Cellular and Molecular Life Sciences

, Volume 67, Issue 4, pp 499–511 | Cite as

Platelets and innate immunity

Multi-author Review


Although platelets are best known as primary mediators of hemostasis, this function intimately associates them with inflammatory processes, and it has been increasingly recognized that platelets play an active role in both innate and adaptive immunity. For example, platelet adhesive interactions with leukocytes and endothelial cells via P-selectin can lead to several pro-inflammatory events, including leukocyte rolling and activation, production of cytokine cascades, and recruitment of the leukocytes to sites of tissue damage. Superimposed on this, platelets express immunologically-related molecules such as CD40L and Toll-like receptors that have been shown to functionally modulate innate immunity. Furthermore, platelets themselves can interact with microorganisms, and several viruses have been shown to cross-react immunologically with platelet antigens. This review discusses the central role that platelets play in inflammation, linking them with varied pathological conditions, such as atherosclerosis, sepsis, and immune thrombocytopenic purpura, and suggests that platelets also act as primary mediators of our innate defences.


Platelets Innate immunity Toll-like receptors CD40L Inflammation 


  1. 1.
    Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedCrossRefGoogle Scholar
  2. 2.
    Fearon DT, Locksley RM (1996) The instructive role of innate immunity in the acquired immune response. Science 272:50–53PubMedCrossRefGoogle Scholar
  3. 3.
    Nathan C (2002) Points of control in inflammation. Nature 420:846–852PubMedCrossRefGoogle Scholar
  4. 4.
    Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54:1–6PubMedGoogle Scholar
  5. 5.
    Janeway CA Jr (1992) The immune system evolved to discriminate infectious non-self from non-infectious self. Immunol Today 13:11–15PubMedCrossRefGoogle Scholar
  6. 6.
    Medzitov R, Janeway CA Jr (2000) Innate immunity. N Engl J Med 343:338–346CrossRefGoogle Scholar
  7. 7.
    Medzitov R, Janeway CA Jr (2003) The innate immune system. In: Paul WE (ed) Fundamental immunology, 5th edn. Lippincott/Williams and Wilkins, PhiladelphiaGoogle Scholar
  8. 8.
    Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91:295–298PubMedCrossRefGoogle Scholar
  9. 9.
    Matzinger P (1994) Tolerance, danger and the extended family. Annu Rev Immunol 12:991–1045PubMedGoogle Scholar
  10. 10.
    Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–214PubMedCrossRefGoogle Scholar
  11. 11.
    Raulet DH (2003) Natural killer cells. In: Paul WE (ed) Fundamental immunology, 5th edn. Lippincott/Williams and Wilkins, PhiladelphiaGoogle Scholar
  12. 12.
    Le Page C, Génin P, Baines MG, Hiscott J (2000) Interferon activation and innate immunity. Rev Immunogenet 2:374–392PubMedGoogle Scholar
  13. 13.
    Elzey BD, Tian J, Jensen RJ, Swanson AK, Lees JR, Lentz SR, Stein CS, Nieswandt B, Wang Y, Davidson BL, Ratliff TL (2003) Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 19:9–19PubMedCrossRefGoogle Scholar
  14. 14.
    Aslam R, Freedman J, Semple JW (2004) Murine platelets express Toll-like receptor 2: a potential regulator of innate and adaptive immunity. Platelets 15:267Google Scholar
  15. 15.
    Shiraki R, Inoue N, Kawasaki S, Takei A, Kadotani M, Ohnishi Y, Ejiri J, Kobayashi S, Hirata K, Kawashima S, Yokoyama M (2004) Expression of Toll-like receptors on human platelets. Thromb Res 113:379–385PubMedCrossRefGoogle Scholar
  16. 16.
    Coppinger JA, Cagney G, Toomey S, Kislinger T, Belton O, McRedmond JP, Cahill DJ, Emili A, Fitzgerald DJ, Maguire PB (2004) Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 103:2096–2104PubMedCrossRefGoogle Scholar
  17. 17.
    Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O (2005) Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol 88:196–198CrossRefGoogle Scholar
  18. 18.
    Ward JR, Bingle L, Judge HM, Brown SB, Storey RF, Whyte MK, Dower SK, Buttle DJ, Sabroe I (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 94:831–838PubMedGoogle Scholar
  19. 19.
    Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P (2005) Platelets express functional Toll-like receptor-4. Blood 106:2417–2423PubMedCrossRefGoogle Scholar
  20. 20.
