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Association of Neutrophils With Platelet Aggregates in Unstable Angina

1996; Lippincott Williams & Wilkins; Volume: 94; Issue: 6 Linguagem: Inglês

10.1161/01.cir.94.6.1206

1524-4539

Mark L. Entman, Christie M. Ballantyne,

Neutrophil, Myeloperoxidase and Oxidative Mechanisms

HomeCirculationVol. 94, No. 6Association of Neutrophils With Platelet Aggregates in Unstable Angina Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBAssociation of Neutrophils With Platelet Aggregates in Unstable AnginaShould We Alter Therapy? Mark L. Entman and Christie M. Ballantyne Mark L. EntmanMark L. Entman the Department of Medicine, Pathology and Biochemistry, DeBakey Heart Center, Baylor College of Medicine, and The Methodist Hospital, Houston, Tex. and Christie M. BallantyneChristie M. Ballantyne the Department of Medicine, Pathology and Biochemistry, DeBakey Heart Center, Baylor College of Medicine, and The Methodist Hospital, Houston, Tex. Originally published15 Sep 1996https://doi.org/10.1161/01.CIR.94.6.1206Circulation. 1996;94:1206–1208In this issue of Circulation, Dr Ott and his colleagues1 have convincingly demonstrated evidence for increased neutrophil-platelet interaction associated with unstable angina not seen in patients with stable angina. Although such interactions have been suggested previously, as duly referenced by the authors, the work by Ott and coworkers has defined these observations and characterized some of the cellular changes in neutrophils consequent to this interaction that are potentially important in consideration of their pathophysiological significance. We intend to provide an alternative perspective to the scholarly discussion provided by Ott and colleagues. We wish to address the potential of these findings as a diagnostic and prognostic tool and as a part of the pathophysiology of unstable angina and to discuss the potential therapeutic implications.Platelet-Neutrophil Interaction as a Diagnostic and Prognostic ToolThe major finding of the study by Ott et al1 is the evidence of augmented platelet-neutrophil interaction in the circulating venous blood of patients with unstable angina. They consider the mechanism of this adhesion and its potential relationship to the pathophysiological process, which is, at least theoretically, occurring on a labile plaque in the coronary circulation. However, activated neutrophils and neutrophil-platelet aggregates will certainly be cleared rapidly from the circulation by both the spleen and the lung. Because the complexes are both rapidly cleared and not likely to be stable (see below), this measurement offers a potential way of following the ongoing metastable interaction. It would be of interest to measure the rate at which these aggregates disappeared as a function of classic treatment approaches to unstable angina. If the complexes truly clear rapidly, then they should disappear rapidly after new complexes are no longer formed, and one would have the opportunity to examine these changes in patients with various treatment regimens. The relationship of platelet-neutrophil aggregates to treatment modalities and changes in symptoms could be followed. It is possible that the relatively simple assay found in Fig 1 of the article by Ott et al1 could be used to observe therapeutic efficacy and/or response in unstable angina or in myocardial infarction under circumstances in which a metastable platelet activation might occur (eg, thrombolytic therapy). Along these lines, it would be useful to know whether the patients in Fig 1 with lower mean fluorescence intensities (<100) might represent patients with a "lesser" syndrome intensity. For example, angina of recent onset is not necessarily as unstable a condition as the remaining classifications of unstable angina. It would be of interest to know whether the platelet-neutrophil aggregates are able to predict the relative severity of the unstable syndromes.Pathophysiological Significance of Platelet-Neutrophil InteractionThe data presented in the article by Ott et al1 do not directly speak to the mechanisms of platelet-neutrophil interaction. The authors suggest several mechanisms, and determination of the mechanisms by which platelet-neutrophil interaction occurs is conceptually important. It is possible that more than one of these mechanisms may actually be pertinent.1. Fibrinogen bridges: Platelet glycoprotein (GP) IIB/IIIA specifically binds fibrinogen2 as part of the platelet-initiated clotting mechanism; fibrinogen was also one of the earliest adhesive ligands discovered for the leukocyte integrin CD11b/CD18.34 Therefore, the potential exists for a fibrinogen bridge between the heterologous cell types. However, such a construct lacks an initiation mechanism to activate CD11b/CD18 to allow its adhesion to fibrinogen. CD11b/CD18 is stored in granules in the neutrophil with a relatively low surface expression. Leukocytotactic