Current Drug Targets - Cardiovascular & Haematological Disorders, 2003, 3, 125-140 125 1568-0061/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. Inhibition of Platelet Adhesion to Collagen as a New Target for Antithrombotic Drugs K. Vanhoorelbeke * , H. Ulrichts, A. Schoolmeester and H. Deckmyn Laboratory for Thrombosis Research; IRC, KU Leuven Campus Kortrijk, Belgium Abstract: Platelet adhesion to a damaged blood vessel is the initial trigger for arterial hemostasis and thrombosis. Platelets adhere to the subendothelium through an interaction with von Willebrand factor (VWF), which forms a bridge between collagen within the damaged vessel wall and the platelet receptor glycoprotein Ib/V/IX (GPIb), an interaction especially important under high shear conditions[1]. This reversible adhesion allows platelets to roll over the damaged area, which is then followed by a firm adhesion mediated by the collagen receptors ( α 2 β 1 , GPVI,…) in addition[2] resulting in platelet activation. This leads to the conformational activation of the platelet α IIb β 3 receptor, fibrinogen binding and finally to platelet aggregation. Over the past decades, modulation of platelet function has been a strategy for the control of cardiovascular disease. Lately, drugs have been developed that target the fibrinogen receptor α IIb β 3 or the ADP receptor and many of these promising compounds have been tested in clinical trials. However the development of products that interfere with the first step of hemostasis, i.e. the platelet adhesion, has lagged behind. In this review we want to discuss (i) the in vivo studies that were performed with compounds that target proteins involved in different adhesion steps i.e. the VWF-GPIb-axis, the collagen-VWF axis and the collagen-collagen receptor axis and (ii) the possible advantages these putative new drugs could have over the current antiplatelet agents. Key Words: von Willebrand factor, glycoprotein Ib/V/IX, integrin α 2 β 1 , glycoprotein VI, antithrombotic, antiplatelet agent, in vivo. INTRODUCTION In well controlled hemostasis, platelets normally do not interact with healthy vessels, but adhere when encountering a zone of vascular injury where several components of the subendothelium are exposed, e.g. fibrillar and non-fibrillar collagens, proteoglycans, elastin, laminin, fibronectin, thrombospondin and VWF [3]. In particular, fibrillar collagens type I and III are major constituents determining the thrombogenicity [4]. Platelet adhesion to these collagens occurs through direct and indirect interactions. In the indirect interaction, especially in conditions of high shear forces, VWF forms a bridge between collagen and the platelet receptor glycoprotein (GP) Ib/V/IX. This GPIb-VWF interaction mediates the initial tethering and subsequent rolling of platelets over collagen in the subendothelium, allowing platelets to slow down on the collagen surface [3, 5]. This event allows the direct interaction through collagen receptors resulting in full arrest. A variety of collagen receptors has been identified on platelets such as α 2 β 1 [6], GP VI [7], Type III Collagen Binding Protein (TIIICBP) [8, 9], P65: collagen type I receptor [10], GPV [11], and an 88kD receptor [12]. After this initial adhesion, platelets become activated resulting in the conformational activation of the platelet α IIb β 3 receptor, leading to fibrinogen binding and finally platelet aggregation [13]. Formation of the platelet plug results in the cessation of bleeding. *Address correspondence to this author at the Laboratory for Thrombosis Research, IRC, K.U. Leuven Campus Kortrijk, E. Sabbelaan 53, 8500 Kortrijk, Belgium; Tel: 003256246422; Fax: 003256246997; E-mail: Karen.Vanhoorelbeke@kulak.ac.be In pathological conditions such as coronary artery disease (CAD) thrombus formation due to atherosclerotic plaque disruption, plays a fundamental role in the development of acute coronary syndromes. Stenosis due to plaque formation may lead to intermittent or transient vessel occlusion and ischemia by the formation of labile thrombi in patients with unstable angina [14]. When a more severe damage occurs, a permanent thrombus and a more chronic occlusion form, resulting in, for example acute myocardial infarction. The concepts regarding the role of platelets in hemostasis should provide a good basis for understanding how thrombotic complications leading to CAD develop. While it is established that platelets play an important role in the onset of thrombosis, their role in initiation and progression of spontaneous and accelerated atherosclerosis is less clear. However, a possible role of platelets in these events has been demonstrated in many ways. Using thrombocytopenic rats, a significant decrease in intimal thickening after carotid artery injury has been demonstrated [15], whereas thrombocytopenic rabbits fed a lipid rich diet, had significantly less injury-induced thromboatherosclerotic lesions [16]. In view of the current knowledge of the role of platelets in thrombus formation, the development of new antithrombotics based on the inhibition of platelet adhesion would have the following anticipated advantages: 1. As the GPIb/V/IX-VWF-collagen interaction is a prerequisite to form a thrombus under high shear conditions, inhibiting this interaction would be more specific for the treatment of arterial thrombosis, with