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Platelets in Inflammation and Atherogenesis

Henry M. Nording, Peter Seizer, Harald F. Langer

Frontiers in Immunology · 2015 · Review

doi:10.3389/fimmu.2015.00098

Abstract

Platelets contribute to processes beyond thrombus formation and may play a so far underestimated role as an immune cell in various circumstances. This review outlines immune functions of platelets in host defense, but also how they may contribute to mechanisms of infectious diseases. A particular emphasis is placed on the interaction of platelets with other immune cells. Furthermore, this article outlines the features of atherosclerosis as an inflammatory vascular disease highlighting the role of platelet crosstalk with cellular and soluble factors involved in atheroprogression. Understanding, how platelets influence these processes of vascular remodeling will shed light on their role for tissue homeostasis beyond intravascular thrombosis. Finally, translational implications of platelet-mediated inflammation in atherosclerosis are discussed.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The vasculature is one of the large networks of the human body and, thus, it needs to be well protected by immune mechanisms. When tissue is injured, the wound is paralleled by a severance of the vascular network, as well. Disruption of the endothelial monolayer lining all vessels from the inside triggers a process referred to as thrombus formation, a well regulated and complex cascade of events. During thrombus formation, other systems located within the vasculature can be activated, the most prominent of which is the immune system and inflammation being a part of its innate response. The inflammatory response to tissue injury triggers various events, which allow for defense against possible intruders and initiate the healing process. Simultaneously and in close proximity, platelets are recruited to the wound to restore endothelial integrity; they are activated and initiate thrombus formation. Given the close spatiotemporal relationship of these molecular processes, it is not surprising that growing evidence suggests that platelets are not only effectors of thrombus formation, but actively participate in inflammation and other processes related to tissue remodeling.

Platelets Preserve Vascular Integrity

Repair of vascular damage while simultaneously preserving the patency of narrow capillaries is a complex task and requires a finely tuned machinery of pro- as well as anti-thrombotic mechanisms. Platelets are the key cells of primary hemostasis and thrombus formation. They mediate thrombus formation through cellular and soluble factors [recently also reviewed in Ref.]. GPIbα is a platelet transmembrane receptor associated with GPIX and GPV. GPIbα binding to von-Willebrand-factor (vWF) initiates primary hemostasis. In a shear-dependent fashion, GPIbα binding to vWF immobilized on collagen enables initial platelet rolling, which precedes all further steps of thrombus formation. Except at sites of high shear rates, stable platelet adhesion requires additional contribution of GPVI and integrins. GPVI is one of the platelet collagen receptors. It provides strong mechanic adhesion but also serves as the primary inducer of platelet activation mediated by its FcRγ-chain. Amongst other signaling events, activation of GPVI causes an elevation of intracellular Ca2+ and subsequent platelet shape change. Platelet activation is paralleled by the secretion of soluble factors from platelet granules, the most important of which are ADP and TxA2, as they activate platelets in an autocrine fashion. C-type lectin-like type II (CLEC-2) supports GPVI as it sustains a similar signaling pathway as the one induced by the GPVI/FcRγ complex. In fact, CLEC-2 was found to be of particular importance for stable aggregate formation under flow conditions. The thrombotic activity of platelets is regulated by controlling the surface density of these major receptors by ectodomain shedding. A central process in platelet-mediated thrombus formation is integrin activation, as integrins connect the ECM to the platelets’ cytoskeleton and enable platelet aggregate formation. The integrin αIIbβ3 has the ability to “crosslink” platelets via fibrinogen-bridging, thus stabilizing the forming thrombus. Due to its central importance, its inside-out activation is referred to as the “final common pathway of platelet activation”. The activation of αIIbβ3 is mediated by the classical platelet agonists ADP or TxA2, and interfering with these pathways was successfully transferred into patient treatment. Similar to other integrins, αIIbβ3 promotes “outside-in” signaling as well as platelet spreading and clot retraction. Finally, platelets also interact with the coagulation system in various ways stabilizing the developing thrombus by fibrin formation, which provides for provisional wound closure.

“Non-Classical” Platelet Functions

Although traditionally not conceived as immune cells, platelets hold important functions in the immune response, particularly in innate immunity. In both host defense and preservation of vascular functions, platelets are helpful in some and harmful in other conditions. In the following, we will aim to exemplify how platelets mediate effects beyond thrombus formation.

Platelets in host defense

Platelets contribute to pathogen recognition by interacting with immune cells, but also by interacting with the bacteria themselves. Recently, it was demonstrated that platelet-rich plasma (PRP) inhibited the growth of bacteria. The various receptor interactions involved in this platelet–bacteria crosstalk were already reviewed elsewhere. For instance, platelets are able to recognize CpG islands upon thrombin activation and subsequent TLR9 expression. Furthermore, platelets react to fungal infections in vitro and in vivo. Finally, platelet “nuclear functions” are increasingly uncovered and recognized. Via transcription of mRNA and post-transcriptional modification, platelets seem to contribute to the inflammasome by producing IL-1β, they are involved in modulating NFκB and may influence endothelial polarization by miRNA secretion.

