Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The role of platelets in acute kidney injury

Nature Reviews Nephrology volume 14, pages 457–471 (2018)Cite this article

Subjects

Abstract

Acute kidney injury (AKI), a major public health problem associated with high mortality and increased risk of progression towards end-stage renal disease, is characterized by the activation of intra-renal haemostatic and inflammatory processes. Platelets, which are present in high numbers in the circulation and can rapidly release a broad spectrum of bioactive mediators, are important acute modulators of inflammation and haemostasis, as they are the first cells to arrive at sites of acute injury, where they interact with endothelial cells and leukocytes. Diminished control of platelet reactivity by endothelial cells and/or an increased release of platelet-activating mediators can lead to uncontrolled platelet activation in AKI. As increased platelet sequestration and increased expression levels of the markers P-selectin, thromboxane A2, CC-chemokine ligand 5 and platelet factor 4 on platelets have been reported in kidneys following AKI, platelet activation likely plays a part in AKI pathology. Results from animal models and some clinical studies highlight the potential of antiplatelet therapies in the preservation of renal function in the context of AKI, but as current strategies also affect other cell types and non-platelet-derived mediators, additional studies are required to further elucidate the extent of platelet contribution to the pathology of AKI and to determine the best therapeutic approach by which to specifically target related pathogenic pathways.

Key points

  • Both ischaemia–reperfusion and systemic inflammation lead to alterations in the renal macrocirculation and microcirculation that often result in poorly controlled inflammatory and haemostatic responses, thereby causing irreversible renal tissue damage.

  • Platelets are the first cells to arrive at sites of acute injury, where they interact with endothelial cells and leukocytes.

  • Activation of platelets during acute kidney injury (AKI) may be exaggerated owing to an excess of platelet stimuli in combination with diminished antiplatelet regulation.

  • Platelets are important acute modulators of haemostasis and likely disturb renal haemodynamic processes during AKI, which leads to sustained hypoxaemic renal tissue injury.

  • Platelets facilitate inflammation during the pathophysiology of AKI, mainly by stimulating endothelial cells as well as by recruiting and activating leukocytes during the inflammatory reaction.

  • Early data from animal and human studies and from randomized clinical trials suggest that antiplatelet therapies will reduce the risk of AKI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The intact endothelium prevents platelet activation.
Fig. 2: Platelet activation at the site of vascular injury.
Fig. 3: Effects of activated platelets on endothelial cells and leukocytes.

Similar content being viewed by others

References

  1. Bellomo, R., Kellum, J. A. & Ronco, C. Acute kidney injury. Lancet 380, 756–766 (2012).

    Article  PubMed  Google Scholar 

  2. Hsu, R. K., McCulloch, C. E., Dudley, R. A., Lo, L. J. & Hsu, C. Y. Temporal changes in incidence of dialysis-requiring AKI. J. Am. Soc. Nephrol. 24, 37–42 (2013).

    Article  PubMed  Google Scholar 

  3. Hsu, C. Y. et al. Community-based incidence of acute renal failure. Kidney Int. 72, 208–212 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Jefferson, J. A., Thurman, J. M. & Schier, R. W. Pathophysiology and etiology of acute kidney injury. Ann. Clin. Biochem. 52, 797–812 (2010).

    Google Scholar 

  5. Zarbock, A., Gomez, H. & Kellum, J. A. Sepsis-induced acute kidney injury revisited: pathophysiology, prevention and future therapies. Curr. Opin. Crit. Care 20, 588–595 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Basile, D. P. & Yoder, M. C. Renal endothelial dysfunction in acute kidney ischemia reperfusion injury. Cardiovasc. Hematol. Disord. Drug Targets 14, 3–14 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Souza, A. C., Yuen, P. S. & Star, R. A. Microparticles: markers and mediators of sepsis-induced microvascular dysfunction, immunosuppression, and AKI. Kidney Int. 87, 1100–1108 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Basile, D. P., Anderson, M. D. & Sutton, T. A. Pathophysiology of acute kidney injury. Compr. Physiol. 2, 1303–1353 (2012).

