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Platelet-leukocyte interactions in thrombosis

  • Chiara Cerletti
    Correspondence
    Corresponding author at: Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, Largo Gemelli, 1, 86100 CAMPOBASSO, Italy. Tel.: +39 0874 312 277; fax: +39 0874 312 710.
    Affiliations
    Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, 86100 Campobasso, Italy
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  • Chiara Tamburrelli
    Affiliations
    Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, 86100 Campobasso, Italy
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  • Author Footnotes
    1 Present address: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
    Benedetta Izzi
    Footnotes
    1 Present address: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
    Affiliations
    Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, 86100 Campobasso, Italy
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  • Francesco Gianfagna
    Affiliations
    Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, 86100 Campobasso, Italy
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  • Giovanni de Gaetano
    Affiliations
    Research Laboratories, Fondazione di Ricerca e Cura “Giovanni Paolo II”, Università Cattolica, 86100 Campobasso, Italy
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  • Author Footnotes
    1 Present address: Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Published:November 11, 2011DOI:https://doi.org/10.1016/j.thromres.2011.10.010

      Abstract

      Activated platelets may adhere to leukocytes and form circulating mixed aggregates. The latter are considered a reliable marker of a prothrombotic state and are associated with several cardiovascular conditions. The molecular mechanisms responsible of this cellular interaction include a central role of platelet P-selectin and of P-selectin glycoprotein ligand-1 (PSGL-1), its counter receptor on leukocytes in a signaling cascade, resulting in the activation of the beta-2 integrin Mac-1 and in the firm adhesion between the two cell types. The interaction of P-selectin with PSGL-1 also induces upregulation of leukocyte tissue factor, biosynthesis of several cytokines and other inflammatory reactions, thereby contributing to the thrombotic progression.
      In this review the main determinants of mixed aggregate formation, the heritability component, the major pathological conditions associated with higher levels of mixed aggregates in the circulation will be discussed. Besides current anti-platelet or antithrombotic drugs, natural compounds, such as the polyphenols present in vegetable foods and red wine, have been tested for their inhibitory effect on mixed aggregate formation. The promising results shown by studies in vitro and in experimental animal models, remain to be carefully investigated in humans. Platelet–leukocyte aggregates provide a novel link between inflammation and thrombosis, two central processes in atherogenesis. A better understanding of the role of platelet–leukocyte interactions in athero-thrombosis will be instrumental for the progress of prevention and treatment of ischaemic cardiovascular disease.

