The role of N-linked glycans in mediating Factor VIII - von Willebrand factor binding and their functional consequences.

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Factor VIII (FVIII) and von Willebrand factor (VWF) are proteins essential for normal blood clotting. They are particularly important because their levels are extremely variable; high levels are associated with an increased tendency to clot and low levels with increased risk of bleeding (affecting approximately 1% of the population). Because they circulate in the blood as a tightly linked complex, they depend on one another for survival and function. Consequently the degree to which they bind to each other is important. Understanding this binding is important for understanding the associated diseases. If we could manipulate this interaction it would be an extremely useful therapeutic tool. The sugar content of VWF has recently emerged as an important factor in determining the structure and function of VWF. We have preliminary evidence that it may affect this important binding between VWF and FVIII. Thus this project will examine the effect of sugars, and other structures, on FVIII-VWF binding. This knowledge will improve our understanding of the associated bleeding disorders, and may help improve existing therapies. In particular it may allow the development of recombinant FVIII and VWF molecules which are more effective, have prolonged survival (meaning fewer injections), fewer side effects and complications.