Platelets contributing to mechanisms of infections

On the other hand, there are a number of reports describing platelets as an important element in the progression of infections. The platelet receptor CLEC-2 has been shown to facilitate the entry of HI-viruses, and platelets contribute to disease progression via CD40L. Furthermore, platelets are involved in the progression of HBV-infection and other viral diseases by the recruitment of cytotoxic T-cells (CTL) to the liver or other organs in a serotonin-dependent manner. Verschoor et al. could recently show that platelets are a relevant factor in the process of immune evasion by intracellular bacteria such as Listeria. Furthermore, platelets play an important role in infections by Leishmania and in the pathogenesis of Hantavirus infection. A fact, which complicates the picture even more, is that platelets can also modulate the function of further cells involved in the response to infections – the leukocyte.

Platelet crosstalk with immune cells

One of the main immune mechanisms of platelets is their capability to recruit leukocytes to sites of infection and inflammation. P-selectin–PSGL-1 binding, ICAM1, and GPIbα play an important role in how platelets bring other immune cells to the scene, particularly under high shear conditions. Platelets have the ability to form aggregates with neutrophils. In periodontitis, aggregate formation of platelets and neutrophils (NPA) enhances neutrophil phagocytosis in a TLR-2-dependent manner. In acute lung injury, NPA formation mediates neutrophil extravasation and platelet-derived platelet factor 4 (PF4) fostered neutrophil survival in a model of arterial occlusion. Furthermore, platelet–leukocyte aggregates can be used as a diagnostic tool, for example as a parameter to assess sepsis severity. Another recently discovered way, how platelets modulate neutrophil function is their involvement in neutrophil extracellular trap (NET) formation to ensnare intruders. Platelet TLR-4 as well as platelet β-defensins have been implicated in NET formation. Specifically, platelet-induced NET formation may play a role in viral infections or transfusion-related lung injury. Rossaint et al. have recently proposed that simultaneous activation of neutrophils via Mac-1 outside-in signaling and Gαi engagement by platelet-derived RANTES–PF4 heterodimers is required for NET formation. Interestingly, platelets seem to form especially stable aggregates with monocytes, and activated platelets induce an inflammatory monocyte phenotype. As this process seems to be partially independent of P-selectin interaction with PSGL-1, paracrine mechanisms to strengthen platelet–monocyte aggregate formation have been proposed as an alternative mechanism. Platelet–monocyte interaction seems to be of functional relevance, as their formation increases the number of circulating monocytes with a higher affinity for adhesion to the endothelium. Furthermore, activated platelets are taken up by monocytes which induces enhancement of cytokine release from macrophages. Other authors, however, report on anti-inflammatory effects of platelet–monocyte interaction via CXCR5 engagement of CXCL13 on monocytes or, following experimental sepsis, by inhibition of macrophage tumor necrosis factor α (TNF-α) and IL-6 secretion. Thus, the effect of platelets on monocytes appears to be context-dependent.

Via P-selectin PSGL-1 interaction, platelets can form aggregates with lymphocytes (PLA), as well. Platelet interaction with T-cells, B-cells, and NK-cells induces their homing, activation, and recruitment as recently reviewed. Platelets may even serve as a bridge directing T-cells to the endothelium. Furthermore, platelets modulate lymphocyte function via direct cell–cell interaction as well as soluble mediators. In rheumatoid arthritis patients, platelet binding to lymphocytes promoted activation-induced proliferation as well as IL-17 and interferon-γ production by GPVI positive CD4+ T-cells. Serotonin from platelet vesicles may also stimulate T-lymphocytes. Through release of PF4 and CCL5, platelets can enhance cytokine production in CD4+ T-cells. Furthermore, in HCV infection, platelet CCL5 causes upregulation of T-lymphocyte helper cells type 1 (Th1). Finally, platelets may also enhance T-cell-mediated germinal center formation and release of specific IgGs from B-cells via CD40L signaling. In fact, platelets may substitute CD40L when few CD40L-positive T-cells are present to stimulate B-cell maturation. However, platelets may also induce anti-inflammatory effects. PF4 released from platelets leads to an increase in regulatory T-lymphocytes (Tregs) and limits Th17 differentiation. Interestingly, T-lymphocytes can activate platelets, which amplify the release of CCL5. Addressing antigen-presenting cells, there are a number of ways in which platelets interact with dendritic cells (DCs). For instance, platelets can recruit DC via Mac-1 interaction with JAM-C and can activate them inducing platelet phagocytosis and subsequently apoptosis of DCs. High shear rates may be a trigger for platelets to recruit DCs and promote their maturation. In fact, direct contact of platelets and DCs seems to induce other effects than crosstalk via soluble factors suggesting that platelets have the ability to differentially regulate a DC response. This conclusion is supported by recent findings demonstrating that platelets can enhance DC-mediated Th-2 cell response in allergy by secreted RANKL. Platelets can, however, also impair DC differentiation or reduce DC production of proinflammatory cytokines IL-12p70 and TNF-α.

Platelets in Atherosclerosis

Atherosclerosis is a chronic inflammatory disease featuring various complex processes contributing to its pathophysiology and the development of the atherosclerotic plaque over decades. Figure 1 summarizes the steps contributing to fatty streak formation, inflammation, progression of the plaque, and finally plaque rupture.

