Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.4)
Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 2, February, p. 277–285

doi: 10.17219/acem/83588

Publication type: review article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Interactions between platelets and leukocytes in pathogenesis of multiple sclerosis

Angela Dziedzic1,A,B,C,D,E, Michał Bijak1,A,B,C,D,E,F

1 Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Poland


Neurodegenerative diseases are an increasing problem in the modern world. Multiple sclerosis (MS) is a major human demyelinating and degenerative disease of the central nervous system (CNS). There are many reports that point to the significant role of platelet–leukocyte interaction in neurodegenerative diseases and cardiovascular disturbances. Epidemiological studies confirm the high risk of cardiovascular diseases in patients with MS. The pathophysiology mechanisms of this multi-component disease are very complex and involve various types of cells. There is increasing evidence that some co-stimulatory pathways affect the function of inflammatory cells, both in the periphery and in the CNS. Interactions of leukocytes and endothelial cells (ECs) could be significantly modulated in the presence of activated blood platelets. The supposed role of activated platelets in the development of vessel inflammatory response is due to their ability to adhere to inflamed ECs or proteins included in the subendothelial layer of the blood vessel wall, as well as to the ability of platelets to form aggregates with leukocytes. Blood platelets are able to directly activate leukocytes through a receptor-dependent mechanism or, indirectly, by biologically active compounds secreted from their granules. Cell–cell interactions provide critical mechanisms by which platelets link thrombosis, inflammation and related processes, such as diapedesis and leukocyte infiltration, to the affected vessel. Determining the relationship between platelet–leukocyte interactions and the development of neuroinflammation in the course of MS may provide new therapeutic targets in the future.

Key words

blood platelets, multiple sclerosis (MS), neuroinflammation, platelet-leukocyte aggregates

References (72)

