Project Details
Projekt
Factor Xa inhibitors as regulators of platelet proteom and function
Subject Area
Cardiology, Angiology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 493400536
Catalytic active thrombin (FIIa) takes a center role in linking the plasmatic and cellular coagulation system during hemostasis. Thrombin inhibition by oral available direct thrombin inhibitor upregulates protease activatable receptor (PAR) expression and alters GPIbα- thrombin complexes, leading to increased platelet reactivity. In contrast chronic oral inhibition of the FXa-platelet axis reduce platelet reactivity. In this context we found that factor Xa (FXa) is capable to activate platelet independently from thrombin. Against this background little is known about the effects of a chronic, oral FXa (or FIIa) inhibition. In preliminary work we could show that a chronic inhibition of the FXa- platelet axis leads to reduced infarct sizes in a murine model of myocardial infarction and stroke. As underlying mechanism, we identified an altered platelet proteome yielding an attenuated platelet activation and granula secretion. The main hypothesis of the proposed project is that a chronic oral Inhibition of the platelet- FXa axis leads to a reduced thromboinflammation during ischemic cardiovascular events due to an altered granula secretion. Aim of the project is to investigate effects of a chronic oral FXa inhibition (i) on molecular level (e.g. granula secretion), (ii) in a murine model of myocardial infarction and stroke, (iii) on thrombus composition and patients suffering from ST-elevation myocardial infarction and stroke (only thrombus analysis). In parallel we will compare the effects under chronic FXa with FIIa inhibition. The project is of high clinical relevance given the increasing usage of chronic oral anticoagulation by oral FXa and FIIa inhibitors. Therefore, our findings will help to improve and better individualize patient treatment.
DFG Programme
Research Grants