Platelet contribution to atherosclerosis

In atherosclerosis, platelets are known to contribute to early steps of this chronic vascular pathology (Figure 2) such as endothelial dysfunction, but also to final events such as rupture of the vulnerable plaque [, see also Figure 4]. For instance, platelets participate in atherogenesis by chemokine release, surface association of oxLDL, direct cell–cell interaction, release of microparticles, and provision of inflammatory mediators [, see also Figure 3]. Platelets within the atherosclerotic plaque may remain activated for a long time providing for proinflammatory IL-1β production [, see also Figure 3]. One of the most considered functions of platelets in atherosclerosis is the recruitment of leukocytes via direct receptor–ligand interactions or augmented by released factors such as chemokines [, see also previous sections and Figure 3]. The role of a particular leukocyte subtype – DCs, the classical antigen presenting cells of our body – has been emphasized recently in the context of atherosclerosis and, interestingly, platelets interact with DCs (Figure 3). In fact, GPIb–Mac-1 interaction may be an interesting signaling mechanism in the context of platelet–DC crosstalk modulating atheroprogression. This is of particular importance, as DCs have been proposed to play a significant role in the different steps of atherosclerosis.

Platelets in the complement system and atherosclerosis

A further part of our innate immune response, the complement system receives increasing attention in the context of atherosclerosis. This cascade of soluble plasma proteins constitutes a phylogenetically very old part of the inherited immune system. Complement activation is important for inflammatory conditions associated with vascular injury. Most interestingly, platelets were reported to express a number of complement receptors relevant for platelet function and their crosstalk with the local microenvironment. Several complement components can be bound to the platelet surface. We found that expression of complement anaphylatoxin receptors on platelets showed a strong and positive correlation with platelet activation markers such as P-selectin in patients with atherosclerosis. Further mechanistic studies will have to address the relevance of this association. In a recent review, the literature on platelets and potential intersection points with the complement system in diverse settings was summarized. Additional profound studies are needed to differentiate our understanding of the intersection points of platelet activation with the immunological elements of atherogenesis such as endothelial inflammation, leukocyte recruitment, antigen presentation, chemokine and cytokine production, or complement activation.

Plaque rupture

At later stages, the atherosclerotic core becomes hypoxic inducing the outgrowth of vasa vasorum from the adventitia toward the intima [, see also Figure 4]. As a consequence, fragile and leaky vessels form, which facilitate further invasion of immune cells and release of soluble factors into the surrounding atherosclerotic tissue. Moreover, red blood cells get stuck in the plaque liberating hemoglobin and iron. These mechanisms ultimately result in plaque destabilization. Foam cells produce tissue factor, and as soon as the thrombogenic lipid core is exposed to the lumen, fibrin generation is initiated. In parallel, platelets as well as the coagulation cascade become activated. Plaque rupture in the region of a thin fibrous cap is the final event, how atherosclerosis causes acute vascular complications such as myocardial infarction or stroke.

Translational relevance

The fact that inflammation plays a key role in central steps of atherosclerosis, is increasingly integrated into clinical considerations. Accordingly, this hypothesis is addressed by two current trials, the CANTOS trial launched in 2011 and the CIRT trial using immunosuppressants to treat atherosclerosis. Earlier in this article, we have aimed at depicting the importance of platelets for inflammation in atherosclerosis. Inhibition of platelet-mediated inflammation may already be everyday clinical practice considering the use of aspirin for the treatment of cardiovascular disease. As an irreversible inhibitor of the enzyme cyclooxygenase, aspirin is a mild inhibitor of platelet function. Despite its widespread use, the definite role of aspirin in the prevention of atherosclerosis and atherosclerosis-related diseases is still under discussion. There is evidence from preclinical studies that aspirin is able to inhibit the initiation and even the progression of experimental atherosclerosis via its effect on prostaglandin synthesis but also by other mechanisms such as the modulation of endothelial NO synthesis, NFκB signaling, CRP, or soluble CD40 ligand (sCD40L). Clinical studies on the use of aspirin for primary prevention of atherosclerosis, however, have also yielded negative results [recently reviewed by Gaziano and Greenland]. A large study in a Japanese population over 60 years of age could demonstrate no benefit of low-dose aspirin therapy. In patients at low risk for cardiovascular events, the use of aspirin needs to be weighed very carefully against an elevated risk of bleeding events or even hemorrhagic stroke.

For the ADP-receptor antagonist clopidogrel, reports on an effect in the context of atherosclerosis exist, too. In animal models, clopidogrel has the ability to slow down the inflammatory progression of atherosclerosis. Clopidogrel reduces platelet activation as measured by P-selectin expression and other inflammatory markers, while others stress that important inflammatory markers such as hsCRP are not affected. On the other hand, platelet–leukocyte aggregate formation is inhibited more effectively by clopidogrel compared to aspirin. In contrast, another group reported that under therapy with clopidogrel, the expression of some inflammatory chemokines may even be increased in peripheral blood mononuclear cells in patients with coronary artery disease. On the platelet surface, a number of inflammatory receptors may represent potential targets for new therapeutic approaches such as CXCL4, CCL5, CD40 ligand, PSGL-1. Further targets may be platelet-activating factor (PAF) or Annexin A5. Finally, we have already described the evidence on complement receptor involvement in atherosclerosis. This class of receptors are involved in a large number of inflammatory processes and are also expressed on platelets. There are a number of substances targeting different parts of the complement system which are evaluated in different stages of clinical trials in conditions such as age-related macular degeneration or hereditary angioedema. Some have even established themselves as first-line treatment such as eculizumab for paroxysmal nocturnal hemoglobinuria. It is tempting to speculate, that these substances might be worth an evaluation in the context of atherosclerosis, as well.

