From ancient leech to direct thrombin inhibitors and beyond: New from old.

Medicinal leeches have been used in health care since before written history, with widely varying popularity over the centuries. Nowadays, medicinal leech therapy is mainly used in plastic and reconstructive microsurgery, with new interesting potential therapeutic applications in many other diseases. The leech's best-known salivary product, hirudin - one of the most powerful natural anticoagulants - was the only remedy to prevent blood clotting until the discovery of heparin. Starting from hirudin, pharmacological research succeeded in developing new anticoagulants, which represent a cornerstone of prevention and treatment of thromboembolic disease. While we are perhaps on the threshold of a new era of anticoagulation, with the development of FXI and XII inhibitors and direct reversible covalent thrombin inhibitors, which promise to achieve effective anticoagulation without bleeding risk. This review retraces the intriguing journey of these drugs in cardiovascular disease, highlighting the fil rouge that links the ancient leech to the current and oncoming antithrombotic therapy. We think that knowledge of the past is key to understanding and appreciating the present and to seize future opportunities.