Thrombosis can manifest as sudden death, acute coronary syndromes (ACS), secondary effects to coronary atherosclerosis, postoperative deep vein thrombosis (DVT), activated protein C deficiency and malignancy among others disorders (Gurm & Bhatt 2005). Because of this central role that thrombosis plays in cardiovascular disease, the need to develop thrombin inhibitors is integral as anti-thrombotic pharmacotherapy.
When the endothelial lining of veins or arteries are injured, subendothelial matrix proteins such as collagen and von Willebrand factor are released making them vulnerable to platelets. These combination will be activated to produce vasoactive and procoagulant substances which then aggregates. These simultaneous activation intiates the coagulation cascade that will derive thrombin from the cleavage of prothrombin (Gurm & Bhatt 2005). The sequence is repeated as thrombin is a potent vasoconstrictor and platelet aggregant, encouraging more platelets to the site of vascular injury (Bar-Shavit et al 1983). Thrombin also catalyses the changes of fibrinogen to fibrin, which then undergoes cross-links forming thrombus.
Antithrombin agents inhibits thrombin action by binding to three sites in the serine protease; the catalytic site, exosite-1 and exosite-2 (Stubbs & Bode 1993). There are primarily four types of antithrombotic drugs; direct thrombin inhibitors (DTIs), indirect thrombin inhibitors, thrombin-generation inhibitors, and recombinant endogenous antocoagulants (Gurm & Bhatt 2005). Currently the commonly used antithrombotic agent is unfractioned heparin (UFH), a type of indirect thrombin inhibitor. There are a number of downsides in the use of UFH that brings on the need to focus on direct thrombin inhibitors such as bivalirudin, hirudin and argatroban that are clinically available as possible replacements.
Bivalirudin for percutaneous coronary intervention (PCI) has lower periprocedural non-Q-wave myocardial infarction and major creatine kinase (CK)-MB elevation compared to heparin (Wolfram et al 2003). Bivalirudin when used for preventing perinterventional ischemic events also has less incidences of major bleeding (Bittl et al 2003). This is because bivalirudin directly affects thrombus and clot-bound thrombin. Bivalirudin unlike UFH is not inactivated by large amounts of platelet factor IV that are released during plaque rupture (Weitz & Buller 2002). Hirudin, a 65 amino acid peptide specific for thrombin is used for patients with heparin-induced thrombocytopenia (HIT) (Nowak et al 1992). Argatroban, a synthetic competitive inhibitor of thrombin, is a heterocyclic peptide that binds near the catalytic site. Agratroban is more effective than hirudin because of its smaller size and its capability to neutralize clot-bound thrombin (Walenga 2004). It also has a short half-life and is primarily metabolized in the liver.
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