Initiation of Thrombus Formation: Novel Role for Thiol Isomerases

Abstract

A fundamental component of protein biosynthesis is the intracellular generation or isomerization of disulfide bonds by thiol isomerases. Nature has apparently borrowed, or more accurately, hijacked this enzymatic machinery to regulate the extracellular initiation of thrombus formation in injured blood vessels. Protein disulfide isomerase, a prototypic thiol isomerase, is of critical import during in vivo arterial thrombus formation. This enzyme is secreted by the stimulated endothelium and activated platelets and is captured within the growing thrombus by b3 integrins, specifically aIIbb3 on platelets and avb3 on the endothelium. Inhibition of PDI blocks both platelet thrombus formation by preventing integrin activation and fibrin generation by preventing the expression of tissue factor activity. High throughput screening of chemical libraries has identified a series of flavonoids, including quercetin, isoquercetin and quercetin rutinoside, that are potent low molecular weight inhibitors of PDI in vitro. ERp5, a PDI-like thiol isomerase, is similarly secreted by platelets and plays a role in thrombus formation in vivo. Low molecular weight thiol isomerase inhibitors block platelet thrombus formation and fibrin generation in vivo and offer a novel target for anti-thrombotic therapy. The precise mechanism by which thiol isomerases control thrombus initiation remains to be unraveled.