Moreover, biomarkers of atherosclerosis are of great importance from a clinical point of view. Due to the high prevalence of cardiovascular disease, it is vital to identify which patient is at particular risk for adverse cardiovascular events and would benefit from preventive diagnostic or therapeutic interventions. A number of platelet surface receptors may be promising candidates to consider in this context. A prominent example is soluble CD40 ligand (sCD40L) released from platelets. In a number of settings such as on hospital admission of patients with acute coronary syndrome or in patients undergoing primary angioplasty, sCD40L levels appear to have predictive capacity. Some authors even discuss sCD40L as a therapeutic target. Apart from sCD40L, soluble P-selectin released from platelets is referred to as a further potential platelet-derived biomarker.

Considering the achievements of platelet research over the last two decades with a bounty of platelet-targeted drugs, which found their way into everyday clinical practice, platelets and platelet-associated molecular mechanisms offer potential translational applications.

Conclusion

In conclusion, platelets – conceived as immune cells and mediators of vascular/tissue remodeling – have a strong impact on atherosclerosis through inflammatory mechanisms discussed here on the basis of selected cellular or soluble platelet-derived mediators. The net effect of platelet-mediated inflammation may be an atheropromoting one, although these anucleate cells may mediate distinct atheroprotective mechanisms, as well. Future investigations will have to identify these specific platelet aspects to enable us to develop better diagnostic markers and therapeutic approaches with fewer undesired side effects.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Pate KAM Lyons CE Dorsey JL Shirk EN Queen SE Adams RJ Platelet activation and platelet-monocyte aggregate formation contribute to decreased platelet count during acute simian immunodeficiency virus infection in pig-tailed macaques. J Infect Dis (2013 ) 208(6):874–83.

    Not in our library10.1093/infdis/jit278

  55. 55.

    Singh MV Davidson DC Jackson JW Singh VB Silva J Ramirez SH Characterization of platelet-monocyte complexes in hiv-1-infected individuals: possible role in HIV-associated neuroinflammation. J Immunol (2014 ) 192(10):4674–84.

    Not in our library10.4049/jimmunol.1302318

  56. 56.

    Iannacone M Sitia G Narvaiza I Ruggeri ZM Guidotti LG. Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus. Clin Vaccine Immunol (2007 ) 14(11):1532–5.

    Not in our library10.1128/cvi.00298-07

  57. 57.

    Iannacone M Sitia G Isogawa M Whitmire JK Marchese P Chisari FV Platelets prevent IFN-α/β-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci U S A (2008 ) 105(2):629–34.

    Not in our library10.1073/pnas.0711200105

  58. 58.

    Iannacone M Sitia G Isogawa M Marchese P Castro MG Lowenstein PR Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med (2005 ) 11(11):1167–9.

    Not in our library10.1038/nm1317

  59. 59.

    Lang PA Contaldo C Georgiev P El-Badry AM Recher M Kurrer M Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med (2008 ) 14(7):756–61.

    Not in our library10.1038/nm1780

  60. 60.

    Goncalves R Zhang X Cohen H Debrabant A Mosser DM. Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. J Exp Med (2011 ) 208(6):1253–65.

    Not in our library10.1084/jem.20101751

  61. 61.

    Vaheri A Strandin T Hepojoki J Sironen T Henttonen H Makela S Uncovering the mysteries of hantavirus infections. Nat Rev Microbiol (2013 ) 11(8):539–50.

    Not in our library10.1038/nrmicro3066

  62. 62.

    Zarbock A Polanowska-Grabowska RK Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev (2007 ) 21(2):99–111.

    Not in our library10.1016/j.blre.2006.06.001

  63. 63.

    Frenette PS Denis CV Weiss L Jurk K Subbarao S Kehrel B P-selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet-endothelial interactions in vivo. J Exp Med (2000 ) 191(8):1413–22.

    Not in our library10.1084/jem.191.8.1413

  64. 64.

    Lam FW Burns AR Smith CW Rumbaut RE. Platelets enhance neutrophil transendothelial migration via P-selectin glycoprotein ligand-1. Am J Physiol Heart Circ Physiol (2011 ) 300(2):H468–75.

    Not in our library10.1152/ajpheart.00491.2010

  65. 65.

    Wong CH Jenne CN Petri B Chrobok NL Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol (2013 ) 14(8):785–92.

    Not in our library10.1038/ni.2631

  66. 66.

    Cao TM Takatani T King MR. Effect of extracellular pH on selectin adhesion: theory and experiment. Biophys J (2013 ) 104(2):292–9.

    Not in our library10.1016/j.bpj.2012.12.005

  67. 67.

    Kuijper P Torres HG Van Der Linden J Lammers J Sixma J Koenderman L Platelet-dependent primary hemostasis promotes selectin and integrin-mediated neutrophil adhesion to damaged endothelium under flow conditions. Blood (1996 ) 87(8):3271–81.

    Not in our library

  68. 68.

    Page C Pitchford S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int Immunopharmacol (2013 ) 17(4):1176–84.

    Not in our library10.1016/j.intimp.2013.06.004

  69. 69.

    Assinger A Laky M Schabbauer G Hirschl AM Buchberger E Binder BR Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. J Thromb Haemost (2011 ) 9(4):799–809.

    Not in our library10.1111/j.1538-7836.2011.04193.x

  70. 70.

    Grommes J Alard J-E Drechsler M Wantha S Mörgelin M Kuebler WM Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Respir Crit Care Med (2012 ) 185(6):628–36.

    Not in our library10.1164/rccm.201108-1533oc

  71. 71.

    Hartwig H Drechsler M Lievens D Kramp B von Hundelshausen P Lutgens E Platelet-derived PF4 reduces neutrophil apoptosis following arterial occlusion. Thromb Haemost (2014 ) 111(3):562–4

    Not in our library10.1160/th13-08-0699

  72. 72.