      Keywords

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      References

        • de Gaetano G.
        Historical overview of the role of platelets in hemostasis and thrombosis.
        Haematologica. 2001; 86: 349-356
        • Danesh J.
        • Collins R.
        • Appleby P.
        • Peto R.
        Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.
        JAMA. 1998; 13: 1477-1482
        • Coller B.S.
        Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene?.
        Arterioscler Thromb Vasc Biol. 2005; 25: 658-670
        • de Gaetano G.
        • Evangelista V.
        • Cerletti C.
        Should cardiologists forget about platelets and take an interest in blood leukocytes?.
        Ital Heart J. 2000; 1: 453-456
        • Landolfi R.
        • Di Gennaro L.
        • Barbui T.
        • De Stefano V.
        • Finazzi G.
        • Marfisi R.
        • et al.
        Marchioli R; European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP). Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.
        Blood. 2007; 109: 2446-2452
        • Gurm H.S.
        • Bhatt D.L.
        • Lincoff A.M.
        • Tcheng J.E.
        • Kereiakes D.J.
        • Kleiman N.S.
        • et al.
        Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials.
        Heart. 2003; 89: 1200-1204
        • de Gaetano G.
        A new blood corpuscle: an impossible interview with Giulio Bizzozero.
        Thromb Haemost. 2001; 86: 973-979
        • Wagner D.D.
        New links between inflammation and thrombosis.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1321-1324
        • Cerletti C.
        • Evangelista V.
        • de Gaetano G.
        P-selectin-beta 2-integrin cross-talk: a molecular mechanism for polymorphonuclear leukocyte recruitment at the site of vascular damage.
        Thromb Haemost. 1999; 82: 787-793
        • Cerletti C.
        • de Gaetano G.
        • Lorenzet R.
        Platelet - leukocyte interactions: multiple links between inflammation, blood coagulation and vascular risk.
        Mediterr J Hematol Infect Dis. 2010; 2: e2010023
        • Evangelista V.
        • Manarini S.
        • Rotondo S.
        • Martelli N.
        • Polischuk R.
        • McGregor J.L.
        • et al.
        Platelet/polymorphonuclear leukocyte interaction in dynamic conditions: evidence of adhesion cascade and cross talk between P-selectin and the beta 2 integrin CD11b/CD18.
        Blood. 1996; 88: 4183-4194
        • Diacovo T.G.
        • Roth S.J.
        • Buccola J.M.
        • Bainton D.F.
        • Springer T.A.
        Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18.
        Blood. 1996; 88: 146-157
        • Weber C.
        • Springer T.A.
        Neutrophil accumulation on activated, surface adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIbbeta3 and stimulated by platelet-activating factor.
        J Clin Invest. 1997; 100: 2085-2093
        • da Costa Martins P.A.
        • van Gils J.M.
        • Mol A.
        • Hordijk P.L.
        • Zwaginga J.J.
        Platelet binding to monocytes increases the adhesive properties of monocytes by up-regulating the expression and functionality of beta1 and beta2 integrins.
        J Leukoc Biol. 2006; 79: 499-507
        • Evangelista V.
        • Pamuklar Z.
        • Piccoli A.
        • Manarini S.
        • Dell'elba G.
        • Pecce R.
        • et al.
        Src family kinases mediate neutrophil adhesion to adherent platelets.
        Blood. 2007; 109: 2461-2469
        • Weyrich A.S.
        • Elstad M.R.
        • McEver R.P.
        • McIntyre T.M.
        • Moore K.L.
        • Morrissey J.H.
        • et al.
        Activated platelets signal chemokine synthesis by human monocytes.
        J Clin Invest. 1996; 97: 1525-1534
        • Henn V.
        • Slupsky J.R.
        • Gräfe M.
        • Anagnostopoulos I.
        • Förster R.
        • Müller-Berghaus G.
        • et al.
        CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.
        Nature. 1998; 391: 591-594
        • Li G.
        • Sanders J.M.
        • Bevard M.H.
        • Sun Z.
        • Chumley J.W.
        • Galkina E.V.
        • et al.
        CD40 ligand promotes Mac-1 expression, leukocyte recruitment, and neointima formation after vascular injury.
        Am J Pathol. 2008; 172: 1141-1152
        • Haselmayer P.
        • Grosse-Hovest L.
        • von Landenberg P.
        • Schild H.
        • Radsak M.P.
        TREM-1 ligand expression on platelets enhances neutrophil activation.
        Blood. 2007; : 1101029-1101035
        • Dai D.F.
        • Thajeb P.
        • Tu C.F.
        • Chiang F.T.
        • Chen C.H.
        • Yang R.B.
        • et al.
        Plasma concentration of SCUBE1, a novel platelet protein, is elevated in patients with acute coronary syndrome and ischemic stroke.
        J Am Coll Cardiol. 2008; 51: 2173-2180
        • Palabrica T.
        • Lobb R.
        • Furie B.C.
        • Aronovitz M.
        • Benjamin C.
        • Hsu Y.M.
        • et al.
        Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets.
        Nature. 1992; 359: 848-851
        • Celi A.
        • Pellegrini G.
        • Lorenzet R.
        • De Blasi A.
        • Ready N.
        • Furie B.C.
        • et al.
        P-selectin induces the expression of tissue factor on monocytes.
        Proc Natl Acad Sci U S A. 1994; 91: 8767-8771
        • Maugeri N.
        • Brambilla M.
        • Camera M.
        • Carbone A.
        • Tremoli E.
        • Donati M.B.
        • et al.
        Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation.
        J Thromb Haemost. 2006; 4: 1323-1330
        • Izzi B.
        • Pampuch A.
        • Costanzo S.
        • Vohnout B.
        • Iacoviello L.
        • Cerletti C.
        • et al.
        Determinants of platelet conjugate formation with polymorphonuclear leukocytes or monocytes in whole blood.
        Thromb Haemost. 2007; 98: 1276-1284
        • Cerletti C.
        • Maugeri N.
        • Evangelista V.
        • de Gaetano G.
        Platelet-leukocyte interaction and atherothrombosis.
        in: Arnout J. de Gaetano G. Hoylaerts M. Peerlinck K. Van Geet C. Verhaeghe R. Thrombosis. Fundamental and clinical aspects. Leuven University Press, 2003: 305-326
        • Maugeri N.
        • Giordano G.
        • Petrilli M.P.
        • Fraticelli V.
        • de Gaetano G.
        • Cerletti C.
        • et al.
        Inhibition of tissue factor expression by hydroxyurea in polymorphonuclear leukocytes from patients with myeloproliferative disorders: a new effect for an old drug?.
        J Thromb Haemost. 2006; 4: 2593-2598
        • Totani L.
        • Evangelista V.
        Platelet-leukocyte interactions in cardiovascular disease and beyond.
        Arterioscler Thromb Vasc Biol. 2010; 30: 2357-2361
      1. Tamburrelli C, Gianfagna F, D'Imperio M, De Curtis A, Rotilio D, Iacoviello L, de Gaetano G, Donati M B, Cerletti C. Postprandial cell inflammatory response to a standardized fatty meal in subjects at intermediate cardiovascular risk. Submitted for publication.

