Oral
anticoagulant therapy has changed by clinical evidence that
coagulation factor Xa (FXa) can be safely and effectively targeted for thromboprophylaxis. Because thrombotic and thrombo-inflammatory diseases are frequently caused by excessive activation of the
tissue factor (TF) pathway, activation of FX by the TF-FVIIa complex is of central importance for understanding the roles of FXa in
thrombosis and hemostasis and functions beyond blood coagulation. Recent data showed that the nascent product FXa associated with TF-FVIIa not only supports
hemostatic cofactor VIII activation, but also broadly influences immune reactions in
inflammation,
cancer, and autoimmunity. These signaling functions of FXa are mediated through
protease activated receptor (PAR) cleavage and PAR2 activation occurs in extravascular environments specifically by macrophage synthesized FX. Cell autonomous FXa-PAR2 signaling is a mechanism for
tumor-promoting macrophage polarization in the tumor microenvironment and tissue penetrance of oral FXa inhibitors favors the reprogramming of tumor-associated macrophages for non-
coagulant therapeutic benefit. It is necessary to decipher the distinct functions of
coagulation factors synthesized by the liver for circulation in blood versus those synthesized by extrahepatic immune cells for activity in tissue milieus. This research will lead to a better understanding of the broader roles of FXa as a central regulator of immune and hematopoietic systems.