Immune Functions of Platelets

  • Rick Kapur
  • John W. Semple


Platelets are megakaryocyte-derived cellular fragments lacking a nucleus and are classically known for their crucial role in supporting hemostasis. Besides their hemostatic function, it is becoming increasingly clear that platelets are much more diverse and that they are capable of a wide range of immune-sensing functions. This chapter will focus on these non-hemostatic immunological aspects, especially in an inflammatory setting. The cross talk between platelets and pathogens as well as between platelets and various target cells will be discussed, in order to highlight the emerging and important immune features of platelets.


  1. Aiolfi R, Sitia G. Chronic hepatitis B: role of anti-platelet therapy in inflammation control. Cell Mol Immunol. 2015;12(3):264–8.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alam R, Forsythe PA, Stafford S, Lett-Brown MA, Grant JA. Macrophage inflammatory protein-1 alpha activates basophils and mast cells. J Exp Med. 1992;176:781–6.CrossRefPubMedGoogle Scholar
  3. Anabel AS, Eduardo PC, Pedro Antonio HC, Carlos SM, Juana NM, Honorio TA, Nicolas VS, Sergio Roberto AR. Human platelets express Toll-like receptor 3 and respond to poly I:C. Hum Immunol. 2014;75:1244–51.CrossRefPubMedGoogle Scholar
  4. Andersson PO, Olsson A, Wadenvik H. Reduced transforming growth factor-beta1 production by mononuclear cells from patients with active chronic idiopathic thrombocytopenic purpura. Br J Haematol. 2002;116:862–7.CrossRefPubMedGoogle Scholar
  5. Andersson PO, Stockelberg D, Jacobsson S, Wadenvik H. A transforming growth factor-beta1-mediated bystander immune suppression could be associated with remission of chronic idiopathic thrombocytopenic purpura. Ann Hematol. 2000;79:507–13.CrossRefPubMedGoogle Scholar
  6. Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood. 2005;106:2417–23.CrossRefPubMedGoogle Scholar
  7. Arraud N, Linares R, Tan S, Gounou C, Pasquet JM, Mornet S, Brisson AR. Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and concentration. J Thromb Haemost. 2014;12:614–27.CrossRefPubMedGoogle Scholar
  8. Asahi A, Nishimoto T, Okazaki Y, Suzuki H, Masaoka T, Kawakami Y, Ikeda Y, Kuwana M. Helicobacter pylori eradication shifts monocyte Fcgamma receptor balance toward inhibitory FcgammaRIIB in immune thrombocytopenic purpura patients. J Clin Invest. 2008;118:2939–49.PubMedPubMedCentralGoogle Scholar
  9. Aslam R, Speck ER, Kim M, Crow AR, Bang KW, Nestel FP, Ni H, Lazarus AH, Freedman J, Semple JW. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood. 2006;107:637–41.CrossRefPubMedGoogle Scholar
  10. Aslam R, Speck ER, Kim M, Freedman J, Semple JW. Transfusion-related immunomodulation by platelets is dependent on their expression of MHC Class I molecules and is independent of white cells. Transfusion. 2008;48:1778–86.CrossRefPubMedGoogle Scholar
  11. Assinger A. Platelets and infection – an emerging role of platelets in viral infection. Front Immunol. 2014;5:649.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Assinger A, Laky M, Badrnya S, Esfandeyari A, Volf I. Periodontopathogens induce expression of CD40L on human platelets via TLR2 and TLR4. Thromb Res. 2012;130:e73–8.CrossRefPubMedGoogle Scholar
  13. Assinger A, Laky M, Schabbauer G, Hirschl AM, Buchberger E, Binder BR, Volf I. Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. J Thromb Haemost. 2011;9:799–809.CrossRefPubMedGoogle Scholar
  14. Assoian RK, Komoriya A, Meyers CA, Miller DM, Sporn MB. Transforming growth factor-beta in human platelets. Identification of a major storage site, purification, and characterization. J Biol Chem. 1983;258:7155–60.PubMedGoogle Scholar
  15. Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23:177–89.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, Hayashi C, Genco CA, Iafrati M, Freedman JE. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res. 2009;104:346–54.CrossRefPubMedGoogle Scholar
  17. Blumberg N, Masel D, Mayer T, Horan P, Heal J. Removal of HLA-AB antigens from platelets. Blood. 1984;63:448–50.PubMedGoogle Scholar
  18. Boilard E, Blanco P, Nigrovic PA. Platelets: active players in the pathogenesis of arthritis and SLE. Nat Rev Rheumatol. 2012;8:534–42.CrossRefPubMedGoogle Scholar
