Abstract 486: Platelet ITAM Signaling is Critical for Maintenance of Vascular Integrity in Inflammation

Abstract

Blood platelets, long recognized for their importance in primary hemostasis, have recently been identified as critical regulators of vascular integrity during inflammation and cancer. Interestingly, the contribution of platelets to the maintenance of vascular integrity in in[[Unable to Display Character: fl]]ammation seems to be independent of their ability to form a clot. However, the underlying molecular mechanism remains unknown. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling but not G protein-coupled receptor (GPCR) signaling is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a novel protocol for the adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from wild-type platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of CLEC-2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into thrombocytopenic mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel anti-thrombotic agents directed towards the ITAM signaling pathway.