Skip to main content
SpringerLink
Log in

Platelets in the Pathogenesis of Vascular Disease and Their Role as a Therapeutic Target

  • Chapter
  • First Online:
Mechanisms of Vascular Disease

  • 1089 Accesses

Abstract

Platelets are the second most abundant cell type in the circulation and play a fundamental role in mediating haemostasis, thereby maintaining the integrity of a high-pressure circulatory system in the context of vascular injury. In this regard, platelets patrol the endothelium and possess machinery allowing them to adhere, activate and aggregate with great alacrity. However, these same processes that underpin physiological haemostasis may become dysregulated leading to the accumulation of platelets at sites of endothelial inflammation, thus propagating vascular disease, and leading to the development of pathological arterial thrombosis at sites of atherosclerotic plaque rupture, culminating in myocardial infarction and ischaemic stroke. Platelets express a set of unique adhesion receptors in addition to containing specialized granules that contain soluble agonists and adhesion matrix proteins. The most abundant platelet adhesion receptor, GPIIb/IIIa, undergoes activation in response to platelet stimulation with soluble agonists such as thrombin, ADP and Thromboxane A2 (TXA2) to allow platelet aggregation and the formation of a platelet rich thrombus.

In vascular disease, platelets adhere to dysfunctional endothelium and play a crucial role in the recruitment of inflammatory cells as a result of their ability to secrete a plethora of pro-inflammatory mediators. Anti-platelet drugs target common pathways mediating platelet activation such as the P2Y12 receptors, TXA2 synthesis and GPIIb/IIIa adhesive function. These drugs have demonstrated efficacy in reducing mortality, myocardial infarction and stroke in large, randomised clinical trials. However, the inherent risk of bleeding with anti-platelet drugs has spurred the identification of a range of novel therapeutic targets that hold promise to differentially treat or prevent thrombosis whilst sparing haemostasis. Therefore, given the fundamental role of platelets in cardiovascular medicine combined with the importance of anti-platelet therapies and the burgeoning field of novel therapeutics, the field of platelet biology represents a complex yet exciting field of medicine.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Wagner CL, Mascelli MA, Neblock DS, Weisman HF, Coller BS, Jordan RE. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood. 1996;88:907–14.

    Article  CAS  PubMed  Google Scholar 

  2. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med. 1995;332:1553–9.

    Article  CAS  PubMed  Google Scholar 

  3. Bennett JS. Structure and function of the platelet integrin alphaIIbbeta3. J Clin Invest. 2005;115:3363–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Weisel JW, Nagaswami C, Vilaire G, Bennett JS. Examination of the platelet membrane glycoprotein IIb-IIIa complex and its interaction with fibrinogen and other ligands by electron microscopy. J Biol Chem. 1992;267:16637–43.

    Article  CAS  PubMed  Google Scholar 

  5. Springer TA, Zhu J, Xiao T. Structural basis for distinctive recognition of fibrinogen gammaC peptide by the platelet integrin alphaIIbbeta3. J Cell Biol. 2008;182:791–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bennett JS. Structural biology of glycoprotein IIb-IIIa. Trends Cardiovasc Med. 1996;6:31–6.

    Article  CAS  PubMed  Google Scholar 

  7. Xiao T, Takagi J, Coller BS, Wang JH, Springer TA. Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature. 2004;432:59–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ginsberg MH, Partridge A, Shattil SJ. Integrin regulation. Curr Opin Cell Biol. 2005;17:509–16.

    Article  CAS  PubMed  Google Scholar 

  9. Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost. 2009;7(Suppl 1):206–9.

    Article  CAS  PubMed  Google Scholar 

  10. Hynes RO. Integrins: bidirectional, allosteric signaling machines. Cell. 2002;110:673–87.

    Article  CAS  PubMed  Google Scholar 

  11. Shattil SJ, Newman PJ. Integrins: dynamic scaffolds for adhesion and signaling in platelets. Blood. 2004;104:1606–15.

    Article  CAS  PubMed  Google Scholar 

  12. Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood. 2003;102:449–61.

    Article  CAS  PubMed  Google Scholar 

  13. Crittenden JR, Bergmeier W, Zhang Y, Piffath CL, Liang Y, Wagner DD, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10:982–6.