  19. Boilard E, Nigrovic PA, Larabee K, Watts GF, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O’Donnell E, Farndale RW, Ware J, Lee DM. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science. 2010;327:580–3.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Boilard E, Pare G, Rousseau M, Cloutier N, Dubuc I, Levesque T, Borgeat P, Flamand L. Influenza virus H1N1 activates platelets through FcgammaRIIA signaling and thrombin generation. Blood. 2014;123:2854–63.CrossRefPubMedGoogle Scholar
  21. Boudreau LH, Duchez AC, Cloutier N, Soulet D, Martin N, Bollinger J, Pare A, Rousseau M, Naika GS, Levesque T, Laflamme C, Marcoux G, Lambeau G, Farndale RW, Pouliot M, Hamzeh-Cognasse H, Cognasse F, Garraud O, Nigrovic PA, Guderley H, Lacroix S, Thibault L, Semple JW, Gelb MH, Boilard E. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood. 2014;124:2173–83.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Brandt E, Petersen F, Ludwig A, Ehlert JE, Bock L, Flad HD. The beta-thromboglobulins and platelet factor 4: blood platelet-derived CXC chemokines with divergent roles in early neutrophil regulation. J Leukoc Biol. 2000;67:471–8.CrossRefPubMedGoogle Scholar
  23. Brown GT, McIntyre TM. Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1beta-rich microparticles. J Immunol. 2011;186:5489–96.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Burkhart JM, Vaudel M, Gambaryan S, Radau S, Walter U, Martens L, Geiger J, Sickmann A, Zahedi RP. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood. 2012;120:e73–82.CrossRefPubMedGoogle Scholar
  25. Buzas EI, Gyorgy B, Nagy G, Falus A, Gay S. Emerging role of extracellular vesicles in inflammatory diseases. Nat Rev Rheumatol. 2014;10:356–64.CrossRefPubMedGoogle Scholar
  26. Caudrillier A, Kessenbrock K, Gilliss BM, Nguyen JX, Marques MB, Monestier M, Toy P, Werb Z, Looney MR. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122:2661–71.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Chapman LM, Aggrey AA, Field DJ, Srivastava K, Ture S, Yui K, Topham DJ, Baldwin WM III, Morrell CN. Platelets present antigen in the context of MHC class I. J Immunol. 2012;189:916–23.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123:3818–27.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Chia WK, Blanchette V, Mody M, Wright JF, Freedman J. Characterization of HIV-1-specific antibodies and HIV-1-crossreactive antibodies to platelets in HIV-1-infected haemophiliac patients. Br J Haematol. 1998;103:1014–22.CrossRefPubMedGoogle Scholar
  30. Cines DB, Cuker A, Semple JW. Pathogenesis of immune thrombocytopenia. Presse Med. 2014;43:e49–59.CrossRefPubMedGoogle Scholar
  31. Clancy L, Freedman JE. New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis. 2014;37:12–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13:463–9.CrossRefPubMedGoogle Scholar
  33. Claushuis TA, van Vught LA, Scicluna BP, Wiewel MA, Klein Klouwenberg PM, Hoogendijk AJ, Ong DS, Cremer OL, Horn J, Franitza M, Toliat MR, Nurnberg P, Zwinderman AH, Bonten MJ, Schultz MJ, van der Poll T. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. Blood. 2016;127:3062–72.CrossRefPubMedGoogle Scholar
  34. Cloutier N, Tan S, Boudreau LH, Cramb C, Subbaiah R, Lahey L, Albert A, Shnayder R, Gobezie R, Nigrovic PA, Farndale RW, Robinson WH, Brisson A, Lee DM, Boilard E. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol Med. 2013;5:235–49.CrossRefPubMedGoogle Scholar
  35. Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O. Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol. 2005;83:196–8.CrossRefPubMedGoogle Scholar
  36. Connor DE, Exner T, Ma DD, Joseph JE. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb Haemost. 2010;103:1044–52.CrossRefPubMedGoogle Scholar
  37. Dankert J, van der Werff J, Zaat SA, Joldersma W, Klein D, Hess J. Involvement of bactericidal factors from thrombin-stimulated platelets in clearance of adherent viridans streptococci in experimental infective endocarditis. Infect Immun. 1995;63:663–71.PubMedPubMedCentralGoogle Scholar
  38. Dasgupta SK, Abdel-Monem H, Niravath P, Le A, Bellera RV, Langlois K, Nagata S, Rumbaut RE, Thiagarajan P. Lactadherin and clearance of platelet-derived microvesicles. Blood. 2009;113:1332–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Dasgupta SK, Le A, Chavakis T, Rumbaut RE, Thiagarajan P. Developmental endothelial locus-1 (Del-1) mediates clearance of platelet microparticles by the endothelium. Circulation. 2012;125:1664–72.CrossRefPubMedGoogle Scholar
