An unexpected link between angiotensinogen and thrombin

► Lamprey angiotensinogen is an effective thrombin inhibitor, in contrast to all orthologs. ► Heparin enhances thrombin inhibition >800-fold with a bell-shaped dose-response curve. ► Dermatan sulfate stimulates thrombin/lamprey angiotensinogen interaction differently. ► Angiotensinogen and heparin cofactor II are derived from a common ancestor. ► An evolutionary scenario of thrombin control by serpins in vertebrates is presented.