Studies of the variable expressivity of the factor V Leiden mutation

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The factor V Leiden mutation (FVL) is the most common thrombophilic risk factor in the Caucasian population. Our group has recently shown that stimulation of thrombin formation in vivo, using recombinant activated factor VII (rFVIIa), resulted in significantly higher plasma concentrations of activated protein C (APC) in FVL carriers than in non-FVL carriers. Furthermore, there was a significant difference between the APC response of FVL carriers with a history of thrombosis and those without. The aim of this research project is to identify the underlying causes of these observed differences. In order to achieve this objective, we will systematically analyze various mechanisms, that regulate APC formation, including the thrombin formation capacity, the endothelial APC generation potential of the endothelium, and APC inhibition kinetics. Using both the patients’ plasma and cells, data will be obtained in the purified system and in the cell culture model, that will be directly compared with already available in vivo data to identify inter-individual differences in the reactivity of the APC system. Causal characterization of the different APC response phenotypes would provide a basis to develop biomarkers for the assessment of the thrombophilic potential of FVL, which would substantially improve treatment of FVL patients.