A short history of anticoagulant therapy.

Anticoagulant therapy has undergone a remarkable evolution over the past century, transforming the prevention and treatment of thromboembolic disease. The accidental discovery of vitamin K antagonists (VKAs) in the 1940s, following investigations of fatal bleeding in cattle fed spoiled sweet clover, led to the identification of dicoumarol and the development of warfarin. Despite limitations in study design, studies from the 1960s onward established the foundations of modern anticoagulation. Subsequent advances refined the dosing and monitoring of heparin and VKAs, while the introduction of weight-based subcutaneous dosing of low molecular weight heparins (LMWH) represented a breakthrough by enabling more predictable, safer, and more convenient parenteral anticoagulation, particularly in the outpatient setting. More recently, direct oral anticoagulants (DOACs) have revolutionized clinical practice as they can be used in fixed doses without routine laboratory monitoring, thereby simplifying oral anticoagulation and are now preferred over VKAs for many indications. Unlike existing anticoagulants which suppress thrombin generation or inhibit factor Xa or thrombin, novel anticoagulants in development selectively target coagulation proteins within the contact activation pathway (such as Factor XI). These novel anticoagulants offer the potential to uncouple bleeding risk from antithrombotic efficacy and may also be effective for conditions in which clotting is driven by the contact activation pathway such as mechanical heart valves, for which DOACs are inadequate. However, their role and clinical indications remain to be defined in ongoing phase III trials.