Factor XI Deficiency Protects Against Atherogenesis

In industrialized societies atherosclerosis is still a major cause of morbidity and mortality, in spite of advances in development of cholesterol lowering drugs such as statins and ezetimibe. The detection of procoagulant proteases within atherosclerotic plaques, and the observation that patients with severe factor XI (FXI) deficiency have a reduced tendency to develop ischemic stroke, lead us to investigate whether absence of FXI would affect the process of atherogenesis. For this purpose, we created mice that are homozygous for null alleles for apolipoprotein E (apoE) and FXI (Double knock out [DKO] mice), and compared development of atherosclerosis in these animals to mice lacking apoE alone. At 24 weeks of age, there was a 32% reduction in atherosclerotic plaque area in the aortic sinus in apoE/FXI DKO mice compared to apoEKOmice (p=0.004). At age 42 weeks, apoE/FXI DKO mice had 25% smaller atherosclerotic plaque area in the aortic sinus compared to apoEKO mice (p=0.024), and aortic plaque area was reduced by 49% (p=0.028). Plasma cholesterol and triglycerides levels and lipoprotein profiles were similar in apoE/FXI DKO and apoE KO mice. In some murine infection models, FXI deficiency or FXI inhibition is associated with reduced markers of inflammation and improved survival. Based on this observation, we explored the possibility that reduced atherogenesis in apoE/FXI DKO mice is associated with reduced inflammation. There was a significant reduction in macrophages within atherosclerotic plaque in apoE/FXI DKO mice compared to apoE KO mice as determined by CD68 immunostaining. In conclusion, this work indicates for the first time that factor XI deficiency significantly reduces early, as well as advanced, atherosclerotic burden in an established animal model. We hypothesize that the effect of FXI on atherosclerosis is related to a proinflammatory effect within the atherosclerotic plaque. and propose that therapeutic targeting of FXI may have a role in preventing development of atherosclerosis. As FXI serves a minor role in hemostasis, treatment directed at this protein should not be associated with a high risk of major bleeding.