Evaluation of the Age-Related Pathophysiology of von Willebrand Factor

Abstract

von Willebrand Factor (VWF) is a plasma multimeric glycoprotein involved in platelet adhesion and aggregation at sites of vascular injury, and the carrier for coagulation Factor VIII (FVIII). Levels of VWF are influenced by many genetic and environmental factors, but appropriate levels are needed for a balanced hemostasis, since high levels of VWF are associated with an increased risk for cardiovascular disease, while low levels result in prolonged bleeding. Aging is associated with both increased levels of VWF and a higher incidence of cardiovascular disease, however, the exact mechanism responsible for this age-related increase remained unknown. In this thesis, we describe the age-related pathophysiology of VWF and the mechanisms responsible for the quantitative changes in VWF using human and mouse models. First, we found that the increase in VWF levels with age is highly dependent on ABO blood type, as both factors exert interrelated influences on VWF levels through secretion and clearance mechanisms. Second, we evaluated if similar age-related increases in VWF levels occurred in mice and found that C57BL/6 mice showed similar increases. Consequently, we used the mouse model to test the three mechanisms that influence VWF levels in plasma: synthesis, secretion and clearance. An age-related increase in Vwf expression was observed in lung, brain, spleen and liver samples obtained from aging mice. In addition, increased secretion of VWF, measured by mouse VWF propeptide levels, was also observed with advancing age. No significant changes with age were observed in VWF clearance, but several findings suggested that the mouse might not be the appropriate model to study age- and ABO-related VWF clearance mechanisms. Finally, we found that despite increased VWF oxidation and reduced ADAMTS13 activity, a neutral effect on VWF function was attained in later life. In conclusion, this is the first detailed study of the age-related pathophysiology of VWF. This thesis provides new insights into the mechanisms that control the increase in VWF levels with aging. The findings of this thesis could also have implications on the prevention of cardiovascular disease in older individuals, and on the treatment of patients with von Willebrand disease and hemophilia A in later life.