BackgroundInhibition of platelet responsiveness is important for controlling thrombosis. It is well established that platelet-endothelial cell adhesion molecule-1 (PECAM-1) serves as a physiological negative regulator of platelet-collagen interactions. We recently demonstrated that leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a negative regulator of platelet production and reactivity. It is however not known if LAIR-1 and PECAM-1 function in the same or different inhibitory pathways. ObjectiveIn this study, we investigate the role of LAIR-1 alongside PECAM-1 in megakaryocyte development and platelet production, and determine the functional redundancy through characterization of a LAIR-1/PECAM-1 double knockout (DKO) mouse model. ResultsWe show that LAIR-1/PECAM-1 DKO mice exhibit a 17% increase in platelet count. Bone marrow-derived megakaryocytes from all three mouse models had normal ploidy in vitro, suggesting neither LAIR-1 nor PECAM-1 regulate megakaryocyte development. Furthermore, relative to wild-type platelets, platelets derived from LAIR-1, PECAM-1 and DKO mice were equally hyper-responsive to collagen in vitro, indicating that LAIR-1 and PECAM-1 participate in the same inhibitory pathway. Interestingly, DKO mice exhibit normal thrombus formation in vivo, due to DKO mouse platelets lacking the enhanced SFK activation previously shown in platelets from LAIR-1-deficient mice. ConclusionsFindings from this study reveal that LAIR-1 and PECAM-1 act to inhibit GPVI-mediated-platelet activation via the same signaling pathway. Mice lacking LAIR-1 and PECAM-1 do not however exhibit an increase in thrombus formation, despite minor increase in platelet count and reactivity to collagen. This study adds to the growing evidence that ITIM-containing receptors are important regulators of platelet count and function.