  40. de Stoppelaar SF, Claushuis TA, Schaap MC, Hou B, van der Poll T, Nieuwland R, van’t Veeer C. Toll-like receptor signalling is not involved in platelet response to Streptococcus pneumoniae in vitro or in vivo. PLoS One. 2016;11:e0156977.CrossRefPubMedPubMedCentralGoogle Scholar
  41. de Stoppelaar SF, van’t Veeer C, van der Poll T. The role of platelets in sepsis. Thromb Haemost. 2014;112:666–77.CrossRefPubMedGoogle Scholar
  42. de Stoppelaar SF, van’t Veer C, van den Boogaard FE, Nieuwland R, Hoogendijk AJ, de Boer OJ, Roelofs JJ, van der Poll T. Protease activated receptor 4 limits bacterial growth and lung pathology during late stage Streptococcus pneumoniae induced pneumonia in mice. Thromb Haemost. 2013;110:582–92.CrossRefPubMedGoogle Scholar
  43. Demers M, Krause DS, Schatzberg D, Martinod K, Voorhees JR, Fuchs TA, Scadden DT, Wagner DD. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci U S A. 2012;109:13076–81.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Demers M, Wong SL, Martinod K, Gallant M, Cabral JE, Wang Y, Wagner DD. Priming of neutrophils toward NETosis promotes tumor growth. Oncoimmunology. 2016;5:e1134073.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Diacovo TG, Catalina MD, Siegelman MH, von Andrian UH. Circulating activated platelets reconstitute lymphocyte homing and immunity in L-selectin-deficient mice. J Exp Med. 1998;187:197–204.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH. Platelet-mediated lymphocyte delivery to high endothelial venules. Science. 1996;273:252–5.CrossRefPubMedGoogle Scholar
  47. Dinkla S, van CB, van der Heijden WA, He X, Wallbrecher R, Dumitriu IE, van der Ven AJ, Bosman GJ, Koenen HJ, Joosten I. Platelet microparticles inhibit IL-17 production by regulatory T cells through P-selectin. Blood. 2016;127:1976–86.CrossRefPubMedGoogle Scholar
  48. Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES, Bergeron A, Kong X, Nagalla S, Mohandas N, Cohen DE, Dong JF, Shaw C, Bray PF. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med. 2013;19:1609–16.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Elzey BD, Schmidt NW, Crist SA, Kresowik TP, Harty JT, Nieswandt B, Ratliff TL. Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood. 2008;111:3684–91.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Elzey BD, Tian J, Jensen RJ, Swanson AK, Lees JR, Lentz SR, Stein CS, Nieswandt B, Wang Y, Davidson BL, Ratliff TL. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity. 2003;19:9–19.CrossRefPubMedGoogle Scholar
  51. Etulain J, Martinod K, Wong SL, Cifuni SM, Schattner M, Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126:242–6.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Flaujac C, Boukour S, Cramer-Borde E. Platelets and viruses: an ambivalent relationship. Cell Mol Life Sci. 2010;67:545–56.CrossRefPubMedGoogle Scholar
  53. Freedman JE, Larson MG, Tanriverdi K, O’Donnell CJ, Morin K, Hakanson AS, Vasan RS, Johnson AD, Iafrati MD, Benjamin EJ. Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart study. Circulation. 2010;122:119–29.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Fuchs TA, Alvarez JJ, Martinod K, Bhandari AA, Kaufman RM, Wagner DD. Neutrophils release extracellular DNA traps during storage of red blood cell units. Transfusion. 2013;53:3210–6.CrossRefPubMedGoogle Scholar
  55. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010;107:15880–5.CrossRefPubMedPubMedCentralGoogle Scholar
  56. Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Lohmann SM, Walter U. Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase A from an NFkappaB-IkappaB complex. J Biol Chem. 2010;285:18352–63.CrossRefPubMedPubMedCentralGoogle Scholar
  57. Garcia BA, Smalley DM, Cho H, Shabanowitz J, Ley K, Hunt DF. The platelet microparticle proteome. J Proteome Res. 2005;4:1516–21.CrossRefPubMedGoogle Scholar
  58. Gawaz M, Dickfeld T, Bogner C, Fateh-Moghadam S, Neumann FJ. Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med. 1997;23:379–85.CrossRefPubMedGoogle Scholar
  59. Ghio M, Contini P, Mazzei C, Brenci S, Barberis G, Filaci G, Indiveri F, Puppo F. Soluble HLA class I, HLA class II, and Fas ligand in blood components: a possible key to explain the immunomodulatory effects of allogeneic blood transfusions. Blood. 1999;93:1770–7.PubMedGoogle Scholar
