Abstract

Platelets are the smallest anucleated cells, in the circulation. Platelets are produced from the megakaryocytes in the bone marrow. Platelets participates in maintaining vascular integrity and hemostasis. However, their role extends beyond hemostasis to thrombosis, inflammation, immunity, wound healing, cancer, and angiogenesis. The multifunctional roles of platelets are achieved through the expression of diverse adhesive and immune receptors, a wide array of bioactive proteins stored in their granules, and the elaboration of membrane lipid mediators upon activation. There is an obvious involvement of platelets in inflammation, immunity, cancer, and angiogenesis. Thus, the concept arises that platelets, at the intersection of these conditions, are multifunctional cells. A better understanding of the exact, as well as the diverse roles and mechanisms of platelets in pathologic conditions is a promising research area and may open a window for new strategies and prevention methods of diseases.

Keywords: Platelets · hemostasis · thrombosis · angiogenesis · immunity · inflammation · cancer

References

  1. 1.Cooper B. Osler’s role in defining the third corpuscle, or “blood plates”. Proc (Bayl Univ Med Cent). 2005;18(4):376–8.
  2. 2.Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol. 2006;133(3):251–
  3. 3.Ribatti D, Crivellato E. Giulio Bizzozero and the discovery of platelets. Leuk Res. 2007;31(10):1339–41.
  4. 4.Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A. Platelets in hemostasis and thrombosis: Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectinmediated protein wave of hemostasis. J Biomed Res [Internet].2015;29 (October):437–44. Available from: http:// www.jbr-pub.org/ch/reader/view_abstract.aspx?file_no=JBR150602&flag=1
  5. 5.Kaushansky K. Thrombopoietin and the physiology of platelet production. Leuk Res. 1996;20(9):705–7.
  6. 6.Kuter DJ. The Physiology of Platelet Production. Stem Cells [Internet]. 1996;14(S1):88–101. Available from:http://doi.wiley.com/10.1002/ stem.5530140711 Acknowledgements
  7. 7.Fritsma GA. Platelet Structure and Function. Clin Lab Sci. 2015;28(2):125–31. The author thanks Drs. Mohamed Suhail
  8. 8.Wendling F. Thrombopoietin: its role from 73 The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 early hematopoiesis to platelet production. Haematologica. 1999;84(2):158–66.
  9. 9.Italiano JE. Unraveling Mechanisms that Control Platelet Production. Semin Thromb Hemost. 2013;39:15–24.
  10. 10.Sabrkhany S, Griffioen AW, oude Egbrink MGA. The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta - Rev Cancer. 2011;1815(2):189–96.
  11. 11.Ghoshal K, Bhattacharyya M. Overview of platelet physiology: Its hemostatic and nonhemostatic role in disease pathogenesis. Sci World J. 2014;2014.
  12. 12.Ali RA, Wuescher LM, Worth RG. Platelets: Essential components of the immune system. Curr Trends Immunol. 2015;16:65–78.
  13. 13.Wagner DD, Burger PC. Platelets in Inflammation and Thrombosis. Arterioscler Thromb Vasc Biol. 2003;23(12):2131–7.
  14. 14.Repsold L, Pool R, Karodia M, Tintinger G, Joubert AM. An overview of the role of platelets in angiogenesis, apoptosis and autophagy in chronic myeloid leukaemia. Cancer Cell Int. 2017;17(1):1–
  15. 15.Gresele P, Lopez JA, Kleiman NS, Page CP. Platelets in thrombotic and nonthrombotic disorders: Pathophysiology, pharmacology and therapeutics: An update. Platelets Thromb Non-Thrombotic Disord Pathophysiol Pharmacol Ther an Updat. 2017;1–1445.