  1. Waubant E. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis Markers. 2006;22(4):235–244.
  2. Chen W, Zhang X, Huang W. Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep. 2016;13(4):3391–3396.
  3. Brola W, Sobolewski P, Flaga S, et al. Prevalence and incidence of multiple sclerosis in central Poland, 2010–2014. BMC Neurol. 2016;16:134.
  4. Wachowicz B, Morel A, Miller E, Saluk J. The physiology of blood platelets and changes of their biological activities in multiple sclerosis. Acta Neurobiol Exp (Wars). 2016;76(4):269–281.
  5. Dziedzic A, Idzikowska K, Saluk J. Tworzenie się kompleksów płytkowo-leukocytarnych we krwi obwodowej u pacjentów z ostrym zespołem wieńcowym. In: Szklarczyk M, Bajek E, eds. Diagnostyka, profilaktyka, leczenie – najnowsze doniesienia. Vol. II. Lublin, Poland: Wydawnictwo Naukowe Tygiel; 2017:42–50.
  6. Drelich DA, Bray PF. The traditional role of platelets in hemostasis (Chapter 2). In: Kerrigan S, Moran N, eds. The Non-Thrombotic Role of Platelets in Health and Disease. London, UK: IntechOpen Ltd.; 2015. doi:10.5772/58357
  7. Morel A, Rywaniak J, Bijak M, Miller E, Niwald M, Saluk J. Flow cytometric analysis reveals the high levels of platelet activation parameters in circulation of multiple sclerosis patients. Mol Cell Biochem. 2017;430(1–2):69–80.
  8. Elzey BD, Tian J, Jensen RJ, et al. Platelet-mediated modulation of adaptive immunity: A communication link between innate and adaptive immune compartments. Immunity. 2003;19(1):9–19.
  9. Bijak M, Saluk J, Ponczek M, Nowak P, Wachowicz B. The synthesis of proteins in unnucleated blood platelets [in Polish]. Postepy Hig Med Dosw. 2013;67:672–679.
  10. King SM, McNamee RA, Houng AK, Patel R, Brands M, Reed GL. Platelet dense granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. ­Circulation. 2009;120(9):785–791.
  11. Srivastava K, Cockburn IA, Swaim AM, et al. Platelet factor 4 mediates inflammation in cerebral malaria. Cell Host Microbe. 2008;4(2):179–187.
  12. Kasper B, Brandt E, Brandau S, Petersen F. Platelet factor 4 (CXC chemokine ligand 4) differentially regulates respiratory burst, survival, and cytokine expression of human monocytes by using distinct signaling pathways. J Immunol. 2007;179(4):2584–2591.
  13. Lasagni L, Grepin R, Mazzinghi B, et al. PF-4/CXCL4 and CXCL41 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion. Blood. 2007;109(10):4127–4134.
  14. Shahrara S, Park CC, Temkin V, Jarvis JW, Volin MV, Pope RM. RANTES modulates TLR-4-induced cytokine secretion in human peripheral blood monocytes. J Immunol. 2006;177(8):5077–5087.
  15. Schober A, Manka D, von Hundelshausen P, et al. Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation. 2002;106(12):1523–1529.
  16. Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ. Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood. 2010;115(17):3632–3639.
  17. Danese S, de la Motte C, Rivera Reyes BM, Sans M, Levine AD, Fiocchi C. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: A novel pathway for immune response amplification. J Immunol. 2004;172(4):2011–2015.
  18. Bennett JS. Structure and function of the platelet integrin αIIbβ3. J Clin Invest. 2005;115(12):3363–3369.
  19. Höök P, Litvinov RI, Kim OV, et al. Strong binding of platelet integrin αIIbβ3 to fibrin clots: Potential target to destabilize thrombi. Sci Rep. 2017;7(1):13001. doi:10.1038/s41598-017-12615-w
  20. von Hundelshausen P, Weber C. Platelets as immune cells: Bridging inflammation and cardiovascular disease. Circ Res. 2007;100(1):27–40.
  21. Lam FW, Vijayan KV, Rumbaut RE. Platelets and their interactions with other immune cells. Compr Physiol. 2015;5(3):1265–1280.
  22. Green SA, Smith M, Hasley RB, et al. Activated platelet–T-cell conjugates in peripheral blood of patients with HIV infection: Coupling coagu-lation/inflammation and T cells. AIDS. 2015;29(11):1297–1308.
  23. Schrottmaier WC, Kral JB, Badrnya S, Assinger A. Aspirin and P2Y12 inhibitors in platelet-mediated activation of neutrophils and monocytes. Thromb Haemost. 2015;114(3):478–489.
