Leeches to hirulogs and other thrombin-directed antithrombotics.
Leeches have been used for various medicinal purposes since before written history. Bloodletting and leeching declined with the advent of modern medicine. Nevertheless, the European medicinal leech has made a comeback in reattachment and plastic surgery. The antithrombotic substance of this leech is the small protein, hirudin, which has recently been cloned and advanced as an antithrombotic. From speculating how hirudin interacted with thrombin and before knowledge of the crystallographic structures of hirudin-thrombin complexes, the bridge-binding double-ligand concept was born and led to the highly specific thrombin inhibitors of the hirulog class. Like heparin, hirulogs and recombinant hirudins are not orally active but should fill needs where heparin and its derivatives have shortcomings. On the other hand, they most likely will be supplanted by small-molecule thrombin inhibitors when sufficiently specific and nontoxic ones are found. Other approaches to antithrombotic therapy include modulating cellular functions of thrombin. Because thrombin has central bioregulatory functions in thrombosis and hemostasis, as well as wound healing, it is an attractive target for antithrombotic intervention.