stimulus initially activates surface CD11b/CD18 to increase its adhesiveness and also results in leukocyte degranulation to increase surface CD11b/CD18.5 The neutrophils in the circulating aggregates have undergone a highly significant activation and increase in their surface CD11b/CD18. Recent studies6 have suggested that activated platelets may secrete interleukin-8, which is a potent neutrophil-specific chemotactic agent.2. Thrombospondin bridges: The possibility that thrombospondin initiates platelet-leukocyte interaction by cross-linking GP4 on these cells is an interesting speculation. The effect of such thrombospondin interactions on neutrophil activation has not been studied, and this speculation emanates primarily from in vitro experiments in monocytes.7 This would be a unique role for thrombospondin and is approachable in vivo (immunologic detection of thrombospondin in isolated platelet-neutrophil aggregates) and in vitro.3. Platelet P-selectin adhesion to neutrophils8 : In the report by Ott et al,1 surface P-selectin expression is increased on the platelets of unstable angina patients. P-selectin is an adhesion molecule found on venular endothelium and platelets and is stored in both platelet granules and Weibel-Palade bodies in the endothelium.9 It is rapidly mobilized to the surface by molecules such as thrombin,10 which is of obvious pertinence to a thrombotic process. P-selectin on endothelium is thought to be critical to the initial margination of leukocytes that precedes their localization early on reperfusion of the previously ischemic myocardial infarct.11 P-selectin is known to adhere to sialated Lewisx residues, and a specific glycoprotein containing these residues, PSGL-1, has recently been localized to neutrophils and shown to be important for "rolling" of neutrophils on the P-selectin surfaces at physiological shear stresses.1213 However, P-selectin adhesion to neutrophils is relatively short-lived and not sufficient for neutrophil stopping and transmigration across the venular endothelial wall. The mechanism of this reduction in adhesion is not completely understood, but recent data suggest it may be intimately associated with activation of the neutrophil.14 In the first place, P-selectin adhesion to neutrophils results in neutrophil activation15 with upregulation of CD11b/CD18 and reduction of L-selectin on the surface of neutrophils quite similar to that observed in the platelet-neutrophil aggregates in the current study. Activation of neutrophils, however, also results in a redistribution of the P-selectin ligand so that there is a reduction in the apparent affinity of neutrophils for P-selectin on platelets.14 From a teleological point of view, the ability of the P-selectin to "let go" after stabilization of integrin adhesion to the endothelium is probably an important process in neutrophil-transendothelium migration. These findings further suggest that platelet-neutrophil aggregates are intrinsically unstable under conditions of shear stress (in the bloodstream) and that finding such significant quantities of such aggregates probably predicts ongoing formation of these aggregates.Platelet Membranes and Neutrophil Activation In VitroOtt and coworkers1 also reported that platelet membranes isolated from unactivated platelets of normal subjects were capable of adhering to neutrophils and initiating neutrophil activation similar to that described for P-selectin–neutrophil interactions. There may be some modest expression of P-selectin in normal platelets isolated from blood, and it would be of interest to know whether anti–P-selectin antibodies are capable of inhibiting this phenomenon. Obviously, the presence of sufficient thrombospondin or fibrinogen to explain the in vitro studies seems very unlikely on the basis of the methods used. In the absence of an effect of a P-selectin antagonist, additional mechanisms of platelet-neutrophil interaction may be uncovered.Pathophysiological Significance of Platelet-Neutrophil Interaction in Unstable AnginaRegardless of the mechanism, it is very likely that the neutrophil encounters the platelet in the coronary artery at the site of an unstable plaque. The breaking off of platelet aggregates associated with activated neutrophils clearly must be occurring, and the intrinsic instability of all of these interactions is compatible with the observations reported in the article by Ott et al. The question remaining is whether this neutrophil-platelet interaction is an epiphenomenon of platelet activation or whether platelet-neutrophil interaction has additional pathophysiological significance in its own right that would require pharmacological intervention. We will consider the labile plaque, the "downstream" coronary microvascular bed, and other organs.1. Coronary artery plaque: The data presented are certainly most easily explained by the association of the neutrophil with platelet thrombi as a result of