Genetic determinants of Von Willebrand factor and the risk of cardiovascular disease

Normal haemostasis requires a delicate balance between procoagulant and anticoagulant factors. Disruption of this balance may lead to bleeding disorders, such as hemophilia, or thrombotic disorders, including deep vein thrombosis of the leg. As Virchow already reported in 1877, properties of the blood vessel wall, the blood flow and blood constituents contribute to the formation of thrombi in either veins or arteries. However, through contemporary research the complexity of this process leading to thrombus formation has become more apparent. An important player in thrombus formation is von Willebrand Factor (VWF), a large multifunctional glycoprotein. VWF initiates adherence of platelets to the injured vessel wall and subsequent platelet aggregation leading inevitably to the formation of thrombi. In addition, VWF is a carrier protein of coagulation factor VIII (FVIII), thereby protecting it from clearance. In healthy subjects normal plasma VWF levels range from 0.60 – 1.40 IU/mL and are characterized by a large variation. This can be partly attributed to a number of lifestyle and environmental factors, but most importantly to genetic factors. The necessity of maintaining normal VWF levels in the circulation is illustrated by two clinical manifestations that may occur when VWF exceeds its normal range. Low levels of VWF may lead to bleeding, which is known as von Willebrand Disease (VWD), the most common inherited bleeding disorder in humans. To the contrary, high VWF antigen (VWF:Ag) levels are associated with an increased risk of venous thrombosis and arterial thrombosis, including myocardial infarction (MI) and ischemic stroke