The integrity of the vascular system is of prime importance for survival. Therefore, several emergency and repair systems safeguard the circulatory system. Multiple processes jointly limit vascular damage and blood loss. In this article, the authors focus on the protein C anticoagulant pathway and the role of activated protein C resistance in thrombotic disease, and they discuss the involvement in thrombosis of mutations other than the Arg506Gln mutation in the gene encoding for factor V.