Move along, nothing to see here: Btk inhibitors stop platelets sticking to plaques

Platelets have evolved an intricate array of overlapping mechanisms to respond effectively to vessel damage by forming a clot to minimize blood loss. Unfortunately, these same responses may also be triggered by atherosclerotic lesions in diseased arteries. Vessels can become occluded when platelets form a thrombus at the site of a ruptured plaque, causing myocardial infarction (MI) or ischemic stroke, depending on where the thrombus forms or where a resulting embolus becomes lodged. Current therapy following MI or ischemic stroke involves treatment with antiplatelet drugs to reduce the risk of recurrent events by inhibiting one or more of the mechanisms that drive the formation of a platelet thrombus. However, the overlap between the mechanisms that drive pathological thrombus formation and those that facilitate hemostasis means that patients receiving antiplatelet medication are at higher risk of hemorrhage, including intracranial hemorrhage and gastrointestinal bleeding. The benefits of current antiplatelet therapy outweigh the risks for patients, but there is still a need for safer antiplatelet therapies that do not compromise hemostasis to better serve this patient population, which is large and growing globally. In order to develop new antiplatelet drugs, researchers must consider the similarities and differences between the pathological process of thrombosis and the physiological process of hemostasis. Platelets skim over the surfaces of vascular endothelial cells, scanning for collagen and other exposed subendothelial matrix proteins that serve as environmental cues indicating that vessel damage has occurred. The initial interaction with exposed collagen occurs via the plasma protein von Willebrand factor, which binds to collagen and undergoes conformational change at high shear rates (present in arteries), enabling the platelet protein glycoprotein (GP) Iba to bind to it. Collagen is also recognized directly by the platelet GPVI receptor and integrin a2b1, which, together, mediate adhesion to collagen and trigger a cascade of intracellular signaling events that ultimately help the aggregate to grow and become stable. Atherosclerotic plaques are rich in collagen and provide a strong environmental cue to platelets to adhere and form an aggregate within the lumen of the vessel. The intracellular signaling processes stimulated in both scenarios are similar, and result in the platelets synthesizing thromboxane A2 and secreting ADP, which, via paracrine and autocrine mechanisms, act as secondary mediators to recruit platelets to the growing aggregate and stabilize it. The antiplatelet drugs aspirin and P2Y12 inhibitors such as clopidogrel or ticagrelor target these positive feedback mechanisms to limit thrombus growth and prevent vessel occlusion. The success of these drugs in providing relatively safe platelet inhibition can be understood in the context of the ‘core’ and ‘shell’ model of thrombus formation, whereby a core of platelets is strongly activated by direct contact with collagen, and is surrounded by an outer shell of weakly activated platelets stimulated by secondary mediators. In this model, the core is required for hemostasis, whereas the shell is partially redundant but serves a pathological role in thrombosis by causing vessel occlusion. However, both aspirin and P2Y12 inhibitors are associated with increased rates of hemorrhage, suggesting that either these drugs are not sufficiently specific in targeting the shell, or the shell is also important for hemostasis. Although the environment of an atherosclerotic plaque and that of a damaged blood vessel have similarities, some in vitro studies have identified differences that could be exploited pharmacologically to provide platelet inhibition specifically in the context of atherothrombosis while sparing normal hemostasis. One such difference concerns the morphologically distinct forms of type I and type III collagen present in atherosclerotic plaques, which trigger Correspondence: Alexander Paul Bye, Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Whiteknights, Reading RG6 6AS, UK Tel.: +44 (0)118 378 4562 E-mail: a.bye@reading.ac.uk