Thrombin Structural and Functional Determinants as Therapeutic Targets

Abstract

Thrombin is the final serine protease generated during blood coagulation. This enzyme possesses a complex and fascinating structure composed not only by an active site but also by two positively charged patches, called anion binding exosites o simply exosites 1 and 2, as well as several surface loops and a Na+ binding region. These complex structural determinants make of thrombin a highly versatile enzyme with multiple and opposed roles within haemostasis by cleaving different substrates, and interacting with diverse cofactors and inhibitors. However, it is well known that thrombin actions are not limited to haemostasis. Thrombin has also multiple functions or pleiotropic effects, interconnecting coagulation to other systems, including the immune and the nervous system. This review focus on thrombin as therapeutic target of direct thrombin inhibitors, and highlights the pharmacology of anticoagulants in clinical use; including unfractionated heparin, low-molecular-weight heparins as well as lepirudin, desirudin, bivalirudin, argatroban and dabigatran etexilate. Adverse effects, antidotes and monitoring of these anticoagulants are discussed in detail. Finally, we also review recent advances on the development of aptamers as thrombin inhibitors.