In healthy conditions, layilin colocalizes with integrin αIIbβ3, detects HA of the glycocalyx, and mitigates Rac1/p21–activated kinase 1 (PAK-1) signaling in platelets, preventing activation and granule secretion. Under inflammatory conditions in patients with IBD with altered vascular glycocalyx and reduced layilin expression, platelets react to low concentrations of thrombin and collagen with shape change, P-selectin presentation, increased integrin αIIbβ3 affinity to matrix proteins, and granule secretion. Professional illustration by Patrick Lane, ScEYEnce Studios.