Skip to main content

Advertisement

SpringerLink
Log in

Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Platelets are chief effector cells in hemostasis. In addition, however, their specializations include activities and intercellular interactions that make them key effectors in inflammation and in the continuum of innate and adaptive immunity. This review focuses on the immune features of human platelets and platelets from experimental animals and on interactions between inflammatory, immune, and hemostatic activities of these anucleate but complex and versatile cells. The experimental findings and evidence for physiologic immune functions include previously unrecognized biologic characteristics of platelets and are paralleled by new evidence for unique roles of platelets in inflammatory, immune, and thrombotic diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Coller BS (2007) A brief history of ideas about platelets in health and disease. In: Alan D, Michelson MD (eds) Platelets, 2nd edn. Elsevier, London, pp xxiii–xlii

    Google Scholar 

  2. Coller BS, Shattil SJ (2008) The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood 112:3011–3025

    PubMed  CAS  Google Scholar 

  3. Weyrich AS, Lindemann S, Zimmerman GA (2003) The evolving role of platelets in inflammation. J Thromb Haemost 1:1897–1905

    PubMed  CAS  Google Scholar 

  4. Weyrich AS, Zimmerman GA (2004) Platelets: signaling cells in the immune continuum. Trends Immunol 25:489–495

    PubMed  CAS  Google Scholar 

  5. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291–295

    PubMed  CAS  Google Scholar 

  6. Danese S, Dejana E, Fiocchi C (2007) Immune regulation by microvascular endothelial cells: directing innate and adaptive immunity, coagulation, and inflammation. J Immunol 178:6017–6022

    PubMed  CAS  Google Scholar 

  7. Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7:803–815

    PubMed  CAS  Google Scholar 

  8. Zimmerman GA, Weyrich AS (2008) Signal-dependent protein synthesis by activated platelets: new pathways to altered phenotype and function. Arterioscler Thromb Vasc Biol 28:s17–s24

    PubMed  CAS  Google Scholar 

  9. Zimmerman GA, Weyrich AS (2010) Immunology. Arsonists in rheumatoid arthritis. Science 327:528–529

    PubMed  CAS  Google Scholar 

  10. Junt T, Schulze H, Chen Z et al (2007) Dynamic visualization of thrombopoiesis within bone marrow. Science 317:1767–1770

    PubMed  CAS  Google Scholar 

  11. Watkins NA, Gusnanto A, de Bono B et al (2009) A HaemAtlas: characterizing gene expression in differentiated human blood cells. Blood 113:e1–e9

    PubMed  CAS  Google Scholar 

  12. O'Connor MN, Salles II, Cvejic A et al (2009) Functional genomics in zebrafish permits rapid characterization of novel platelet membrane proteins. Blood 113:4754–4762

    PubMed  Google Scholar 

  13. Weyrich AS, Zimmerman GA (2009) Comparative genomics: fishing nets hemostatic catch. Blood 113:4479–4480

    PubMed  CAS  Google Scholar 

  14. Denis MM, Tolley ND, Bunting M et al (2005) Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122:379–391

    PubMed  CAS  Google Scholar 

  15. Patel SR, Hartwig JH, Italiano JE Jr (2005) The biogenesis of platelets from megakaryocyte proplatelets. J Clin Invest 115:3348–3354

    PubMed  CAS  Google Scholar 

  16. Schwertz H, Tolley ND, Foulks JM et al (2006) Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 203:2433–2440

    PubMed  CAS  Google Scholar 

  17. Landry P, Plante I, Ouellet DL et al (2009) Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 16:961–966

    PubMed  CAS  Google Scholar 

  18. Schwertz H, Koster S, Kahr WH et al (2010) Anucleate platelets generate progeny. Blood 115:3801–3809

    PubMed  CAS  Google Scholar 

  19. Quintana-Murci L, Alcais A, Abel L et al (2007) Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nat Immunol 8:1165–1171

    PubMed  CAS  Google Scholar 

  20. Nachman RL, Polley M (1979) The platelet as an inflammatory cell. In: Weissmann G et al (eds) Advances in inflammation research, vol 1. Raven, New York, pp 169–173

    Google Scholar 

  21. Herd CM, Page CP (1995) Do platelets have a role as inflammatory cells? In: Joseph M (ed) Immunopharmacology of platelets. Academic, San Diego, pp 1–20

  22. Klinger MH (1997) Platelets and inflammation. Anat Embryol (Berl) 196:1–11

    CAS  Google Scholar 

  23. Diaz-Gonzalez F, Ginsberg MH (2005) Platelets and rheumatic diseases. In: Harris ED et al (eds) Kelley's textbook of rheumatology. Elsevier Saunders, Philadelphia, pp 252–259

    Google Scholar 

  24. Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384

    PubMed  CAS  Google Scholar 

  25. Fitzgerald JR, Foster TJ, Cox D (2006) The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 4:445–457

    PubMed  CAS  Google Scholar 

  26. von Hundelshausen P, Weber C (2007) Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 100:27–40

    Google Scholar 

  27. Bergmeier W, Wagner DD (2007) Inflammation. In: Alan D, Michelson MD (eds) Platelets, 2nd edn. Elsevier, London, pp 713–726

    Google Scholar 

  28. Yeaman MR, Bayer AS (2007) Antimicrobial host defense. In: Alan D, Michelson MD (eds) Platelets, 2nd edn. Elsevier, London, pp 727–755

    Google Scholar 

  29. Bozza FA, Shah AM, Weyrich AS et al (2009) Amicus or adversary: platelets in lung biology, acute injury, and inflammation. Am J Respir Cell Mol Biol 40:123–134

    PubMed  CAS  Google Scholar 

  30. Smyth SS, McEver RP, Weyrich AS et al (2009) Platelet functions beyond hemostasis. J Thromb Haemost 7:1759–1766

    PubMed  CAS  Google Scholar 

  31. Semple JW, Freedman J (2010) Platelets and innate immunity. Cell Mol Life Sci 67:499–511

    PubMed  CAS  Google Scholar 

  32. Peerschke EI, Yin W, Ghebrehiwet B (2010) Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol 47:2170–2175

    PubMed  CAS  Google Scholar 

  33. Shi G, Morrell CN (2011) Platelets as initiators and mediators of inflammation at the vessel wall. Thromb Res 127:387–390

    PubMed  CAS  Google Scholar 

  34. Li Z, Yang F, Dunn S et al (2011) Platelets as immune mediators: their role in host defense responses and sepsis. Thromb Res 127:184–188

    PubMed  CAS  Google Scholar 

  35. Baldwin WM III, Kuo H-H, Morrell CN (2011) Platelets: versatile modifiers of innate and adaptive immune responses to transplants. Curr Opin Org Trans 16:41–46

