Dr James O'Donnell

Figure 1 Activation of protein C on the surface of human endothelial cells.

(a) Von Willebrand factor Von Willebrand factor (VWF) is a multimeric plasma glycoprotein. It plays an important role in mediating the interaction between platelets and the blood vessel wall, as well as serving as a carrier molecule for procoagulant factor VIII (FVIII). Both functions are essential for normal haemostasis. Plasma VWF concentrations varies over a wide range in the normal population. This variation is of direct clinical relevance: deficiency of VWF is responsible for the most common inherited bleeding tendency (von Willebrand disease), while elevated VWF levels are associated with increased risk of coronary heart disease, cerebral artery disease, and venous thromboembolism. We are interested in determining the factors which determine the variation in plasma VWF levels, principally, whether carbohydrate structures on the surface of the VWF molecule play a central role in defining VWF activity.

(b) Protein C anticoagulant and antiinflammatroy pathway Another major focus of our current research programme involves examining the cross-talk between blood coagulation and inflammation in vivo. The only effective therapy currently available for patients admitted to Intensive Care Units with severe sepsis is a recombinant anticoagulant protein called Activated Protein C (APC). Interestingly, studies have shown that the beneficial effects of APC in such patients are not entirely attributable to the anticoagulant effects of APC. Rather, APC can also directly modulate the inflammatory response. Our laboratory is involved in determining the molecular and cellular basis through which the anticoagulant and anti-inflammatory effects of APC are mediated.

Figure 2 Factor VIII structure function analysis:- surface electrostatic potential of native factor VIII A2 domain and the triple Ala mutant at factor VIII 489-3A.

(c) Factor VIII The plasma glycoprotein factor VIII (FVIII) is a central component of normal haemostasis. Deficiency of FVIII results in the bleeding disorder haemophilia A, in contrast elevated FVIII levels are associated with increased risk of thrombosis. The importance of FVIII lies in its role as cofactor to the serine protease factor IXa in the conversion of the zymogen factor X to its activated form. Factor Xa in turn catalyses thrombin generation and formation of a fibrin clot. Factor VIIIa interaction with factor IXa increases the enzyme's catalytic activity by two orders of magnitude. Our research focuses on the nature of the interaction of FVIIIa with FIXa on the phospholipid surface. We are examining the role of various domains of FVIIIa in the protein's light chain in contributing to both the interaction with FIXa and phospholipid surface. The Haemostasis Research group has been successful in obtaining in excess of €2 million in competitive grant awards over the past year. These include grants from:

• Science Foundation Ireland – President of Ireland Young Researcher Award
• Health Research Board Ireland
• Irish Heart Foundation
• The Wellcome Trust

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