Thrombin plays a role in the generation of the thrombus and coagulation. It is the most potent biological activator of platelets and is involved in cell migration, activation of the vascular epithelium and in stabilization of the clot.

Thrombin inhibitors were developed after the crystalline structure of thrombin was identified. Thrombin inhibitors act at particular sites on the thrombin molecule. These sites are the active site, fibrinogen exosite and the heparin-binding site. The active site is located in a pocket within the molecule. This site is responsible for most of the proteolytic activity. The fibrinogen binding exosite is responsible for platelet activation. It is also the site where substrates are tethered so they can be cleaved by the active site. The heparin-binding site is the place where heparin binds to the thrombin molecule.

Heparin is often used as an anticoagulant. Heparin has several limitations including variable bioavailability, increases in affinity of thrombin for fibrin, and stimulation of platelet aggregation. Because of these limitations, alternative drugs such as thrombin antagonists were developed.

2 classes of thrombin antagonists are available: bivalent antagonists and monovalent or univalent antagonists. Univalent antagonists are small molecules that sit in the active site and block the access of substrates to this site. Argatroban is a typical drug in this class.

Bivalent antagonists are larger molecules whose N-terminus sits over the active site and the carboxyterminus fits over the exosite. The bivalent antagonist prevents access to both of these sites. Herudin is the prototypic bivalent antagonist. It is the most potent and binds with the highest affinity.

The advantages of thrombin antagonists are predictable bioavailability, predictable anti-coagulant responses, no known pro-coagulation effects, no rebound, and more effective and consistent penetration of the thrombus.

Clinical trials have reported safety concerns with herudin and include major bleeding and a narrow therapeutic window. In contrast, univalent compounds are associated with fewer acute ischemic events and a reduction in bleeding complications. As a result, Dr. Kleiman concluded univalent compounds are safer than heparin. Combination thrombolytic therapy using a fibrinolytic with a thrombin antagonist has not proven effective, and is not recommended.