    Google Scholar 

  36. Freedman JE (2005) Molecular regulation of platelet-dependent thrombosis. Circulation 112:2725–2734

    PubMed  Google Scholar 

  37. Bouchard BA, Tracy PB (2001) Platelets, leukocytes, and coagulation. Curr Opin Hematol 8:263–269

    PubMed  CAS  Google Scholar 

  38. Ruggeri ZM, Mendolicchio GL (2007) Adhesion mechanisms in platelet function. Circ Res 100:1673–1685

    PubMed  CAS  Google Scholar 

  39. Furie B, Furie BC (2008) Mechanisms of thrombus formation. N Engl J Med 359:938–949

    PubMed  CAS  Google Scholar 

  40. Rivera J, Lozano ML, Navarro-Nunez L et al (2009) Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 94:700–711

    PubMed  CAS  Google Scholar 

  41. Smyth SS, Woulfe DS, Weitz JI et al (2009) G-protein-coupled receptors as signaling targets for antiplatelet therapy. Arterioscler Thromb Vasc Biol 29:449–457

    PubMed  CAS  Google Scholar 

  42. Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494

    PubMed  CAS  Google Scholar 

  43. Perez-Pujol S, Marker PH, Key NS (2007) Platelet microparticles are heterogeneous and highly dependent on the activation mechanism: studies using a new digital flow cytometer. Cytometry A 71:38–45

    PubMed  Google Scholar 

  44. McIntyre TM, Prescott SM, Weyrich AS et al (2003) Cell–cell interactions: leukocyte–endothelial interactions. Curr Opin Hematol 10:150–158

    PubMed  CAS  Google Scholar 

  45. Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451:914–918

    PubMed  CAS  Google Scholar 

  46. Panes O, Matus V, Saez CG et al (2007) Human platelets synthesize and express functional tissue factor. Blood 109:5242–5250

    PubMed  CAS  Google Scholar 

  47. Massberg S, Grahl L, von Bruehl ML et al (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887–896

    PubMed  CAS  Google Scholar 

  48. Goerge T, Ho-Tin-Noe B, Carbo C et al (2008) Inflammation induces hemorrhage in thrombocytopenia. Blood 111:4958–4964

    PubMed  CAS  Google Scholar 

  49. Washington AV, Gibot S, Acevedo I et al (2009) TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans. J Clin Invest 119:1489–1501

    PubMed  CAS  Google Scholar 

  50. Tucker EI, Marzec UM, Berny MA et al (2010) Safety and antithrombotic efficacy of moderate platelet count reduction by thrombopoietin inhibition in primates. Sci Transl Med 2:37ra45

    PubMed  Google Scholar 

  51. London NR, Zhu W, Bozza FA et al (2010) Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med 2:23ra19

    PubMed  Google Scholar 

  52. Schaphorst KL, Chiang E, Jacobs KN et al (2003) Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products. Am J Physiol Lung Cell Mol Physiol 285:L258–L267

    PubMed  CAS  Google Scholar 

  53. Camerer E, Regard JB, Cornelissen I et al (2009) Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J Clin Invest 119:1871–1879

    PubMed  CAS  Google Scholar 

  54. Brinkmann V, Cyster JG, Hla T (2004) FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 4:1019–1025

    PubMed  CAS  Google Scholar 

  55. Clawson CC (1995) Platelets in bacterial infections. In: Joseph M (ed) Immunopharmacology of platelets. Academic, San Diego, pp 83–124

  56. Pancre V, Auriault C (1995) Platelets in parasitic diseases. In: Joseph M (ed) Immunopharmacology of platelets. Academic, San Diego, pp 125–135

  57. Zucker-Franklin D (1995) Platelets in viral infections. In: Joseph M (ed) Immunopharmacology of platelets. Academic, San Diego, pp 137–149

  58. Hickey MJ, Kubes P (2009) Intravascular immunity: the host–pathogen encounter in blood vessels. Nat Rev Immunol 9:364–375

    PubMed  CAS  Google Scholar 

  59. Mueller KL (2010) Innate immunity. Recognizing the first responders. Introduction. Science 327:283

    PubMed  CAS  Google Scholar 

  60. Yeaman MR (2010) Platelets in defense against bacterial pathogens. Cell Mol Life Sci 67:525–544

    PubMed  CAS  Google Scholar 

  61. Lekstrom-Himes JA, Gallin JI (2000) Immunodeficiency diseases caused by defects in phagocytes. N Engl J Med 343:1703–1714

    PubMed  CAS  Google Scholar 

  62. Zimmerman GA (2009) LAD syndromes: FERMT3 kindles the signal. Blood 113:4485–4486

    PubMed  CAS  Google Scholar 

  63. Youssefian T, Drouin A, Masse JM et al (2002) Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood 99:4021–4029

    PubMed  CAS  Google Scholar 

  64. Zander DM, Klinger M (2009) The blood platelets contribution to innate host defense—what they have learned from their big brothers. Biotechnol J 4:914–926

    PubMed  CAS  Google Scholar 

  65. Sun H, Wang X, Degen JL et al (2009) Reduced thrombin generation increases host susceptibility to group A streptococcal infection. Blood 113:1358–1364

    PubMed  CAS  Google Scholar 

  66. McRedmond JP, Fitzgerald DJ (2002) A growing set of platelet-activating bacterial proteins. Blood 99:387–388

    PubMed  CAS  Google Scholar 

  67. White JG (2006) Why human platelets fail to kill bacteria. Platelets 17:191–200

    PubMed  CAS  Google Scholar 

  68. Clark SR, Ma AC, Tavener SA et al (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469

    PubMed  CAS  Google Scholar 

  69. Brinkmann V, Reichard U, Goosmann C et al (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535

    PubMed  CAS  Google Scholar 

  70. Fuchs TA, Abed U, Goosmann C et al (2007) Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 176:231–241

    PubMed  CAS  Google Scholar 

  71. Wartha F, Henriques-Normark B (2008) ETosis: a novel cell death pathway. Sci Signal 1:pe25

    PubMed  Google Scholar 

  72. Yost CC, Cody MJ, Harris ES et al (2009) Impaired neutrophil extracellular trap (NET) formation: a novel innate immune deficiency of human neonates. Blood 113:6419–6427

    PubMed  CAS  Google Scholar 

  73. Papayannopoulos V, Zychlinsky A (2009) NETs: a new strategy for using old weapons. Trends Immunol 30:513–521

    PubMed  CAS  Google Scholar 

  74. Fuchs TA, Brill A, Duerschmied D et al (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 107:15880–15885

    PubMed  CAS  Google Scholar 

  75. Kessenbrock K, Krumbholz M, Schonermarck U et al (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15:623–625

    PubMed  CAS  Google Scholar 

  76. Hakkim A, Furnrohr BG, Amann K et al (2010) Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci U S A 107:9813–9818

    PubMed  CAS  Google Scholar 

  77. Klinger MH, Jelkmann W (2002) Role of blood platelets in infection and inflammation. J Interferon Cytokine Res 22:913–922