  16. 16.Golebiewska EM, Poole AW. Platelet secretion: From haemostasis to wound healing and beyond. Blood Rev [Internet]. 2015;29(3):153–62. Available from: http://dx.doi.org/10.1016/j. blre.2014.10.003 doi:10.1016/j
  17. 17.Klinger MHF, Jelkmann W. Review: Role of Blood Platelets in Infection and Inflammation. J Interf Cytokine Res [Internet]. 2002;22(9):913–22. Available from: http://www.liebertonline.com/doi/ abs/10.1089/10799900260286623 doi:10.1089/10799900260286623
  18. 18.Collins CE, Rampton DS. Platelets in inflammatory bowel disease - Pathogenetic role and therapeutic implications. Aliment Pharmacol Ther. 1997;11(2):237–
  19. 19.Cui MM, Li N, Liu X, Yun ZY, Niu Y, Zhang Y, et al. Platelet distribution width correlates with prognosis of non-small cell lung cancer. Sci Rep. 2017;7(1):1–6.
  20. 20.Cerletti C, Tamburrelli C, Izzi B, Gianfagna F, De Gaetano G. Plateletleukocyte interactions in thrombosis. Thromb Res. 2012;129(3):263–6.
  21. 21.Cerletti C, de Gaetano G, Lorenzet R. Platelet - leukocyte interactions: multiple links between inflammation, blood coagulation and vascular risk. Mediterr J Hematol Infect Dis. 2010;2(3):e2010023.
  22. 22.ZG F, RA C, AS W, MT. R. Plateletleukocyte interactions link inflammatory and thromboembolic events in ischemic stroke. Ann N Y Acad Sci. 2010;1207:11–
  23. 23.Ghasemzadeh M, Hosseini E. Platelet-leukocyte crosstalk: Linking proin- The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis 74 Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 flammatory responses to procoagulant state. Thromb Res. 2013;131(3):191–7.
  24. 24.Herter JM, Rossaint J, Zarbock A. Platelets in inflammation and immunity. J Thromb Haemost. 2014;12(11):1764–75.
  25. 25.Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood. 2014;123(18):2759–67.
  26. 26.Michelson A. Platelets. Academic Press; 2012. 1398 p.
  27. 27.White JG. Platelets Structure. 2007. Academic Press.
  28. 28.White JG. The Dense Bodies of Human Platelets: Inherent Electron Opacity of the Serotonin Storage Particles. Blood. 1969;33(4).
  29. 29.Saboor M, Chotani R, Ilyas S, Usman MM. Anatomy and physiology of platelets. J Public Heal Biol Sci 2013;2(2)2016. 2013;2(2):201–6.
  30. 30.Zelen JSJ. The role of the platelet cytoskeleton in platelet function. ThesisUniversitat Utr. 2012;1–25.
  31. 31.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.
  32. 32.Smyth S, McEver R, Weyrich A, Morrell C, Hoffman M, Arepally G, et al. Platelet functions beyond hemostasis. J Thromb Haemost. 2009;7(11):1759–66. 75
  33. 33.Blair P, Flaumenhaft R. Platelet Alpha–granules: Basic biology and clinical correlates Price. Blood Rev [Internet]. 2009;23(4):177–89. Available from: http://www.sciencedirect.com/science/ article/pii/S0268960X09000290
  34. 34.Semple J, Italiano J, Freedman J. Platelets and the immune continuum. Nat Rev Immunol. 2011;11(4):264–74.
  35. 35.Mezger M, Nording H, Sauter R, Graf T, Heim C, von Bubnoff N, et al. Platelets and Immune Responses During Thromboinflammation. Front Immunol [Internet]. 2019;10:1371. Available from: doi: 10.3389/fimmu.2019.01731 doi:10.3389/fimmu.2019.01731
  36. 36.Caudrillier A, Kessenbrock K, Gilliss B, Nguyen J, Marques M, Monestier M, et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest. 2012;122(7):2661–
  37. 37.McDonald B, Urrutia R, Yipp BG, Jenne CN, Kubes P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe. 2012;12(3):324–33.
  38. 38.Stocker TJ, Ishikawa-Ankerhold H, Massberg S, Schulz C. Small but mighty: Platelets as central effectors of host defense. Thromb Haemost. 2017;117(4):651–61.