    Article  CAS  PubMed  Google Scholar 

  14. Cifuni SM, Wagner DD, Bergmeier W. CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin alphaIIbbeta3 in platelets. Blood. 2008;112:1696–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Watanabe N, Bodin L, Pandey M, Krause M, Coughlin S, Boussiotis VA, et al. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin alphaIIbbeta3. J Cell Biol. 2008;181:1211–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tadokoro S, Shattil SJ, Eto K, Tai V, Liddington RC, de Pereda JM, et al. Talin binding to integrin beta tails: a final common step in integrin activation. Science. 2003;302:103–6.

    Article  CAS  PubMed  Google Scholar 

  17. Han J, Lim CJ, Watanabe N, Soriani A, Ratnikov B, Calderwood DA, et al. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol. 2006;16:1796–806.

    Article  CAS  PubMed  Google Scholar 

  18. Ma YQ, Yang J, Pesho MM, Vinogradova O, Qin J, Plow EF. Regulation of integrin alphaIIbbeta3 activation by distinct regions of its cytoplasmic tails. Biochemist. 2006;45:6656–62.

    Article  CAS  Google Scholar 

  19. Moser M, Nieswandt B, Ussar S, Pozgajova M, Fassler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14:325–30.

    Article  CAS  PubMed  Google Scholar 

  20. Loftus JC, Albrecht RM. Redistribution of the fibrinogen receptor of human platelets after surface activation. J Cell Biol. 1984;99:822–9.

    Article  CAS  PubMed  Google Scholar 

  21. Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ. Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proc Natl Acad Sci U S A. 2003;100:13298–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hartwig JH, Kung S, Kovacsovics T, Janmey PA, Cantley LC, Stossel TP, et al. D3 phosphoinositides and outside-in integrin signaling by glycoprotein IIb-IIIa mediate platelet actin assembly and filopodial extension induced by phorbol 12-myristate 13-acetate. J Biol Chem. 1996;271:32986–93.

    Article  CAS  PubMed  Google Scholar 

  23. Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function. Nature. 1999;401:808–11.

    Article  CAS  PubMed  Google Scholar 

  24. Judd BA, Myung PS, Leng L, Obergfell A, Pear WS, Shattil SJ, et al. Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors. Proc Natl Acad Sci U S A. 2000;97:12056–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Obergfell A, Judd BA, del Pozo MA, Schwartz MA, Koretzky GA, Shattil SJ. The molecular adapter SLP-76 relays signals from platelet integrin alphaIIbbeta3 to the actin cytoskeleton. J Biol Chem. 2001;276:5916–23.

    Article  CAS  PubMed  Google Scholar 

  26. Phillips DR, Prasad KS, Manganello J, Bao M, Nannizzi-Alaimo L. Integrin tyrosine phosphorylation in platelet signaling. Curr Opin Cell Biol. 2001;13:546–54.

    Article  CAS  PubMed  Google Scholar 

  27. Schlaepfer DD, Hunter T. Integrin signalling and tyrosine phosphorylation: just the FAKs? Trends Cell Biol. 1998;8:151–7.

    Article  CAS  PubMed  Google Scholar 

  28. Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL. Interaction of focal adhesion kinase with cytoskeletal protein talin. J Biol Chem. 1995;270:16995–9.

    Article  CAS  PubMed  Google Scholar 

  29. Hildebrand JD, Schaller MD, Parsons JT. Paxillin, a tyrosine phosphorylated focal adhesion-associated protein binds to the carboxyl terminal domain of focal adhesion kinase. Mol Biol Cell. 1995;6:637–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cipolla L, Consonni A, Guidetti G, Canobbio I, Okigaki M, Falasca M, et al. The proline-rich tyrosine kinase Pyk2 regulates platelet integrin alphaIIbbeta3 outside-in signaling. J Thromb Haemost. 2013;11:345–56.

    Article  CAS  PubMed  Google Scholar 

  31. Bergmeier W, Piffath CL, Goerge T, Cifuni SM, Ruggeri ZM, Ware J, et al. The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A. 2006;103:16900–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nurden AT, Caen JP. Specific roles for platelet surface glycoproteins in platelet function. Nature. 1975;255:720–2.

    Article  CAS  PubMed  Google Scholar 

  33. Li R, Emsley J. The organizing principle of the platelet glycoprotein Ib-IX-V complex. J Thromb Haemost. 2013;11:605–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kobe B, Deisenhofer J. The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci. 1994;19:415–21.

    Article  CAS  PubMed  Google Scholar 

  35. Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med. 1999;190:803–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bradford HN, Pixley RA, Colman RW. Human factor XII binding to the glycoprotein Ib-IX-V complex inhibits thrombin-induced platelet aggregation. J Biol Chem. 2000;275:22756–63.

