Anticoagulants direct thrombin inhibitors

Activated partial thromboplastin time aPTT is performed by adding calcium phospholipids and kaolin to citrated blood and measures the time required for a fibrin clot to form. In this manner, aPTT measures the activity of intrinsic and common pathways. Prolongation of aPTT may be due to a deficiency or inhibitor for factors II, V, VIII, IX, X, XI, and XII. It also may be due to heparin, direct thrombin inhibitors, vitamin K deficiency, liver disease, or lupus anticoagulant. 

Finally, with the use of direct thrombin inhibitors such as hirudin for anticoagulant therapy, laboratory tests such as APTT may not be sensitive enough to follow therapy. 

AstraZeneca first launch for AstraZeneca s Exanta (TM) (ximelagatran) the first oral anticoagulant in new class of direct thrombin inhibitors (DTIs), AstraZeneca. 

Another type of anticoagulant are the direct thrombin inhibitors. Current members of this class include argatroban, lepirudin, and bivalirudin. 

Mechanism of Action A direct thrombin inhibitor that reversibly binds to thrombin-active sites. Inhibits thrombin-catalyzed or thrombin-induced reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII also inhibits protein C formation, and platelet aggregation. Therapeutic Effect Produces anticoagulation. Pharmacokinetics Following IV administration, distributed primarily in extracellular fluid. Protein binding 54%. Metabolized in the liver. Primarily excreted in the feces, presumably through biliary secretion. Half-life 39-51 min. 

A. General description Bivalirudin, a 20 amino-acid synthetic peptide, is a direct thrombin inhibitor. It is an analogue of recombinant hirudin (Refludan), a 65 amino-acid anticoagulant derived from the leech. The molecular weight of bivalirudin is about 2.2kDa (anhydrous free base peptide). 

F. Role in therapy The potential advantages of Angiomax—a direct thrombin inhibitor—over heparin include activity against clot-bound thrombin, more predictable anticoagulation, and no inhibition by components of the platelet release reaction. The place in therapy of Angiomax will be determined by further comparisons with heparin, low-molecular weight heparins, and recombinant hirudin. 

Morbidity and mortality in HIT are related to thrombotic events. Venous thrombosis occurs most commonly, but occlusion of peripheral or central arteries is not infrequent. If an indwelling catheter is present, the risk of thrombosis is increased in that extremity. Skin necrosis has been described, particularly in individuals treated with warfarin in the absence of a direct thrombin inhibitor, presumably due to acute depletion of the vitamin -dependent anticoagulant protein C occurring in the presence of high levels of procoagulant proteins and an active hypercoagulable state. 

The direct thrombin inhibitors (DTIs) exert their anticoagulant effect by directly binding to the active site of thrombin, thereby inhibiting thrombin s downstream effects. This is in contrast to indirect thrombin inhibitors such as heparin and LMWH (see above), which act through antithrombin. Hirudin and bivalirudin are bivalent DTIs in that they bind at both the catalytic or active site of thrombin as well as at a substrate recognition site. Argatroban and melagatran are small molecules that bind only at the thrombin active site. 

In ACS patients, LMWH has now been compared with newer anticoagulants such as direct thrombin inhibitors, such as bivalirudin [ACUITYtrial (25)], and a pentasaccharide, such as fondaparinux [OASIS-5 and -6 trials (26,27)]. These new... 

The direct thrombin inhibitors have theoretical advantages over the indirect anticoagulants that include more predictable dose-responses, and efficacy against clot bound thrombin. With bivalirudin, clinical trials suggest superiority compared with heparin alone and comparable outcomes when... 

Due to its large molecular size in comparison with direct thrombin inhibitors (DTIs), UFH is unable to penetrate into fibrin clot and to inhibit thrombin trapped in a clot. Hence, its anticoagulant activity is limited only to the inhibition of thrombin in the process of thrombi formation. 

In the meta-analysis with I I randomized studies, anticoagulant effects in ACS and PCI were compared between a direct antithrombin agent and UFH, The direct thrombin inhibitor showed better outcome in death or myocardial infarction than UFH (19). DTIs are expected to be an alternative to UFH for PCI. 

Hellgren M, Johansson S, Eriksson UG, et al, The oral direct thrombin inhibitor, ximelagatran, an alternative for anticoagulant treatment during the puerperium and lactation. Bjog 2005 I 12 579-583. 

Morishima Y Tanabe K, Terada Y et al. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor comparison with a direct thrombin inhibitor and antithrombin Ill-dependent anticoagulants. Thromb Haemost 1997 78 1366-1371. 

Kokolis S, Cavusoglu E, Clark LT Marmur JD. Anticoagulation strategies for patients undergoing percutaneous coronary intervention Unfractionated heparin, low-molecular-weight heparins, and direct thrombin inhibitors. Prog Cardiovasc Dis 2004 46(6) 506-523. 

Nutescu EA, Wittkowsky AK. Direct thrombin inhibitors for anticoagulation. Ann Pharmacother 2004 38 99-109. 

Direct thrombin inhibitors are able to inactivate thrombin in blood by directly binding to the catalytic site of thrombin rather than by acting through antithrombin molecule. Hirudin, a naturally occurring anticoagulant, was one of the first direct thrombin inhibitors to be tested for its utility in ACS. The Global Use of... 

---