  39. 39.Yeaman M. The Role of Platelets in Antimicrobial Host Defense. Clin Infect Dis [Internet]. 1997;25(5):951–68. Available from: https://academic.oup.com/cid/ The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441
  40. 40.Yeaman M, Yount N, Waring A, Gank K, Kupferwasser D, Wiese R, et al. Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins. Biochim Biophys Acta - Biomembr. 2007;1768(3):609–19.
  41. 41.Scott T, Owens MD. Thrombocytes respond to lipopolysaccharide through Toll-like receptor‑4, and MAP kinase and NF‑κB pathways leading to expression of interleukin‑6 and cyclooxygenase‑2 with production of prostaglandin E2. Mol Immunol. 2008;45(4):1001–8.
  42. 42.Hamzeh-Cognasse, H. Damien P, Chabert A, Pozzetto B, Cognasse F, Garraud O. Platelets and infections - complex interactions with bacteria. Front Immunol 2015 Feb 26;682. 2015;6(28).
  43. 43.Czapiga M, Kirk A, Lekstrom-Himes J. Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immuneactivation. Exp Hematol. 2004;32(2):135–9.
  44. 44.Shiraki R, Inoue N, Kawasaki S, Takei A, Kadotani M, Ohnishi Y, et al. Expression of Toll-like receptors on human platelets. Thromb Res. 2004;113(6):379–85.
  45. 45.Aslam R, Speck ER, Kim M, Crow AR, Bang KWA, Nestel FP, et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo. Blood. 2006;107(2):637–
  46. 46.article-lookup/doi/10.1086/516120 doi:10.1086/516120
  47. 47.Cognasse F, Nguyen K, Damien P, McNicol A, Pozzetto B, Hamzeh-Cognasse H, et al. The inflammatory role of platelets via their TLRs and Siglec receptors. Front Immunol [Internet]. 2015;6(83). Available from: doi: 10.3389/ fimmu.2015.00083
  48. 48.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(2):196–8.
  49. 49.Zhang G, Han J, Welch E, Ye R, Voyno-Yasenetskaya T, Malik A, et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol. 2009;182(12):7997–8004.
  50. 50.Pancré V, Monte D, Delanoye A, Capron A, Aurialt C. Interleukin‑6, the main mediator of interaction between monocytes and platelets in killing of Schistosoma mansoni. Eur Cytokine Net (1990). 1990;1(1):15–9.
  51. 51.Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, et al. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3‑kinase. Circ Res. 2009;104(3):346–54.
  52. 52.Berthet J, Damien P, Hamzeh-Cognasse H, Arthaud C, Eyraud M, Zéni F, et al. Human platelets can discriminate between various bacterial LPS iso- The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis 76 Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 forms via TLR4 signaling and differential cytokine secretion. Clin Immunol. 2012;145(3):189–200.
  53. 53.Yeaman M. Platelets: at the nexus of antimicrobial defence. Nat Rev Microbiol. 2014;12(6):426–37.
  54. 54.Clemetson K, Clemetson J, Proudfoot A, Power C, Baggiolini M, Wells T. Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood. 2000;96(13):4046– 4054.
  55. 55.Scheuerer B, Ernst M, DürrbaumLandmann I, Fleischer J, Grage-Griebenow E, Brandt E, et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood [Internet]. 2000;95(4):1158–66. Available from: http://www.ncbi.nlm.nih.gov/ pubmed/10666185
  56. 56.Sonmez O, Sonmez M. Role of platelets in immune system and inflammation [Internet]. Porto Biomedical Journal. 2017. Available from: http:// linkinghub.elsevier.com/retrieve/pii/ S2444866417300107
  57. 57.Hundelshausen P, Weber C. Platelets as Immune Cells Bridging Inflammation and Cardiovascular Disease. Circ Res. 2007;100(1):27–40.
  58. 58.Yeaman M. Bacterial–platelet interactions: virulence meets host defense. Futur Microbiol. 2010;5:471–506.
  59. 59.77 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.
