The landscape of anticoagulant therapy is rapidly changing with the expanding clinical use of direct, non-vitamin K-dependent oral anticoagulants (NOACs) targeting selectively thrombin or coagulation factor Xa. The development of additional drugs directed to FXIa and FVIIa may add additional options for targeted anticoagulant therapy, but how these drugs interfere with the cellular functions of the hemostatic system and differ in this context from standard oral Vitamin K antagonists with global attenuation of pro- and anti-coagulant pathways has not been studied in detail. Initial preclinical evidence indicates that FXa-directed NOACs have unique efficacy in interrupting pro-inflammatory pathways and our results show that cells of the innate immune system synthesize specifically the upstream coagulation factors VII and X and thereby can activate cell autonomously coagulation proteases. The aims of this project are to define how the phenotype of immune cells and their microenvironment is altered by the selective loss of targets for NOACs in comparison to global decreases of all γ-carboxylated coagulation factors under therapy with vitamin K antagonists. We will study mice made genetically deficient in myelo-monocytic cells for FVII, FX, or vitamin K epoxide reductase complex subunit 1 (VKORC1), the target for vitamin K antagonists. We will combine genome wide transcriptome analysis with newly developed bioinformatics tools to define pathways controlled by ectopically synthesized coagulation proteases and capture the dynamics of macrophage phenotypes at baseline and under inflammatory conditions. The identified network markers for drug action enable interrogation of living animals in order to find out how antithrombotic doses of vitamin K antagonists or targeted anticoagulants will interfere with the cellular functions of the hemostatic system in mouse models of atherosclerosis where benefits of NOACs are emerging. This project is exquisitely positioned to interface with the existing platform structure of the CTH and strives to develop statistical bioinformatics approaches and infrastructure in collaboration with the IMBEI that will be of broader applicability for pathway interrogation in epidemiological and clinical programs.