    PubMed  PubMed Central  Google Scholar 

  9. Vogel, S. et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J. Clin. Invest. 125, 4638–4654 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dole, V. S., Bergmeier, W., Mitchell, H. A., Eichenberger, S. C. & Wagner, D. D. Activated platelets induce Weibel-Palade-body secretion and leukocyte rolling in vivo: role of P-selectin. Blood 106, 2334–2339 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Gawaz, M., Dickfeld, T., Bogner, C., Fateh-Moghadam, S. & Neumann, F. J. Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med. 23, 379–385 (1997).

    Article  PubMed  CAS  Google Scholar 

  12. Boilard, E. et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 327, 580–583 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Lievens, D. et al. Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 116, 4317–4327 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Hu, H. et al. Clopidogrel protects from cell apoptosis and oxidative damage in a mouse model of renal ischaemia-reperfusion injury. J. Pathol. 225, 265–275 (2011).

    Article  PubMed  CAS  Google Scholar 

  16. Jansen, M. P. et al. Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps. Kidney Int. (2016).

  17. Saboor, M., Ayub, Q., Ilyas, S. & Moinuddin, S. Platelet receptors; an instrumental of platelet physiology. Pak.J. Med. Sci. 29, 891–896 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Maynard, D. M., Heijnen, H. F., Horne, M. K., White, J. G. & Gahl, W. A. Proteomic analysis of platelet a-granules using mass spectrometry. J. Thromb. Haemost 5, 1945–1955 (2007).

    Article  PubMed  CAS  Google Scholar 

  19. Wijten, P. et al. High precision platelet releasate definition by quantitative reversed protein profiling — brief report. Arterioscler Thromb. Vasc. Biol. 33, 1635–1638 (2013).

    Article  PubMed  CAS  Google Scholar 

  20. Gidlöf, O. et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 21, 3908–3917 (2013).

    Article  CAS  Google Scholar 

  21. Kirschbaum, M. et al. Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation. Blood 126, 798–806 (2015).

    Article  PubMed  CAS  Google Scholar 

  22. Chappell, D. et al. [Expedition glycocalyx. A newly discovered “Great Barrier Reef]. Anaesthesist 57, 959–969 (2008).

    Article  PubMed  CAS  Google Scholar 

  23. de Melo Bezerra Cavalcante, C. T. et al. Syndecan-1 improves severe acute kidney injury prediction after pediatric cardiac surgery. J. Thorac Cardiovasc. Surg. 152, 178–186 (2016).

    Article  PubMed  CAS  Google Scholar 

  24. Chelazzi, C., Villa, G., Mancinelli, P., De Gaudio, A. R. & Adembri, C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit. Care 19, 26 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Adembri, C. et al. Sepsis induces albuminuria and alterations in the glomerular filtration barrier- a morphofunctional study in the rat. Crit. Care 15, R277 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chappell, D. et al. Protection of glycocalyx decreases platelet adhesion after ischaemia/reperfusion: an animal study. Eur. J. Anaesthesiol 31, 474–481 (2014).

    Article  PubMed  CAS  Google Scholar 

  27. Chappell, D. et al. Antithrombin reduces shedding of the endothelial glycocalyx following ischaemia/reperfusion. Cardiovasc. Res. 83, 388–396 (2009).

    Article  PubMed  CAS  Google Scholar 

  28. Chappell, D. et al. Sevoflurane reduces leukocyte and platelet adhesion after ischemia-reperfusion by protecting the endothelial glycocalyx. Anesthesiology 115, 482–491 (2011).

    Article  CAS  Google Scholar 

  29. Rex, S. & Freedman, J. E. in Platelets Second Edition (ed. Michelson, A.) 251–267 (Elsevier, 2006).

  30. Noiri, E., Peresleni, T., Miller, F. & Goligorsky, M. S. In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J. Clin. Invest. 97, 2377–2383 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Goligorsky, M. S., Brodsky, S. V. & Noiri, E. Nitric oxide in acute renal failure: NOS versus NOS. Kidney Int. 61, 855–861 (2002).