    Article  CAS  PubMed  Google Scholar 

  38. Kroll MH, Hellums JD, McIntire LV, Schafer AI, Moake JL. Platelets and shear stress. Blood. 1996;88:1525–41.

    Article  CAS  PubMed  Google Scholar 

  39. Yago T, Lou J, Wu T, Yang J, Miner JJ, Coburn L, et al. Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J Clin Invest. 2008;118:3195–207.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kulkarni S, Dopheide SM, Yap CL, Ravanat C, Freund M, Mangin P, et al. A revised model of platelet aggregation. J Clin Invest. 2000;105:783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ruggeri ZM, Mendolicchio GL. Adhesion mechanisms in platelet function. Circ Res. 2007;100:1673–85.

    Article  CAS  PubMed  Google Scholar 

  42. Clemetson JM, Polgar J, Magnenat E, Wells TN, Clemetson KJ. The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcalphaR and the natural killer receptors. J Biol Chem. 1999;274:29019–24.

    Article  CAS  PubMed  Google Scholar 

  43. Suzuki-Inoue K, Tulasne D, Shen Y, Bori-Sanz T, Inoue O, Jung SM, et al. Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling. J Biol Chem. 2002;277:21561–6.

    Article  CAS  PubMed  Google Scholar 

  44. Berlanga O, Bori-Sanz T, James JR, Frampton J, Davis SJ, Tomlinson MG, et al. Glycoprotein VI oligomerization in cell lines and platelets. J Thromb Haemost. 2007;5:1026–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Watson SP, Auger JM, McCarty OJ, Pearce AC. GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost. 2005;3:1752–62.

    Article  CAS  PubMed  Google Scholar 

  46. Jung SM, Tsuji K, Moroi M. Glycoprotein (GP) VI dimer as a major collagen-binding site of native platelets: direct evidence obtained with dimeric GPVI-specific Fabs. J Thromb Haemost. 2009;7:1347–55.

    Article  CAS  PubMed  Google Scholar 

  47. Kojima H, Moroi M, Jung SM, Goto S, Tamura N, Kozuma Y, et al. Characterization of a patient with glycoprotein (GP) VI deficiency possessing neither anti-GPVI autoantibody nor genetic aberration. J Thromb Haemost. 2006;4:2433–42.

    Article  CAS  PubMed  Google Scholar 

  48. Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell. 1998;94:657–66.

    Article  CAS  PubMed  Google Scholar 

  49. Navarro-Nunez L, Langan SA, Nash GB, Watson SP. The physiological and pathophysiological roles of platelet CLEC-2. Thromb Haemost. 2013;109:991–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Podrez EA, Byzova TV, Febbraio M, Salomon RG, Ma Y, Valiyaveettil M, et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med. 2007;13:1086–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood. 2005;106:2417–23.

    Article  CAS  PubMed  Google Scholar 

  52. King SM, Reed GL. Development of platelet secretory granules. Semin Cell Dev Biol. 2002;13:293–302.

    Article  CAS  PubMed  Google Scholar 

  53. Reed GL. Platelet secretory mechanisms. Semin Thromb Hemost. 2004;30:441–50.

    Article  CAS  PubMed  Google Scholar 

  54. Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23:177–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lhermusier T, Chap H, Payrastre B. Platelet membrane phospholipid asymmetry: from the characterization of a scramblase activity to the identification of an essential protein mutated in Scott syndrome. J Thromb Haemost. 2011;9:1883–91.

    Article  CAS  PubMed  Google Scholar 

  56. Chap HJ, Zwaal RF, van Deenen LL. Action of highly purified phospholipases on blood platelets. Evidence for an asymmetric distribution of phospholipids in the surface membrane. Biochim Biophys Acta. 1977;467:146–64.

    Article  CAS  PubMed  Google Scholar 

  57. Tracy PB, Eide LL, Mann KG. Human prothrombinase complex assembly and function on isolated peripheral blood cell populations. J Biol Chem. 1985;260:2119–24.

    Article  CAS  PubMed  Google Scholar 

  58. Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium-dependent phospholipid scrambling by TMEM16F. Nature. 2010;468:834–8.

    Article  CAS  PubMed  Google Scholar 

  59. Gratacap MP, Guillermet-Guibert J, Martin V, Chicanne G, Tronchere H, Gaits-Iacovoni F, et al. Regulation and roles of PI3Kbeta, a major actor in platelet signaling and functions. Adv Enzym Regul. 2011;51:106–16.

