 mo old were utilized. SAH was induced using the endovascular perforation model. Behavioral assessment was performed on days 1, 3, 5, and 7 post-SAH. Animals were euthanized at 2 and 7 d post-SAH. To investigate the role of platelets in microthrombi formation after SAH, we used prototypic inhibitors of platelet activation (PAF, P2Y1,12, TP?/??R, PAR-1, −4) and platelet aggregation (GP aIIb/IIIa). RESULTS Mice with SAH had a higher microthrombi count compared to shams. Treatment with platelet inhibitors significantly reduced the number of microthrombi compared to placebo and provided protection against functional deficits. CONCLUSION SAH induces microthrombi formation, which may be a major contributor to delayed neurological deficits. Inhibition of platelet function reduces the number of microthrombi formed and confers protection against delayed functional deficits in mice models of SAH.