Abstract
Rationale: Microthrombosis has been suggested as a major factor contributing to delayed neurological deterioration in patients after subarachnoid hemorrhage (SAH). Autopsy studies in humans show microthrombi throughout the brain in SAH patients. However, experimental studies on the role of platelets in microthrombosis after SAH have not investigated. Our hypothesis is that hyper active platelets will increase the microthrombi count, causing more deficits, and that preventing platelet activation will attenuate microthrombi following SAH in mice, improving outcome. Methods: SAH was induced in 4 month old male wild-type and LIGHT-/- mice via endovascular perforation. LIGHT-/- mice have hyperactive platelets. Mice were randomly assigned into (n=8/group/strain): Sham, SAH + saline, and SAH + tirofiban (GP IIb/IIIa antagonist, 0.25 mg/kg, IV). Neurobehavior was performed on days 1-3, 5, and 7 post-SAH using a composite neuroscore. One cohort of animals was sacrificed 2 days post-SAH, and the other at 7 days post-SAH. Microthrombi count was performed using serial sections of brains stained for fibrinogen, blood vessels (DiI), and platelets. Neurobehavioral testing performed and all data was analyzed by a blinded investigator. Results: Mice subjected to SAH have significantly more microthrombi and performed significantly worse in neurobehavior tests compared to Sham animals on days 2 and 7. Wild-type mice receiving tirofiban have fewer microthrombi and improved behavior. Platelet hyperactive (LIGHT-/-) mice are expected to have greater microthrombi count and preventing platelet aggregation is expected to reduce microthrombi count. Conclusions: The expected conclusions are that preventing platelet aggregation after SAH attenuates the formation of microthrombi, thereby reducing functional deficits. This work is expected to highlight platelets as a therapeutic target for preventing delayed neurological deterioration in SAH patients.
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