  24. Hirata T, Merrill-Skoloff G, Aab M, Yang J, Furie BC, Furie B. P-selectin glycoprotein ligand 1 (PSGL-1) is a physiological ligand for E-selectin in mediating T helper 1 lymphocyte migration. J Exp Med. 2000;192(11):1669–1675.
  25. Frenette PS, Denis CV, Weiss L, et al. P-selectin glycoprotein ligand 1 (PSGL-1) is expressed on platelets and can mediate platelet–endothelial interactions in vivo. J Exp Med. 2000;191(8):1413–1422.
  26. Wang Y, Sakuma M, Chen Z, et al. Leukocyte engagement of platelet glycoprotein Ib via integrin Mac-1 is critical for the biological response to vascular injury. Circulation. 2005;112(19):2993–3000.
  27. Simon DI, Chen Z, Xu H, et al. Platelet glycoprotein Iba is a counter-receptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med. 2000;192(2):193–204.
  28. Woodfin A, Voisin M, Imhof BA, Dejana E, Engelhardt B, Nourshargh S. Endothelial cell activation leads to neutrophil transmigration as supported by the sequential roles of ICAM-2, JAM-A and PECAM-1. Blood. 2009;113(24):6246–6257.
  29. Weber A, Przytulski B, Schumacher M, et al. Flow cytometry analysis of platelet cyclooxygenase-2 expression: Induction of platelet cycloox-ygenase-2 in patients undergoing coronary artery bypass grafting. Br J Haematol. 2002;117(2):424–426.
  30. Dixon DA, Tolley ND, Bemis-Standoli K, et al. Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation in-volving adhesion and cytokine signaling. Clin Invest. 2006;116(10):2727–2738.
  31. Glenister KM, Payne KA, Sparrow RL. Proteomic analysis of supernatant from pooled buffy-coat platelet concentrates throughout 7-day storage. Transfusion. 2008;48(1):99–107.
  32. Lindemann S, Tolley ND, Dixon DA, et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis. J Cell Biol. 2001;154(3):485–490.
  33. Beaulieu LM, Lin E, Mick E, et al. Interleukin 1 receptor 1 and interleukin 1β regulated megakaryocyte maturation, platelet activation and transcript profile during inflammation in mice and humans. ­Arterioscler Thromb Vasc Biol. 2014;34(3):552–564.
  34. Neumann H. Molecular mechanisms of axonal damage in inflammatory central nervous system diseases. Curr Opin Neurol. 2003;16(3):267–273.
  35. Thorsteinsdottir S, Bjerrum OW, Hasselbach HC. Myeloproliferative neoplasms in five multiple sclerosis patients. Leuk Res Rep. 2013;2(2):61–63.
  36. Christiansen CF, Christensen S, Farkas DK, Miret M, Sørensen HT, Pedersen L. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study. Neuroepidemiology. 2010;35(4):267–274.
  37. Jadidi E, Mohammadi M, Moradi T. High risk of cardiovascular diseases after diagnosis of multiple sclerosis. Mult Scler. 2013;19(10):1336–1340.
  38. Brønnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in Danish patients with multiple sclerosis. Brain. 2004;127(Pt 4):844–850.
  39. Shah SM, Khan S, Rehman SU, Khan ZA, Wisal A, Wisal Z. Addressing the impact of stroke risk factors in a case control study in tertiary care hospitals: A case-control study in Tertiary Care Hospitals of Peshawar, Khyber Phukhtoonkhwa (KPK), Pakistan. BMC Res Notes. 2013;6:268.
  40. Ocak G, Vossen CY, Verduijn M, et al. Risk of venous thrombosis in patients with major illnesses: Results from the MEGA study. J Thromb Haemost. 2013;11(1):116–123.
  41. Arpaia G, Bavera PM, Caputo D, et al. Risk of deep venous thrombosis (DVT) in bedridden or wheelchair-bound multiple sclerosis patients: A prospective study. Thromb Res. 2010;125(4):315–317.
  42. Sternberg Z, Leung C, Sternberg D, Yu J, Hojnacki D. Disease-modifying therapies modulate cardiovascular risk factors in patients with multiple sclerosis. Cardiovasc Ther. 2014;32(2):33–39.
  43. Pankratz S, Bittner S, Kehrel BE, et al. The inflammatory role of platelets: Translational insights from experimental studies of autoimmune disorders. Int J Mol Sci. 2016;17(10):1723.
  44. Behari M, Shrivastava M. Role of platelets in neurodegenerative diseases: A universal pathophysiology. Int J Neurosci. 2013;123(5):287–299. doi:10.3109/00207454.2012.751534
  45. Nathanson M, Savitsky JP. Platelet adhesive index studies in multiple sclerosis and other neurologic disorders. Bull N Y Acad Med. 1952;28(7):462–468.