    Gawaz M Fateh-Moghadam S Pilz G Gurland HJ Werdan K. Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure. Eur J Clin Invest (1995 ) 25(11):843–51.

    Not in our library10.1111/j.1365-2362.1995.tb01694.x

  73. 73.

    Andrews RK Arthur JF Gardiner E Neutrophil extracellular traps (NETs) and the role of platelets in infection. Thromb Haemost (2014 ) 112(4):659–65

    Not in our library10.1160/th14-05-0455

  74. 74.

    Clark SR Ma AC Tavener SA McDonald B Goodarzi Z Kelly MM Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med (2007 ) 13(4):463–9.

    Not in our library10.1038/nm1565

  75. 75.

    McDonald B Urrutia R Yipp BG Jenne CN Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe (2012 ) 12(3):324–33.

    Not in our library10.1016/j.chom.2012.06.011

  76. 76.
    Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation · 2011
    No notice
  77. 77.

    Jenne CN Wong CH Zemp FJ McDonald B Rahman MM Forsyth PA Neutrophils recruited to sites of infection protect from virus challenge by releasing neutrophil extracellular traps. Cell Host Microbe (2013 ) 13(2):169–80.

    Not in our library10.1016/j.chom.2013.01.005

  78. 78.

    Caudrillier A Kessenbrock K Gilliss BM Nguyen JX Marques MB Monestier M Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest (2012 ) 122(7):2661.

    Not in our library10.1172/jci61303

  79. 79.

    Rossaint J Herter JM Van Aken H Napirei M Döring Y Weber C Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood (2014 ) 123(16):2573–84.

    Not in our library10.1182/blood-2013-07-516484

  80. 80.

    van Gils JM Zwaginga JJ Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol (2009 ) 85(2):195–204.

    Not in our library10.1189/jlb.0708400

  81. 81.

    Stephen J Emerson B Fox KA Dransfield I. The uncoupling of monocyte-platelet interactions from the induction of proinflammatory signaling in monocytes. J Immunol (2013 ) 191(11):5677–83.

    Not in our library10.4049/jimmunol.1301250

  82. 82.
    Monocyte-Platelet Interaction Induces a Pro-Inflammatory Phenotype in Circulating Monocytes · 2011
    No notice
  83. 83.

    Scull CM Hays WD Fischer TH. Macrophage pro-inflammatory cytokine secretion is enhanced following interaction with autologous platelets. J Inflamm (Lond) (2010 ) 7:53.

    Not in our library10.1186/1476-9255-7-53

  84. 84.

    Halvorsen B Smedbakken LM Michelsen AE Skjelland M Bjerkeli V Sagen EL Activated platelets promote increased monocyte expression of CXCR5 through prostaglandin E2-related mechanisms and enhance the anti-inflammatory effects of CXCL13. Atherosclerosis (2014 ) 234(2):352–9.

    Not in our library10.1016/j.atherosclerosis.2014.03.021

  85. 85.

    Xiang B Zhang G Guo L Li X-A Morris AJ Daugherty A Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat Commun (2013 ) 4:2657.

    Not in our library10.1038/ncomms3657

  86. 86.

    Gudbrandsdottir S Hasselbalch HC Nielsen CH. Activated platelets enhance IL-10 secretion and reduce TNF-α secretion by monocytes. J Immunol (2013 ) 191(8):4059–67.

    Not in our library10.4049/jimmunol.1201103

  87. 87.

    Li N. Platelet-lymphocyte cross-talk. J Leukoc Biol (2008 ) 83(5):1069–78.

    Not in our library10.1189/jlb.0907615

  88. 88.

    Diacovo TG Catalina MD Siegelman MH Von Andrian UH. Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin-deficient mice. J Exp Med (1998 ) 187(2):197–204.

    Not in our library10.1084/jem.187.2.197

  89. 89.

    Zamora C Cantó E Nieto JC Ortiz MA Diaz-Torné C Diaz-Lopez C Functional consequences of platelet binding to T lymphocytes in inflammation. J Leukoc Biol (2013 ) 94(3):521–9.

    Not in our library10.1189/jlb.0213074

  90. 90.

    León-Ponte M Ahern GP O’Connell PJ. Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor. Blood (2007 ) 109(8):3139–46.

    Not in our library10.1182/blood-2006-10-052787

  91. 91.

    Katsounas A Schlaak JF Lempicki RA. CCL5: a double-edged sword in host defense against the hepatitis C virus. Int Rev Immunol (2011 ) 30(5–6):366–78.

    Not in our library10.3109/08830185.2011.593105

  92. 92.

    Elzey BD Ratliff TL Sowa JM Crist SA. Platelet CD40L at the interface of adaptive immunity. Thromb Res (2011 ) 127(3):180–3.

    Not in our library10.1016/j.thromres.2010.10.011

  93. 93.

    Liu CY Battaglia M Lee SH Sun Q-H Aster RH Visentin GP. Platelet factor 4 differentially modulates CD4+ CD25+ (regulatory) versus CD4+ CD25-(nonregulatory) T cells. J Immunol (2005 ) 174(5):2680–6.

    Not in our library10.4049/jimmunol.174.5.2680

  94. 94.

    Shi G Field DJ Ko KA Ture S Srivastava K Levy S Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J Clin Invest (2014 ) 124(2):543.

