Murine cadherin-6 mediates thrombosis in vivo in a platelet-independent manner

Abstract

Background: Platelet adhesion is the critical process mediating stable thrombus formation. Previous reports of cadherin-6 on human platelets have demonstrated its role in platelet aggregation and thrombus formation. Objectives: We aimed to further characterize the importance of cadherin-6 in thrombosis in vivo. Methods: Cadherin-6 platelet expression was evaluated by western blotting, flow cytometry, and immunoprecipitation. Thrombosis was evaluated using the FeCl3 and Rose Bengal carotid artery models in C57Bl6 mice treated with anti–cadherin-6 or IgG and wild-type or Cdh6−/− mice. Platelet function was compared in wild-type and Cdh6−/− mice using tail-clip assays, aggregometry, and flow cytometry. Results: Human platelet expression of cadherin-6 was confirmed at ~3000 copies per platelet. Cdh6−/− mice or those treated with anti–cadherin-6 antibody showed an increased time to occlusion in both thrombosis models. Cadherin-6 was not expressed on mouse platelets, and there were no differences in tail bleeding times, platelet aggregation, or platelet activation in wild-type versus Cdh6−/− mice. Conclusions: Cadherin-6 plays an essential role in thrombosis in vivo. However, cadherin-6 is not expressed on murine platelets. These data are in contrast to human platelets, which express a functional cadherin-6/catenin complex. The essential, platelet-independent role for cadherin-6 in hemostasis may allow it to be an effective and safe therapeutic target.