    Article  PubMed  CAS  Google Scholar 

  32. Horn, P. et al. Circulating microparticles carry a functional endothelial nitric oxide synthase that is decreased in patients with endothelial dysfunction. J. Am. Heart Assoc. 2, e003764 (2012).

    PubMed  Google Scholar 

  33. Yamasowa, H., Shimizu, S., Inoue, T., Takaoka, M. & Matsumura, Y. Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning. J. Pharmacol. Exp. Ther. 312, 153–159 (2005).

    Article  PubMed  CAS  Google Scholar 

  34. Piepot, H. A., Boer, C., Groeneveld, A. B., Van Lambalgen, A. A. & Sipkema, P. Lipopolysaccharide impairs endothelial nitric oxide synthesis in rat renal arteries. Kidney Int. 57, 2502–2510 (2000).

    Article  PubMed  CAS  Google Scholar 

  35. Wang, W. et al. Endothelial nitric oxide synthase-deficient mice exhibit increased susceptibility to endotoxin-induced acute renal failure. Am. J. Physiol. Renal Physiol. 287, F1044–F1048 (2004).

    Article  PubMed  CAS  Google Scholar 

  36. Kwon, O., Hong, S. M. & Ramesh, G. Diminished NO generation by injured endothelium and loss of macula densa nNOS may contribute to sustained acute kidney injury after ischemia-reperfusion. Am. J. Physiol. Renal Physiol. 296, F25–F33 (2009).

    Article  PubMed  CAS  Google Scholar 

  37. Kawabe, J., Ushikubi, F. & Hasebe, N. Prostacyclin in vascular diseases. Circ. J. 74, 836–843 (2010).

    Article  PubMed  CAS  Google Scholar 

  38. Bonventre, J. V. & Nemenoff, R. Renal tubular arachidonic acid metabolism. Kidney Int. 39, 438–449 (1991).

    Article  PubMed  CAS  Google Scholar 

  39. Yokoyama, C. et al. Prostacyclin-deficient mice develop ischemic renal disorders, including nephrosclerosis and renal infarction. Circulation 106, 2397–2403 (2002).

    Article  PubMed  CAS  Google Scholar 

  40. Wang, W. et al. Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice. Am. J. Physiol. Renal Physiol. 293, F1131–F1136 (2007).

    Article  PubMed  CAS  Google Scholar 

  41. Eltzschig, H. K. et al. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J. Exp. Med. 198, 783–796 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Paul, S., Feoktistov, I., Hollister, A. S., Robertson, D. & Biaggioni, I. Adenosine inhibits the rise in intracellular calcium and platelet aggregation produced by thrombin: evidence that both effects are coupled to adenylate cyclase. Mol. Pharmacol. 37, 870–875 (1990).

    PubMed  CAS  Google Scholar 

  43. Koziak, K., Sévigny, J., Robson, S. C., Siegel, J. B. & Kaczmarek, E. Analysis of CD39/ATP diphosphohydrolase (ATPDase) expression in endothelial cells, platelets and leukocytes. Thromb. Haemost. 82, 1583–1544 (1999).

    Article  Google Scholar 

  44. Candinas, D. et al. Loss of rat glomerular ATP diphosphohydrolase activity during reperfusion injury is associated with oxidative stress reactions. Thromb. Haemost. 76, 807–812 (1996).

    Article  PubMed  CAS  Google Scholar 

  45. Takahashi-Sato, K., Murakawa, M., Kimura, J., Ito, M. A. & Matsuoka, I. Loss of ectonucleotidases from the coronary vascular bed after ischemia-reperfusion in isolated rat heart. BMC Cardiovasc. Disord. 13, 53 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Robson, S. C. et al. Loss of ATP diphosphohydrolase activity with endothelial cell activation. J. Exp. Med. 185, 153–164 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kohler, D. et al. CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 116, 1784–1794 (2007).