  60. 60.Zielinski T, Wachowicz B, SalukJuszczak J, Kaca W. The generation of superoxide anion in blood platelets in response to different forms of Proteus mirabilis lipopolysaccharide: effects of staurosporin, wortmannin, and indomethacin. Thromb Res. 2001;103:149–55.
  61. 61.Lopes-Pires M, Casarin A, PereiraCunha F, Lorand-Metze I, Antunes E, Marcondes S. Lipopolysaccharide treatment reduces rat platelet aggregation independent of intracellular reactiveoxygen species generation. Platelets. 2012;23(3):195–201.
  62. 62.Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y, et al. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811.
  63. 63.Hagihara M, Higuchi A, Tamura N, Ueda Y, Hirabayashi K, Ikeda Y, et al. Platelets, after Exposure to a High Shear Stress, Induce IL-10-Producing, Mature Dendritic Cells In Vitro. J Immunol [Internet]. 2004;172(9):5297–303. Available from: http://www.jimmunol.org/cgi/ doi/10.4049/jimmunol.172.9.5297 doi:10.4049/jimmunol.172.9.5297
  64. 64.Clark S, Ma A, Tavener S, McDonald B, Goodarzi Z, Kelly M, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 Nat Med. 2007;13(4):463–9.
  65. 65.Kraemer B, Campbell R, Schwertz H, Cody M, Franks Z, Tolley N, et al. Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation. PLoS Pathog. 2011;7(11):e1002355.
  66. 66.Elzey B, Grant J, Sinn H, Nieswandt B, Waldschmidt T, Ratliff T. Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation. J Leukoc Biol. 2005;78(1):80–4.
  67. 67.Elzey B, Tian J, Jensen R, Swanson A, Lees J, Lentz S, et al. Platelet-mediated modulation ofadaptive immunity. A communication link between innate and adaptive immunecompartments. Immunity. 2003;19(1):9–19.
  68. 68.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), α v β 3 Integrin, and GPIbα. J Exp Med [Internet]. 1998;187(3):329–39. Available from: http://www.jem.org/lookup/doi/10.1084/ jem.187.3.329
  69. 69.Mezger M, Göbel K, Kraft P, Meuth S, Kleinschnitz C, Langer H. Platelets and vascular inflammation of the brain. Hamostaseologie. 2015;35(3):244–51.
  70. 70.Winning J, Neumann J, Kohl M, Claus R, Reinhart K, Bauer M, et al. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med. 2010;38(1):32–7.
  71. 71.Erlich J, Talmor D, Cartin-Ceba R, Gajic O, Kor D. Prehospitalization Acute, antiplatelet therapy is associated with a reduced incidence of Study., lung injury: a population-based cohort. Chest. 2011;139(2):289–95.
  72. 72.Pitchford S. Novel uses for anti-platelet agents as anti-inflammatory drugs. Br J Pharmacol. 2007;152(7):987–1002.
  73. 73.Müller K, Chatterjee M, Rath D, Geisler T. Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD. Thromb Haemost. 2015;114(3):498–518.
  74. 74.Hundelshausen P, Schmitt M. Platelets and their chemokines in atherosclerosis—clinical applications. Front Physiol. 2014;5:294.
  75. 75.Ross R, Glomset J. The pathogenesis of atherosclerosis (first of two parts). N Engl J Med. 1976;295:369–77.
  76. 76.Ross R, Glomset J. The pathogenesis of atherosclerosis (second of two parts). N Engl J Med. 1976;295:420–5.
  77. 77.Herbin O, Regelmann A, Ramkhelawon B, Weinstein E, Moore K, Alexandropoulos K. Monocyte Adhesion and Plaque Recruitment During Atherosclerosis Development Is Regulated by the Adapter Protein Chat-H/SHEP1. Arter Thromb Vasc Biol. 2016;36(9):1791–801.
  78. 78.Heijnen H, van der Sluijs P. Platelet The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis 78 Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 secretory behaviour: As diverse as the granules... or not? J Thromb Haemost. 2015;13(12):2141–51.
