The pharmacologic evolution of anticoagulants: From serendipity to precision therapy

Abstract

Anticoagulant therapy is the cornerstone of thrombosis prevention and treatment. It has a rich history that began with the chance discovery of hirudin in leech saliva in the late 19th century. This early finding laid the groundwork for subsequent breakthroughs, including the isolation of heparin from canine liver by Jay McLean in 1916. Heparin, first used clinically in the 1930s, marked the beginning of a new era in anticoagulation, albeit with significant limitations, such as the need for continuous laboratory monitoring and dose adjustments. Chan et al.(2025) chronicle the transformative journey of anticoagulant therapy. This is a field that has indeed traversed centuries, from serendipitous discoveries to meticulous, structurebased design. In their manuscript, the authors provide a narrative that is a luminous testament to human ingenuity and the relentless pursuit of scientific advancement. The coagulation system is a rather delicately woven tapestry. Its cascade is a series of intricately coordinated reactions involving plasma proteins and blood cells. It culminates in the formation of an insoluble clot. This process is modulated by multiple inhibitory pathways, including the protein C anticoagulant pathway, tissue factor pathway inhibitor, and antithrombin. The highly orchestrated balance between procoagulant and anticoagulant forces is critical for maintaining vascular homeostasis and hemostasis. Disruptions in this balance can lead to thrombotic or bleeding disorders, underscoring the importance of targeted anticoagulant therapy. The mechanism of heparin’s action, closely related to the serine protease inhibitor antithrombin, was elucidated over several decades. It was indeed a pivotal understanding that pinpointed the complex interplay between heparin, antithrombin, and various coagulation enzymes. The purification and characterization of antithrombin by Abildgaard in 1968, and the subsequent elucidation of the heparin-antithrombin interaction by Rosenberg and Lindahl further solidified our comprehension of this anticoagulant’s mode of action. The advent of low molecular weight heparin in the late 20th century represented a significant milestone. By shortening the chains of heparin, molecular weight heparin offered reduced variability in dose response. This allowed for subcutaneous administration without the necessity for laboratory monitoring. Indeed, such innovation was to become a forerunner of the precision and relative ease that would become hallmarks of modern anticoagulant therapy.