Editorial [Hot Topic:The Search for Novel Anti-Thrombotic Drug Targets (Executive Editor: Dermot Cox)]

Atherosclerosis is the leading cause of death in the Western world and anti-thrombotic therapy plays a key role in the management of this disease. However, despite the importance of platelets in the disease process there has been little progress in developing novel anti-thrombotic agents. Current anti-thrombotic therapy revolves around aspirin, a drug that has been around for thousands of years. More recently GPIIb/IIIa antagonists were hailed as the future of anti-thrombotic therapy. However, with the failure of the oral GPIIb/IIIa antagonists [1] these drugs have been restricted to high-risk patients under-going interventions [2]. Clopidogrel has proven to be a significant breakthrough as it is orally active and is very effective at inhibiting platelet aggregation [3]. So do we need another anti-platelet agent? There is convincing evidence for aspirin resistance and this has been shown to be associated with poor outcome in cardiovascular patients [4]. The requirement for intravenous administration has restricted the use of GPIIb/IIIa antagonists. Clopidogrel is the most effective anti-platelet agent available today however, there are problems associated with its use. Patients who have had a stent implanted can develop in-stent thrombosis even when on clopidogrel [5]. Since this can be fatal there is a definite need for more effective anti-thrombotic agents. There are three potential reasons for the failure of aspirin and clopidogrel to prevent thrombosis. The first is due to underdosing. The recommendations for the use of clopidogrel have all moved towards increased loading dose and to extending the treatment period [6]. A second potential problem is inherent resistance to the effect of anti-platelet agents. There is evidence that some people do not respond to aspirin and continue to have normal platelet function despite aspirin therapy [7, 8]. A similar phenomenon appears to exist with clopidogrel although not as well characterized. Some patients appear to be resistant to both anti-platelet agents [9]. A third limitation with aspirin and clopidogrel is their mechanism of action. Aspirin acts to inhibit cyclooxygenase-mediated events while clopidogrel inhibits ADP-mediated events. However, non-COX and non-ADPmediated events can occur as well. Thrombin will activate platelets in a COX-independent manner and does not require ADP for its action although secreted ADP may enhance its actions. Thus, existing anti-platelet agents may be effective in situations where there is collagen exposure but would be ineffective if thrombin generation is occurring. While there is a case to be made for the development of new anti-platelet agents improved versions of aspirin or clopidogrel are unlikely to be effective as they will still be limited by their mechanism of action. Thus it is necessary to identify novel drug targets. There are two approaches that can be used. The first is to target proteins that are known to play a role in thrombus formation. The second approach is to identify novel proteins that may be involved. In this issue we look at both approaches to developing new platelet drug targets. One key receptor in platelet function is GPIb. It is well known to mediate platelet adhesion to von Willebrand factor under high shear. Since thrombosis in the coronary vessels usually occurs in a high shear environment the GPIb-vWf interaction is an ideal target. It also promises to be free of the major adverse effect of other anti-thrombotics as it should not prolong bleeding as this usually occurs in a low shear environment. Many companies have tried to develop inhibitors of this interaction with little success. Hans Deckmyn's group in Leuven, Belgium has many years of experience working with GPIb. Karen Vanhoorelbeke from this group writes about the progress in developing inhibitors of GPIb. In most cases these are antibodies or proteins which will restrict them to acute use. However, this is not necessarily a problem since these agents will only inhibit the initial step of platelet adhesion and will have no effect on thrombus growth. Thus they are likely to be most effective when given early such as prior to angioplasty. Another promising target is the collagen receptors. The interaction between platelets and collagen is central to thrombus formation and thus is an ideal drug target. However, there are two different collagen receptors and we are only beginning to understand the interplay between the two and their role in thrombosis.........