    Not in our library10.1172/jci71858

  95. 95.

    Danese S de la Motte C Reyes BMR Sans M Levine AD Fiocchi C. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol (2004 ) 172(4):2011–5.

    Not in our library10.4049/jimmunol.172.4.2011

  96. 96.

    Langer HF Daub K Braun G Schönberger T May AE Schaller M Platelets recruit human dendritic cells via Mac-1/JAM-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol (2007 ) 27(6):1463–70.

    Not in our library10.1161/atvbaha.107.141515

  97. 97.

    Hagihara M Higuchi A Tamura N Ueda Y Hirabayashi K Ikeda Y Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro. J Immunol (2004 ) 172(9):5297–303.

    Not in our library10.4049/jimmunol.172.9.5297

  98. 98.

    Hamzeh-Cognasse H Cognasse F Palle S Chavarin P Olivier T Delézay O Direct contact of platelets and their released products exert different effects on human dendritic cell maturation. BMC Immunol (2008 ) 9(1):54.

    Not in our library10.1186/1471-2172-9-54

  99. 99.

    Nakanishi T Inaba M Inagaki-Katashiba N Tanaka A Vien PTX Kibata K Platelet-derived RANK ligand enhances CCL17 secretion from dendritic cells mediated by thymic stromal lymphopoietin. Platelets (2014 ):1–7.

    Not in our library10.3109/09537104.2014.920081

  100. 100.

    Kissel K Berber S Nockher A Santoso S Bein G Hackstein H. Human platelets target dendritic cell differentiation and production of proinflammatory cytokines. Transfusion (2006 ) 46(5):818–27.

    Not in our library10.1111/j.1537-2995.2006.00802.x

  101. 101.

    Panigrahi S Ma Y Hong L Gao D West XZ Salomon RG Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res (2013 ) 112(1):103–12.

    Not in our library10.1161/circresaha.112.274241

  102. 102.

    Massberg S Brand K Grüner S Page S Müller E Müller I A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med (2002 ) 196(7):887–96.

    Not in our library10.1084/jem.20012044

  103. 103.

    Michelson AD Barnard MR Krueger LA Valeri CR Furman MI. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation (2001 ) 104(13):1533–7.

    Not in our library10.1161/hc3801.095588

  104. 104.

    Koenen RR von Hundelshausen P Nesmelova IV Zernecke A Liehn EA Sarabi A Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med (2009 ) 15(1):97–103.

    Not in our library10.1038/nm.1898

  105. 105.

    Strüßmann T Tillmann S Wirtz T Bucala R von Hundelshausen P Bernhagen J Platelets are a previously unrecognised source of MIF. Thromb Haemost (2013 ) 110(5):1004–13.

    Not in our library10.1160/th13-01-0049

  106. 106.

    Daub K Seizer P Stellos K Krämer BF Bigalke B Schaller M Oxidized LDL-activated platelets induce vascular inflammation. Semin Thromb Hemost (2010 ) 36(02):146–56.

    Not in our library10.1055/s-0030-1251498

  107. 107.

    Burger PC Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood (2003 ) 101(7):2661–6.

    Not in our library10.1182/blood-2002-07-2209

  108. 108.

    Lievens D Zernecke A Seijkens T Soehnlein O Beckers L Munnix IC Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood (2010 ) 116(20):4317–27.

    Not in our library10.1182/blood-2010-01-261206

  109. 109.

    Mause SF Weber C. Microparticles protagonists of a novel communication network for intercellular information exchange. Circ Res (2010 ) 107(9):1047–57.

    Not in our library10.1161/circresaha.110.226456

  110. 110.

    Gawaz M Brand K Dickfeld T Pogatsa-Murray G Page S Bogner C Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis (2000 ) 148(1):75–85.

    Not in our library10.1016/s0021-9150(99)00241-5

  111. 111.

    Lindemann S Tolley ND Dixon DA McIntyre TM Prescott SM Zimmerman GA Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J Cell Biol (2001 ) 154(3):485–90.

    Not in our library10.1083/jcb.200105058

  112. 112.

    Gawaz M Langer H May AE. Platelets in inflammation and atherogenesis. J Clin Invest (2005 ) 115(12):3378–84.

    Not in our library10.1172/jci27196

  113. 113.

    Lievens D von Hundelshausen P Platelets in atherosclerosis. Thromb Haemost (2011 ) 106(5):827

    Not in our library10.1160/th11-08-0592

  114. 114.

    Simon DI. Inflammation and vascular injury: basic discovery to drug development. Circ J (2011 ) 76(8):1811–8.

    Not in our library10.1253/circj.cj-12-0801

  115. 115.

    Simon DI Chen Z Xu H Li CQ Dong JF McIntire LV Platelet glycoprotein Ibα is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med (2000 ) 192(2):193–204.

    Not in our library10.1084/jem.192.2.193

  116. 116.

    Manthey HD Zernecke A. Dendritic cells in atherosclerosis: functions in immune regulation and beyond. Thromb Haemost (2011 ) 106(5):772.

    Not in our library10.1160/th11-05-0296

  117. 117.

    Ricklin D Hajishengallis G Yang K Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol (2010 ) 11(9):785–97.

    Not in our library10.1038/ni.1923

  118. 118.

    Acosta J Qin X Halperin J. Complement and complement regulatory proteins as potential molecular targets for vascular diseases. Curr Pharm Des (2004 ) 10(2):203–11.

    Not in our library10.2174/1381612043453441

  119. 119.

