Compositions and methods are disclosed that relate to novel plasmin-inhibiting polypeptides that are structural variants of a human TFPI-2 Kunitz-type proteinase first inhibitor domain (KD1). The polypeptides are potent plasmin inhibitors and in certain embodiments have anti-fibrinolytic activity and/or decreased anti-coagulation activity relative to wild-type TFPI-2 KD1 and are not highly immunogenic. The plasmin-inhibiting polypeptides will find uses as anti-cancer agents, as antifibrinolytic agents, as protease inhibitors, and in other contexts.