  46. Sheremata WA, Jy W, Horstman LL, Ahn YS, Alexander JS, Minagar A. Evidence of platelet activation in multiple sclerosis. J Neuroinflammation. 2008;5:27. doi:10.1186/1742-2094-5-27
  47. Starossom SC, Veremeyko T, Yung AW, et al. Platelets play differential role during the initiation and progression of autoimmune neuroinflammation. Circ Res. 2015;117(9):779–792.
  48. Morel A, Bijak M, Miller E, Rywaniak J, Miller S, Saluk J. Relationship between the increased haemostatic properties of blood platelets and oxidative stress level in multiple sclerosis patients with the secondary progressive stage. Oxid Med Cell Longev. 2015;2015:240918. doi:10.1155/2015/240918
  49. Morel A, Miller E, Bijak M, Saluk J. The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients. Mol Cell Biochem. 2016;420(1–2):85–94. doi:10.1007/s11010-016-2770-6
  50. Langer HF, Chavakis T. Platelets and neurovascular inflammation. Thromb Haemost. 2013;110(5):888–893.
  51. Langer HF, Choi EY, Zhou H, et al. Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res. 2012;110(9):1202–1210. doi:10.1161/CIRCRESAHA.111.256370
  52. Hon GM, Hassan MS, van Rensburg SJ, Erasmus RT, Matsha T. The haematological profile of patients with multiple sclerosis. Open J Mod Neurosurg. 2012;2(3):36–44.
  53. Farrokhi M, Beni AA, Etemadifar M, et al. Effect of fingolimod on platelet count among multiple sclerosis patients. Int J Prev Med. 2015;6:125. doi:10.4103/2008-7802.172539
  54. Obermann M, Ruck T, Pfeuffer S, Baum J, Wiendl H, Meuth SG. Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler. 2016;22(9):1235–1241. doi:10.1177/1352458516638558
  55. May AE, Kälsch T, Massberg S, Schmidt R, Gawaz M. Engagement of glycoprotein IIb/IIIa (αIIbβ3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation. 2002;106(16):2111–2117.
  56. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115(12):3378–3384.
  57. Lievens D, Zernecke A, Seijkens T, et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood. 2010;116(20):4317–4327.
  58. Gerdes N, Zhu L, Ersoy M, et al. Platelets regulate CD4+ T-cell differentiation via multiple chemokines in humans. Thromb Haemost. 2011;106(2):353–362.
  59. Fletcher JM, Lalor SJ, Sweeney CM, Tubridy N, Mills KH. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162(1):1–11.
  60. Kempuraj D, Thangavel R, Natteru PA, et al. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine. 2016;1(1):1003.
  61. Shahrara S, Pickens SR, Mandelin AM, et al. IL-17-mediated monocyte migration occurs partially through CCL2/MCP-1 induction. J Immunol. 2010;184(8):4479–4487.
  62. Drolet AM, Thivierge M, Turcotte S, et al. Platelet-activating factor induces Th17 cell differentiation. Mediators Inflamm. 2011;2011:913802.
  63. Li N. CD4+ T cells in atherosclerosis: Regulation by platelets. Thromb Haemost. 2013;109(6):980–990.
  64. Dinkla S, van Cranenbroek B, van der Heijden W, et al. Platelet microparticles inhibit IL 17 production by regulatory T cells through P-selectin. Blood. 2016;127(16):1976–1986.
  65. Horstman LL, Jy W, Ahn YS, et al. Role of platelets in neuroinflammation: A wide-angle perspective. J Neuroinflammation. 2010;7:10.
  66. Duerschmied D, Suidan GL, Demers M, et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood. 2013;121(6):1008–1015.
  67. Morrell CN, Aggrey AA, Chapman LM, Modjeski KL. Emerging roles for platelets as immune and inflammatory cells. Blood. 2014;123(18):2759–2767.
  68. Centonze D, Muzio L, Rossi S, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009;29(11):3442–3452.
  69. Seizer P, May AE. Platelets and matrix metalloproteinases. Thromb Haemost. 2013;110(5):903–909.
  70. Bar-Or A, Nuttall RK, Duddy M, et al. Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major in-flammatory mediators in multiple sclerosis. Brain. 2003;126(Pt 12):2738–2749.
  71. Saluk-Juszczak J, Wachowicz B, Kaca W. Endotoxins stimulate generation of superoxide radicals and lipid peroxidation in blood platelets. Microbios. 2000;103(404):17–25.
  72. Gironi M, Borgiani B, Mariani E, et al. Oxidative stress is differentially present in multiple sclerosis courses, early evident and unrelated to treatment. J Immunol Res. 2014;2014:961863. doi:10.1155/2014/961863