Malignant tumor cells leave their original site and migrate via the vascular system to settle up metastases. A critical step in this process is extravasation, the ability of circulating tumor cells to adhere to and pass the endothelium as the physiological barrier between blood and tissue. This multistep process requires efficient communication between tumor cells and endothelium. In the present study, we analyzed melanoma-derived soluble factors interacting with endothelial thrombin receptor (PAR1) the principal mediator of endothelial cell activation. Soluble MMP-1 canonically cleaves endothelial PAR1 receptors displayed by calcium fluxes and acute release of von Willebrand factor (+230%, n = 12), a core protein for the initiation of thrombus formation. We further observe, that melanoma cell lines (A375, WM9, A7) secrete soluble agonists that induce an acute prothromotic, proinflammatory and cell adhesive endothelial surface. By specific antagonism of endothelial PAR1 and melanoma derived soluble MMP-1 we demonstrate a successful interference in the process of tumor derived initiation of thrombosis and cell adhesion. These findings demonstrate a so far undescribed pathway of tumor-endothelial crosstalk via an intravascular MMP1/PAR1 axis and might serve as a future target for therapeutical prevention of tumor-derived thrombosis.