Project 15

primary: Prof. Dr. Hugo ten Cate/Dr. Paola van der Meijden/Dr. Henri Spronk (CARIM), secondary: Prof. Dr. Philipp Wild (CTH), tertiary, Dr. Gillian Mimnagh (2M)

CARIM (Maastricht, Netherlands), CTH (Mainz, Germany), 2M (Valkenswaard, Netherlands)

Universities of Maastricht and Mainz

Hypercoagulability, the tendency for thrombosis as a result of certain inherited and/or acquired molecular defects, and cell signalling by protease-activated receptors contribute to the risk of atherothrombotic events and are likely linked to venous thrombosis and recurrence. The consequences of hypercoagulability may be different depending on the population background (genetic and phenotypic) and the cardiovascular risk profile. We hypothesize that hypercoagulability aggravates atherosclerosis, contributes to plaque instability, and promotes atherothrombosis in patients at increased cardiovascular risk as well as in healthy subjects.

ESR15 will assess associations between hypercoagulability and inflammation in plasma from patients with thrombotic diseases, in comparison to healthy subjects. Associations are determined by targeted assays, a novel point-of-care platelet counter (in collaboration with 2M), in situ platelet activity and integral coagulation assays. ESR15 will combine state-of-the-art genetics and laboratory testing with modern cardiovascular phenotyping. These phenotypes are being collected in the SIHD cohort study at CARIM (patients with severe but stable coronary artery disease). ESR15 will assess the plasma coagulation status and compare this with other cardiovascular properties. Patient plasma samples with low/high thrombotic and/or inflammatory propensities will be used to evaluate the therapeutic potential of new pathway inhibitors, identified in the consortium. At the CTH, the results will be compared with data from the population-based Gutenberg Health Study (GSH), regarding risk associations between hypercoagulability, inflammation markers, cardiovascular complications and coagulation phenotypes, linked to genomics analyses. Additional measurements in a sub-cohort are: (i) platelet count and activity assays; (ii) coagulation protease activity measurements by Multiplex assays for coagulation protease-inactivation complexes; (iii) multi-marker inflammation and vascular activation array; (iv) integrated coagulation testing including thrombin generation and thromboelastography. At the non-academic partner 2M engineering, ESR15 will participate in the development and use of the prototype point-of-care test for assessing platelet reactivity.

• Eggebrecht L, Prochaska JH, Schulz A, Arnold N, et al. Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population-Based Gutenberg Health Study. J Am Heart Assoc. 2018;7(17):e008650
• Van der Meijden PEJ, Heemskerk JWM. Platelet biology and functions: new concepts and future clinical perspectives. Nat Rev Cardiol. 2018 Nov 14. doi: 10.1038/s41569-018-0110-0.
• Borissoff JI, Spronk HM, ten Cate H. The hemostatic system as a modulator of atherosclerosis. N Engl J Med. 2011 May 5;364(18):1746-60.