Anticoagulants: From chance discovery to structure-based design

Taking a historical perspective, we review the discovery, pharmacology, and clinical evaluation of the old and new anticoagulants that have been approved for clinical use. The drugs are discussed chronologically, starting in the 1880s, and progressing through to 2024. The innovations in technology used to develop novel anticoagulants came in fits and starts and reflected the advances in science and technology over these decades, whereas the shift from anecdote to evidence-based use of anticoagulants was delayed until the principles of epidemiology and biostatistics were introduced into clinical trial design and to the approval process. Hirudin, heparin, and vitamin K antagonists were discovered by chance, and were used clinically before their mechanism of action was elucidated and before their net clinical benefits were evaluated in randomized clinical trials. Subsequent anticoagulants were designed based on a better understanding of the structure and function of coagulation proteins, including antithrombin, thrombin, and factor Xa, and underwent more rigorous preclinical and clinical evaluation before regulatory approval. By simplifying oral anticoagulation, the direct oral anticoagulants have revolutionized anticoagulation care and have enhanced the uptake of anticoagulation, but bleeding has not been eliminated and there is a need for more effective and convenient anticoagulants for thrombosis triggered by the contact pathway of coagulation. The newly developed factor XIa and XIIa inhibitors have the potential to address these unmet clinical needs and are undergoing clinical evaluation for several indications. SIGNIFICANCE STATEMENT: Anticoagulant therapy is the cornerstone of treatment and prevention of thrombosis, which remains a leading cause of morbidity and mortality worldwide. Elucidation of the structure and function of coagulation enzymes, their cofactors, and inhibitors, coupled with advances in structure-based design led to the discovery of more convenient, safer, and more effective anticoagulants that have revolutionized the management of thrombotic disorders.