    Aslam R, Speck ER, Kim M, Crow AR, Bang KW, Nestel FP, Ni H, Lazarus AH, Freedman J, Semple JW (2006) Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood 107:637–641PubMedCrossRefGoogle Scholar
  21. 21.
    Patrignani P, Di Febbo C, Tacconelli S, Moretta V, Baccante G, Sciulli MG, Ricciotti E, Capone ML, Antonucci I, Guglielmi MD, Stuppia L, Porreca E (2006) Reduced thromboxane biosynthesis in carriers of Toll-Like receptor 4 polymorphisms in vivo. Blood 107:3572–3574PubMedCrossRefGoogle Scholar
  22. 22.
    Ståhl AL, Svensson M, Mörgelin M, Svanborg C, Tarr PI, Mooney JC, Watkins SL, Johnson R, Karpman D (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets via TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood 108:167–176PubMedCrossRefGoogle Scholar
  23. 23.
    Jayachandran M, Brunn GJ, Karnicki K, Miller RS, Owen WG, Miller VM (2007) In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk. J Appl Physiol 102:429–433PubMedCrossRefGoogle Scholar
  24. 24.
    Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469PubMedCrossRefGoogle Scholar
  25. 25.
    Semple JW, Aslam R, Kim M, Speck ER, Freedman J (2007) Platelet-bound lipopolysaccharide enhances Fc receptor-mediated phagocytosis of IgG opsonized platelets. Blood 109:4803–4805PubMedCrossRefGoogle Scholar
  26. 26.
    von Hundelshausen P, Weber C (2007) Platelets as immune cells. Bridging inflammation and cardiovascular disease. Circ Res 100:27–40CrossRefGoogle Scholar
  27. 27.
    Cognasse F, Semple JW, Garraud O (2007) Platelets as potential immunomodulators: is there a role for platelet toll like receptors? Curr Immunol Rev 3:109–115CrossRefGoogle Scholar
  28. 28.
    Tremblay T, Aubin E, Lemieux R, Bazin R (2007) Picogram doses of lipopolysaccharide exacerbate antibody-mediated thrombocytopenia and reduce the therapeutic efficacy of intravenous immunoglobulin in mice. Br J Haematol 139:297–302PubMedCrossRefGoogle Scholar
  29. 29.
    Scott T, Owens MD (2007) Thrombocytes respond to lipopolysaccharide through Toll-like receptor 4, MAP kinase and NFK beta. Mol Immunol 45:1001–1008PubMedCrossRefGoogle Scholar
  30. 30.
    Ma AC, Kubes P (2008) Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 6:415–420PubMedCrossRefGoogle Scholar
  31. 31.
    Kuckleburg CJ, Tiwari R, Czuprynski CJ (2008) Endothelial cell apoptosis induced by bacteria-activated platelets requires caspase-8 and -9 and generation of reactive oxygen species. Thromb Haemost 99:363–372PubMedGoogle Scholar
  32. 32.
    Kuckleburg CJ, McClenahan DJ, Czuprynski CJ (2008) Platelet activation by Histophilus somni and its lipooligosaccharide induces endothelial cell proinflammatory responses and platelet internalization. Shock 29:189–196PubMedGoogle Scholar
  33. 33.
    Hose JE, Martin GG, Gerard AS (1990) A decapod hemocyte classification scheme integrating morphology, cytochemistry, and function. Biol Bull 178:33–45CrossRefGoogle Scholar
  34. 34.
    Götz P, Boman HG (1985) Insect immunity. In: Kerkut GA, Gilbert LI (eds) Comprehensive insect physiology. Biochemistry and pharmacology. Pergamon, Oxford, pp 453–485Google Scholar
  35. 35.
    Gillespie JP, Kanost MR, Trenczek T (1997) Biological mediators of insect immunity. Annu Rev Entomol 42:611–643PubMedCrossRefGoogle Scholar
  36. 36.
    Nappi AJ, Vass E (1993) Melanogenesis and the generation of cytotoxic molecules during insect cellular immune reactions. Pigment Cell Res 6:117–126PubMedCrossRefGoogle Scholar
  37. 37.
    Stenberg PE, McEver RP, Shuman MA, Jacques YV, Bainton DF (1985) A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol 101:880–886PubMedCrossRefGoogle Scholar
  38. 38.
    Bonfanti R, Furie BC, Furie B, Wagner DD (1989) PADGEM (GMP140) is a component of Weibel–Palade bodies of human endothelial cells. Blood 73:1109–1112PubMedGoogle Scholar
  39. 39.
    Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA (1996) Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood 88:146–157PubMedGoogle Scholar
  40. 40.
    Kuijper PH, Gallardo Torres HI, van der Linden JA, Lammers JW, Sixma JJ, Koenderman L, Zwaginga JJ (1996) Platelet-dependent primary hemostasis promotes selectin- and integrin-mediated neutrophil adhesion to damaged endothelium under flow conditions. Blood 87:3271–3281PubMedGoogle Scholar
  41. 41.
    Dole VS, Bergmeier W, Patten IS, Hirahashi J, Mayadas TN, Wagner DD (2007) PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets. Thromb Haemost 98:806–812PubMedGoogle Scholar
  42. 42.
    Gawaz M, Neumann FJ, Dickfeld T, Koch W, Laugwitz KL, Adelsberger H, Langenbrink K, Page S, Neumeier D, Schomig A, Brand K (1998) Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. Circulation 98:1164–1171PubMedGoogle Scholar
  43. 43.
    von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C (2001) RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 103:1772–1777Google Scholar
  44. 44.
    Frenette PS, Mayadas TN, Rayburn H, Hynes RO, Wagner DD (1996) Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell 84:563–574PubMedCrossRefGoogle Scholar
  45. 45.
    Bullard DC, Kunkel EJ, Kubo H, Hicks MJ, Lorenzo I, Doyle NA, Doerschuk CM, Ley K, Beaudet AL (1996) Infectious susceptibility and severe deficiency of leukocyte rolling and recruitment in E-selectin and P-selectin double mutant mice. J Exp Med 5:2329–2336CrossRefGoogle Scholar
  46. 46.
    Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD (1993) Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74:541–554PubMedCrossRefGoogle Scholar
  47. 47.
    Berndt MC, Karunakaran D, Gardiner EE, Andrews RK (2007) Programmed autologous cleavage of platelet receptors. J Thromb Haemost 5(Suppl 1):212–219PubMedCrossRefGoogle Scholar
  48. 48.
    Merten M, Thiagarajan P (2000) P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 102:1931–1936PubMedGoogle Scholar
  49. 49.
    Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, McIntire LV, Berndt MC, Lopez JA (1999) The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med 190:803–814PubMedCrossRefGoogle Scholar
  50. 50.
    Yang H, Reheman A, Chen P, Zhu G, Hynes RO, Freedman J, Wagner DD, Ni H (2006) Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo. J Thromb Haemost 4:2230–2237PubMedCrossRefGoogle Scholar
  51. 51.
    Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD (2000) Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106:385–392PubMedCrossRefGoogle Scholar
  52. 52.
    Ross R (1999) Atherosclerosis: an inflammatory disease. N Engl J Med 340:115–126PubMedCrossRefGoogle Scholar
  53. 53.
    Dong ZM, Brown AA, Wagner DD (2000) Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation 101:2290–2295PubMedGoogle Scholar
  54. 54.
    Collins RG, Velji R, Guevara NV, Hicks MJ, Chan L, Beaudet AL (2000) P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 191:189–194PubMedCrossRefGoogle Scholar
  55. 55.
    Burger PC, Wagner DD (2003) Platelet P-selectin facilitates atherosclerotic lesion development. Blood 101:2661–2666PubMedCrossRefGoogle Scholar
  56. 56.
    Larsen E, Celi A, Gilbert GE, Furie BC, Erban JK, Bonfanti R, Wagner DD, Furie B (1989) PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 59:305–312PubMedCrossRefGoogle Scholar
  57. 57.
    Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K (1998) Direct demonstration of P-selectin- and VCAM-1 dependent mono-nuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circ Res 84:1237–1244Google Scholar
  58. 58.
    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 100:2085–2093PubMedCrossRefGoogle Scholar
  59. 59.
    Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, Weyrich AS (2001) Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 154:485–490PubMedCrossRefGoogle Scholar
  60. 60.
    Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594PubMedCrossRefGoogle Scholar
  61. 61.
    Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K (2003) Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 9:61–67PubMedCrossRefGoogle Scholar
  62. 62.
    Andre P, Nannizzi-Alaimo L, Prasad SK, Phillips DR (2002) Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 106:896–899PubMedCrossRefGoogle Scholar
  63. 63.
    Ross R (1985) Platelets, platelet-derived growth factor, growth control, their interactions with the vascular wall. J Cardiovasc Pharmacol 7(Suppl 3):S186–S190PubMedCrossRefGoogle Scholar
  64. 64.
