Abstract 355: Autologous Cleavage of the GPIbalpha Receptor Promotes Platelet Dysfunction Following Trauma
Background: Trauma is the most common cause of death in individuals 0-50 years of age and is responsible for more year of life lost than cancer, heart disease, and stroke combined. One quarter of all trauma patients experience some degree of prolonged hemorrhage due to impaired blood clotting, or trauma-induced coagulopathy (TIC). Protein C activation and hyperfibrinolysis have been proposed as key drivers in developing TIC. While primary hemostasis is mediated by von Willebrand factor (vWF) binding to the GPIbα receptor on the platelet surface, tethering them to damaged endothelium. Whether this interaction is altered in TIC remains unexplored. Data from our laboratory has previously shown a significant reduction in platelet-vWF adhesion over time following injury as measured by platelet aggregation response to ristocetin. The aim of this study was to determine the mechanisms behind defective platelet-vWF adhesion in trauma patients.
Methods and Results: We obtained samples from 25 transfused trauma patients on admission and at 3, 5, 12, 24, and 120 hours later. Expression of the GPIbα receptor on the platelet surface and circulating in the plasma was measured by flow cytometry and western blot, respectively. We observed a time-dependent decrease in platelet bound GPIbα receptor expression (p=0.01) which was accompanied by up to a 6-fold increase in GPIbα shed into the plasma. Due to its role in proteolytic regulation of platelet aggregation through cleavage of GPIbα, we then measured expression of tumor necrosis factor-α converting enzyme (TACE). Membrane-bound TACE was analyzed by flow cytometry on platelets and leukocytes. We found a significant increase in platelet-derived TACE compared to healthy controls (p<0.01) and over time in trauma patients (p<0.05). The highest expression of platelet TACE corresponded to the time at which we observed the lowest GPIbα expression and lowest platelet-vWF adhesion in these patients.
Conclusions: These data suggest that upregulation of platelet-derived TACE results in increased proteolytic cleavage of the GPIbα receptor and reduced platelet-vWF adhesion. These results have important implications for the use of TACE inhibitors to promote effective primary hemostasis in severely injured patients.
- © 2013 by American Heart Association, Inc.