Synthetic and recombinant antithrombin drugs

Abstract

As the final enzyme in the activation of the coagulation system, the serine protease, thrombin, is believed to be an important target for the development of new anticoagulant/antithrombotic drugs. Direct thrombin inhibitors are either derived from natural sources, such as hirudin or are chemically synthesised, such as argatroban. The coupling of hirudin or parts of it with other entities leads to novel agents with different pharmacokinetic and pharmacodynamic characteristics, such as polyethylene glycol (PEG)-hirudin or the hirulogs. Due to the reversible or irreversible inactivation of the enzyme, thrombin inhibitors exert strong anticoagulant effects that can be measured in global clotting assays. Furthermore, these compounds inhibit thrombin-induced platelet reactions and influence other cellular, receptor-mediated actions of thrombin, e.g., on vascular cells. Directly acting thrombin inhibitors prevent blood clotting and are also capable of inhibiting clot-associated thrombin; however, they do not effectively block the further generation of the enzyme. Comprehensive experimental studies suggest that thrombin inhibitors may be effective drugs in a wide range of intravascular thrombus formation, also including the inhibition of vascular restenosis. Recent clinical trials revealed the effectiveness of direct thrombin inhibitors in various thrombotic and cardiovascular indications, but also a tendency to an increased risk of bleeding complications. At present, thrombin inhibitors are the most promising class of drugs for the initial therapy of patients with heparin-induced thrombocytopaenia (HIT) or the heparin-induced thrombocytopaenia and thrombosis syndrome (HITTS). They are also useful for the management of venous thrombosis and for acute ischaemic syndromes as well as for invasive procedures. However, with regard to the long-term outcome, a superiority of thrombin inhibitors over heparin has not yet been demonstrated. Several important issues, such as monitoring, pharmacological antagonism and drug interactions will also play an important role in the development of these new drugs. Further clinical trials are required to confirm the effectiveness of direct thrombin inhibitors in the prophylaxis and treatment of various thromboembolic and cardiovascular disorders.

• anticoagulants
• antithrombotics
• clinical use
• clot-bound thrombin
• haemorrhagic effects
• thrombin generation
• thrombin inhibitors