    Yamashita S, Hirano K, Kuwasako T, Janabi M, Toyama Y, Ishigami M, Sakai N (2007) Physiological and pathological roles of a multi-ligand receptor CD36 in atherogenesis; insights from CD36-deficient patients. Mol Cell Biochem 299:19–22PubMedCrossRefGoogle Scholar
  65. 65.
    Kuchibhotla S, Vanegas D, Kennedy DJ, Guy E, Nimako G, Morton RE, Febbraio M (2008) Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II. Cardiovasc Res 78:185–196PubMedCrossRefGoogle Scholar
  66. 66.
    Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384PubMedCrossRefGoogle Scholar
  67. 67.
    Langer HF, Gawaz M (2008) Platelet-vessel wall interactions in atherosclerotic disease. Thromb Haemost 99:480–486PubMedGoogle Scholar
  68. 68.
    Davi G, Patrono C (2007) Platelet activation and atherothrombosis. N Engl J Med 357:2482–2494PubMedCrossRefGoogle Scholar
  69. 69.
    Wagner DD, Burger PC (2003) Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 23:2131–2137PubMedCrossRefGoogle Scholar
  70. 70.
    Baughman RP, Lower EE, Flessa HC, Tollerud DJ (1993) Thrombocytopenia in the intensive care unit. Chest 104:1243–1247PubMedCrossRefGoogle Scholar
  71. 71.
    Gawaz M, Dickfeld T, Bogner C, Fateh-Moghadam S, Neumann FJ (1997) Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med 23:379–385PubMedCrossRefGoogle Scholar
  72. 72.
    Russwurm S, Vickers J, Meier-Hellmann A, Spangenberg P, Bredle D, Reinhart K, Lösche W (2002) Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock 17:263–268PubMedCrossRefGoogle Scholar
  73. 73.
    Gawaz M, Fateh-Moghadam S, Pilz G, Gurland HJ, Werdan K (1995) Platelet activation and interaction with leukocytes in patients with sepsis or multiple organ failure. Eur J Clin Invest 25:843–851PubMedCrossRefGoogle Scholar
  74. 74.
    Gawaz M, Fateh-Moghadam S, Pilz G, Gurland HJ, Werdan K (1995) Severity of multiple organ failure (MOF) but not sepsis correlates with irreversible platelet degranulation. Infection 23:16–23PubMedCrossRefGoogle Scholar
  75. 75.
    Jacoby RC, Owings JT, Holmes J, Battistella FD, Gosselin RC, Paglieroni TG (2001) Platelet activation and function after trauma. J Trauma 51:639–647PubMedCrossRefGoogle Scholar
  76. 76.
    Ogura H, Kawasaki T, Tanaka H, Koh T, Tanaka R, Ozeki Y, Hosotsubo H, Kuwagata Y, Shimazu T, Sugimoto H (2001) Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma 50:801–809PubMedCrossRefGoogle Scholar
  77. 77.
    Vincent J-L, Yagushi A, Pradier O (2002) Platelet function in sepsis. Crit Care Med 30(Suppl 5):S313–S317PubMedCrossRefGoogle Scholar
  78. 78.
    Boldt J, Menges T, Wöllbruck M, Sonneborn S, Hempelmann G (1994) Platelet function in critically ill patients. Chest 106:899–903PubMedCrossRefGoogle Scholar
  79. 79.
    Matera C, Falzarano C, Berrino L, Rossi F (1992) Effects of tetanus toxin, Salmonella typhimurium porin, and bacterial lipopolysaccharides on platelet aggregation. J Med 23:327–338PubMedGoogle Scholar
  80. 80.
    Isogai E, Kitagawa H, Isogai H, Matsuzawa T, Shimizu T, Yanagihara Y, Kitami K (1992) Effect of leptospiral lipopolysaccharide on rabbit platelets. Int J Med Microbiol 271:186–196Google Scholar
  81. 81.
    Saba HI, Saba SR, Morelli G, Hartmann RC (1984) Endotoxin-mediated inhibition of human platelet aggregation. Thromb Res 34:19–33PubMedCrossRefGoogle Scholar
  82. 82.
    Sheu JR, Hsiao G, Lee C, Chang W, Lee L, Su C, Lin C (2000) Antiplatelet activity of Staphylococcus aureus lipoteichoic acid is mediated through a cyclic AMP pathway. Thromb Res 99:249–258PubMedCrossRefGoogle Scholar
  83. 83.