    PubMed  CAS  Google Scholar 

  78. Dominguez M, Torano A (2001) Leishmania immune adherence reaction in vertebrates. Parasite Immunol 23:259–265

    PubMed  CAS  Google Scholar 

  79. Yong EC, Chi EY, Fritsche TR et al (1991) Human platelet-mediated cytotoxicity against Toxoplasma gondii: role of thromboxane. J Exp Med 173:65–78

    PubMed  CAS  Google Scholar 

  80. McMorran BJ, Marshall VM, de Graaf C et al (2009) Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 323:797–800

    PubMed  CAS  Google Scholar 

  81. Peyron F, Polack B, Lamotte D et al (1989) Plasmodium falciparum growth inhibition by human platelets in vitro. Parasitology 99(Pt 3):317–322

    PubMed  Google Scholar 

  82. Cox D, McConkey S (2010) The role of platelets in the pathogenesis of cerebral malaria. Cell Mol Life Sci 67:557–568

    PubMed  CAS  Google Scholar 

  83. Elzey BD, Tian J, Jensen RJ et al (2003) Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 19:9–19

    PubMed  CAS  Google Scholar 

  84. Iannacone M, Sitia G, Isogawa M et al (2008) Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus. Proc Natl Acad Sci U S A 105:629–634

    PubMed  CAS  Google Scholar 

  85. Iannacone M, Sitia G, Isogawa M et al (2005) Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med 11:1167–1169

    PubMed  CAS  Google Scholar 

  86. Lang PA, Contaldo C, Georgiev P et al (2008) Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 14:756–761

    PubMed  CAS  Google Scholar 

  87. Lisman T, Porte RJ (2010) The role of platelets in liver inflammation and regeneration. Semin Thromb Hemost 36:170–174

    PubMed  Google Scholar 

  88. Boukour S, Masse JM, Benit L et al (2006) Lentivirus degradation and DC-SIGN expression by human platelets and megakaryocytes. J Thromb Haemost 4:426–435

    PubMed  CAS  Google Scholar 

  89. Chaipan C, Soilleux EJ, Simpson P et al (2006) DC-SIGN and CLEC-2 mediate human immunodeficiency virus type 1 capture by platelets. J Virol 80:8951–8960

    PubMed  CAS  Google Scholar 

  90. Torre D, Pugliese A (2008) Platelets and HIV-1 infection: old and new aspects. Curr HIV Res 6:411–418

    PubMed  CAS  Google Scholar 

  91. Ghosh K, Gangodkar S, Jain P et al (2008) Imaging the interaction between dengue 2 virus and human blood platelets using atomic force and electron microscopy. J Electron Microsc (Tokyo) 57:113–118

    Google Scholar 

  92. Mourao MP, Lacerda MV, Macedo VO et al (2007) Thrombocytopenia in patients with dengue virus infection in the Brazilian Amazon. Platelets 18:605–612

    PubMed  CAS  Google Scholar 

  93. Gavrilovskaya IN, Brown EJ, Ginsberg MH et al (1999) Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins. J Virol 73:3951–3959

    PubMed  CAS  Google Scholar 

  94. Hamaia S, Li C, Allain JP (2001) The dynamics of hepatitis C virus binding to platelets and 2 mononuclear cell lines. Blood 98:2293–2300

    PubMed  CAS  Google Scholar 

  95. Zahn A, Jennings N, Ouwehand WH et al (2006) Hepatitis C virus interacts with human platelet glycoprotein VI. J Gen Virol 87:2243–2251

    PubMed  CAS  Google Scholar 

  96. de Almeida AJ, Campos-de-Magalhaes M, Brandao-Mello CE et al (2007) Detection of hepatitis C virus in platelets: evaluating its relationship to viral and host factors. Hepatogastroenterology 54:964–968

    PubMed  Google Scholar 

  97. Pugliese A, Gennero L, Cutufia M et al (2004) HCV infective virions can be carried by human platelets. Cell Biochem Funct 22:353–358

    PubMed  CAS  Google Scholar 

  98. Tareda H, Baldini M, Ebbe S et al (1966) Interaction of influenza viruses with blood platelets. Blood 28:213–227

    Google Scholar 

  99. Rocca B, Secchiero P, Ciabattoni G et al (2002) Cyclooxygenase-2 expression is induced during human megakaryopoiesis and characterizes newly formed platelets. Proc Natl Acad Sci U S A 99:7634–7639

    PubMed  CAS  Google Scholar 

  100. Freishtat RJ, Natale J, Benton AS et al (2009) Sepsis alters the megakaryocyte–platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. Am J Respir Crit Care Med 179:467–473

    PubMed  CAS  Google Scholar 

  101. Kasirer-Friede A, Kahn ML, Shattil SJ (2007) Platelet integrins and immunoreceptors. Immunol Rev 218:247–264

    PubMed  CAS  Google Scholar 

  102. Qian K, Xie F, Gibson AW et al (2008) Functional expression of IgA receptor FcalphaRI on human platelets. J Leukoc Biol 84:1492–1500

    PubMed  CAS  Google Scholar 

  103. Falet H, Pollitt AY, Begonja AJ et al (2010) A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function. J Exp Med 207:1967–1979

    PubMed  CAS  Google Scholar 

  104. Tomer A (2004) Human marrow megakaryocyte differentiation: multiparameter correlative analysis identifies von Willebrand factor as a sensitive and distinctive marker for early (2N and 4N) megakaryocytes. Blood 104:2722–2727

    PubMed  CAS  Google Scholar 

  105. Calverley DC, Hacker MR, Loda KA et al (2003) Increased platelet Fc receptor expression as a potential contributing cause of platelet hypersensitivity to collagen in diabetes mellitus. Br J Haematol 121:139–142

    PubMed  CAS  Google Scholar 

  106. Moroi M, Jung SM (2004) Platelet glycoprotein VI: its structure and function. Thromb Res 114:221–233

    PubMed  CAS  Google Scholar 

  107. Boilard E, Nigrovic PA, Larabee K et al (2010) Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327:580–583

    PubMed  CAS  Google Scholar 

  108. Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814

    PubMed  CAS  Google Scholar 

  109. Weyrich AS, Dixon DA, Pabla R et al (1998) Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets. Proc Natl Acad Sci U S A 95:5556–5561

    PubMed  CAS  Google Scholar 

  110. Weyrich AS, Denis MM, Schwertz H et al (2007) mTOR-dependent synthesis of Bcl-3 controls the retraction of fibrin clots by activated human platelets. Blood 109:1975–1983

    PubMed  CAS  Google Scholar 

  111. Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9:324–337

    PubMed  CAS  Google Scholar 

  112. Michelson AD (2008) P2Y12 antagonism: promises and challenges. Arterioscler Thromb Vasc Biol 28:s33–s38

    PubMed  CAS  Google Scholar 

  113. Evangelista V, Manarini S, Dell'Elba G et al (2005) Clopidogrel inhibits platelet–leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost 94:568–577