    Article  CAS  Google Scholar 

  60. Li Z, Delaney MK, O'Brien KA, Du X. Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol. 2010;30:2341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mikoshiba K. The IP3 receptor/Ca2+ channel and its cellular function. Biochem Soc Symp. 2007;74:9–22.

    Article  CAS  Google Scholar 

  62. Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer. 2007;7:281–94.

    Article  CAS  PubMed  Google Scholar 

  63. Yacoub D, Theoret JF, Villeneuve L, Abou-Saleh H, Mourad W, Allen BG, et al. Essential role of protein kinase C delta in platelet signaling, alpha IIb beta 3 activation, and thromboxane A2 release. J Biol Chem. 2006;281:30024–35.

    Article  CAS  PubMed  Google Scholar 

  64. Sims PJ, Wiedmer T, Esmon CT, Weiss HJ, Shattil SJ. Assembly of the platelet prothrombinase complex is linked to vesiculation of the platelet plasma membrane. Studies in Scott syndrome: an isolated defect in platelet procoagulant activity. J Biol Chem. 1989;264:17049–57.

    Article  CAS  PubMed  Google Scholar 

  65. Dale GL. Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost. 2005;3:2185–92.

    Article  CAS  PubMed  Google Scholar 

  66. Toti F, Satta N, Fressinaud E, Meyer D, Freyssinet JM. Scott syndrome, characterized by impaired transmembrane migration of procoagulant phosphatidylserine and hemorrhagic complications, is an inherited disorder. Blood. 1996;87:1409–15.

    Article  CAS  PubMed  Google Scholar 

  67. Murugappa S, Kunapuli SP. The role of ADP receptors in platelet function. Front Biosci. 2006;11:1977–86.

    Article  PubMed  Google Scholar 

  68. Leon C, Hechler B, Freund M, Eckly A, Vial C, Ohlmann P, et al. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice. J Clin Invest. 1999;104:1731–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Foster CJ, Prosser DM, Agans JM, Zhai Y, Smith MD, Lachowicz JE, et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest. 2001;107:1591–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fabre JE, Nguyen M, Latour A, Keifer JA, Audoly LP, Coffman TM, et al. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice. Nat Med. 1999;5:1199–202.

    Article  CAS  PubMed  Google Scholar 

  71. Savi P, Beauverger P, Labouret C, Delfaud M, Salel V, Kaghad M, et al. Role of P2Y1 purinoceptor in ADP-induced platelet activation. FEBS Lett. 1998;422:291–5.

    Article  CAS  PubMed  Google Scholar 

  72. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res. 2006;99:1293–304.

    Article  CAS  PubMed  Google Scholar 

  73. Ohlmann P, Laugwitz KL, Nurnberg B, Spicher K, Schultz G, Cazenave JP, et al. The human platelet ADP receptor activates Gi2 proteins. Biochem J. 1995;312:775–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jantzen HM, Milstone DS, Gousset L, Conley PB, Mortensen RM. Impaired activation of murine platelets lacking G alpha(i2). J Clin Invest. 2001;108:477–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Andre P, Delaney SM, LaRocca T, Vincent D, DeGuzman F, Jurek M, et al. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest. 2003;112:398–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232–5.

    Article  CAS  PubMed  Google Scholar 

  77. Offermanns S, Laugwitz KL, Spicher K, Schultz G. G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets. Proc Natl Acad Sci U S A. 1994;91:504–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296:539–41.

    Article  CAS  PubMed  Google Scholar 

  79. Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, et al. A dual thrombin receptor system for platelet activation. Nature. 1998;394:690–4.

    Article  CAS  PubMed  Google Scholar 

  80. Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest. 1999;103:879–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature. 2001;413:74–8.

    Article  CAS  PubMed  Google Scholar 

  82. Brass LF. Thrombin and platelet activation. Chest. 2003;124(Suppl 3):18S–25S.

    Article  CAS  PubMed  Google Scholar 

  83. Woulfe DS. Platelet G protein-coupled receptors in hemostasis and thrombosis. J Thromb Haemost. 2005;3:2193–200.

    Article  CAS  PubMed  Google Scholar 

  84. Kim S, Foster C, Lecchi A, Quinton TM, Prosser DM, Jin J, et al. Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling. Blood. 2002;99:3629–36.

    Article  CAS  PubMed  Google Scholar 

  85. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.

    Article  CAS  PubMed  Google Scholar 

  86. McFadyen JD, Jackson SP. Differentiating haemostasis from thrombosis for therapeutic benefit. Thromb Haemost. 2013;110:859–67.