    Youssefian T, Drouin A, Masse JM, Guichard J, Cramer EM (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 99:4021–4029PubMedCrossRefGoogle Scholar
  84. 84.
    Zucker-Franklin D, Seremetis S, Zheng ZY (1990) Internalization of human immunodef-iciency virus type I and other retroviruses by megakaryocytes and platelets. Blood 75:1920–1923PubMedGoogle Scholar
  85. 85.
    White JG, Clawson CC (1981) Effects of large latex particle uptake of the surface connected canalicular system of blood platelets: a freeze-fracture and cytochemical study. Ultrastruct Pathol 2:277–287PubMedCrossRefGoogle Scholar
  86. 86.
    White JG, Clawson CC (1982) Effects of small latex particle uptake on the surface connected canalicular system of blood platelets: a freeze-fracture and cytochemical study. Diagn Histopathol 2:3–10Google Scholar
  87. 87.
    White JG (2005) Platelets are covercytes, not phagocytes: uptake of bacteria involves channels of the open canalicular system. Platelets 16:121–131PubMedCrossRefGoogle Scholar
  88. 88.
    Koo SP, Bayer AS, Sahl HG, Proctor RA, Yeaman MR (1996) Staphylocidal action of thrombin-induced platelet microbicidal protein is not solely dependent on transmembrane potential. Infect Immun 64:1070–1074PubMedGoogle Scholar
  89. 89.
    Klinger MH, Wilhelm D, Bubel S, Sticherling M, Schroder JM, Kuhnel W (1995) Immunocytochemical localization of the chemokines RANTES and MIP-1 alpha within human platelets and their release during storage. Int Arch Allergy Immunol 107:541–546PubMedCrossRefGoogle Scholar
  90. 90.
    Lewis JC, Maldonado JE, Mann KG (1946) Phagocytosis in human platelets: localization of acid phosphatase-positive phagosomes following latex uptake. Blood 47:833–840Google Scholar
  91. 91.
    Welbourn CR, Young Y (1992) Endotoxin, septic shock and acute lung injury: neutrophils, macrophages and inflammatory mediators. Br J Surg 79:998–1003PubMedCrossRefGoogle Scholar
  92. 92.
    McClenahan DJ, Evanson OA, Walcheck BK, Weiss DJ (2000) Association among filamentous actin content, CD11b expression, and membrane deformability in stimulated and unstimulated bovine neutrophils. Am J Vet Res 61:380–386PubMedCrossRefGoogle Scholar
  93. 93.
    Zarbock A, Polanowska-Grabowska R, Ley K (2007) Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 21:99–111PubMedCrossRefGoogle Scholar
  94. 94.
    Peters MJ, Heyderman RS, Hatch DJ, Klein NJ (1997) Investigation of plateletneutrophil interactions in whole blood by flow cytometry. J Immunol Methods 209:125–135PubMedCrossRefGoogle Scholar
  95. 95.
    Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S (2000) Coagulation system and platelets are fully activated in uncomplicated sepsis. Crit Care Med 28:451–457PubMedCrossRefGoogle Scholar
  96. 96.
    Nathan C (2006) Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 6:173–182PubMedCrossRefGoogle Scholar
  97. 97.
    Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedCrossRefGoogle Scholar
  98. 98.
    Hollenbaugh D, Mischel-Petty N, Edwards CP, Simon JC, Denfeld RW, Kiener PA, Aruffo A (1995) Expression of functional CD40 by vascular endothelial cells. J Exp Med 182:32–40CrossRefGoogle Scholar
  99. 99.
    Henn V, Steinbach S, Büchner K, Presek P, Kroczek RA (2001) The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 98:1047–1054PubMedCrossRefGoogle Scholar
  100. 100.
    Prasad KSS, André P, He M, Bao M, Manganello J, Phillips DR (2003) Soluble CD40 ligand induces β3 integrin tyrosine phosphorylation and triggers platelet activation by outside-in signaling. Proc Natl Acad Sci USA 100:12367–12371PubMedCrossRefGoogle Scholar
  101. 101.
    Inwald DP, McDowall A, Peters MJ, Callard RE, Klein NJ (2003) CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ Res 92:1041–1048PubMedCrossRefGoogle Scholar
  102. 102.
    Hammwöhner M, Ittenson A, Dierkes J, Bukowska A, Klein HU, Lendeckel U, Goette A (2007) Platelet expression of CD40/CD40 ligand and its relation to inflammatory markers and adhesion molecules in patients with atrial fibrillation. Exp Biol Med 232:581–589Google Scholar
  103. 103.