    PubMed  CAS  Google Scholar 

  114. Duffau P, Seneschal J, Nicco C et al (2010) Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med 2:47ra63

    PubMed  Google Scholar 

  115. Graff J, Harder S, Wahl O et al (2005) Anti-inflammatory effects of clopidogrel intake in renal transplant patients: effects on platelet–leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers. Clin Pharmacol Ther 78:468–476

    PubMed  CAS  Google Scholar 

  116. Narumiya S, FitzGerald GA (2001) Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 108:25–30

    PubMed  CAS  Google Scholar 

  117. Petrucci G, De Cristofaro R, Rutella S et al (2011) Prostaglandin E2 differentially modulates human platelet function through the prostanoid EP2 and EP3 receptors. J Pharmacol Exp Ther 336:391–402

    PubMed  CAS  Google Scholar 

  118. Tilley SL, Coffman TM, Koller BH (2001) Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest 108:15–23

    PubMed  CAS  Google Scholar 

  119. Muhlestein JB (2010) Effect of antiplatelet therapy on inflammatory markers in atherothrombotic patients. Thromb Haemost 103:71–82

    PubMed  CAS  Google Scholar 

  120. Prescott SM, Zimmerman GA, Stafforini DM et al (2000) Platelet-activating factor and related lipid mediators. Annu Rev Biochem 69:419–445

    PubMed  CAS  Google Scholar 

  121. Groscurth P, Huracek J, Filgueira L et al (1988) Effects of platelet activating factor (PAF) on human citrated whole blood. Eur J Haematol 41:37–416

    PubMed  CAS  Google Scholar 

  122. Lindemann S, Tolley ND, Dixon DA et al (2001) Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 154:485–490

    PubMed  CAS  Google Scholar 

  123. Keating FK, Schneider DJ (2009) The influence of platelet activating factor on the effects of platelet agonists and antiplatelet agents in vitro. J Thromb Thrombolysis 28:38–45

    PubMed  CAS  Google Scholar 

  124. Harris ES, Rondina MT, Schwertz H et al (2010) Pathogenesis of sepsis and sepsis-induced acute lung injury. In: Choi AMK (ed) Acute respiratory distress syndrome, 2nd edn. Informa, Zug, pp 369–419

    Google Scholar 

  125. Coyle AJ, Vargaftig BB (1995) Animal models for investigating the allergic and inflammatory properties of platelets. In: Joseph M (ed) Immunopharmacology of platelets. Academic, San Diego, pp 21–30

  126. Yost CC, Weyrich AS, Zimmerman GA (2010) The platelet activating factor (PAF) signaling cascade in systemic inflammatory responses. Biochimie 92:692–697

    PubMed  CAS  Google Scholar 

  127. Brass LF, Stalker TJ, Zhu L et al (2007) Signal transduction during platelet plug formation. In: Michelson AD (ed) Platelets, 2nd edn. Elsevier, London, pp 319–346

    Google Scholar 

  128. Boehlen F, Clemetson KJ (2001) Platelet chemokines and their receptors: what is their relevance to platelet storage and transfusion practice? Transfus Med 11:403–417

    PubMed  CAS  Google Scholar 

  129. Brass LF, Zhu L, Stalker TJ (2008) Novel therapeutic targets at the platelet vascular interface. Arterioscler Thromb Vasc Biol 28:s43–s50

    PubMed  CAS  Google Scholar 

  130. Clemetson JK, Clemetson JM (2007) Platelet receptors. In: Michelson AD (ed) Platelets, 2nd edn. Elsevier, London, pp 117–143

    Google Scholar 

  131. Garraud O, Cognasse F (2010) Platelet Toll-like receptor expression: the link between “danger” ligands and inflammation. Inflamm Allergy Drug Targets 9:322–333

    PubMed  CAS  Google Scholar 

  132. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820

    PubMed  CAS  Google Scholar 

  133. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32:305–315

    PubMed  CAS  Google Scholar 

  134. Zhang Q, Raoof M, Chen Y et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107

    PubMed  CAS  Google Scholar 

  135. Des Prez RM, Horowitz HI, Hook EW (1961) Effects of bacterial endotoxin on rabbit platelets. I. Platelet aggregation and release of platelet factors in vitro. J Exp Med 114:857–874

    PubMed  CAS  Google Scholar 

  136. Ginsberg MH, Henson PM (1978) Enhancement of platelet response to immune complexes and IgG aggregates by lipid A-rich bacterial lipopolysaccharides. J Exp Med 147:207–217

    PubMed  CAS  Google Scholar 

  137. Romano M, Hawiger J (1990) Interaction of endotoxic lipid A and lipid X with purified human platelet protein kinase C. J Biol Chem 265:1765–1770

    PubMed  CAS  Google Scholar 

  138. Berg M, Offermanns S, Seifert R et al (1994) Synthetic lipopeptide Pam3CysSer(Lys)4 is an effective activator of human platelets. Am J Physiol 266:C1684–C1691

    PubMed  CAS  Google Scholar 

  139. Zhao L, Ohtaki Y, Yamaguchi K et al (2002) LPS-induced platelet response and rapid shock in mice: contribution of O-antigen region of LPS and involvement of the lectin pathway of the complement system. Blood 100:3233–3239

    PubMed  CAS  Google Scholar 

  140. Shiraki R, Inoue N, Kawasaki S et al (2004) Expression of Toll-like receptors on human platelets. Thromb Res 113:379–385

    PubMed  CAS  Google Scholar 

  141. Cognasse F, Hamzeh H, Chavarin P et al (2005) Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol 83:196–198

    PubMed  CAS  Google Scholar 

  142. Andonegui G, Kerfoot SM, McNagny K et al (2005) Platelets express functional Toll-like receptor-4. Blood 106:2417–2423

    PubMed  CAS  Google Scholar 

  143. Aslam R, Speck ER, Kim M et al (2006) Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107:637–641

    PubMed  CAS  Google Scholar 

  144. Freedman JE, Larson MG, Tanriverdi K et al (2010) Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham Heart Study. Circulation 122:119–129

    PubMed  Google Scholar 

  145. Coban C, Igari Y, Yagi M et al (2010) Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host Microbe 7:50–61

    PubMed  CAS  Google Scholar 

  146. Rumbaut RE, Bellera RV, Randhawa JK et al (2006) Endotoxin enhances microvascular thrombosis in mouse cremaster venules via a TLR4-dependent, neutrophil-independent mechanism. Am J Physiol Heart Circ Physiol 290:H1671–H1679

    PubMed  CAS  Google Scholar 

  147. Shashkin PN, Brown GT, Ghosh A et al (2008) Lipopolysaccharide is a direct agonist for platelet RNA splicing. J Immunol 181:3495–3502

    PubMed  CAS  Google Scholar 

  148. Ward JR, Bingle L, Judge HM et al (2005) Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb Haemost 94:831–838

    PubMed  Google Scholar 

  149. Rondina MT, Schwertz H, Harris ES et al (2011) The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost 9:748–758

