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The current review discusses the role of coagulation in microcirculatory abnormalities and whether anticoagulants may improve microvascular perfusion.Microvascular alterations frequently occur in sepsis and ischemia–reperfusion injury. These alterations are due to endothelial dysfunction and interaction of endothelium and circulating cells. Although the activation of coagulation has been extensively shown to occur in these conditions, microthrombosis seems not to be a predominant factor. Nevertheless, the interplay between coagulation, inflammation and the endothelium seems to favor microvascular dysfunction. Several agents with anticoagulant properties, especially activated protein C and antithrombin, improve the diseased microcirculation, but these agents have pleiotropic effects, and it seems unlikely that these beneficial effects are linked to direct inhibition of coagulation. Current evidence does not support the use of pure anticoagulant agents to improve microvascular perfusion.The activation of coagulation may play an indirect role in microvascular dysfunction, through interplay with endothelium and inflammation.