    Anand SX, Viles-Gonzalez JF, Badimon JJ (2003) Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost 90:377–384PubMedGoogle Scholar
  104. 104.
    Slupsky JR, Kalbas M, Willuweit A (1998) Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost 80:1008–1014PubMedGoogle Scholar
  105. 105.
    Zhou L, Stordeur P, de Lavareille A (1998) CD40 engagement on endothelial cells promotes tissue factor-dependent proco-agulant activity. Thromb Haemost 79:1025–1028PubMedGoogle Scholar
  106. 106.
    Grewal IS, Flavell RA (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16:111–135PubMedCrossRefGoogle Scholar
  107. 107.
    Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, Orpana A, Ristimaki A, Heikinheimo M, Joensuu H (1998) Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 80:171–175PubMedGoogle Scholar
  108. 108.
    Webb NJ, Bottomley MJ, Watson CJ (1998) Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci 94:395–404PubMedGoogle Scholar
  109. 109.
    Choudhury A, Freeston B, Patel J, Lip GYH (2007) Relationship of soluble CD40 ligand to vascular endothelial growth factor, angiopoietins, and tissue factor in atrial fibrillation. Chest 132:1913–1919PubMedCrossRefGoogle Scholar
  110. 110.
    Sprague DL, Elzey BD, Crist SA, Waldschmidt TJ, Jensen RJ, Ratliff TL (2008) Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles. Blood 111:5028–5036. doi:10.1182/blood-2007-06-097410 PubMedCrossRefGoogle Scholar
  111. 111.
    Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH (1996) Platelet-mediated lymphocyte delivery to high endothelial venules. Science 273:252–255PubMedCrossRefGoogle Scholar
  112. 112.
    Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB (1983) Transforming growth factor-β in human platelets: identification of a major storage site, purification, and characterization. J Biol Chem 258:7155–7160PubMedGoogle Scholar
  113. 113.
    Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL (2008) Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood 111:1227–1233PubMedCrossRefGoogle Scholar
  114. 114.
    White GC, Rompietti R (2007) Platelet secretion: indiscriminately spewed forth or highly orchestrated? J Thromb Haemost 5:2006–2008PubMedCrossRefGoogle Scholar
  115. 115.
    Austrup F, Vestweber D, Borges E, Lohning M, Brauer R, Herz U, Renz H, Hallmann R, Scheffold A, Radbruch A, Hamann A (1997) P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature 385:81–83PubMedCrossRefGoogle Scholar
  116. 116.
    Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164:4991–4995PubMedGoogle Scholar
  117. 117.
    Bouchon A, Facchetti F, Weigand MA, Colonna M (2001) TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410:1103–1107PubMedCrossRefGoogle Scholar
  118. 118.
    Klesney-Tait J, Turnbull IR, Colonna M (2006) The TREM receptor family and signal integration. Nat Immunol 7:1266–1273PubMedCrossRefGoogle Scholar
  119. 119.
    Fortin CF, Lesur O, Fulop T Jr (2007) Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4. Int Immunol 19:41–50PubMedCrossRefGoogle Scholar
  120. 120.
    Radsak MP, Salih HR, Rammensee HG, Schild H (2004) Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: differential regulation of activation and survival. J Immunol 172:4956–4963PubMedGoogle Scholar
  121. 121.
    Haselmayer P, Grosse-Hovest L, von Landenberg P, Schild H, Radsak MP (2007) TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 110:1029–1035PubMedCrossRefGoogle Scholar
  122. 122.
    Cines DB, Blanchette VS (2002) Immune thrombocytopenic purpura. N Engl J Med 346:995–1008PubMedCrossRefGoogle Scholar
  123. 123.
    Blanchette V (2002) Childhood chronic immune thrombocytopenic purpura (ITP). Blood Rev 16:23–26PubMedCrossRefGoogle Scholar
  124. 124.
    Wright JF, Blanchette V, Wang H, Arya N, Petric M, Semple JW, Freedman J (1996) Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP). Br J Haematol 95:145–152PubMedCrossRefGoogle Scholar
  125. 125.
    Chia WK, Blanchette VS, Mody M, Wright JF, Freedman J (1998) Characterization of HIV-1-specific antibodies and HIV-1-crossreactive antibodies to platelets in HIV-1-infected haemophiliac patients Br. J Haematol 103:1365–2141CrossRefGoogle Scholar
  126. 126.
