The endothelial cells that line the vasculature contain a storage organelle, Weibel-Palade Bodies (WPB). The major content protein of WPB is von Willebrand factor (VWF), an adhesive glycoprotein that plays a major role in primary haemostasis. As a rapid-response system, the WPB are thus of critical importance in initiating haemostatic responses within the rapidly-changing vascular environment.

Mutations within VWF are the commonest cause of the inherited bleeding disorder Von Willebrands Disease. In addition to mutations causing a loss of platelet binding or other direct haemostatic problems, mutations in VWF can affect the formation of the protein tubules, leading to formation of damaged, poorly functional WPB.

Advances in microscopy and in bioinformatics revealed that WPB size increases in half-micron steps. VWF subunits, "quanta" are brought together in the trans-Golgi where they assemble into organelles with a 10-fold range in length. By manipulating WPB length, we have shown that short WPB are much less efficient at supporting platelet recruitment, and thus initiating primary haemostasis.

We then went on to discover how the cell controls the size of WPB in response to metabolic changes, thereby controlling the haemostatic response to physiological circumstances.

We are now exploring the effect of using human licensed drugs identified by screens to shrink WPB, as a way to counteract excess haemostasis in models of disease.