  60. Gidlof O, van der Brug M, Ohman J, Gilje P, Olde B, Wahlestedt C, Erlinge D. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood. 2013;121:3908–26.CrossRefPubMedGoogle Scholar
  61. Gitz E, Pollitt AY, Gitz-Francois JJ, Alshehri O, Mori J, Montague S, Nash GB, Douglas MR, Gardiner EE, Andrews RK, Buckley CD, Harrison P, Watson SP. CLEC-2 expression is maintained on activated platelets and on platelet microparticles. Blood. 2014;124:2262–70.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Gleissner CA. Macrophage phenotype modulation by CXCL4 in atherosclerosis. Front Physiol. 2012;3:1.CrossRefPubMedPubMedCentralGoogle Scholar
  63. Goodall AH, Burns P, Salles I, Macaulay IC, Jones CI, Ardissino D, de BB, Bray SL, Deckmyn H, Dudbridge F, Fitzgerald DJ, Garner SF, Gusnanto A, Koch K, Langford C, O’Connor MN, Rice CM, Stemple D, Stephens J, Trip MD, Zwaginga JJ, Samani NJ, Watkins NA, Maguire PB, Ouwehand WH. Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function. Blood. 2010;116:4646–56.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Gouttefangeas C, Diehl M, Keilholz W, Hornlein RF, Stevanovic S, Rammensee HG. Thrombocyte HLA molecules retain nonrenewable endogenous peptides of megakaryocyte lineage and do not stimulate direct allocytotoxicity in vitro. Blood. 2000;95:3168–75.PubMedGoogle Scholar
  65. Gramaglia I, Velez J, Combes V, Grau GE, Wree M, van der Heyde HC. Platelets activate a pathogenic response to blood-stage Plasmodium infection but not a protective immune response. Blood. 2017;129:1669–79.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Gupta N, Li W, Willard B, Silverstein RL, McIntyre TM. Proteasome proteolysis supports stimulated platelet function and thrombosis. Arterioscler Thromb Vasc Biol. 2014;34:160–8.CrossRefPubMedGoogle Scholar
  67. Gyorgy B, Szabo TG, Turiak L, Wright M, Herczeg P, Ledeczi Z, Kittel A, Polgar A, Toth K, Derfalvi B, Zelenak G, Borocz I, Carr B, Nagy G, Vekey K, Gay S, Falus A, Buzas EI. Improved flow cytometric assessment reveals distinct microvesicle (cell-derived microparticle) signatures in joint diseases. PLoS One. 2012;7:e49726.CrossRefPubMedPubMedCentralGoogle Scholar
  68. Hachem A, Yacoub D, Zaid Y, Mourad W, Merhi Y. Involvement of nuclear factor kappaB in platelet CD40 signaling. Biochem Biophys Res Commun. 2012;425:58–63.CrossRefPubMedGoogle Scholar
  69. Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI. Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation. 2006;113:2278–84.CrossRefPubMedGoogle Scholar
  70. Henn V, Steinbach S, Buchner K, Presek P, Kroczek RA. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood. 2001;98:1047–54.CrossRefPubMedGoogle Scholar
  71. Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotti LG. Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nat Med. 2005;11:1167–9.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Italiano JE Jr, Richardson JL, Patel-Hett S, Battinelli E, Zaslavsky A, Short S, Ryeom S, Folkman J, Klement GL. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111:1227–33.CrossRefPubMedPubMedCentralGoogle Scholar
  73. Janeway CA Jr. The immune system evolved to discriminate infectious nonself from noninfectious self. Immunol Today. 1992;13:11–6.CrossRefPubMedGoogle Scholar
  74. Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197–216.CrossRefPubMedGoogle Scholar
  75. Jayachandran M, Brunn GJ, Karnicki K, Miller RS, Owen WG, Miller VM. In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: implications for thrombotic risk. J Appl Physiol (1985). 2007;102:429–33.CrossRefGoogle Scholar
  76. Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med. 2017;23:279–87.CrossRefPubMedGoogle Scholar
  77. Kao KJ. Plasma and platelet HLA in normal individuals: quantitation by competitive enzyme-linked immunoassay. Blood. 1987;70:282–6.PubMedGoogle Scholar
  78. Kao KJ. Selective elution of HLA antigens and beta 2-microglobulin from human platelets by chloroquine diphosphate. Transfusion. 1988;28:14–7.CrossRefPubMedGoogle Scholar
  79. Kao KJ, Cook DJ, Scornik JC. Quantitative analysis of platelet surface HLA by W6/32 anti-HLA monoclonal antibody. Blood. 1986;68:627–32.PubMedGoogle Scholar
