Coronary thrombosis causing acute myocardial infarction (MI) is driven by pro-coagulant activity on circulating monocytes that by expression of tissue factor (TF) forming a complex with FVIIa for FXa generation significantly contributes to multifaceted intravascular cell activation in immunothrombosis. Targeting coagulation factors and their receptors may be beneficial in MI, but the potential of targeting infiltrating myeloid cell derived TF signaling to the transforming growth factor b1 (TGF-b1) dependent cardiac remodeling has not been explored.

We identified a pro-fibrotic phospho-proteomic signature in the Mitogen activated protein kinase (MAPK) pathway in human ischemic myocardium isolated from end the stage of heart failure patients. In a murine model of permanent myocardial infarction (MI), we found that TGF-b1 dependent cardiac fibrosis and heart failure is depended on extracellular signal-regulated kinases (ERK) and was blockable by the mitogen-activated extracellular signal-regulated kinases (MEK) inhibitor trametinib in vivo. Further experiments on myeloid specific tissue factor (TF) deleted mice revealed, MAPK activation in MI requires myeloid cell specific signaling linked to tissue factor cytoplasmic tail (TF-CT) regulates pro-oxidant NADPH oxidase leading to pro-fibrotic TGF-b1 activation. 

We established TF-CT phosphorylation in circulating monocytes of patients with subacute MI as potential thrombo-inflammatory biomarker to indicate excess risk of ischemic heart failure (IHF) which is suitable for patient selection to receive TF inhibitor therapy. We conclude, that exploitation of particular hetrotypic functions of coagulation proteases shutting down the MAPK/TGF-b1 pathway may prevent detrimental sequels of MI.