    Giannakopoulos B Passam F Rahgozar S Krilis SA. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood (2007 ) 109(2):422–30.

    Not in our library10.1182/blood-2006-04-001206

  120. 120.

    Peerschke E Yin W Grigg S Ghebrehiwet B. Blood platelets activate the classical pathway of human complement. J Thromb Haemost (2006 ) 4(9):2035–42.

    Not in our library10.1111/j.1538-7836.2006.02065.x

  121. 121.

    Peerschke EI Yin W Ghebrehiwet B Platelet mediated complement activation. Adv Exp Med Biol (2008 ) 632:81–91.

    Not in our library10.1007/978-0-387-78952-1_7

  122. 122.

    Peerschke EI Yin W Ghebrehiwet B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol (2010 ) 47(13):2170–5.

    Not in our library10.1016/j.molimm.2010.05.009

  123. 123.

    Bäck J Huber Lang M Elgue G Kalbitz M Sanchez J Nilsson Ekdahl K Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces. Biomaterials (2009 ) 30(34):6573–80.

    Not in our library10.1016/j.biomaterials.2009.07.052

  124. 124.

    Hamad OA Nilsson PH Wouters D Lambris JD Ekdahl KN Nilsson B. Complement component C3 binds to activated normal platelets without preceding proteolytic activation and promotes binding to complement receptor 1. J Immunol (2010 ) 184(5):2686–92.

    Not in our library10.4049/jimmunol.0902810

  125. 125.

    Patzelt J Mueller K Breuning S Karathanos A Schleicher R Seizer P Expression of anaphylatoxin receptors on platelets in patients with coronary heart disease. Atherosclerosis (2015 ) 238(2):289–95.

    Not in our library10.1016/j.atherosclerosis.2014.12.002

  126. 126.

    Verschoor A Langer HF Pan R Wang J Nardi M Li Z Crosstalk between platelets and the complement system in immune protection and disease. Thromb Haemost (2013 ) 110(5):910–9.

    Not in our library10.1160/th13-02-0102

  127. 127.

    McCarthy MJ Loftus IM Thompson MM Jones L London NJ Bell PR Angiogenesis and the atherosclerotic carotid plaque: an association between symptomatology and plaque morphology. J Vasc Surg (1999 ) 30(2):261–8.

    Not in our library10.1016/s0741-5214(99)70136-9

  128. 128.

    von Birgelen C Klinkhart W Mintz GS Papatheodorou A Herrmann J Baumgart D Plaque distribution and vascular remodeling of ruptured and nonruptured coronary plaques in the same vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol (2001 ) 37(7):1864–70.

    Not in our library10.1016/s0735-1097(01)01234-7

  129. 129.

    Tenaglia AN Peters KG Sketch MH Jr Annex BH. Neovascularization in atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J (1998 ) 135(1):10–4.

    Not in our library10.1016/s0002-8703(98)70336-9

  130. 130.

    Slevin M Turu MM Rovira N Luque A Baldellou M Krupinski J Identification of a ‘snapshot’ of co-expressed angiogenic markers in laser-dissected vessels from unstable carotid plaques with targeted arrays. J Vasc Res (2009 ) 47(4):323–35.

    Not in our library10.1159/000265566

  131. 131.

    Kolodgie FD Gold HK Burke AP Fowler DR Kruth HS Weber DK Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med (2003 ) 349(24):2316–25.

    Not in our library10.1056/nejmoa035655

  132. 132.

    Virmani R Kolodgie FD Burke AP Finn AV Gold HK Tulenko TN Atherosclerotic plaque progression and vulnerability to rupture angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol (2005 ) 25(10):2054–61.

    Not in our library10.1161/01.atv.0000178991.71605.18

  133. 133.

    Hutter R Valdiviezo C Sauter BV Savontaus M Chereshnev I Carrick FE Caspase-3 and tissue factor expression in lipid-rich plaque macrophages evidence for apoptosis as link between inflammation and atherothrombosis. Circulation (2004 ) 109(16):2001–8.

    Not in our library10.1161/01.cir.0000125526.91945.ae

  134. 134.

    Fernández-Ortiz A Badimon JJ Falk E Fuster V Meyer B Mailhac A Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol (1994 ) 23(7):1562–9.

    Not in our library10.1016/0735-1097(94)90657-2

  135. 135.

    Toschi V Gallo R Lettino M Fallon JT Gertz SD Ferna A Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation (1997 ) 95(3):594–9.

    Not in our library10.1161/01.cir.95.3.594

  136. 136.

    Badimon JJ Lettino M Toschi V Fuster V Berrozpe M Chesebro JH Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques effects of tissue factor pathway inhibitor on plaque thrombogenicity under flow conditions. Circulation (1999 ) 99(14):1780–7.

    Not in our library10.1161/01.cir.99.14.1780

  137. 137.

    Day SM Reeve JL Pedersen B Farris DM Myers DD Im M Macrovascular thrombosis is driven by tissue factor derived primarily from the blood vessel wall. Blood (2005 ) 105(1):192–8.

    Not in our library10.1182/blood-2004-06-2225

  138. 138.

    Bhattacharjee G Ahamed J Pedersen B El-Sheikh A Mackman N Ruf W Regulation of tissue factor-mediated initiation of the coagulation cascade by cell surface grp78. Arterioscler Thromb Vasc Biol (2005 ) 25(8):1737–43.

    Not in our library10.1161/01.atv.0000173419.31242.56

  139. 139.