  79. 79.Franco AT, Corken A, Ware J. Platelets at the interface of thrombosis , in fl ammation , and cancer. Blood [Internet]. 2015;126(5):582–8. Available from: http://www.bloodjournal.org/content/126/5/582
  80. 80.Gawaz M, Stellos K, Langer H. Platelets modulate atherogenesis and progression of atherosclerotic plaques via interaction with progenitor and dendritic cells. J Thromb Haemost. 2008;6(2):235–42.
  81. 81.Gawaz M, Langer H, May A. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115:3378–84.
  82. 82.Petersen F, Bock L, Flad HD, Brandt E. A chondroitin sulfate proteoglycan on human neutrophils specifically binds platelet factor 4 and is involved in cell activation. J Immunol [Internet]. 1998;161(8):4347–
  83. 83.Available from: http://www.ncbi.nlm. nih.gov/pubmed/9780212
  84. 84.Varki A. Trousseau’s syndrome: multiple definitions and multiple mechanisms. Blood. 2007;110(6):1723–9.
  85. 85.Gasic G, Gasic T, Galanti N, Johnson T, Murphy S. Platelet-tumor-cellinteractions in mice. The role of platelets in the spread of malignant disease. Int J Cancer. 1973;11(3):704–18.
  86. 86.Jain S, Harris J, Ware J. Platelets: linking hemostasis and cancer. Arter Thromb Vasc Biol. 2010;30(12):2362–7. 79
  87. 87.Nieswandt B, Hafner M, Echtenacher B, Mannel D. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res. 1999;59:1295–300.
  88. 88.Palumbo J, Talmage K, Massari J, La Jeunesse C, Flick M, Kombrinck K, et al. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell mediated elimination of tumor cells. Blood. 2005;105:178–85.
  89. 89.Elaskalani O, Berndt M, Falasca M, Metharom P. Targeting Platelets for theTreatment of Cancer. Cancers (Basel). 2017;22(9).
  90. 90.Rachidi S, Kaur M, Lautenschlaeger T, Li Z. Platelet count correlates with stage and predicts survival in melanoma. Platelets. 2019;13:1–5.
  91. 91.Pinedo H, Verheul H, D’Amato R, Folkman J. Involvement of platelets in tumour angiogenesis? Lancet. 1998;352(9142):1775–7.
  92. 92.Verheul H, Hoekman K, Luykx-de B, Eekman C, Folman C, Broxterman H, et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res. 1997;3(12):2187–90.
  93. 93.Dobbs S, Brown L, Ireland D, Abrams K, Murray J, Gatter K, et al. Plateletderived endothelial cell growth factor expression and angiogenesis in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix. Ann Diagn Pathol. 2000;4(5):286–92.
  94. 94.Aiello L, Avery R, Arrigg P, Keyt B, The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 Jampel H, Shah S, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331(22):480–1487.
  95. 95.Monzavi-Karbassi B, Stanley J, Hennings, L. Jousheghany F, Artaud C, Shaaf S, Kieber-Emmons T. Chondroitin sulfate glycosaminoglycans as major P-selectin ligands on metastatic breast cancer cell lines. Int J Cancer. 2007;120:1179–91.
  96. 96.Kim Y, Borsig L, Varki N, Varki A. P-selectin deficiency attenuates tumor growth and metastasis. Proc Natl Acad Sci U S A. 1998;95:9325–9330.
  97. 97.Borsig L, Wong R, Hynes R, Varki N, Varki A. Synergistic effects of L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancers of metastasis. Proc Natl Acad Sci U S A. 2002;99:2193–2198.
  98. 98.Jain S, Zuka M, Liu J, Russell S, Dent J, Guerrero J, et al. Platelet glycoprotein Iba supports experimental lung metastasis. Proc Natl Acad Sci U S A. 2007;104:9024–9.
  99. 99.Jain S, Russell S, Ware J. Platelet glycoprotein VI facilitates experimental lung metastasis in syngenic mouse models. J. Thromb Haemost. 2009;7:1713–7.
