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Platelet Activation and Atherothrombosis

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Platelet Activation and Atherothrombosis T h e new england journal o f medicine review article Mechanisms of Disease Platelet Activation and Atherothrombosis Giovanni Davì, M.D., and Carlo Patrono, M.D. From the Center of Excellence on Aging, latelets are essential for primary hemostasis and repair of the G. d’Annunzio University Foundation, Chi- endothelium, but they also play a key role in the development of acute coro- eti (G.D.), and the Department of Pharma- cology, Catholic University School of Medi- nary syndromes and contribute to cerebrovascular events. In addition, they cine, Rome (C.P.) — both in Italy. Address P participate in the process of forming and extending atherosclerotic plaques. Athero- reprint requests to Dr. Patrono at Univer- sclerosis is a chronic inflammatory process,1 and inflammation is an important sità Cattolica del S. Cuore, Largo F. Vito 1, 2 00168 Rome, Italy, or at carlo.patrono@ component of acute coronary syndromes. The relation between chronic and acute rm.unicatt.it. vascular inflammation is unclear, but platelets are a source of inflammatory me- diators,3 and the activation of platelets by inflammatory triggers may be a critical N Engl J Med 2007;357:2482-94. 4 Copyright © 2007 Massachusetts Medical Society. component of atherothrombosis. This review article describes the role of platelets in atherothrombosis by integrating our knowledge of basic mechanisms with the results of mechanistic studies in humans and clinical trials of inhibitors of platelet function. Platelets in Primary Hemostasis Platelets are produced by megakaryocytes as anucleate cells that lack genomic DNA5 but contain megakaryocyte-derived messenger RNA (mRNA) and the translational machinery needed for protein synthesis.6 Pre-mRNA splicing, a typical nuclear function, has been detected in the cytoplasm of platelets,7 and the platelet tran- scriptome contains approximately 3000 to 6000 transcripts. Analysis of the platelet proteome is more complex.8-11 After leaving the bone marrow, platelets circulate for about 10 days. Their primary function is to stop hemorrhage after tissue trauma and vascular injury. Platelet Activation The initial tethering of platelets at sites of vascular injury is mediated by glycopro- tein Ib/V/IX, a structurally unique receptor complex expressed in megakaryocytes and platelets. Von Willebrand factor is the major ligand for one component of this complex, glycoprotein Ib, and the absence of the factor causes defects in primary hemostasis and coagulation.12 Besides glycoprotein Ib, several collagen receptors with a tethering function are found on the platelet surface, notably glycoprotein VI and glycoprotein Ia, members of the immunoglobulin superfamily.4 After the initial adhesion of platelets to the extracellular matrix, the repair process requires a rapid response to autocrine and paracrine mediators, including adenosine diphosphate (ADP), thrombin, epinephrine, and thromboxane A2. These mediators amplify and sustain the initial platelet response (Fig. 1), and they recruit circulating platelets from the flowing blood to form a growing hemostatic plug. Most agonists that activate platelets operate through G-protein–coupled receptors.14 The final pathway for all agonists is the activation of the platelet integrin glyco- protein IIb/IIIa (αIIbβ3), the main receptor for adhesion and aggregation.15 The 2482 n engl j med 357;24 www.nejm.org december 13, 2007 The New England Journal of Medicine Downloaded from www.nejm.org by JESUS RUEDA on November 8, 2010. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. Mechanisms of Disease phenotype of mice lacking the β3 integrin re- Clinical Implications sembles that of patients with Glanz­mann’s The importance of the role of thromboxane A2 thrombasthenia, in which platelets cannot ag- and ADP in amplifying platelet activation during gregate and have a greatly reduced uptake of fi- hemostasis is supported by the twofold increase brinogen.16 in the incidence of major bleeding complications Several adhesive substrates bind to glycopro- (mostly in the upper gastrointestinal tract) asso- tein IIb/IIIa.13,16 Fibrinogen plays an important ciated with the use of low-dose aspirin or the role in maintaining the stability of a thrombus, thienopyridines ticlopidine and clopidogrel.24 The by bridging glycoprotein IIb/IIIa integrins be- clinical relevance of adhesive interactions with tween platelets; von Willebrand factor is neces- platelet glycoprotein IIb/IIIa in primary hemosta- sary to facilitate interplatelet bridges at low shear sis is known largely from the study of Glanz­- rates in vitro (Fig. 1). Quiescent platelets contain mann’s