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.