    PubMed  CAS  Google Scholar 

  150. Stahl AL, Svensson M, Morgelin M et al (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108:167–176

    PubMed  CAS  Google Scholar 

  151. Cognasse F, Hamzeh-Cognasse H, Lafarge S et al (2008) Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets. Br J Haematol 141:84–91

    PubMed  CAS  Google Scholar 

  152. Zhang G, Han J, Welch EJ et al (2009) Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol 182:7997–8004

    PubMed  CAS  Google Scholar 

  153. Smiley ST, King JA, Hancock WW (2001) Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 167:2887–2894

    PubMed  CAS  Google Scholar 

  154. Kuhns DB, Priel DA, Gallin JI (2007) Induction of human monocyte interleukin (IL)-8 by fibrinogen through the toll-like receptor pathway. Inflammation 30:178–188

    PubMed  CAS  Google Scholar 

  155. Blair P, Rex S, Vitseva O et al (2009) Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res 104:346–354

    PubMed  CAS  Google Scholar 

  156. Rex S, Beaulieu LM, Perlman DH et al (2009) Immune versus thrombotic stimulation of platelets differentially regulates signalling pathways, intracellular protein–protein interactions, and alpha-granule release. Thromb Haemost 102:97–110

    PubMed  CAS  Google Scholar 

  157. Blumberg N, Spinelli SL, Francis CW et al (2009) The platelet as an immune cell-–CD40 ligand and transfusion immunomodulation. Immunol Res 45:251–260

    CAS  Google Scholar 

  158. Phipps RP, Kaufman J, Blumberg N (2001) Platelet derived CD154 (CD40 ligand) and febrile responses to transfusion. Lancet 357:2023–2024

    PubMed  CAS  Google Scholar 

  159. Blumberg N, Gettings KF, Turner C et al (2006) An association of soluble CD40 ligand (CD154) with adverse reactions to platelet transfusions. Transfusion 46:1813–1821

    PubMed  CAS  Google Scholar 

  160. Damas JK, Jensenius M, Ueland T et al (2006) Increased levels of soluble CD40L in African tick bite fever: possible involvement of TLRs in the pathogenic interaction between Rickettsia africae, endothelial cells, and platelets. J Immunol 177:2699–2706

    PubMed  CAS  Google Scholar 

  161. Amelot AA, Tagzirt M, Ducouret G et al (2007) Platelet factor 4 (CXCL4) seals blood clots by altering the structure of fibrin. J Biol Chem 282:710–720

    PubMed  CAS  Google Scholar 

  162. Deuel TF, Senior RM, Chang D et al (1981) Platelet factor 4 is chemotactic for neutrophils and monocytes. Proc Natl Acad Sci U S A 78:4584–4587

    PubMed  CAS  Google Scholar 

  163. Scheuerer B, Ernst M, Durrbaum-Landmann I et al (2000) The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 95:1158–1166

    PubMed  CAS  Google Scholar 

  164. Gleissner CA, Shaked I, Little KM et al (2010) CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages. J Immunol 184:4810–4818

    PubMed  CAS  Google Scholar 

  165. Srivastava K, Cockburn IA, Swaim A et al (2008) Platelet factor 4 mediates inflammation in experimental cerebral malaria. Cell Host Microbe 4:179–187

    PubMed  CAS  Google Scholar 

  166. Srivastava K, Field DJ, Aggrey A et al (2010) Platelet factor 4 regulation of monocyte KLF4 in experimental cerebral malaria. PLoS One 5:e10413

    PubMed  Google Scholar 

  167. Essien EM, Ebhota MI (1983) Platelet secretory activities in acute malaria (Plasmodium falciparum) infection. Acta Haematol 70:183–188

    PubMed  CAS  Google Scholar 

  168. Greinacher A (2009) Heparin-induced thrombocytopenia. J Thromb Haemost 7(Suppl 1):9–12

    PubMed  CAS  Google Scholar 

  169. Levy JA (2009) The unexpected pleiotropic activities of RANTES. J Immunol 182:3945–3946

    PubMed  CAS  Google Scholar 

  170. Kameyoshi Y, Dorschner A, Mallet AI et al (1992) Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med 176:587–592

    PubMed  CAS  Google Scholar 

  171. Weyrich AS, Elstad MR, McEver RP et al (1996) Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest 97:1525–1534

    PubMed  CAS  Google Scholar 

  172. Klinger MH, Wilhelm D, Bubel S et al (1995) Immunocytochemical localization of the chemokines RANTES and MIP-1 alpha within human platelets and their release during storage. Int Arch Allergy Immunol 107:541–546

    PubMed  CAS  Google Scholar 

  173. Pabla R, Weyrich AS, Dixon DA et al (1999) Integrin-dependent control of translation: engagement of integrin alphaIIbbeta3 regulates synthesis of proteins in activated human platelets. J Cell Biol 144:175–184

    PubMed  CAS  Google Scholar 

  174. Mause SF, von Hundelshausen P, Zernecke A et al (2005) Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 25:1512–1518

    PubMed  CAS  Google Scholar 

  175. Danese S, de la Motte C, Reyes BM et al (2004) Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol 172:2011–2015

    PubMed  CAS  Google Scholar 

  176. Hawrylowicz CM, Santoro SA, Platt FM et al (1989) Activated platelets express IL-1 activity. J Immunol 143:4015–4018

    PubMed  CAS  Google Scholar 

  177. Hawrylowicz CM, Howells GL, Feldmann M (1991) Platelet-derived interleukin 1 induces human endothelial adhesion molecule expression and cytokine production. J Exp Med 174:785–790

    PubMed  CAS  Google Scholar 

  178. Kaplanski G, Porat R, Aiura K et al (1993) Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event. Blood 81:2492–2495

    PubMed  CAS  Google Scholar 

  179. Loppnow H, Bil R, Hirt S et al (1998) Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. Blood 91:134–141

    PubMed  CAS  Google Scholar 

  180. Braddock M, Quinn A (2004) Targeting IL-1 in inflammatory disease: new opportunities for therapeutic intervention. Nat Rev Drug Discov 3:330–339

    PubMed  CAS  Google Scholar 

  181. Gawaz M, Brand K, Dickfeld T et al (2000) Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 148:75–85

    PubMed  CAS  Google Scholar 

  182. Henn V, Slupsky JR, Grafe M et al (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594

    PubMed  CAS  Google Scholar 

  183. Weber C, Springer TA (1997) 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 100:2085–2093

    PubMed  CAS  Google Scholar 

  184. Ostrovsky L, King AJ, Bond S et al (1998) A juxtacrine mechanism for neutrophil adhesion on platelets involves platelet-activating factor and a selectin-dependent activation process. Blood 91:3028–3036

    PubMed  CAS  Google Scholar 

  185. Zarbock A, Muller H, Kuwano Y et al (2009) PSGL-1-dependent myeloid leukocyte activation. J Leukoc Biol 86:1119–1124