thrombasthenia25 and the association of the pre-mRNA of the molecule termed tissue fac- bleeding complications with the use of pharma- tor, the primary initiator of the coagulation cas- cologic blockers of glycoprotein IIb/IIIa.24 cade that leads to the conversion of prothrombin The impairment of primary hemostasis by to thrombin and fibrinogen to fibrin.17 Signal- antiplatelet drugs cannot be dissociated from dependent splicing of tissue-factor pre-mRNA their effects in the prevention of arterial throm- allows for the synthesis of bioactive tissue-factor bosis, which suggests that similar molecular protein and therefore provides platelet-derived tis- mechanisms contribute to both processes. How- sue factor for propagating and stabiliz­ing the ever, the transient incomplete blockade of plate- thrombus.17 let COX-1 and of glycoprotein IIb/IIIa by some The vascular endothelium controls platelet traditional nonsteroidal antiinflammatory drugs reactivity by means of three pathways: the arachi- and oral inhibitors of glycoprotein IIb/IIIa, respec- donic acid–prostacyclin pathway, the L-arginine– tively, has been associated with an increased risk nitric oxide pathway, and the endothelial ecto- of bleeding and a lack of antithrombotic effica- adenosine diphosphatase (ecto-ADPase) pathway.18 cy.24 This suggests that the extent and duration Endothelial cells convert arachidonic acid into of platelet inhibition required to impair hemo- prostacyclin with the help of cyclooxygenase-1 or stasis may differ from that required to prevent cyclooxygenase-2 (COX-1 or COX-2) and prostacy- atherothrombosis. clin synthase. COX-2 appears to be important in The ex vivo measurement of platelet respons- prostacyclin synthesis, on the basis of the effects es to various agonists provides an index of the of selective COX-2 inhibitors on the excretion of functional capacity of platelets,26-29 but such mea- prostacyclin metabolites.19-21 Prostacyclin inhibits surements by no means reflect the extent of platelet function by elevating intracellular cyclic platelet activation in vivo.30-32 The maximum ca- 22 AMP levels. pacity of platelets to synthesiz­e thromboxane A2 Nitric oxide diffuses into platelets, stimulates in vitro is approximately 5000 times the basal rate the production of cyclic guanosine monophos- of thromboxane biosynthesis in vivo,32 and only phate (GMP), and regulates cyclic GMP–depen- a fraction of this biosynthetic capacity appears to dent protein kinases, causing a secondary de- contribute to platelet activation, as reflected by crease in intracellular Ca2+ flux. This reduction excretion of thromboxane metabolites.30,32 in intracellular Ca2+ levels suppresses the confor- mational change in glycoprotein IIb/IIIa that is Platelets and Development required for binding of the integrin to fibrinogen, of Atherosclerotic Lesions thereby decreasing the number and affinity of fi- brinogen binding sites on the platelet’s surface.22 Platelets that adhere to the vessel wall at sites of Ecto-ADPase, an integral component of the endothelial-cell activation contribute to the de- endothelial-cell surface, limits the plasma level of velopment of chronic atherosclerotic lesions, and nucleotides (ADP and ATP) and is substrate-acti- when these lesions rupture, they trigger the acute vated. The activity of this enz­yme abrogates the onset of arterial thrombosis. Platelets adhere to critical recruitment phase of platelet reactivity, the endothelium of carotid arteries in apolipo- because it removes nucleotides from the fluid protein E (apoE)−/− mice before atherosclerotic environment.23 lesions are visible.33 Von Willebrand factor, when n engl j med 357;24 www.nejm.org december 13, 2007 2483 The New England Journal of Medicine Downloaded from www.nejm.org by JESUS RUEDA on November 8, 2010. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine Figure 1 (facing page). Agonists, Receptors, and Effector Systems in Platelet Activation. The activation of platelets is induced by the interaction of several agonists with receptors expressed on the platelet membrane. Panels A, B, and C depict outside-in signaling mediated by thromboxane A2 (TXA2), adenosine diphos- phate (ADP), and thrombin, respectively. TXA2 is synthesized by activated platelets from arachidonic acid (AA) through the cyclooxygenase (COX) pathway (Panel A). Once formed, TXA2 can diffuse across the membrane and acti- vate other platelets. In platelets, there are two splice variants of the TXA2 receptor: TPα and TPβ, which differ in their cytoplasmic tail. TPα and TPβ couple to the proteins Gq and G12 or G13, all of which activate phospholipase C (PLC). This enzyme degrades the membrane phosphoinositides (such as phosphatidylinositol 4,5-bisphosphate [PIP2]), re-
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