Direct thrombin inhibitors
Introduction
Venous thrombi, which form under conditions of low shear, are comprised mainly of red cells and fibrin. In contrast, arterial thrombi, which form under high shear conditions, are largely composed of platelet aggregates held together by fibrin strands. Venous thrombosis is often triggered by vascular injury at the time of surgery or trauma, or by mechanical damage secondary to indwelling central venous catheters. In contrast, most arterial thrombi are superimposed on disrupted atherosclerotic plaques [1].
Injury to the endothelial lining of veins or arteries exposes subendothelial matrix proteins such as collagen and von Willebrand factor. Platelets adhere to these matrix proteins where they become activated, release vasoactive and procoagulant substances, and aggregate. Simultaneous exposure of tissue factor initiates coagulation and leads to thrombin generation. A potent platelet agonist, thrombin recruits additional platelets to the site of vascular injury. Thrombin also converts fibrinogen to fibrin, which serves to stabilize the platelet aggregates [1].
Heparin is a cornerstone of therapy for venous and arterial thrombosis. Although effective for the treatment of venous thrombosis, heparin has limitations. It must be given parenterally and it requires careful laboratory monitoring to ensure that the anticoagulant response is therapeutic [2], [3], [4]. When used in patients with acute coronary syndromes, the addition of heparin to aspirin reduces the risk of cardiovascular death and recurrent myocardial ischemia. Despite its widespread use, however, patients remain at risk for recurrent thrombotic events which can be fatal. This suggests that the process of thrombus formation is incompletely attenuated by heparin.
Although the mechanism by which thrombin generation occurs during or after heparin therapy remains controversial, recent investigations have shed some light on this process. High concentrations of thrombin are generated by tissue factor exposed at sites of vascular injury [5]. Thrombin bound to fibrin [6], [7], fibrin degradation products [8] or the subendothelial matrix [9] is resistant to inactivation by the heparin/antithrombin complex. Bound thrombin, which remains enzymatically active, can amplify its own generation by activating factors V, VIII and XI [10]. Consequently, the thrombus serves as a reservoir of active thrombin that triggers thrombus growth and locally activates platelets.
Because thrombin plays a central role in thrombogenesis, the goal of most treatment regimens is to block thrombin generation or inhibit its activity. Direct thrombin inhibitors were developed to overcome the inability of the heparin/antithrombin complex to inactivate bound thrombin [6], [7], [8], [9]. In contrast to heparin and low-molecular-weight heparin, which catalyze the inactivation of thrombin and activated factor X (factor Xa) by antithrombin [11], [12], direct thrombin inhibitors bind to thrombin and block its interaction with its substrates. This paper will (a) review the limitations of heparin and low-molecular-weight heparin, (b) describe the potential advantages of direct thrombin inhibitors, (c) review the clinical data with hirudin, bivalirudin (formerly known as hirulog), argatroban, and ximelagatran, and (d) outline the opportunities and challenges for direct thrombin inhibitors in the face of new anticoagulant drugs currently under development.
Section snippets
Limitations of heparin and low-molecular-weight heparin
Heparin has both pharmacokinetic and biophysical limitations (Table 1). The pharmacokinetic limitations of heparin reflect its propensity to bind to plasma proteins the levels of which vary between patients [11]. The levels of heparin binding proteins vary because some are acute phase reactants, whereas others, such as platelet factor 4 and high-molecular-weight multimers of von Willebrand factor, are released from platelets when they are activated by thrombin. Endothelial cells activated by
Direct thrombin inhibitors
Hirudin, bivalirudin and argatroban are the three parenteral direct thrombin inhibitors currently approved by the FDA. Hirudin and argatroban are licensed for treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is approved as a heparin substitute in patients undergoing coronary angioplasty. Ximelagatran is an orally available prodrug which, once absorbed, is rapidly converted to melagatran.
Potential advantages of direct thrombin inhibitors over heparin
Direct thrombin inhibitors have potential advantages over heparin (Table 2). Because they do not bind to plasma proteins, direct thrombin inhibitors produce a more predictable anticoagulant response than heparin. Unlike heparin, direct thrombin inhibitors do not interact with platelet factor 4 or high-molecular-weight multimers of von Willebrand factor. Consequently, the activity of direct thrombin inhibitors in the vicinity of a platelet-rich thrombus is not compromised. Finally, thrombin
Unstable angina
The largest phase II study to compare hirudin with heparin, the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 pilot trial, randomized 909 with unstable angina or non-ST-elevation myocardial infarction to a 72-h infusion of hirudin, in either low or medium dose, or to heparin [39]. Doses of hirudin and heparin were adjusted to maintain the activated partial thromboplastin time (APTT) between 60 and 100 s. Compared with heparin, hirudin produced a promising reduction in the
Conclusions and future directions
Based on randomized trials, parenteral direct thrombin inhibitors are more effective than heparin for treatment of arterial thrombosis. Thus, hirudin is superior to heparin in patients with unstable angina [40], and both hirudin and bivalirudin are at least as effective as heparin in patients undergoing coronary angioplasty [48], [52], [53]. In patients with unstable angina, hirudin reduces the risk of recurrent ischemia to an extent similar to that produced by glycoprotein IIb/IIIa antagonists
Acknowledgements
The authors are indebted to Sue Crnic for her excellent secretarial support. This work was supported by grants from the Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the Ontario Research and Development Challenge Fund. Dr. Weitz is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada and holds the Heart and Stroke Foundation of Ontario/J. Fraser Mustard Chair in Cardiovascular Research and the Canada Research Chair in
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