    PubMed  CAS  Google Scholar 

  186. Kornerup KN, Salmon GP, Pitchford SC et al (2010) Circulating platelet-neutrophil complexes are important for subsequent neutrophil activation and migration. J Appl Physiol 109:758–767

    PubMed  CAS  Google Scholar 

  187. Flick MJ, Du X, Witte DP et al (2004) Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2/Mac-1 is critical for host inflammatory response in vivo. J Clin Invest 113:1596–1606

    PubMed  CAS  Google Scholar 

  188. Hara T, Shimizu K, Ogawa F et al (2010) Platelets control leukocyte recruitment in a murine model of cutaneous arthus reaction. Am J Pathol 176:259–269

    PubMed  CAS  Google Scholar 

  189. Keating FK, Fung MK, Schneider DJ (2008) Induction of platelet white blood cell (WBC) aggregate formation by platelets and WBCs in red blood cell units. Transfusion 48:1099–1105

    PubMed  Google Scholar 

  190. Evangelista V, Pamuklar Z, Piccoli A et al (2007) Src family kinases mediate neutrophil adhesion to adherent platelets. Blood 109:2461–2469

    PubMed  CAS  Google Scholar 

  191. Lorant DE, Patel KD, McIntyre TM et al (1991) Coexpression of GMP-140 and PAF by endothelium stimulated by histamine or thrombin: a juxtacrine system for adhesion and activation of neutrophils. J Cell Biol 115:223–234

    PubMed  CAS  Google Scholar 

  192. Simon DI, Chen Z, Xu H et al (2000) Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 192:193–204

    PubMed  CAS  Google Scholar 

  193. Santoso S, Sachs UJ, Kroll H et al (2002) The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 196:679–691

    PubMed  CAS  Google Scholar 

  194. Ehlers R, Ustinov V, Chen Z et al (2003) Targeting platelet-leukocyte interactions: identification of the integrin Mac-1 binding site for the platelet counter receptor glycoprotein Ibalpha. J Exp Med 198:1077–1088

    PubMed  CAS  Google Scholar 

  195. Li N, Hu H, Lindqvist M et al (2000) Platelet–leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol 20:2702–2708

    PubMed  CAS  Google Scholar 

  196. Hidari KI, Weyrich AS, Zimmerman GA et al (1997) Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J Biol Chem 272:28750–28756

    PubMed  CAS  Google Scholar 

  197. Lindemann SW, Yost CC, Denis MM et al (2004) Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs. Proc Natl Acad Sci U S A 101:7076–7081

    PubMed  CAS  Google Scholar 

  198. Goel MS, Diamond SL (2001) Neutrophil enhancement of fibrin deposition under flow through platelet-dependent and -independent mechanisms. Arterioscler Thromb Vasc Biol 21:2093–2098

    PubMed  CAS  Google Scholar 

  199. McCarty OJ, Tien N, Bochner BS et al (2003) Exogenous eosinophil activation converts PSGL-1-dependent binding to CD18-dependent stable adhesion to platelets in shear flow. Am J Physiol Cell Physiol 284:C1223–C1234

    PubMed  CAS  Google Scholar 

  200. de Bruijne-Admiraal LG, Modderman PW, Von dem Borne AE et al (1992) P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry. Blood 80:134–142

    PubMed  Google Scholar 

  201. Michetti N, Weyrich AS, Zimmerman GA (2009) Platelet–leukocyte interactions in inflammation and thrombosis. US Hematology 2:24–27

    Google Scholar 

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

    PubMed  Google Scholar 

  203. Kirchhofer D, Riederer MA, Baumgartner HR (1997) Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model. Blood 89:1270–1278

    PubMed  CAS  Google Scholar 

  204. Rinder HM, Bonan JL, Rinder CS et al (1991) Dynamics of leukocyte–platelet adhesion in whole blood. Blood 78:1730–1737

    PubMed  CAS  Google Scholar 

  205. Li N (2008) Platelet–lymphocyte cross-talk. J Leukoc Biol 83:1069–1078

    PubMed  CAS  Google Scholar 

  206. Rinder HM, Tracey JL, Rinder CS et al (1994) Neutrophil but not monocyte activation inhibits P-selectin-mediated platelet adhesion. Thromb Haemost 72:750–756

    PubMed  CAS  Google Scholar 

  207. Lorant DE, McEver RP, McIntyre TM et al (1995) Activation of polymorphonuclear leukocytes reduces their adhesion to P-selectin and causes redistribution of ligands for P-selectin on their surfaces. J Clin Invest 96:171–182

    PubMed  CAS  Google Scholar 

  208. Michelson AD, Barnard MR, Krueger LA et al (2001) 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 104:1533–1537

    PubMed  CAS  Google Scholar 

  209. Larsen E, Celi A, Gilbert GE et al (1989) PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 59:305–312

    PubMed  CAS  Google Scholar 

  210. Weyrich AS, McIntyre TM, McEver RP et al (1995) Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest 95:2297–2303

    PubMed  CAS  Google Scholar 

  211. Silverstein RL, Asch AS, Nachman RL (1989) Glycoprotein IV mediates thrombospondin-dependent platelet–monocyte and platelet–U937 cell adhesion. J Clin Invest 84:546–552

    PubMed  CAS  Google Scholar 

  212. Gawaz MP, Loftus JC, Bajt ML et al (1991) Ligand bridging mediates integrin alpha IIb beta 3 (platelet GPIIB-IIIA) dependent homotypic and heterotypic cell–cell interactions. J Clin Invest 88:1128–1134

    PubMed  CAS  Google Scholar 

  213. da Costa Martins PA, van Gils JM, Mol A et al (2006) 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 79:499–507

    PubMed  Google Scholar 

  214. Fernandes LS, Conde ID, Smith CW et al (2003) Platelet–monocyte complex formation: effect of blocking PSGL-1 alone, and in combination with alphaIIbbeta3 and alphaMbeta2, in coronary stenting. Thromb Res 111:171–177

    PubMed  CAS  Google Scholar 

  215. Ahn KC, Jun AJ, Pawar P et al (2005) Preferential binding of platelets to monocytes over neutrophils under flow. Biochem Biophys Res Commun 329:345–355

    PubMed  CAS  Google Scholar 

  216. Galt SW, Lindemann S, Medd D et al (2001) Differential regulation of matrix metalloproteinase-9 by monocytes adherent to collagen and platelets. Circ Res 89:509–516

    PubMed  CAS  Google Scholar 

  217. Brittain JE, Knoll CM, Ataga KI et al (2008) Fibronectin bridges monocytes and reticulocytes via integrin alpha4beta1. Br J Haematol 141:872–881

    PubMed  CAS  Google Scholar 

  218. Dixon DA, Tolley ND, Bemis-Standoli K et al (2006) Expression of COX-2 in platelet–monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. J Clin Invest 116:2727–2738

