DNase 1 Protects From Increased Thrombin Generation and Venous Thrombosis During Aging: Cross-Sectional Study in Mice...

Background Human aging is associated with increased risk of thrombosis, but the mechanisms are poorly defined. We hypothesized that aging induces peroxide-dependent release of neutrophil extracellular traps that contribute to thrombin generation and thrombosis. Methods and Results We studied C57BL6J mice and littermates of glutathione peroxidase-1 transgenic and wild-type mice at young (4 month) and old (20 month) ages and a healthy cohort of young (18-39 years) or middle-aged/older (50-72 years) humans. In plasma, we measured thrombin generation potential and components of neutrophil extracellular traps (cell-free DNA and citrullinated histone). Aged wild-type mice displayed a significant increase in thrombin generation that was decreased in aged glutathione peroxidase-1 transgenic mice. Both aged wild-type and aged glutathione peroxidase-1 transgenic mice demonstrated similar elevation of plasma cell-free DNA compared with young mice. In contrast, plasma levels of citrullinated histone were not altered with age or genotype. Release of neutrophil extracellular traps from neutrophils in vitro was also similar between young and aged wild-type or glutathione peroxidase-1 transgenic mice. Treatment of plasma or mice with DNase 1 decreased age-associated increases in thrombin generation, and DNase 1 treatment blocked the development of experimental venous thrombi in aged C57BL6J mice. Similarly, thrombin generation potential and plasma cell-free DNA, but not citrullinated histone, were higher in middle-aged/older humans, and treatment of plasma with DNase 1 reversed the increase in thrombin generation. Conclusions We conclude that DNase 1 limits thrombin generation and protects from venous thrombosis during aging, likely by hydrolyzing cell-free DNA.