Role of thiol pathways in TF procoagulant regulation

Abstract

The generation of procoagulant Tissue Factor (TF) is crucial for thrombosis. TF contains a surface exposed allosteric disulfide bond that stabilizes the carboxyl-terminal domain involved in ligand interactions with coagulation factors VIIa and X. TF procoagulant activation typically occurs following cellular perturbations that also cause the appearance of procoagulant phosphatidylserine in the outer leaflet of cell membranes. However, thiol modifying agents, without suppressing phosphatidylserine exposure, can prevent TF activation, implicating thiol-disulfide exchange reactions in the regulation of TF procoagulant activity of primary cells. Protein disulfide isomerase (PDI), a regulator of extracellular thiol exchange, is associated with cell surface TF and required for TF-dependent thrombosis in vivo. PDI regulates the thiol-dependent biogenesis of procoagulant microparticles that are released from myeloid cells and smooth muscle cells following activation of the purinergic P2X7 receptor. Genetic deletion of P2X7 signaling attenuates FeCl3-induced carotid artery thrombosis in mice, indicating that TF prothrombotic activity is regulated by specific cell signaling pathways in vivo.