    Li Z, Nardi MA, Karpatkin S (2005) Role of molecular mimicry to HIV-1 peptides in HIV-1–related immunologic thrombocytopenia. Blood 106:572–576PubMedCrossRefGoogle Scholar
  127. 127.
    Musaji A, Cormont F, Thirion G, Cambiaso CL, Coutelier J-P (2004) Exacerbation of autoantibody-mediated thrombocytopenic purpura by infection with mouse viruses. Blood 104:2102–2106PubMedCrossRefGoogle Scholar
  128. 128.
    Emilia G, Longo G, Luppi M, Gandini G, Morselli M, Ferrara L, Amarri S, Cagossi K, Torelli G (2001) Helicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura. Blood 97:812–814PubMedCrossRefGoogle Scholar
  129. 129.
    Gasbarrini A, Franceschi F, Tartaglione R, Landolfi R, Pola P, Gasbarrini G (1998) Regression of autoimmune thrombocytopenia after eradication of Helicobacter pylori. Lancet 352:878–879PubMedCrossRefGoogle Scholar
  130. 130.
    Stasi R, Rossi Z, Stipa E, Amadori S, Newland AC, Provan D (2005) Helicobacter pylori eradication in the management of patients with idiopathic thrombocytopenic purpura. Am J Med 118:420–421CrossRefGoogle Scholar
  131. 131.
    Jarque I, Andreu R, Llopis I, De la Rubia J, Gomis F, Senent L, Jiménez C, Martín G, Martínez JA, Sanz GF, Ponce J, Sanz MA (2001) Absence of platelet response after eradication of Helicobacter pylori infection in patients with chronic idiopathic thrombocytopenic purpura. Br J Haematol 115:1002–1003PubMedCrossRefGoogle Scholar
  132. 132.
    Bang A, Speck ER, Blanchette VS, Freedman J, Semple JW (1996) Recipient humoral immunity against allogeneic leukoreduced platelets is inhibited by aminoguanidine, a selective inhibitor of inducible nitric oxide synthase (iNOS). Blood 88:2959–2966PubMedGoogle Scholar
  133. 133.
    Bang KWA, Speck ER, Blanchette VS, Freedman J, Semple JW (2000) Unique processing pathways within recipient antigen presenting cells determine IgG immune responsiveness against donor platelet MHC antigens. Blood 95:1735–1742PubMedGoogle Scholar
  134. 134.
    Semple JW, Freedman J (2002) Recipient antigen processing pathways of allogeneic platelet antigens: essential mediators of immunity. Transfusion 42:958–961PubMedCrossRefGoogle Scholar
  135. 135.
    Sayeh E, Sterling K, Speck ER, Freedman J, Semple JW (2004) IgG anti-platelet immunity is dependent on an early innate natural killer cell-derived interferon-γ response that is regulated by CD8 + T cells. Blood 103:2705–2709PubMedCrossRefGoogle Scholar
  136. 136.
    Sayeh E, Aslam R, Speck ER, Letien H, Lazarus AH, Freedman J, Semple JW (2004) Immune responsiveness against allogeneic platelet transfusions is determined by the recipient’s MHC class II phenotype. Transfusion 44:1572–1578PubMedCrossRefGoogle Scholar
  137. 137.
    Semple JW, Speck ER, Fabron A Jr, Aslam R, Kim M, Freedman J (2008) A novel immunosuppressive pathway involving peroxynitrate-mediated nitration of platelet antigens within antigen presenting cells. Transfusion 48:1917–1924PubMedCrossRefGoogle Scholar
  138. 138.
    Aslan M, Ryan TM, Townes TM, Coward L, Kirk MC, Barnes S (2003) Nitric oxide-dependent generation of reactive species in sickle cell disease. Actin tyrosine nitration induces defective cytoskeletal polymerization. J Biol Chem 278:4194–4204PubMedCrossRefGoogle Scholar
  139. 139.
    Eiserich JP, Estévez AG, Bamberg TV (1999) Microtubule dysfunction by posttranslational nitrotyrosination of α-tubulin: a nitric oxide-dependent mechanism of cellular injury. Proc Nat Acad Sci USA 96:6365–6370PubMedCrossRefGoogle Scholar
  140. 140.