    Sakakura K Nakano M Otsuka F Ladich E Kolodgie FD Virmani R. Pathophysiology of atherosclerosis plaque progression. Heart Lung Circ (2013 ) 22(6):399–411.

    Not in our library10.1016/j.hlc.2013.03.001

  140. 140.

    Shah PK Falk E Badimon JJ Fernandez-Ortiz A Mailhac A Villareal-Levy G Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation (1995 ) 92(6):1565–9.

    Not in our library

  141. 141.

    Geng Y-J Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol (1995 ) 147(2):251.

    Not in our library

  142. 142.

    Ehara S Kobayashi Y Yoshiyama M Shimada K Shimada Y Fukuda D Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction an intravascular ultrasound study. Circulation (2004 ) 110(22):3424–9.

    Not in our library10.1161/01.cir.0000148131.41425.e9

  143. 143.

    Maldonado N Kelly-Arnold A Vengrenyuk Y Laudier D Fallon JT Virmani R A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture. Am J Physiol Heart Circ Physiol (2012 ) 303(5):H619–28.

    Not in our library10.1152/ajpheart.00036.2012

  144. 144.

    Libby P Ridker PM Maseri A Inflammation and atherosclerosis. Circulation (2002 ) 105(9):1135–43

    Not in our library10.1161/hc0902.104353

  145. 145.

    Ridker PM Thuren T Zalewski A Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS). Am Heart J (2011 ) 162(4):597–605.

    Not in our library10.1016/j.ahj.2011.06.012

  146. 146.

    Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost (2009 ) 7(1):332–9.

    Not in our library10.1111/j.1538-7836.2009.03404.x

  147. 147.

    Gaziano JM Greenland P When should aspirin be used for prevention of cardiovascular events? JAMA (2014 ) 312(23):2503–4

    Not in our library10.1001/jama.2014.16047

  148. 148.

    Verheugt FW Gersh BJ Aspirin beyond platelet inhibition. Am J Cardiol (2002 ) 90(1):39–41

    Not in our library10.1016/s0002-9149(02)02383-4

  149. 149.

    Cyrus T Sung S Zhao L Funk CD Tang S Praticò D. Effect of low-dose aspirin on vascular inflammation, plaque stability, and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation (2002 ) 106(10):1282–7.

    Not in our library10.1161/01.cir.0000027816.54430.96

  150. 150.

    Tous M Ferré N Vilella E Riu F Camps J Joven J. Aspirin attenuates the initiation but not the progression of atherosclerosis in apolipoprotein E-deficient mice fed a high-fat, high-cholesterol diet. Basic Clin Pharmacol Toxicol (2004 ) 95(1):15–9.

    Not in our library10.1111/j.1742-7843.2004.pto950104.x

  151. 151.

    Paul-Clark MJ van Cao T Moradi-Bidhendi N Cooper D Gilroy DW. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med (2004 ) 200(1):69–78.

    Not in our library10.1084/jem.20040566

  152. 152.

    Kopp E Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science (1994 ) 265(5174):956–9.

    Not in our library10.1126/science.8052854

  153. 153.

    Steinhubl SR Badimon JJ Bhatt DL Herbert J-M Lüscher TF. Clinical evidence for anti-inflammatory effects of antiplatelet therapy in patients with atherothrombotic disease. Vasc Med (2007 ) 12(2):113–22.

    Not in our library10.1177/1358863x07077462

  154. 154.

    Ikeda Y Shimada K Teramoto T Uchiyama S Yamazaki T Oikawa S Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial. JAMA (2014 ) 312(23):2510–20.

    Not in our library10.1001/jama.2014.15690

  155. 155.

    Huynh K Atherosclerosis: low-dose aspirin failed to improve cardiovascular outcomes. Nat Rev Cardiol (2015 ) 12(1):3

    Not in our library10.1038/nrcardio.2014.194

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    Ewing MM de Vries MR Nordzell M Pettersson K de Boer HC van Zonneveld AJ Annexin A5 therapy attenuates vascular inflammation and remodeling and improves endothelial function in mice. Arterioscler Thromb Vasc Biol (2011 ) 31(1):95–101.

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    Hamad OA Bäck J Nilsson PH Nilsson B Ekdahl KN. Platelets, complement, and contact activation: partners in inflammation and thrombosis. Adv Exp Med Biol (2012 ) 946:185–205.

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    Hill A Hillmen P Richards SJ Elebute D Marsh JC Chan J Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood (2005 ) 106(7):2559–65.

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    Röth A Hock C Konik A Christoph S Dührsen U. Chronic treatment of paroxysmal nocturnal hemoglobinuria patients with eculizumab: safety, efficacy, and unexpected laboratory phenomena. Int J Hematol (2011 ) 93(6):704–14.

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    Setianto BY Hartopo AB Achadiono DN Gharini PP. Association between levels of circulating soluble CD40 ligand on admission and in-hospital events among acute coronary syndrome patients. Acta Med Indones (2011 ) 43(2):82–7.

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    Pamukcu B Lip GY Snezhitskiy V Shantsila E. The CD40-CD40L system in cardiovascular disease. Ann Med (2011 ) 43(5):331–40.

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    Ridker PM Buring JE Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation (2001 ) 103(4):491–5.

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    Kisucka J Chauhan AK Zhao B-Q Patten IS Yesilaltay A Krieger M Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis. Blood (2009 ) 113(23):6015–22.

    Not in our library10.1182/blood-2008-10-186650

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