Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT)， chronic kidney disease， sepsis and diabetes. Loss of the glycocalyx， a thin glycosaminoglycan (GAG)-rich layer on the EC surface， is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins， which are involved in platelet binding to ECs. Once bound， platelets cause thrombus formation and an increased inflammatory response. We have developed a GAG derived， selectin targeting anti-adhesive coating (termed EC-SEAL) consisting of a dermatan sulfate backbone and multiple selectin-binding peptides designed to bind to inflamed endothelium and prevent platelet binding to create a more quiescent endothelial state. Multiple EC-SEAL variants were evaluated and the lead variant was found to preferentially bind to selectin-expressing ECs and smooth muscle cells (SMCs) and inhibit platelet binding and activation in a dose-dependent manner. In an in vivo model of DVT， treatment with the lead variant resulted in reduced thrombus formation. These results indicate that EC-SEAL has promise as a potential therapeutic in the treatment of endothelial dysfunction.