  80. Kapur R, Heitink-Polle KM, Porcelijn L, Bentlage AE, Bruin MC, Visser R, Roos D, Schasfoort RB, de HM, van der Schoot CE, Vidarsson G. C-reactive protein enhances IgG-mediated phagocyte responses and thrombocytopenia. Blood. 2015a;125:1793–802.CrossRefPubMedGoogle Scholar
  81. Kapur R, Semple JW. Platelets as immune-sensing cells. Blood Adv. 2016a;1:10–4.CrossRefPubMedPubMedCentralGoogle Scholar
  82. Kapur R, Semple JW. The nonhemostatic immune functions of platelets. Semin Hematol. 2016b;53(Suppl 1):S2–6.CrossRefPubMedGoogle Scholar
  83. Kapur R, Zufferey A, Boilard E, Semple JW. Nouvelle cuisine: platelets served with inflammation. J Immunol. 2015b;194:5579–87.CrossRefPubMedGoogle Scholar
  84. Karim ZA, Zhang J, Banerjee M, Chicka MC, Al HR, Hamilton TR, Roche PA, Whiteheart SW. IkappaB kinase phosphorylation of SNAP-23 controls platelet secretion. Blood. 2013;121:4567–74.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Kerrigan SW, Cox D. Platelet-bacterial interactions. Cell Mol Life Sci. 2010;67:513–23.CrossRefPubMedGoogle Scholar
  86. Kissel K, Berber S, Nockher A, Santoso S, Bein G, Hackstein H. Human platelets target dendritic cell differentiation and production of proinflammatory cytokines. Transfusion. 2006;46:818–27.CrossRefPubMedGoogle Scholar
  87. Koupenova M, Vitseva O, MacKay CR, Beaulieu LM, Benjamin EJ, Mick E, Kurt-Jones EA, Ravid K, Freedman JE. Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood. 2014;124:791–802.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Kraemer BF, Campbell RA, Schwertz H, Cody MJ, Franks Z, Tolley ND, Kahr WH, Lindemann S, Seizer P, Yost CC, Zimmerman GA, Weyrich AS. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathog. 2011;7:e1002355.CrossRefPubMedPubMedCentralGoogle Scholar
  89. Laffont B, Corduan A, Ple H, Duchez AC, Cloutier N, Boilard E, Provost P. Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood. 2013;122:253–61.CrossRefPubMedGoogle Scholar
  90. Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009;16:961–6.CrossRefPubMedPubMedCentralGoogle Scholar
  91. Lefrancais E, Ortiz-Munoz G, Caudrillier A, Mallavia B, Liu F, Sayah DM, Thornton EE, Headley MB, David T, Coughlin SR, Krummel MF, Leavitt AD, Passegue E, Looney MR. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature. 2017;544:105–9.CrossRefPubMedPubMedCentralGoogle Scholar
  92. Li Z, Nardi MA, Karpatkin S. Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood. 2005;106:572–6.CrossRefPubMedPubMedCentralGoogle Scholar
  93. Liu F, Morris S, Epps J, Carroll R. Demonstration of an activation regulated NF-kappaB/I-kappaBalpha complex in human platelets. Thromb Res. 2002;106:199–203.CrossRefPubMedGoogle Scholar
  94. Lood C, Amisten S, Gullstrand B, Jonsen A, Allhorn M, Truedsson L, Sturfelt G, Erlinge D, Bengtsson AA. 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. 2010;116:1951–7.CrossRefPubMedGoogle Scholar
  95. Machlus KR, Italiano JE Jr. The incredible journey: from megakaryocyte development to platelet formation. J Cell Biol. 2013;201:785–96.CrossRefPubMedPubMedCentralGoogle Scholar
  96. Malaver E, Romaniuk MA, D’Atri LP, Pozner RG, Negrotto S, Benzadon R, Schattner M. NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost. 2009;7:1333–43.CrossRefPubMedGoogle Scholar
  97. Martinod K, Witsch T, Erpenbeck L, Savchenko A, Hayashi H, Cherpokova D, Gallant M, Mauler M, Cifuni SM, Wagner DD. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J Exp Med. 2017;214:439–58.CrossRefPubMedPubMedCentralGoogle Scholar
  98. Martinod K, Witsch T, Farley K, Gallant M, Remold-O’Donnell E, Wagner DD. Neutrophil elastase-deficient mice form neutrophil extracellular traps in an experimental model of deep vein thrombosis. J Thromb Haemost. 2016;14:551–8.CrossRefPubMedPubMedCentralGoogle Scholar
  99. Mazzucco L, Borzini P, Gope R. Platelet-derived factors involved in tissue repair-from signal to function. Transfus Med Rev. 2010;24:218–34.CrossRefPubMedGoogle Scholar
  100. McManus DD, Beaulieu LM, Mick E, Tanriverdi K, Larson MG, Keaney JF Jr, Benjamin EJ, Freedman JE. Relationship among circulating inflammatory proteins, platelet gene expression, and cardiovascular risk. Arterioscler Thromb Vasc Biol. 2013;33:2666–73.CrossRefPubMedPubMedCentralGoogle Scholar
