Vein Wall and Circulating P-selectin Promote Venous Thrombogenesis During Aging in a Rodent Model

Background: The incidence of deep venous thrombosis (DVT) significantly increases 45 years of age. Our objective was to identify the direct relationship between aging and adhesion molecule activation during venous thrombosis in mice of varying ages. A mixed patient population was also evaluated for age-related effects during DVT. Methods: DVT was induced in 4 and 18 month old C57BL/6 mice using the electrolytic inferior vena cava model (EIM). Mice were euthanized at baseline (non-thrombosed, TC), 6 hours (6H), and 2 days (2D) postthrombosis. Blood and tissue samples were collected for the following analysis: thrombus weight (TW), soluble P (sP) and soluble E-selectin (sE) by ELISA, vein wall Pand E-selectin protein by ELISA, vein wall Pand E-selectin gene expression, vein wall inflammatory cell analysis by light microscopy, and hematology. In a patient population (n335), the relationship between patients with and without DVT, sP levels, and age (above and below 45 years) was evaluated. Results: Older mice had significantly larger venous thrombi versus younger mice at the 6H and 2D (x10-3 grams, P < .01; Fig 1). These same mice had significantly higher sP-selectin levels versus younger mice at 6 hours and 2 days (ng/mg, P < .01). Older mouse sE levels were significantly lower versus younger animals at baseline (pg/mg, P < .05). Older animals had significantly elevated vein wall P-selectin versus younger mice at 6H and 2D post-thrombosis (P < .01). Post-thrombosis, significantly increased vein wall E-selectin in younger mice versus older animals at 6H (P < .05). All mice showed active vein wall inflammatory cell extravasation post thrombosis. Older animals had significantly more circulating platelets versus younger mice at baseline, 6H, and 2D post-thrombosis (K/mL, P < .01). DVT-positive patients greater than 45 years (n 1⁄4 135) of age had significantly higher levels of soluble P-selectin versus patients positive for DVT less than 45 years (n 1⁄4 51) of age (ng/mL sP, P < .05; Fig 2). Conclusions: Aging significantly increased vein wall P-selectin, sP, and circulating platelets that amplified venous thrombosis in mice. For the first time, we have documented the translational role of soluble P-selectin as a biomarker for thrombosis in aged rodents and DVT-positive patients. These important findings will provide supporting evidence for the use of selectin targeted therapeutics in future clinical trials for the prophylaxis and treatment of DVT in the aged population.