    PubMed  CAS  Google Scholar 

  219. Weyrich AS, Denis MM, Kuhlmann-Eyre JR et al (2005) Dipyridamole selectively inhibits inflammatory gene expression in platelet–monocyte aggregates. Circulation 111:633–642

    PubMed  CAS  Google Scholar 

  220. Mahoney TS, Weyrich AS, Dixon DA et al (2001) Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes. Proc Natl Acad Sci U S A 98:10284–10289

    PubMed  CAS  Google Scholar 

  221. Neumann FJ, Marx N, Gawaz M et al (1997) Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation 95:2387–2394

    PubMed  CAS  Google Scholar 

  222. Eligini S, Barbieri SS, Arenaz I et al (2007) Paracrine up-regulation of monocyte cyclooxygenase-2 by platelets: role of transforming growth factor-beta1. Cardiovasc Res 74:270–278

    PubMed  CAS  Google Scholar 

  223. Christersson C, Johnell M, Siegbahn A (2008) Tissue factor and IL8 production by P-selectin-dependent platelet-monocyte aggregates in whole blood involves phosphorylation of Lyn and is inhibited by IL10. J Thromb Haemost 6:986–994

    PubMed  CAS  Google Scholar 

  224. Celi A, Pellegrini G, Lorenzet R et al (1994) P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A 91:8767–8771

    PubMed  CAS  Google Scholar 

  225. Lindmark E, Tenno T, Siegbahn A (2000) Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 20:2322–2328

    PubMed  CAS  Google Scholar 

  226. Steiner S, Seidinger D, Huber K et al (2003) Effect of glycoprotein IIb/IIIa antagonist abciximab on monocyte–platelet aggregates and tissue factor expression. Arterioscler Thromb Vasc Biol 23:1697–1702

    PubMed  CAS  Google Scholar 

  227. Barnard MR, Linden MD, Frelinger AL 3rd et al (2005) Effects of platelet binding on whole blood flow cytometry assays of monocyte and neutrophil procoagulant activity. J Thromb Haemost 3:2563–2570

    PubMed  CAS  Google Scholar 

  228. Brambilla M, Camera M, Colnago D et al (2008) Tissue factor in patients with acute coronary syndromes: expression in platelets, leukocytes, and platelet–leukocyte aggregates. Arterioscler Thromb Vasc Biol 28:947–953

    PubMed  CAS  Google Scholar 

  229. Elstad MR, McIntyre TM, Prescott SM et al (1995) The interaction of leukocytes with platelets in blood coagulation. Curr Opin Hematol 2:47–54

    PubMed  CAS  Google Scholar 

  230. Freedman JE, Loscalzo J (2002) Platelet–monocyte aggregates: bridging thrombosis and inflammation. Circulation 105:2130–2132

    PubMed  Google Scholar 

  231. Ammon C, Kreutz M, Rehli M et al (1998) Platelets induce monocyte differentiation in serum-free coculture. J Leukoc Biol 63:469–476

    PubMed  CAS  Google Scholar 

  232. Lang D, Dohle F, Terstesse M et al (2002) Down-regulation of monocyte apoptosis by phagocytosis of platelets: involvement of a caspase-9, caspase-3, and heat shock protein 70-dependent pathway. J Immunol 168:6152–6158

    PubMed  CAS  Google Scholar 

  233. Li G, Kim YJ, Mantel C et al (2003) P-selectin enhances generation of CD14 + CD16+ dendritic-like cells and inhibits macrophage maturation from human peripheral blood monocytes. J Immunol 171:669–677

    PubMed  CAS  Google Scholar 

  234. Chen J, Lopez JA (2005) Interactions of platelets with subendothelium and endothelium. Microcirculation 12:235–246

    PubMed  CAS  Google Scholar 

  235. Diacovo TG, Puri KD, Warnock RA et al (1996) Platelet-mediated lymphocyte delivery to high endothelial venules. Science 273:252–255

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  237. Pitchford SC, Momi S, Giannini S et al (2005) Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood 105:2074–2081

    PubMed  CAS  Google Scholar 

  238. Diacovo TG, deFougerolles AR, Bainton DF et al (1994) A functional integrin ligand on the surface of platelets: intercellular adhesion molecule-2. J Clin Invest 94:1243–1251

    PubMed  CAS  Google Scholar 

  239. Atarashi K, Hirata T, Matsumoto M et al (2005) Rolling of Th1 cells via P-selectin glycoprotein ligand-1 stimulates LFA-1-mediated cell binding to ICAM-1. J Immunol 174:1424–1432

    PubMed  CAS  Google Scholar 

  240. Li N, Ji Q, Hjemdahl P (2006) Platelet–lymphocyte conjugation differs between lymphocyte subpopulations. J Thromb Haemost 4:874–881

    PubMed  CAS  Google Scholar 

  241. Katz IR, Hoffmann MK, Zucker MB et al (1985) A platelet-derived immunoregulatory serum factor with T cell affinity. J Immunol 134:3199–3203

    PubMed  CAS  Google Scholar 

  242. Matsuda H, Ushio H, Geba GP et al (1997) Human platelets can initiate T cell-dependent contact sensitivity through local serotonin release mediated by IgE antibodies. J Immunol 158:2891–2897

    PubMed  CAS  Google Scholar 

  243. Weyrich AS, Schwertz H, Kraiss LW et al (2009) Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 7:241–246

    PubMed  CAS  Google Scholar 

  244. Santoso S, Kalb R, Kiefel V et al (1993) The presence of messenger RNA for HLA class I in human platelets and its capability for protein biosynthesis. Br J Haematol 84:451–456

    PubMed  CAS  Google Scholar 

  245. Wang L, Erling P, Bengtsson AA et al (2004) Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus. J Thromb Haemost 2:1436–1442

    PubMed  CAS  Google Scholar 

  246. Healy AM, Pickard MD, Pradhan AD et al (2006) Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 113:2278–2284

    PubMed  CAS  Google Scholar 

  247. Potti A, Bild A, Dressman HK et al (2006) Gene-expression patterns predict phenotypes of immune-mediated thrombosis. Blood 107:1391–1396

    PubMed  CAS  Google Scholar 

  248. Raghavachari N, Xu X, Harris A et al (2007) Amplified expression profiling of platelet transcriptome reveals changes in arginine metabolic pathways in patients with sickle cell disease. Circulation 115:1551–1562

    PubMed  CAS  Google Scholar 

  249. Gnatenko DV, Zhu W, Xu X et al (2010) Class prediction models of thrombocytosis using genetic biomarkers. Blood 115:7–14

    PubMed  CAS  Google Scholar 

  250. Lood C, Amisten S, Gullstrand B et al (2010) Platelet transcriptional profile and protein expression in patients with systemic lupus erythematosus: up-regulation of the type I interferon system is strongly associated with vascular disease. Blood 116:1951–1957

    PubMed  CAS  Google Scholar 

  251. Pawlinski R, Wang JG, Owens AP 3rd et al (2010) Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood 116:806–814

    PubMed  CAS  Google Scholar 

  252. Spinelli SL, Maggirwar SB, Blumberg N et al (2010) Nuclear emancipation: a platelet tour de force. Sci Signal 3:pe37