    Article  CAS  PubMed  Google Scholar 

  87. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359:938–49.

    Article  CAS  PubMed  Google Scholar 

  88. Heemskerk JW, Mattheij NJ, Cosemans JM. Platelet-based coagulation: different populations, different functions. J Thromb Haemost. 2013;11:2–16.

    Article  CAS  PubMed  Google Scholar 

  89. Ivanciu L, Krishnaswamy S, Camire RM. New insights into the spatiotemporal localization of prothrombinase in vivo. Blood. 2014;124:1705–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Coughlin SR. How the protease thrombin talks to cells. Proc Natl Acad Sci U S A. 1999;96:11023–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Osdoit S, Rosa JP. Fibrin clot retraction by human platelets correlates with alpha(IIb)beta(3) integrin-dependent protein tyrosine dephosphorylation. J Biol Chem. 2001;276:6703–10.

    Article  CAS  PubMed  Google Scholar 

  92. Schoenwaelder SM, Ono A, Nesbitt WS, Lim J, Jarman K, Jackson SP. Phosphoinositide 3-kinase p110 beta regulates integrin alpha IIb beta 3 avidity and the cellular transmission of contractile forces. J Biol Chem. 2010;285:2886–96.

    Article  CAS  PubMed  Google Scholar 

  93. McFadyen JD, Kaplan ZS. Platelets are not just for clots. Transfus Med Rev. 2015;29:110–9.

    Article  PubMed  Google Scholar 

  94. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115:3378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med. 1998;187:329–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Massberg S, Enders G, Matos FC, Tomic LI, Leiderer R, Eisenmenger S, et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood. 1999;94:3829–38.

    Article  CAS  PubMed  Google Scholar 

  97. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular diseases. Circ Res. 2013;112:1506–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Gerard C, Rollins BJ. Chemokines and disease. Nat Immunol. 2001;2:108–15.

    Article  CAS  PubMed  Google Scholar 

  99. Weber C. Platelets and chemokines in atherosclerosis: partners in crime. Circ Res. 2005;96:612–6.

    Article  CAS  PubMed  Google Scholar 

  100. Massberg S, Brand K, Gruner S, Page S, Muller E, Muller I, et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002;196:887–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006;116:3211–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Xu Y, Huo Y, Toufektsian MC, Ramos SI, Ma Y, Tejani AD, et al. Activated platelets contribute importantly to myocardial reperfusion injury. Am J Physiol Heart Circ Physiol. 2006;290:H692–9.

    Article  CAS  PubMed  Google Scholar 

  103. Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmerman GA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol. 2001;154:485–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yu G, Rux AH, Ma P, Bdeir K, Sachais BS. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner. Blood. 2005;105:3545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998;391:591–4.

    Article  CAS  PubMed  Google Scholar 

  106. Gawaz M. Role of platelets in coronary thrombosis and reperfusion of ischemic myocardium. Cardiovasc Res. 2004;61:498–511.

    Article  CAS  PubMed  Google Scholar 

  107. Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood. 1996;88:146–57.

    Article  CAS  PubMed  Google Scholar 

  108. Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med. 2002;196:679–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, et al. RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001;103:1772–7.

    Article  Google Scholar 

  110. 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.

    Article  CAS  PubMed  Google Scholar 

  111. Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol. 2010;30:2357–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Salter JW, Krieglstein CF, Issekutz AC, Granger DN. Platelets modulate ischemia/reperfusion-induced leukocyte recruitment in the mesenteric circulation. Am J Physiol Gastrointest Liver Physiol. 2001;281:G1432–9.

    Article  CAS  PubMed  Google Scholar 

  113. Chignard M, Selak MA, Smith JB. Direct evidence for the existence of a neutrophil-derived platelet activator (neutrophilin). Proc Natl Acad Sci U S A. 1986;83:8609–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Falk E. Stable versus unstable atherosclerosis: clinical aspects. Am Heart J. 1999;138:S421–5.

    Article  CAS  PubMed  Google Scholar 

  115. von zur Muhlen C, Peter K, Ali ZA, Schneider JE, McAteer MA, Neubauer S, et al. Visualization of activated platelets by targeted magnetic resonance imaging utilizing conformation-specific antibodies against glycoprotein IIb/IIIa. J Vasc Res. 2009;46:6–14.

    Article  CAS  Google Scholar 

  116. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68:1082–115.

    Article  PubMed  Google Scholar 

  117. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the task force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213–60.

