Background: Platelet activation results in platelet aggregation and the secretion of granules, which contain a variety of constituents including nonprotein molecules, adhesive proteins and hydrolases. The platelet-derived supernatant (PDS), which contains these granules, is known to trigger the activation of endothelium and chemotaxis of monocytes. Methods and Results: PDS derived from collagen-activated platelets stimulated human umbilical vein endothelial cell (HUVEC) migration and invasion, as measured through the use of a Boyden chamber. This collagen-induced PDS also triggered integrin α<sub>v</sub>β<sub>3</sub> upregulation in HUVECs. The inclusion of a neutralizing antibody to platelet-derived growth factor (PDGF)-B abolished HUVEC migration/invasion and integrin α<sub>v</sub>β<sub>3</sub> upregulation, showing that PDGF-AB mediates the proangiogenic effects of collagen-activated PDS. Saxatilin, a snake venom disintegrin known to interrupt platelet aggregation by antagonizing integrin α<sub>IIb</sub>β<sub>3</sub>, inhibited the collagen-induced platelet activation and abolished the angiogenic properties of PDS. Saxatilin also inhibited the collagen-induced phosphorylation of Syk, a key mediator of inside-out signaling in platelet activation. Conclusion: Saxatilin inhibits platelet activation, platelet PDGF-AB release as well as subsequent endothelial cell migration and invasion.