        • Nemmar A.
        • Hoet P.H.
        • Vandervoort P.
        • Dinsdale D.
        • Nemery B.
        • Hoylaerts M.F.
        Enhanced peripheral thrombogenicity after lung inflammation is mediated by platelet-leukocyte activation: role of P-selectin.
        J Thromb Haemost. 2007; 5: 1217-1226
        • Ray M.R.
        • Mukherjee S.
        • Roychoudhury S.
        • Bhattacharya P.
        • Banerjee M.
        • Siddique S.
        • et al.
        Platelet activation, upregulation of CD11b/ CD18 expression on leukocytes and increase in circulating leukocyte-platelet aggregates in Indian women chronically exposed to biomass smoke.
        Hum Exp Toxicol. 2006; 25: 627-635
        • Alberti S.
        • Angeloni G.
        • Tamburrelli C.
        • Pampuch A.
        • Izzi B.
        • Messano L.
        • et al.
        Platelet-leukocyte mixed conjugates in patients with atrial fibrillation.
        Platelets. 2009; 20: 235-241
      2. Gianfagna F, Tamburrelli C, Vohnout B, Crescente M, Izzi B, Pampuch A, De Curtis A, Di Castelnuovo A, Cutrone A, Napoleone E, Tayo B, Lorenzet R, Nanni L, Arca M, Donati M B, de Gaetano G, Cerletti C and Iacoviello L on behalf of the Moli-family Study Investigators. Platelet-leukocyte interactions in families with and without early myocardial infarction. Submitted for publication.

        • Freedman J.E.
        • Larson M.G.
        • Tanriverdi K.
        • et al.
        Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart study.
        Circulation. 2010; 122: 119-129
        • Graff J.
        • Harder S.
        • Wahl O.
        • Scheuermann E.H.
        • Gossmann J.
        Anti-inflammatory effects of clopidogrel intake in renal transplant patients: effects on plateletleukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers.
        Clin Pharmacol Ther. 2005; 78: 468-476
        • Braun O.O.
        • Johnell M.
        • Varenhorst C.
        • James S.
        • Brandt J.T.
        • Jakubowski J.A.
        • et al.
        Greater reduction of platelet activation markers and platelet–monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease.
        Thromb Haemost. 2008; 100: 626-633
        • Steiner S.
        • Seidinger D.
        • Huber K.
        • Kaun C.
        • Minar E.
        • Kopp C.W.
        Effect of glycoprotein IIb/IIIa antagonist abciximab on monocyte-platelet aggregates and tissue factor expression.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1697-1702
        • Del Maschio A.
        • Evangelista V.
        • Rajtar G.
        • Chen Z.M.
        • Cerletti C.
        • de Gaetano G.
        Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents.
        Am J Physiol. 1990; 258: H870-H879
        • Lukasik M.
        • Dworacki G.
        • Michalak S.
        • Kufel-Grabowska J.
        • Golanski J.
        • Watala C.
        • et al.
        Aspirin treatment influences platelet-related inflammatory biomarkers in healthy individuals but not in acute stroke patients.
        Thromb Res. 2011; 128: e78-e80
        • Tamburrelli C.
        • Crescente M.
        • Izzi B.
        • Barisciano M.
        • Donati M.B.
        • de Gaetano G.
        • et al.
        Epoprostenol inhibits human platelet-leukocyte mixed conjugate and platelet microparticle formation in whole blood.
        Thrombosis Research. 2011; 128: 446-451
        • Maugeri N.
        • Di Fabio G.
        • Barbanti M.
        • de Gaetano G.
        • Donati M.B.
        • Cerletti C.
        Parnaparin, a low-molecular-weight heparin, prevents P-selectin-dependent formation of platelet-leukocyte aggregates in human whole blood.
        Thromb Haemost. 2007; 97: 965-973
        • Gresele P.
        • Cerletti C.
        • Guglielmini G.
        • Pignatelli P.
        • de Gaetano G.
        • Violi F.
        Effects of resveratrol and other wine polyphenols on vascular function: an update.
        J Nutr Biochem. 2011; 22: 201-211