activation on a labile plaque site with denuded endothelium. The pathophysiological significance of neutrophils deposited on platelets at such a site is unknown. Neutrophils secrete vasoactive substances, such as thromboxane A2 and leukotriene B4, that are important vasoconstrictors, platelet-activating agents, and leukocytotactic agents.1617 It is conceivable that these agents might aggravate the thrombotic and ischemic process. In addition, several experimental models of coronary occlusion have demonstrated localized neutrophil infiltration at the site of coronary occlusion associated with abnormalities of endothelial function.1819 On the other hand, neutrophils and monocytes also have been shown to inhibit platelet aggregation by release of a nitric oxide–like factor,20 a function that is facilitated by aspirin.212. Microvascular bed in the myocardium: Neutrophil infiltration associated with reperfusion of a myocardial infarction is a potential source of reperfusion injury.11 Current concepts of the mechanisms involved suggest that neutrophils marginate the venular beds early on reperfusion as a result of adhesion interactions involving both L-selectin on neutrophils and P-selectin on endothelial cells with their associated ligands. This is followed by a stable adhesion resulting from activation of leukocyte integrins and adhesion to intercellular adhesion molecule-1 in cardiac endothelium to allow transendothelial migration into the tissue.11 The circulating neutrophils associated with platelet-neutrophil aggregates described by Ott et al1 have markedly downregulated L-selectin. In general, reduction of surface L-selectin markedly reduces the likelihood of neutrophil rolling and adhesion to venular endothelium.22 In addition, the intravascular stimulus that markedly upregulates CD11b/CD18 and activates the neutrophil reduces the effectiveness of extravascular leukocytotactic stimuli. These factors do not preclude the possibility of capillary trapping of neutrophil-platelet aggregates in the microcirculation, where they might secrete vasoactive substances, but these aggregates would be quite ephemeral. Thus, intravascular activation of neutrophils might actually preclude or protect the tissue from neutrophil infiltration.3. Systemic inflammation: Ott and coworkers1 briefly speculate on systemic inflammatory response syndromes that result from platelet-neutrophil interaction in unstable coronary syndromes. We would agree that intravascular platelet-neutrophil interaction and intravascular neutrophil activation are potentially important factors in systemic inflammatory states, presumably acting by sequestration in remote organs. The observation of such systemic inflammatory states, which frequently are associated with remote pulmonary dysfunction, indicates that they usually involve much larger stimuli, such as passive complement activation resulting from oxygenators, crush injuries, or other potent proteolytic challenges. In view of the relative instability of these aggregates and the much lesser quantity of activation anticipated from an active atherosclerotic plaque, it seems unlikely that such a possibility would be associated with unstable angina. Certainly there are no reports of such a syndrome.The cited work of Maseri and coworkers23 suggesting a poor prognosis for unstable angina associated with elevations of C-reactive protein may stem from an inflammatory reaction at a different site. C-reactive protein is excreted from the liver in response to elevations of circulating interleukin-6. Interleukin-6 is a cytokine that is rapidly induced after reperfusion of the infarcted myocardium24 and has been found clinically in patients with myocardial infarction.2526 It is possible that elevations of C-reactive proteins seen in unstable angina result from the coincidence of myocardial infarction.Therapeutic SignificanceObviously, alteration of the therapeutic approach to unstable angina as a result of the observations within this report is premature without an understanding of the issues described above. The most conservative position would be that approaches involving antiplatelet and antithrombin therapy should be sufficient. Thus, by altering the thrombotic process, one would markedly reduce or preclude the formation of platelet-neutrophil aggregates. We would favor this position, because platelet-neutrophil aggregates are not particularly stable and appropriate treatment of the thrombotic process should be sufficient to eliminate the platelet-neutrophil aggregate as a pathophysiological entity. In view of the ability of neutrophils and neutrophils plus aspirin to reduce platelet aggregation,2021 antileukocyte therapy should be approached with caution. More information will be required to justify a more aggressive approach.SummaryIn summary, the study by Ott and coworkers1 provides an excellent basis for further investigation into the mechanisms of unstable angina. It clearly provides a potential laboratory approach to following the thrombotic activity at the surface of a coronary plaque that is unstable. Further documentation of the relationship between clinical markers of unstable angina and the laboratory tests described herein is clearly of great importance. The potential pathophysiological role of the addition of neutrophils to the thrombotic process is less clear.