An Aptamer‐Based EXACT Anticoagulant as a Sustainable, Animal‐Free Alternative to Unfractionated Heparin

Abstract Unfractionated heparin (UFH), designated as an essential medicine by the World Health Organization (WHO), is indispensable in cardiac surgery and various clinical applications. However, its production depends on the farming of over a billion large animals annually, posing sustainability challenges, especially amidst increasing efforts to mitigate greenhouse gas (GHG) emissions by reducing animal farming. The rising demand for UFH has outpaced its supply, and previous attempts to develop synthetic alternatives have fallen short because of their limited potency and reversibility. Here, HD1‐12dmA‐DAB is presented, a novel synthetic anticoagulant developed through chemical conjugation of a thrombin exosite‐binding aptamer (HD1) with a thrombin active‐site inhibitor (dabigatran). By optimizing dual‐site synergistic binding, HD1‐12dmA‐DAB achieves an enhancement of over three orders of magnitude in thrombin‐binding affinity and specificity compared to HD1 alone. It also demonstrates superior plasma stability and anticoagulant efficacy comparable to UFH, as validated in in vitro, in vivo, and ex vivo clotting models. This breakthrough highlights a promising step toward a sustainable, animal‐free alternative to UFH, addressing the growing clinical demand and advancing environmental sustainability objectives.