The role of the platelet in the pathogenesis of atherothrombosis.
Platelet adhesion, activation, and aggregation at sites of vascular endothelial disruption caused by atherosclerosis are key events in arterial thrombus formation. Platelet tethering and adhesion to the arterial wall, particularly under high shear forces, are achieved through multiple high-affinity interactions between platelet membrane receptors (integrins) and ligands within the exposed subendothelium, most notably collagen and von Willebrand factor (vWF). Platelet adhesion to collagen occurs both indirectly, via binding of the platelet glycoprotein (GP) Ib-V-IX receptor to circulating vWF, which binds to exposed collagen, and directly, via interaction with the platelet receptors GP VI and GP Ia/IIb. Platelet activation, initiated by exposed collagen and locally generated soluble platelet agonists (primarily thrombin, ADP, and thromboxane A2), provides the stimulus for the release of platelet-derived growth factors, adhesion molecules and coagulation factors, activation of adjacent platelets, and conformational changes in the platelet alpha(IIb)beta3 integrin (GP IIb/IIIa receptor). Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb/IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of a platelet-rich thrombus. Currently available antiplatelet drugs (aspirin [acetylsalicylic acid], dipyridamole, clopidogrel, ticlopidine, abciximab, eptifibatide, tirofiban) act on specific targets to inhibit platelet activation and aggregation. Elucidation of the multiple mechanisms involved in platelet thrombus formation provides opportunities for selectively inhibiting the pathways most relevant to the pathophysiology of atherothrombosis.
Steinhubl
Steven R
SR
The Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0284, USA. Steinhubl@uky.edu
Moliterno
David J
DJ
D000244:Adenosine Diphosphate; D000818:Animals; D050197:Atherosclerosis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D023201:CD40 Ligand / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D006801:Humans; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D019007:P-Selectin / Q000378:metabolism; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood* / Q000188:drug therapy / Q000276:immunology
D019007:P-Selectin; D010975:Platelet Aggregation Inhibitors; D023201:CD40 Ligand; D000244:Adenosine Diphosphate; D003094:Collagen; D013917:Thrombin