    PubMed  Google Scholar 

  253. Schubert S, Schwertz H, Weyrich AS et al (2011) Staphylococcus aureus alpha-toxin triggers the synthesis of B-cell lymphoma 3 by human platelets. Toxins 3:120–133

    PubMed  CAS  Google Scholar 

  254. Gerrits AJ, Koekman CA, van Haeften TW et al (2010) Platelet tissue factor synthesis in type 2 diabetic patients is resistant to inhibition by insulin. Diabetes 59:1487–1495

    PubMed  CAS  Google Scholar 

  255. Mezzano D, Matus V, Saez CG et al (2008) Tissue factor storage, synthesis and function in normal and activated human platelets. Thromb Res 122(Suppl 1):S31–S36

    PubMed  CAS  Google Scholar 

  256. Anthoni C, Russell J, Wood KC et al (2007) Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med 204:1595–1601

    PubMed  CAS  Google Scholar 

  257. Elzey BD, Sprague DL, Ratliff TL (2005) The emerging role of platelets in adaptive immunity. Cell Immunol 238:1–9

    PubMed  CAS  Google Scholar 

  258. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449:419–426

    PubMed  CAS  Google Scholar 

  259. Hilf N, Singh-Jasuja H, Schwarzmaier P et al (2002) Human platelets express heat shock protein receptors and regulate dendritic cell maturation. Blood 99:3676–3682

    PubMed  CAS  Google Scholar 

  260. Kaneider NC, Kaser A, Tilg H et al (2003) CD40 ligand-dependent maturation of human monocyte-derived dendritic cells by activated platelets. Int J Immunopathol Pharmacol 16:225–231

    PubMed  CAS  Google Scholar 

  261. Czapiga M, Kirk AD, Lekstrom-Himes J (2004) Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immune activation. Exp Hematol 32:135–139

    PubMed  CAS  Google Scholar 

  262. Martinson J, Bae J, Klingemann HG et al (2004) Activated platelets rapidly up-regulate CD40L expression and can effectively mature and activate autologous ex vivo differentiated DC. Cytotherapy 6:487–497

    PubMed  CAS  Google Scholar 

  263. Hagihara M, Higuchi A, Tamura N et al (2004) Platelets, after exposure to a high shear stress, induce IL-10-producing, mature dendritic cells in vitro. J Immunol 172:5297–5303

    PubMed  CAS  Google Scholar 

  264. Kissel K, Berber S, Nockher A et al (2006) Human platelets target dendritic cell differentiation and production of proinflammatory cytokines. Transfusion 46:818–827

    PubMed  CAS  Google Scholar 

  265. Langer HF, Daub K, Braun G et al (2007) Platelets recruit human dendritic cells via Mac-1/JAM-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol 27:1463–1470

    PubMed  CAS  Google Scholar 

  266. Hamzeh-Cognasse H, Cognasse F, Palle S et al (2008) Direct contact of platelets and their released products exert different effects on human dendritic cell maturation. BMC Immunol 9:54

    PubMed  Google Scholar 

  267. Katoh N, Soga F, Nara T et al (2006) Effect of serotonin on the differentiation of human monocytes into dendritic cells. Clin Exp Immunol 146:354–361

    PubMed  CAS  Google Scholar 

  268. Suzuki-Inoue K, Fuller GL, Garcia A et al (2006) A novel Syk-dependent mechanism of platelet activation by the C-type lectin receptor CLEC-2. Blood 107:542–549

    PubMed  CAS  Google Scholar 

  269. Suzuki-Inoue K, Inoue O, Ding G et al (2010) Essential in vivo roles of the C-type lectin receptor CLEC-2: embryonic/neonatal lethality of CLEC-2-deficient mice by blood/lymphatic misconnections and impaired thrombus formation of CLEC-2-deficient platelets. J Biol Chem 285:24494–24507

    PubMed  CAS  Google Scholar 

  270. Uhrin P, Zaujec J, Breuss JM et al (2010) Novel function for blood platelets and podoplanin in developmental separation of blood and lymphatic circulation. Blood 115:3997–4005

    PubMed  CAS  Google Scholar 

  271. Bertozzi CC, Schmaier AA, Mericko P et al (2010) Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 116:661–670

    PubMed  CAS  Google Scholar 

  272. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476

    PubMed  CAS  Google Scholar 

  273. Sprague DL, Elzey BD, Crist SA et al (2008) Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 111:5028–5036

    PubMed  CAS  Google Scholar 

  274. Elzey BD, Grant JF, Sinn HW et al (2005) Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation. J Leukoc Biol 78:80–84

    PubMed  CAS  Google Scholar 

  275. Italiano JE Jr, Mairuhu AT, Flaumenhaft R (2010) Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 17:578–584

    PubMed  Google Scholar 

  276. Elzey BD, Schmidt NW, Crist SA et al (2008) Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood 111:3684–3691

    PubMed  CAS  Google Scholar 

  277. Lindemann SW, Weyrich AS, Zimmerman GA (2005) Signaling to translational control pathways: diversity in gene regulation in inflammatory and vascular cells. Trends Cardiovasc Med 15:9–17

    PubMed  CAS  Google Scholar 

  278. Meshorer E, Misteli T (2005) Splicing misplaced. Cell 122:317–318

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank our colleagues, co-investigators, and collaborators for many relevant observations and discussions and for contributions to work cited in this review. We also thank Jenny Pierce and Diana Lim for invaluable and creative efforts in the preparation of the manuscript and figures. Work cited in this review was supported by the National Institutes of Health (HL044525, HL066277, HL091754, HL092746, HL048872, HL090870, and K231440921), public health service grants ULI-RRO25764 and CO6-RR11234 from the National Center for Research Resources, a Deutsche Forschlungsgemenschaft (DFG) grant (SCHW 1167/1-2), and Western States Affiliate American Heart Association awards 0625098Y and 09BGIA2250381 and by Conselho Nacional de Pesquisa e Desenvolvimento Technológico (CNPq).

Author information

Authors and Affiliations

  1. Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Adriana Vieira-de-Abreu, Robert A. Campbell, Andrew S. Weyrich & Guy A. Zimmerman

  2. Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

    Adriana Vieira-de-Abreu, Robert A. Campbell & Andrew S. Weyrich

  3. Labrotorio de Immunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil

    Adriana Vieira-de-Abreu

Authors
  1. Adriana Vieira-de-Abreu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert A. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew S. Weyrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guy A. Zimmerman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy A. Zimmerman.

Additional information

This article is published as part of the Special Issue on Coagulation and Inflammation [34:1].

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vieira-de-Abreu, A., Campbell, R.A., Weyrich, A.S. et al. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 34, 5–30 (2012). https://doi.org/10.1007/s00281-011-0286-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-011-0286-4

Keywords

Search

Navigation