The Role of p16INK4a Expression in the Age-related Risk of Venous Thromboembolism Public Deposited

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  • March 22, 2019
  • Cardenas, Jessica Caroline
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Venous thromboembolism (VTE) is a pathophysiologically complex disease involving dysregulation of pro and anticoagulant processes in the vasculature. Aging is the strongest risk factor for VTE, although the mechanism is not well understood. Senescence is a physiologic process limiting cellular proliferation, caused by age-dependent expression of the cell cycle inhibitor p16INK4a. p16INK4a expression and senescence could promote vascular dysfunction and predispose elderly individuals to VTE. This dissertation is focused on researching the contribution of p16INK4a expression and aging to venous thrombosis. Murine in vivo vascular injury models are commonly used to study venous and arterial thrombosis. We found that p16INK4a overexpression in mice was associated with augmented venous thrombosis and increased thrombin generation. Bone marrow transplantation analysis demonstrated that this phenotype was dependent on p16INK4a expression in hematopoietic cells. Furthermore, p16INK4a transgenic mice display significant elevation monocyte and macrophage marker, F4/80 staining following IVC ligation. Depletion of monocytes and macrophages, abolished the difference in thrombus mass between p16INK4a overexpressing and wild-type mice. This suggests that p16INK4a expression in hematopoeitic cells, and specifically monocytes and macrophages, contribute to venous thrombosis. Senescence in vascular endothelial cells is associated with phenotypic changes that could promote vascular dysfunction. We observed that senescence induced by serial passaging in vitro caused more rapid rates of clot formation, increased thrombin generation, and formation of denser fibrin networks on the endothelial cell surface. Furthermore, senescent endothelial cells generate less activated protein C due to downregulation of thrombomodulin expression. These results suggest that endothelial cell senescence promotes a procoagulant phenotype. Age-related changes in venous thrombus formation and resolution have not been well defined. Aged mice display a prothrombotic phenotype in a FeCl?3? injury to the saphenous vein, however there was no difference compared to young mice in thrombus mass after IVC-ligation. This suggests the susceptibility of aged mice to venous thrombosis is coagulation stimulus dependent. Additionally, aging in mice is associated with changes in blood composition and plasma coagulability that differ from changes observed in human aging, suggesting mice are a challenging model to study hemostasis during aging. Collectively these studies suggest that p16INK4a expression and cellular senescence contribute to venous thrombosis.
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  • Church, Frank C.
  • Doctor of Philosophy
Graduation year
  • 2012

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