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.The authors are supported by a grant (HL-42550) from the NHLBI and by the American Heart Association. Dr Ballantyne is an Established Investigator of the American Heart Association. The authors wish to thank Sharon Malinowski for her assistance in the preparation of the manuscript.FootnotesCorrespondence to Mark L. Entman, MD, Baylor College of Medicine, Department of Medicine, Section of Cardiovascular Sciences, One Baylor Plaza, Houston, TX 77030. E-mail: [email protected] References 1 Ott I, Neumann F-J, Gawaz M, Schmitt M, Scho¨mig A. Increased neutrophil-platelet adhesion in patients with unstable angina. Circulation.1996; 94:1239-1246.CrossrefMedlineGoogle Scholar2 Gawaz M, Loftus JC, Bajt ML, Frojmoviv MM, Plow EF, Ginsberg MH. Ligand bridging mediates integrin (platelet GPIIb-IIIa) dependent homotypic and heterotypic cell-cell interactions. J Clin Invest.1991; 88:1128-1134.CrossrefMedlineGoogle Scholar3 Altieri DC, Bader R, Mannucci PM, Edgington TS. Oligospecificity of the cellular adhesion receptor Mac-1 encompasses an inducible recognition specificity for fibrinogen. J Cell Biol.1988; 107:1893-1900.CrossrefMedlineGoogle Scholar4 Wright SD, Levin SM, Jong MTC, Chad Z, Kabbash LG. CR3 (CD11b/CD18) expresses one binding site for Arg-Gly-Asp-containing peptides and a second site for bacterial lipopolysaccharide. J Exp Med.1989; 169:175-183.CrossrefMedlineGoogle Scholar5 Hughes BJ, Hollers JC, Crockett-Torabi E, Smith CW. Recruitment of CD11b/CD18 to the neutrophil surface and adherence-dependent cell locomotion. 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P-selectin- and CD18-mediated recruitment of canine neutrophils under conditions of shear stress. Vet Pathol.1995; 32:258-268.CrossrefMedlineGoogle Scholar16 Michael LH, Zhang Z, Hartley CJ, Bolli R, Taylor AA, Entman ML. Thromboxane B2 in cardiac lymph: effect of superoxide dismutase and catalase during myocardial ischemia and reperfusion. Circ Res.1990; 66:1040-1044.CrossrefMedlineGoogle Scholar17 Mullane KM, Salmon JA, Kraemer R. Leukocyte-derived metabolites of arachidonic acid in ischemia-induced myocardial injury. Fed Proc.1987; 46:2422-2433.MedlineGoogle Scholar18 Viehman GE, Ma X-L, Lefer DJ, Lefer AM. Time course of endothelial dysfunction and myocardial injury during coronary arterial occlusion. Am J Physiol.1991; 261:H874-H881.MedlineGoogle Scholar19 Sheridan FM, Dauber IM, McMurtry IF, Lesnefsky EJ, Horwitz LD. Role of leukocytes in coronary vascular endothelial injury due to ischemia and reperfusion. Circ Res.1991; 69:1566-1574.CrossrefMedlineGoogle Scholar20 Salvemini D, deNucci G, Gryglewski RJ, Vane JR. Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor. Proc Natl Acad Sci U S A.1989; 86:6328-6332.CrossrefMedlineGoogle Scholar21 Lopez-Farre A, Caramelo C, Esteban A, Alberola ML, Millas I, Monton M, Casado S. Effects of aspirin on platelet-neutrophil interactions. Circulation.1995; 91:2080-2088.CrossrefMedlineGoogle Scholar22 Kishimoto TK, Jutila MA, Berg EL, Butcher EC. Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. Science.1989; 245:1238-1241.CrossrefMedlineGoogle Scholar23 Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med.1994; 331:417-424.CrossrefMedlineGoogle Scholar24 Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML. Induction of interleukin-6 synthesis in the myocardium: potential role in postreperfusion inflammatory injury. Circulation.1995; 92:1866-1875.CrossrefMedlineGoogle Scholar25 Ikeda U, Ohkawa F, Seino Y, Yamamoto K, Hidaka Y, Kasahara T, Kawai T, Shimada K. Serum interleukin 6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol.1992; 24:579-584.CrossrefMedlineGoogle Scholar26 Miyao Y, Yasue H, Ogawa H, Misumi I, Masuda T, Sakamoto T, Morita E. Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J.1993; 126:1299-1304.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Huang J, Xiao Y, Xu A and Zhou Z (2016) Neutrophils in type 1 diabetes, Journal of Diabetes Investigation, 10.1111/jdi.12469, 7:5, (652-663), Online publication date: 1-Sep-2016. 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Doré M (1998) Platelet-leukocyte interactions, American Heart Journal, 10.1016/S0002-8703(98)70242-X, 135:5, (S146-S151), Online publication date: 1-May-1998. September 15, 1996Vol 94, Issue 6 Advertisement Article InformationMetrics Copyright © 1996 by American Heart Associationhttps://doi.org/10.1161/01.CIR.94.6.1206 Originally publishedSeptember 15, 1996 KeywordsEditorialsblood cellsplateletsangina Advertisement