Search

Purpose of Review: The present review will provide an overview of several recent advances in the field of vascular thiol isomerase function., Recent Findings: The initial observation that protein disulfide isomerase (PDI) functions in thrombus formation occurred approximately a decade ago. At the time, there was little understanding regarding how PDI or other vascular thiol isomerases contribute to thrombosis. Although this problem is far from solved, the past few years have seen substantial progress in several areas that will be reviewed in this article. The relationship between PDI structure and its function has been investigated and applied to identify domains of PDI that are critical for thrombus formation. The mechanisms that direct thiol isomerase storage and release from platelets and endothelium have been studied. New techniques including kinetic-based trapping have identified substrates that vascular thiol isomerases modify during thrombus formation. Novel inhibitors of thiol isomerases have been developed that are useful both as tools to interrogate PDI function and as potential therapeutics. Human studies have been conducted to measure circulating PDI in disease states and evaluate the effect of oral administration of a PDI inhibitor on ex-vivo thrombin generation., Summary: Current findings indicate that thiol isomerase-mediated disulfide bond modification in receptors and plasma proteins is an important layer of control of thrombosis and vascular function more generally.

Purpose of Review: This review will provide an overview of several recent advances in the field of platelet granule biology., Recent Findings: The past few years have witnessed a substantial evolution in our knowledge of platelet granules based on a number of discoveries and new experimental approaches. This article will cover recent studies in five areas. First, the vesicle trafficking pathways responsible for α-granule formation are beginning to be assembled as a result of the characterization of patients with α-granule deficiencies. Second, a revision of our understanding of which SNARE isoforms mediate platelet granule exocytosis has occurred following evaluation of patients with defects in platelet granule exocytosis and the generation of mice lacking specific SNAREs. Third, investigators have begun to establish how cargos are segregated among α-granules and determine whether or not different α-granule subpopulations exist in platelets. Fourth, an unanticipated role for α-granules in platelet spreading has been identified. Fifth, single-cell amperometry has revealed secretion kinetics with submillisecond temporal resolution enabling evaluation of the molecular control of the platelet fusion pore., Summary: These new observations reveal a previously unappreciated complexity to platelet granule formation and exocytosis and challenge our earlier notions of how these granules are organized within platelets and contribute to the multitude of physiological activities in which platelets function.