VEGF is an important growth factor in embryonic development and functional maintenance of adult organs. Single allele inactivation of VEGF leads to embryonic lethality and many conditional disruptions show dramatic phenotypes or reduced viabilities. To overcome this burden, a reversible system, which was used in the regulation of VEGF expression and functional studies of many tissues and organs in adult, was developed. VEGF is known for expression in many tissues and high expression in platelets. Repression of VEGF expression showed significant defect in bleeding time and clotting time. In mouse model of LPS-induced blood hypercoagulation, significant reduction of plasma thrombin-antithrombin formation was observed in VEGF repressed mice, and tissues expressed different modes of damages. These results indicate that VEGF regulates coagulation cascade and may affect sepsis. This is the first genetic evidence of direct link between VEGF transcription and coagulation cascade. Studies using this system may help us to find out how VEGF regulates coagulation cascade and provide new strategies in treating coagulation related diseases.