The role of von Willebrand Factor in endothelial platelet capture

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Von Willebrand Factor (VWF) is a blood protein with a vital role in forming blood clots at sites of blood vessel injury thus helping to stop blood loss. VWF is unusual in that it is made in the cells lining blood vessels known as endothelial cells (EC), whereas almost all other blood-clotting proteins are made within the liver. Once it is made, VWF is released into the circulation, deposited in the blood vessel wall or stored in EC. VWF is a very large molecule and circulates in a rolled-up bundle. Once a blood vessel has been damaged, VWF can attach to structures in the blood vessel wall that are normally hidden but which have now become exposed. The effect of blood flowing past the VWF causes the rolled-up molecule to unravel allowing it to capture circulating cell fragments, called platelets, from the blood. More and more platelets are captured at this site of blood vessel injury and stick together, forming a platelet plug. This is the first step in forming a blood clot to stop blood loss. However, VWF and platelets can also cause blood vessel damage by sticking to the vessel wall. Heart disease and stroke, collectively known as cardiovascular disease (CVD), remain the leading cause of death in the United Kingdom. They result in part from formation of abnormal blood clots within the circulation and high levels of VWF are associated with an increased risk of heart attacks and strokes. However, at present it is not clear whether the high levels play a role in causing the blood clots or whether they simply result from damaged vessels which have responded by making more VWF. Nonetheless, it has been shown in animal studies that VWF plays a direct role in the formation of the fatty deposits that build up in the blood vessels before a heart attack or stroke. One of the first steps in the formation of a fatty deposit is the attachment of platelets to the EC of the blood vessel wall. A deficiency of VWF activity results in a bleeding disorder known as von Willebrand Disease (VWD). It might be predicted that people with VWD would have fewer heart attacks and strokes than people with normal or high levels. So far, there are few research studies in animals and humans attempting to answer this question and they have given conflicting results. Recently, improved understanding of how VWF is made and functions has indicated why these studies are flawed. This improved understanding has come from our studies of VWF within the EC from normal controls and from patients with VWD. In brief, these studies show that VWF has a profound effect on the way these cells grow and the effect is not closely related to the resulting level in the blood. From these various lines of evidence we have strong reasons to suspect that VWF plays an important role in heart attack and stroke. The drawback of these studies to date is that they do not show how the VWF does this and whether it is primarily VWF circulating in our blood or VWF stored within the EC that is responsible. This distinction is essential if we want to target VWF for therapy in the prevention and treatment of CVD.Animal models are imprecise and incomplete models of human cardiovascular disease and population studies are oversimplified. We propose to overcome these problems by using human endothelial cells isolated from normal and VWD patients to study directly the interaction between VWF, EC, the damaged blood vessel wall and platelets. Moreover, whilst growing these cells in special chambers, we can reproduce the stresses that they are exposed to in the normal or abnormal circulation: this is likely to be a major determinant of how VWF is made by EC and how it captures platelets. Better understanding of these crucial interactions at the beginning of vascular disease, would allow us to target accurately new treatments to prevent heart attacks and strokes.