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The

n e w e ng l a n d j o u r na l

of

m e dic i n e

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, G. d’Annunzio University Foundation, Chieti (G.D.), and the Department of Pharmacology, Catholic University School of Medicine, Rome (C.P.) — both in Italy. Addressreprint requests to Dr. Patrono at Università Cattolica del S. Cuore, Largo F. Vito 1, 00168 Rome, Italy, or at carlo.patrono@ rm.unicatt.it. N Engl J Med 2007;357:2482-94.
Copyright © 2007 Massachusetts Medical Society.

P

latelets are essential for primary hemostasis and repair of the endothelium, but they also play a key role in the development of acute coronary syndromes and contributeto cerebrovascular events. In addition, they participate in the process of forming and extending atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process,1 and inflammation is an important component of acute coronary syndromes.2 The relation between chronic and acute vascular inflammation is unclear, but platelets are a source of inflammatory mediators,3 and the activation ofplatelets by inflammatory triggers may be a critical component of atherothrombosis.4 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.

Pl atel e t s in Pr im a r y He mos ta sis
Platelets are produced by megakaryocytes asanucleate 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 transcriptome contains approximately 3000 to 6000 transcripts. Analysis of the platelet proteome is more complex.8-11 Afterleaving 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 glycoprotein Ib/V/IX, a structurally unique receptor complex expressed in megakaryocytes and platelets. Von Willebrand factor is the major ligand for onecomponent 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 throughG-protein–coupled receptors.14 The final pathway for all agonists is the activation of the platelet integrin glycoprotein IIb/IIIa (αIIbβ3), the main receptor for adhesion and aggregation.15 The

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n engl j med 357;24

www.nejm.org

december 13, 2007

Downloaded from www.nejm.org by DANIEL X. XIBILLE MD on September 15, 2009 . Copyright © 2007 Massachusetts Medical Society. All rightsreserved.

Mechanisms of Disease

phenotype of mice lacking the β3 integrin resembles that of patients with Glanz­mann’s thrombasthenia, in which platelets cannot aggregate and have a greatly reduced uptake of fibrinogen.16 Several adhesive substrates bind to glycoprotein IIb/IIIa.13,16 Fibrinogen plays an important role in maintaining the stability of a thrombus, by bridging glycoprotein...
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