    Matsushita K, Morrell CN, Cambien B, Yang SX, Yamakuchi M, Bao C, Hara MR, Quick RA, Cao W, O’Rourke B, Lowenstein JM, Pevsner J, Wagner DD, Lowenstein CJ (2003) Nitric oxide regulates exocytosis by S-nitrosylation of N-ethylmaleimide-sensitive factor. Cell 115:139–150PubMedCrossRefGoogle Scholar
  141. 141.
    Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2:907–916PubMedCrossRefGoogle Scholar
  142. 142.
    Bogdan C (1998) The multiplex function of nitric oxide in (auto)immunity. J Exp Med 187:1361–1365PubMedCrossRefGoogle Scholar
  143. 143.
    Coleman JW (2001) Nitric oxide in immunity and inflammation. Int Immunopharmacol 1:1397–1406PubMedCrossRefGoogle Scholar
  144. 144.
    Popovsky MA, Abel MD, Moore SB (1983) Transfusion-related acute lung injury associated with passive transfer of antileukocyte antibodies. Am Rev Respir Dis 128:185–189PubMedGoogle Scholar
  145. 145.
    Popovsky MA, Moore SB (1985) Diagnostic and pathogenetic considerations in transfusion-related acute lung injury. Transfusion 25:573–577PubMedCrossRefGoogle Scholar
  146. 146.
    Jawa RS, Anillo S, Kulaylat MN (2008) Transfusion-related acute lung injury. J Intensive Care Med 23:109–121PubMedCrossRefGoogle Scholar
  147. 147.
    Looney MR, Gropper MA, Matthay MA (2004) Transfusion-related acute lung injury: a review. Chest 126:249–258PubMedCrossRefGoogle Scholar
  148. 148.
    Toy P, Gajic O (2004) Transfusion-related acute lung injury. Anesth Analg 99:1623–1624PubMedCrossRefGoogle Scholar
  149. 149.
    Bux J (2004) Transfusion-related acute lung injury: a neglected but life-threatening transfusion reaction. Infusionsther Transfusionsmed 29:271–276Google Scholar
  150. 150.
    Khan SY, Kelher MR, Heal JM, Blumberg N, Boshkov LK, Phipps R, Gettings KF, McLaughlin NJ, Silliman CS (2006) Soluble CD40 ligand accumulates in stored blood components, primes neutrophils through CD40, and is a potential cofactor in the development of transfusion-related acute lung injury. Blood 108:2455–2462PubMedCrossRefGoogle Scholar
  151. 151.
    Cognasse F, Lafarge S, Chavarin P, Acquart S, Garraud O (2007) Lipopolysaccharide induces sCD40L release through human platelets TLR4, but not TLR2 and TLR9. Intensive Care Med 33:382–384PubMedCrossRefGoogle Scholar
  152. 152.
    Damås JK, Jensenius M, Ueland T, Otterdal K, Yndestad A, Frøland SS, Rolain JM, Myrvang B, Raoult D, Aukrust P (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 177:2699–2706PubMedGoogle Scholar
  153. 153.
    Cognasse F, Hamzeh-Cognasse H, Lafarge S, Delezay O, Pozzetto B, McNicol A, Garraud O (2008) Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets. Br J Haematol 141:84–91PubMedCrossRefGoogle Scholar
  154. 154.
    Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, Hayashi C, Genco CA, Iafrati M, Freedman JE (2009) Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res 104:346–354PubMedCrossRefGoogle Scholar
  155. 155.
    Zhang G, Han J, Welch EJm, Yem RD, Voyno-Yasenetskaya TA, Malik AB, Du X, Li Z (2009) Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol 182:7997–8004PubMedCrossRefGoogle Scholar
  156. 156.
    Cognasse F, Hamzeh-Cognasse H, Garraud O (2008) Platelets “Toll-like receptor” engagement stimulates the release of immunomodulating molecules. Transfusion Clin Biol 15:139–147CrossRefGoogle Scholar
  157. 157.
    Miller VM, Jayachandran M, Hashimoto K, Heit JA, Owen WG (2008) Estrogen, inflammation, and platelet phenotype. Gend Med 5(Suppl A):S91–S102PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  1. 1.Keenan Research Centre, Li Ka Shing Knowledge InstituteSt. Michael’s HospitalTorontoCanada
  2. 2.Department of PharmacologyUniversity of TorontoTorontoCanada
  3. 3.Department of MedicineUniversity of TorontoTorontoCanada
  4. 4.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  5. 5.Canadian Blood ServicesTorontoCanada
  6. 6.The Toronto Platelet Immunobiology GroupTorontoCanada

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