Abstract 112: Roles Of Platelets In Aneurysm Formation And Rupture

Abstract

Platelets were once exclusively connected to thrombus; however, they play more diverse roles. Platelets have been found to be mediators of adhesion and transmigration of leukocytes at sites of inflammation. Inflammation is emerging as a key factor in the formation and subsequent rupture of intracranial aneurysms. In the presence of endothelial damage as well as increased shear stress, platelets are activated and, thus, become capable of modulating inflammation. Both conditions are present at the site of intracranial aneurysm. Evaluation of ruptured and unruptured aneurysms have demonstrated the presence of thrombus intramurally and intraluminally. Furthermore, multiple cohort studies on the use of aspirin, an inhibitor of platelet aggregation, have shown a significant reduction in the incidence of aneurysmal rupture. We hypothesize that platelets promote the formation and rupture of intracranial aneurysm. To evaluate this hypothesis, c-mpl receptor knockout mice were used. These mice are thrombocytopenic due to impaired megakaryocyte function, making them an ideal model to test our hypothesis. Intracranial aneurysm was induced in mice by a combination of systemic hypertension and a single injection of elastase into the cerebrospinal fluid. The rate of aneurysm formation and rupture were used as endpoints. To evaluate systemic thrombocytopenia in study mice, platelet count in plasma samples was assessed. Platelets in c-mpl knockout mice were 85% lower than in wild-type controls (mean ± SD: 226*10 3 ± 9*10 3 /μL vs 1438*10 3 ± 183*10 3 /μL, P< 0.05). Formation rate of aneurysm was reduced in c-mpl knockout as opposed to wild-type counterparts (65% vs 87%, P<0.05). More importantly, there was also a reduction in rupture rate of aneurysms in c-mpl knockout compared to wild-type (45% vs 72%, P<0.05). Our findings show that systemic reduction of platelets results in a decreased rate of aneurysm formation and rupture. We plan to investigate more specific interactions at the site of intracranial aneurysm between platelets and leukocytes or endothelial factors. We aim to find the molecules mediating these interactions in hopes that a therapeutic target can be identified.