  100. 100.Varon D, Dardik R, Shenkman B, Kotev-Emeth S, Farzame N, Tamarin I, et al. A new method for quantitative analysis of whole blood platelet interaction with extracellular matrix under flow conditions. Throm Res. 1997;85:283–94.
  101. 101.Trikha M, Zhou Z, Timar J, Raso E, Kennel M, Emmell E, et al. Multiple roles for platelet GPIIb/IIIa and alphavbeta3 integrins in tumor growth, angiogenesis, and metastasis. Cancer Res. 2002;62:2824–33.
  102. 102.Amirkhosravi A, Amaya M, Siddiqui F, Biggerstaff J, Meyer T, JL. F. Blockade of GpIIb/ IIIa inhibits the release of vascular endothelial growth factor (VEGF) from tumor cell-activated platelets and experimental metastasis. Platelets. 1999;10:285–92.
  103. 103.Pietras K, Ostman A, Sjöquist M, Buchdunger E, Reed R, Heldin C, et al. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001;61(7):2929–34.
  104. 104.Heuchel R, Berg A, Tallquist, Ahlén M, Reed R, Rubin K, et al. Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci U S A. 1999;96(20):11410–5.
  105. 105.Cairns R, Papandreou I, Denko N. Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment. Mol Cancer Res. 2006;4(2):61–70.
  106. 106.Alsina-Sanchís E, Figueras A, Lahiguera A, Gil-Martín M, Pardo B, Piulats J, et al. TGFβ Controls Ovarian The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis 80 Majmaah Journal of Health Sciences ,Vol. 8, Issue 1, January - 2020 , Jumadil Awwal - 1441 Cancer Cell Proliferation. Int J Mol Sci. 2017;18(8):1658.
  107. 107.Apte S, Fan D, Killion J, Fidler I. Targeting the Platelet-Derived Growth Factor Receptor in Antivascular Therapy for Human Ovarian Carcinoma. Clin Cancer Res. 2004;10(3):897–908.
  108. 108.Liu C, Jernigan D, Zhang Y, Fatatis A. Implication of platelet-derived growth factor receptor alpha in prostate cancer skeletal metastasis. Chin J Cancer. 2011;30(9):612–9.
  109. 109.Lindberg N, Holland E. PDGF in gliomas: more than just a growth factor? Ups J Med Sci. 2012;117(2):92–8.
  110. 110.Wojtukiewicz M, Hempel D, Sierko E, Tucker S, Honn K. Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past? Cancer Metastasis Rev. 2017;36(2):305–29. 2013;118(5):1359–69.
  111. 111.Milovanovic M, Nilsson E, Jaremo P. Relationships between platelets and inflammatory markers in rheumatoid arthritis. Clin Chim Acta. 2004;343:237–40.
  112. 112.Berrettini M, Parise P, Constantini V, Grasselli S, Nenci G. Platelet activation in psoriasis. Thromb Haemost. 1985;53:195–7.
  113. 113.Ho-Tin-Noe B, Goerge T, Cifuni S, Duerschmied D, Wagner D. Platelet granule secretion continuously prevents intratumor hemorrhage. Cancer Res. 2008;68:6851–8.
  114. 114.Yamashiro K, Tsujikawa A, Ishida S, Usui T, Kaji Y, Honda Y, et al. Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood-retinal barrier breakdown. Am J Pathol. 2003;163:253–9.
  115. 115.Walsh T, Metharom P, Berndt M. The functional role of platelets in the regulation of angiogenesis. Platelets. 2015;26(3):199–211.
  116. 116.Carmeliet P. Angiogenesis in life, disease and medicine. Nat 2005. 2005;438:932–936.
  117. 117.Battinelli EM, Markens BA, Italiano JE, Dc W, Jr JEI. Release of angiogenesis regulatory proteins from platelet alpha granules : modulation of physiologic and pathologic angiogenesis Release of angiogenesis regulatory proteins from platelet alpha granules : modulation of physiologic and pathologic angiogenes. 81 The Mighty Role Of Platelets In Immunity, Inflammation, Cancer And Angiogenesis

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