Project 14

primary: Prof. Dr. Philipp Wild (CTH), secondary: Dr. Henri Spronk/Prof. Dr. Hugo ten Cate (CARIM), Dr. Stefan Heitmeier (Bayer)

CTH (Mainz, Germany), CARIM (Maastricht, Netherlands), Bayer (Wuppertal, Germany)

Universities of Mainz and Maastricht

The Gutenberg Health Study (GHS) in Mainz is a powerful population-based infrastructure that addresses determinants of thrombo-inflammation linked to cardiovascular disease and venous thrombo-embolism in the young. Such longitudinal studies with large population cohorts are needed for the diagnosis of early stages of venous thrombosis, linked to altered coagulation and inflammation. Our hypothesis is that the GHS (15,010 subjects) can uncover new mechanisms of thrombosis by state-of-the-art molecular/subclinical profiling and by integrating multi-dimensional datasets in a bioinformatics approach.

ESR14 will integrate multi-faceted data (proteomics, thrombin generation, genetics, clinical data) from the unique, large bio-database of the GHS to identify intermediate phenotypes of venous thrombo-inflammatory disorders. This will be achieved by comparing the prothrombotic state and the broad inflammatory profile. For data analysis and interpretation, ESR14 will be in continuous interaction with ESR13 and ESR15. ESR14 will perform a comprehensive, pathway-integrating multi-dimensional modelling of information on the modifying role of genetic variability in relation to protein profiling. ESR14 will complete the population-based work by adding information of already available bio-databases from individuals with acute venous thromboembolism (VTEval and FOCUS-Bioseq studies: 1,200 subjects). During the time at Bayer, ESR14 will acquire state-of-the-art expertise in analysing large datasets and get expert-insights into new analytical methodology. To link the population-based analyses to mechanistic insights, ESR14 will employ in-silico models of thrombin generation to better comprehend and analyze lab data from an endothelial cell-based thrombin generation assay, allowing the modelling of alternative thrombo-inflammation pathways. Forward translational insight will be obtained by determining in vivo, in vitro, and in silico effects of distinct types of anticoagulants, thus, mimicking common antithrombotics prescribed to individuals with venous thromboembolism. Herein, ESR14 will also collaborate with ESR15 to develop mechanistic models of thrombin generation and to quantify the effect of anticoagulants.

• Panova-Noeva M, Schulz A, Spronk HM, et al. Clinical Determinants of Thrombin Generation Measured in Presence and Absence of Platelets-Results from the Gutenberg Health Study. Thromb Haemost. 2018 May;118(5):873-882.
• Geenen IL, Post MJ, Molin DG, et al. Coagulation on endothelial cells: the underexposed part of Virchow's Triad. Thromb Haemost. 2012 Nov;108(5):863-71.
• Prochaska JH, Frank B, Nagler M, et al. Age-related diagnostic value of D-dimer testing and the role of inflammation in patients with suspected deep vein thrombosis. Sci Rep. 2017 Jul 4;7(1):4591