Abstract: The presently disclosed subject matter provides a mechanism in which DVTs form when reduced muscular activity results in loss of oscillatory shear-dependent transcriptional and ant-thrombotic phenotypes in peri-valvular venous endothelial cells. Endothelial cells surrounding the venous valve, where DVTs originate, experience oscillatory shear forces in response to muscular activity. Peri-valvular venous endothelial cells express high levels of FOXC2 and PROX1, transcription factors known to be activated by oscillatory shear stress, exhibit an anti-thrombotic phenotype characterized by low levels of the procoagulant proteins von Willebrands Factor (vWF), P-selectin and intercellular adhesion molecule 1 (ICAM1), high levels of the anticoagulant proteins thrombomodulin (THBD), endothelial protein C receptor (EPCR) and tissue factor pathway inhibitor (TFPI), and resistance to thrombin-induced clot formation.