    Article  PubMed  Google Scholar 

  118. McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol. 2018;15:181–91.

    Article  CAS  PubMed  Google Scholar 

  119. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE 3rd, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309:396–403.

    Article  PubMed  Google Scholar 

  120. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2:349–60.

    Google Scholar 

  121. Antithrombotic Trialists C. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86.

    Article  Google Scholar 

  122. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med. 2018;379:1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009;30:1964–77.

    Article  CAS  PubMed  Google Scholar 

  124. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494–502.

    Article  CAS  PubMed  Google Scholar 

  125. Franchi F, Rollini F, Muniz-Lozano A, Cho JR, Angiolillo DJ. Cangrelor: a review on pharmacology and clinical trial development. Expert Rev Cardiovasc Ther. 2013;11:1279–91.

    Article  CAS  PubMed  Google Scholar 

  126. Bhatt DL, Stone GW, Mahaffey KW, Gibson CM, Steg PG, Hamm CW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368:1303–13.

    Article  CAS  PubMed  Google Scholar 

  127. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3:1800–14.

    Article  CAS  PubMed  Google Scholar 

  128. Bonaca MP, Steg PG, Feldman LJ, Canales JF, Ferguson JJ, Wallentin L, et al. Antithrombotics in acute coronary syndromes. J Am Coll Cardiol. 2009;54:969–84.

    Article  CAS  PubMed  Google Scholar 

  129. Morrow DA, Braunwald E, Bonaca MP, Ameriso SF, Dalby AJ, Fish MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404–13.

    Article  CAS  PubMed  Google Scholar 

  130. Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol. 2015;12:30–47.

    Article  CAS  PubMed  Google Scholar 

  131. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366:20–33.

    Article  CAS  PubMed  Google Scholar 

  132. Armstrong PC, Peter K. GPIIb/IIIa inhibitors: from bench to bedside and back to bench again. Thromb Haemost. 2012;107:808–14.

    Article  CAS  PubMed  Google Scholar 

  133. Bosch X, Marrugat J, Sanchis J. Platelet glycoprotein IIb/IIIa blockers during percutaneous coronary intervention and as the initial medical treatment of non-ST segment elevation acute coronary syndromes. Cochrane Database Syst Rev. 2013;11:CD002130.

    Google Scholar 

  134. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol. 2004;75:40–7.

    Article  CAS  PubMed  Google Scholar 

  135. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Koopman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387:2605–13.

    Article  PubMed  Google Scholar 

  136. McFadyen JD, Peter K. Novel antithrombotic drugs on the horizon: the ultimate promise to prevent clotting while avoiding bleeding. Circ Res. 2017;121:1133–5.

    Article  CAS  PubMed  Google Scholar 

Further Reading

  • Armstrong PC, Peter K. GPIIb/IIIa inhibitors: from bench to bedside and back to bench again. Thromb Haemost. 2012;107:808–14.

    Article  CAS  PubMed  Google Scholar 

  • Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.

    Article  CAS  PubMed  Google Scholar 

  • Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med. 2008;359:938–49.

    Article  CAS  PubMed  Google Scholar 

  • Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115:3378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2016;68:1082–115.

    Article  PubMed  Google Scholar 

  • McFadyen JD, Schaff M, Peter K. Current and future antiplatelet therapies: emphasis on preserving haemostasis. Nat Rev Cardiol. 2018;15:181–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful for Tobias Ziegler for preparing the schematic drawings (Figs. 11.1, 11.2, 11.3, and 11.4).

Author information

Authors and Affiliations

  1. Atherothrombosis and Vascular Biology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia

    James McFadyen & Karlheinz Peter

  2. Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia

    James McFadyen

  3. Australian Centre of Blood Diseases, Monash University, Melbourne, VIC, Australia

    James McFadyen

  4. Central Clinical School Monash University, Melbourne, VIC, Australia

    James McFadyen & Karlheinz Peter

  5. Heart Centre, The Alfred Hospital, Melbourne, VIC, Australia

    Karlheinz Peter

Authors
  1. James McFadyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karlheinz Peter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karlheinz Peter .

Editor information

Editors and Affiliations

  1. Discipline of Surgery, The University of Adelaide, Adelaide, SA, Australia

    Robert Fitridge

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

McFadyen, J., Peter, K. (2020). Platelets in the Pathogenesis of Vascular Disease and Their Role as a Therapeutic Target. In: Fitridge, R. (eds) Mechanisms of Vascular Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-43683-4_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-43683-4_11

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-43682-7

  • Online ISBN: 978-3-030-43683-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation