Structural Basis of Molecular Recognition in Haemostasis

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Blood coagulation is a complex process under tight regulatory control. In response to blood vessel rupture, a cascade of events leads to the rapid and localised deposition of a blood clot which staunches the flow of blood from the wound. Bleeding results if the clotting response is insufficiently rapid and robust, however, if coagulation is not limited, the clot will over-grow resulting in thrombosis. This ‘haemostatic balance‘ is critical for human health, and understanding the regulatory mechanisms is crucial for the diagnosis, prevention and treatment of thrombosis, the leading cause of morbidity and mortality in the industrialised world. The goal of this study is to understand the factors which tip blood clotting from its precarious balance to cause diseases such as haemophilia, deep vein thrombosis, pulmonary embolism, heart attack, and stroke. This will be achieved by obtaining molecular pictures of the multi-protein complexes which are formed at critical stages of blood coagulation, primarily by using the technique of X-ray crystallography. Such detailed pictures will help determine why certain people are more susceptible to coagulation disorders, and will underpin the development of novel therapies to prevent and treat thrombosis.