  101. McMorran BJ, Marshall VM, de GC, Drysdale KE, Shabbar M, Smyth GK, Corbin JE, Alexander WS, Foote SJ. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science. 2009;323:797–800.CrossRefPubMedGoogle Scholar
  102. McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ. Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum. Science. 2012;338:1348–51.CrossRefPubMedGoogle Scholar
  103. Melki I, Tessandier N, Zufferey A, Boilard E. Platelet microvesicles in health and disease. Platelets. 2017;28(3):1–8.CrossRefGoogle Scholar
  104. Morel O, Jesel L, Freyssinet JM, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol. 2011;31:15–26.CrossRefPubMedGoogle Scholar
  105. Mott PJ, Lazarus AH. CD44 antibodies and immune thrombocytopenia in the amelioration of murine inflammatory arthritis. PLoS One. 2013;8:e65805.CrossRefPubMedPubMedCentralGoogle Scholar
  106. Neumuller J, Tohidast-Akrad M, Fischer M, Mayr WR. Influence of chloroquine or acid treatment of human platelets on the antigenicity of HLA and the ‘thrombocyte-specific’ glycoproteins Ia/IIa, IIb, and IIb/IIIa. Vox Sang. 1993;65:223–31.PubMedGoogle Scholar
  107. Nurden AT. Platelets, inflammation and tissue regeneration. Thromb Haemost. 2011;105(Suppl 1):S13–33.PubMedGoogle Scholar
  108. Owens AP III, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res. 2011;108:1284–97.CrossRefPubMedPubMedCentralGoogle Scholar
  109. Panigrahi S, Ma Y, Hong L, Gao D, West XZ, Salomon RG, Byzova TV, Podrez EA. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res. 2013;112:103–12.Google Scholar
  110. Patrignani P, Di FC, Tacconelli S, Moretta V, Baccante G, Sciulli MG, Ricciotti E, Capone ML, Antonucci I, Guglielmi MD, Stuppia L, Porreca E. Reduced thromboxane biosynthesis in carriers of toll-like receptor 4 polymorphisms in vivo. Blood. 2006;107:3572–4.CrossRefPubMedGoogle Scholar
  111. Perez-Pujol S, Marker PH, Key NS. Platelet microparticles are heterogeneous and highly dependent on the activation mechanism: studies using a new digital flow cytometer. Cytometry A. 2007;71:38–45.CrossRefPubMedGoogle Scholar
  112. Petersen F, Bock L, Flad HD, Brandt E. Platelet factor 4-induced neutrophil-endothelial cell interaction: involvement of mechanisms and functional consequences different from those elicited by interleukin-8. Blood. 1999;94:4020–8.PubMedGoogle Scholar
  113. Ple H, Maltais M, Corduan A, Rousseau G, Madore F, Provost P. Alteration of the platelet transcriptome in chronic kidney disease. Thromb Haemost. 2012;108:605–15.CrossRefPubMedPubMedCentralGoogle Scholar
  114. Raghavachari N, Xu X, Harris A, Villagra J, Logun C, Barb J, Solomon MA, Suffredini AF, Danner RL, Kato G, Munson PJ, Morris SM Jr, Gladwin MT. Amplified expression profiling of platelet transcriptome reveals changes in arginine metabolic pathways in patients with sickle cell disease. Circulation. 2007;115:1551–62.CrossRefPubMedPubMedCentralGoogle Scholar
  115. Rama Kishore Y, Prashantha B, Girish M, Manaswitha B. Increased C-reactive protein levels at diagnosis negatively predict platelet count recovery after steroid-treatment in newly diagnosed adult immune thrombocytopenia patients. Thromb Res. 2017;152:61–3.CrossRefPubMedGoogle Scholar
  116. Ray DM, Spinelli SL, Pollock SJ, Murant TI, O’Brien JJ, Blumberg N, Francis CW, Taubman MB, Phipps RP. Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles. Thromb Haemost. 2008;99:86–95.PubMedPubMedCentralGoogle Scholar
  117. Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth. 2012;109:503–13.CrossRefPubMedGoogle Scholar
  118. Risitano A, Beaulieu LM, Vitseva O, Freedman JE. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood. 2012;119:6288–95.CrossRefPubMedPubMedCentralGoogle Scholar
  119. Rondina MT, Weyrich AS. Regulation of the genetic code in megakaryocytes and platelets. J Thromb Haemost. 2015;13(Suppl 1):S26–32.CrossRefPubMedPubMedCentralGoogle Scholar
  120. Rousseau M, Belleannee C, Duchez AC, Cloutier N, Levesque T, Jacques F, Perron J, Nigrovic PA, Dieude M, Hebert MJ, Gelb MH, Boilard E. Detection and quantification of microparticles from different cellular lineages using flow cytometry. Evaluation of the impact of secreted phospholipase A2 on microparticle assessment. PLoS One. 2015;10:e0116812.CrossRefPubMedPubMedCentralGoogle Scholar
