Von Willebrand factor and von Willebrand disease in ageing: mechanisms, evolving phenotypes, and clinical...

The global population is ageing and this demographic shift has profound effects on haemostasis, notably a progressive tilt towards a hypercoagulable state. A major age-associated change in haemostasis is the increase in von Willebrand factor (VWF), a plasma glycoprotein essential for primary and secondary haemostasis. VWF deficiency causes von Willebrand disease, which is the most common inherited bleeding disorder and affects approximately 1% of the population. Conversely, elevated VWF concentrations are linked to increased thrombotic risk; VWF concentrations increase with age by approximately 10-15 IU/dL per decade. Moreover, longitudinal data indicate that VWF concentrations might normalise over time in individuals initially diagnosed with von Willebrand disease. Understanding the mechanisms underlying age-related increases in VWF is crucial for refining the disease classification and optimising management. Given the strong association between VWF, coagulation factor VIII (which is stabilised and transported by VWF), and thrombotic risk, the interplay between ageing and VWF dynamics has clinical implications. This Review examines age-related changes in VWF synthesis, storage, multimeric structure, and clearance. We also discuss the consequences of rising VWF concentrations in older adults on bleeding symptoms, von Willebrand disease diagnosis and management, and the related risks of thrombosis and cardiovascular complications. Finally, we identify essential knowledge gaps and outline priorities for future research and clinical practice.