Significance Serine protease inhibitors (SERPINs) regulate vital physiological processes. Considerable research effort has gone into the development of SERPINs as therapeutic agents. One of the development goals is SERPIN modification for improved specificity toward desired target(s). The specificity and potency of SERPINs can be altered by changing their reactive center loop (RCL). Currently, predicting these properties of a RCL sequence is almost impossible. By characterizing 160 α1-antitrypsin RCL variants with single–amino acid substitutions, we developed a SERPIN RCL-based platform that predicts the inhibitory behavior for SERPIN variants with compounded RCL mutations. This platform was applied to design a next-generation SERPIN against activated protein C and provides evidence for its value in the treatment of hemophilia A.