  121. Rowley JW, Oler AJ, Tolley ND, Hunter BN, Low EN, Nix DA, Yost CC, Zimmerman GA, Weyrich AS. Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood. 2011;118:e101–11.CrossRefPubMedPubMedCentralGoogle Scholar
  122. Rowley JW, Schwertz H, Weyrich AS. Platelet mRNA: the meaning behind the message. Curr Opin Hematol. 2012;19:385–91.CrossRefPubMedPubMedCentralGoogle Scholar
  123. Russwurm S, Vickers J, Meier-Hellmann A, Spangenberg P, Bredle D, Reinhart K, Losche W. Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock. 2002;17:263–8.CrossRefPubMedGoogle Scholar
  124. Schall TJ, Bacon K, Camp RD, Kaspari JW, Goeddel DV. Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. J Exp Med. 1993;177:1821–6.CrossRefPubMedGoogle Scholar
  125. Schubert S, Weyrich AS, Rowley JW. A tour through the transcriptional landscape of platelets. Blood. 2014;124:493–502.CrossRefPubMedPubMedCentralGoogle Scholar
  126. Sehgal S, Storrie B. Evidence that differential packaging of the major platelet granule proteins von Willebrand factor and fibrinogen can support their differential release. J Thromb Haemost. 2007;5:2009–16.CrossRefPubMedGoogle Scholar
  127. Semple JW, Aslam R, Kim M, Speck ER, Freedman J. Platelet-bound lipopolysaccharide enhances Fc receptor-mediated phagocytosis of IgG-opsonized platelets. Blood. 2007;109:4803–5.CrossRefPubMedGoogle Scholar
  128. Semple JW, Italiano JE Jr, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11:264–74.CrossRefPubMedGoogle Scholar
  129. Shi G, Field DJ, Ko KA, Ture S, Srivastava K, Levy S, Kowalska MA, Poncz M, Fowell DJ, Morrell CN. Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection. J Clin Invest. 2014a;124:543–52.CrossRefPubMedPubMedCentralGoogle Scholar
  130. Shi DS, Smith MC, Campbell RA, Zimmerman PW, Franks ZB, Kraemer BF, Machlus KR, Ling J, Kamba P, Schwertz H, Rowley JW, Miles RR, Liu ZJ, Sola-Visner M, Italiano JE Jr, Christensen H, Kahr WH, Li DY, Weyrich AS. Proteasome function is required for platelet production. J Clin Invest. 2014b;124:3757–66.CrossRefPubMedPubMedCentralGoogle Scholar
  131. Shulman NR, Aster RH, Pearson HA, Hiller MC. Immunoreactions involving platelet. VI. Reactions of maternal isoantibodies responsible for neonatal purpura. Differentiation of a second platelet antigen system. J Clin Invest. 1962;41:1059–69.CrossRefPubMedPubMedCentralGoogle Scholar
  132. Simon LM, Edelstein LC, Nagalla S, Woodley AB, Chen ES, Kong X, Ma L, Fortina P, Kunapuli S, Holinstat M, McKenzie SE, Dong JF, Shaw CA, Bray PF. Human platelet microRNA-mRNA networks associated with age and gender revealed by integrated plateletomics. Blood. 2014;123:e37–45.CrossRefPubMedPubMedCentralGoogle Scholar
  133. Spinelli SL, Casey AE, Pollock SJ, Gertz JM, McMillan DH, Narasipura SD, Mody NA, King MR, Maggirwar SB, Francis CW, Taubman MB, Blumberg N, Phipps RP. Platelets and megakaryocytes contain functional nuclear factor-kappaB. Arterioscler Thromb Vasc Biol. 2010;30:591–8.CrossRefPubMedGoogle Scholar
  134. Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi MD, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A. Neutrophils scan for activated platelets to initiate inflammation. Science. 2014;346:1234–8.CrossRefPubMedPubMedCentralGoogle Scholar
  135. Stahl AL, Svensson M, Morgelin M, Svanborg C, Tarr PI, Mooney JC, Watkins SL, Johnson R, Karpman D. 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. 2006;108:167–76.CrossRefPubMedPubMedCentralGoogle Scholar
  136. Sun D, Popescu NI, Raisley B, Keshari RS, Dale GL, Lupu F, Coggeshall KM. Bacillus anthracis peptidoglycan activates human platelets through FcgammaRII and complement. Blood. 2013;122:571–9.CrossRefPubMedPubMedCentralGoogle Scholar
  137. Takahashi T, Yujiri T, Shinohara K, Inoue Y, Sato Y, Fujii Y, Okubo M, Zaitsu Y, Ariyoshi K, Nakamura Y, Nawata R, Oka Y, Shirai M, Tanizawa Y. Molecular mimicry by Helicobacter pylori CagA protein may be involved in the pathogenesis of H. pylori-associated chronic idiopathic thrombocytopenic purpura. Br J Haematol. 2004;124:91–6.CrossRefPubMedGoogle Scholar
  138. Takeda T, Unno H, Morita H, Futamura K, Emi-Sugie M, Arae K, Shoda T, Okada N, Igarashi A, Inoue E, Kitazawa H, Nakae S, Saito H, Matsumoto K, Matsuda A. Platelets constitutively express IL-33 protein and modulate eosinophilic airway inflammation. J Allergy Clin Immunol. 2016;138:1395–403.CrossRefPubMedGoogle Scholar
