Platelets play critical roles in thrombosis, inflammation, and wound healing, which are essential in response to trauma. These processes are primarily driven through the immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2). This study aimed to investigate; (i) the effects of Alarmins released following trauma on platelet reactivity and the mechanisms involved; (ii) establish whether soluble GPVI (sGPVI), a platelet activation marker is elevated in trauma and other inflammatory conditions; (iii) determine whether the CLEC-2 ligand, podoplanin, is elevated in inflammatory conditions and (iv) establishing the role of GPVI and platelets in cutaneous wound healing. The nuclear-related Alarmin, histones, induced robust platelet activation both in vitro and in vivo. Histone-induced platelet activation was mediated through GPVI in vitro However, this pathway was found not to underlie histone-induced lowering of platelet count in vivo and is most likely to result from mediators released following vascular damage. GPVI shedding was shown to be induced following activation by thrombin, through a pathway dependent on fibrin generation. sGPVI was found to be a marker for platelet activation during a variety of inflammatory disorders, notably in association with sepsis. Furthermore, GPVI shedding reflects platelet activation by collagen and potentially thrombin-induced fibrin generation.