  139. Tersteeg C, Heijnen HF, Eckly A, Pasterkamp G, Urbanus RT, Maas C, Hoefer IE, Nieuwland R, Farndale RW, Gachet C, de Groot PG, Roest M. FLow-induced PRotrusions (FLIPRs): a platelet-derived platform for the retrieval of microparticles by monocytes and neutrophils. Circ Res. 2014;114:780–91.CrossRefPubMedGoogle Scholar
  140. Thomas GM, Carbo C, Curtis BR, Martinod K, Mazo IB, Schatzberg D, Cifuni SM, Fuchs TA, von Andrian UH, Hartwig JH, Aster RH, Wagner DD. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood. 2012;119:6335–43.CrossRefPubMedPubMedCentralGoogle Scholar
  141. Tremblay T, Aubin E, Lemieux R, Bazin R. Picogram doses of lipopolysaccharide exacerbate antibody-mediated thrombocytopenia and reduce the therapeutic efficacy of intravenous immunoglobulin in mice. Br J Haematol. 2007;139:297–302.CrossRefPubMedGoogle Scholar
  142. van den Boogaard FE, Schouten M, de Stoppelaar SF, Roelofs JJ, Brands X, Schultz MJ, Van’t Veer C, van der Poll T. Thrombocytopenia impairs host defense during murine Streptococcus pneumoniae pneumonia. Crit Care Med. 2015;43:e75–83.CrossRefPubMedGoogle Scholar
  143. Verschoor A, Neuenhahn M, Navarini AA, Graef P, Plaumann A, Seidlmeier A, Nieswandt B, Massberg S, Zinkernagel RM, Hengartner H, Busch DH. A platelet-mediated system for shuttling blood-borne bacteria to CD8alpha+ dendritic cells depends on glycoprotein GPIb and complement C3. Nat Immunol. 2011;12:1194–201.CrossRefPubMedGoogle Scholar
  144. von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res. 2007;100:27–40.CrossRefGoogle Scholar
  145. Washington AV, Gibot S, Acevedo I, Gattis J, Quigley L, Feltz R, De La Mota A, Schubert RL, Gomez-Rodriguez J, Cheng J, Dutra A, Pak E, Chertov O, Rivera L, Morales J, Lubkowski J, Hunter R, Schwartzberg PL, McVicar DW. TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans. J Clin Invest. 2009;119:1489–501.CrossRefPubMedPubMedCentralGoogle Scholar
  146. White GC, Rompietti R. Platelet secretion: indiscriminately spewed forth or highly orchestrated? J Thromb Haemost. 2007;5:2006–8.CrossRefPubMedGoogle Scholar
  147. Wolf P. The nature and significance of platelet products in human plasma. Br J Haematol. 1967;13:269–88.CrossRefPubMedGoogle Scholar
  148. Wong SL, Demers M, Martinod K, Gallant M, Wang Y, Goldfine AB, Kahn CR, Wagner DD. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med. 2015;21:815–9.CrossRefPubMedPubMedCentralGoogle Scholar
  149. Wong CH, Jenne CN, Petri B, Chrobok NL, Kubes P. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013;14:785–92.CrossRefPubMedPubMedCentralGoogle Scholar
  150. Wright JF, Blanchette VS, Wang H, Arya N, Petric M, Semple JW, Chia WK, Freedman J. Characterization of platelet-reactive antibodies in children with varicella-associated acute immune thrombocytopenic purpura (ITP). Br J Haematol. 1996;95:145–52.CrossRefPubMedGoogle Scholar
  151. Yeaman MR. Bacterial-platelet interactions: virulence meets host defense. Future Microbiol. 2010a;5:471–506.CrossRefPubMedGoogle Scholar
  152. Yeaman MR. Platelets in defense against bacterial pathogens. Cell Mol Life Sci. 2010b;67:525–44.CrossRefPubMedGoogle Scholar
  153. Youssefian T, Drouin A, Masse JM, Guichard J, Cramer EM. Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood. 2002;99:4021–9.CrossRefPubMedGoogle Scholar
  154. Zhang G, Han J, Welch EJ, Ye RD, Voyno-Yasenetskaya TA, Malik AB, Du X, Li Z. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol. 2009a;182:7997–8004.CrossRefPubMedPubMedCentralGoogle Scholar
  155. Zhang W, Nardi MA, Borkowsky W, Li Z, Karpatkin S. Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood. 2009b;113:4086–93.CrossRefPubMedPubMedCentralGoogle Scholar
  156. Zufferey A, Schvartz D, Nolli S, Reny JL, Sanchez JC, Fontana P. Characterization of the platelet granule proteome: evidence of the presence of MHC1 in alpha-granules. J Proteome. 2014;101:130–40.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology and Transfusion MedicineLund UniversityLundSweden
  2. 2.Keenan Research Centre for Biomedical Science, St. Michael’s HospitalTorontoCanada
  3. 3.The Toronto Platelet Immunobiology Group, St. Michael’s HospitalTorontoCanada
  4. 4.Canadian Blood ServicesTorontoCanada
  5. 5.Departments of Pharmacology, Medicine, and Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada

Personalised recommendations