    Article  PubMed  CAS  Google Scholar 

  48. Sun, X. et al. Liver damage and systemic inflammatory responses are exacerbated by the genetic deletion of CD39 in total hepatic ischemia. Purinergic Signal. 7, 427–434 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Guckelberger, O. et al. Beneficial effects of CD39/ecto-nucleoside triphosphate diphosphohydrolase-1 in murine intestinal ischemia-reperfusion injury. Thromb. Haemost. 91, 576–586 (2004).

    PubMed  CAS  Google Scholar 

  50. Grenz, A. et al. Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury. FASEB J. 21, 2863–2873 (2007).

    Article  PubMed  CAS  Google Scholar 

  51. Crikis, S. et al. Transgenic overexpression of CD39 protects against renal ischemia-reperfusion and transplant vascular injury. Am. J. Transplant 10, 2586–2595 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Sutton, T. A., Fisher, C. J. & Molitoris, B. A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int. 62, 1539–1549 (2002).

    Article  PubMed  CAS  Google Scholar 

  53. Basile, D. P. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 72, 151–156 (2007).

    Article  PubMed  CAS  Google Scholar 

  54. Vischer, U. M., Jornot, L., Wollheim, C. B. & Theler, J. M. Reactive oxygen intermediates induce regulated secretion of von willebrand factor from cultured human vascular endothelial cells. Blood 85, 3164–3172 (1995).

    PubMed  CAS  Google Scholar 

  55. Hechler, B. et al. Arterial thrombosis: relevance of a model with two levels of severity assessed by histologic, ultrastructural and functional characterization. J. Thromb. Haemost. 8, 173–184 (2010).

    Article  PubMed  CAS  Google Scholar 

  56. Miller, D. L., Yaron, R. & Yellin, M. J. CD40L-CD40 interactions regulate endothelial cell surface tissue factor and thrombomodulin expression. J. Leukoc. Biol. 63, 373–379 (1998).

    Article  PubMed  CAS  Google Scholar 

  57. Szotowski, B., Antoniak, S., Poller, W., Schultheiss, H. P. & Rauch, U. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circ. Res. 96, 1233–1239 (2005).

    Article  PubMed  CAS  Google Scholar 

  58. Andrews, R. K., Berndt, M. C. & Lopez, J. A. in Platelets Second Edition (ed. Michelson, A.) 145–163 (Elsevier, 2006).

  59. Kim, M. G. et al. The ADAMTS13-von Willebrand factor axis is involved in the pathophysiology of kidney ischemia-reperfusion injury. Nephrology 22, 913–920 (2016).

    Article  CAS  Google Scholar 

  60. Litvinov, R. I., Farrell, D. H., Weisel, J. W. & Bennett, J. S. The platelet integrin alphaIIbbeta3 differentially interacts with fibrin versus fibrinogen. J. Biol. Chem. 291, 7858–7867 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Alshehri, O. M. et al. Fibrin activates GPVI in human and mouse platelets. Blood 126, 1601–1608 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Mangin, P. H. et al. Immobilized fibrinogen activates human platelets through GPVI. Haematologica https://doi.org/10.3324/haematol.2017.182972 (2018).

  63. Kahn, M. L., Nakanishi-Matsui, M., Shapiro, M. J., Ishihara, H. & Coughlin, S. R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest. 103, 879–887 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ushigome, H. et al. The role of tissue factor in renal ischemic reperfusion injury of the rat. Journal of surgical research 102, 102–109 (2002).

    Article  PubMed  CAS  Google Scholar 

  65. Erlich, J., Fearns, C., Mathison, J., Ulevitch, R. J. & Mackman, N. Lipopolysaccharide induction of tissue factor expression in rabbits. Infect. Immun. 67, 2540–2546 (1999).

    PubMed  PubMed Central  CAS  Google Scholar 

  66. Sevastos, J. et al. Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood 109, 577–583 (2007).

    Article  PubMed  CAS  Google Scholar 

  67. Welty-Wolf, K. E. et al. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. Am. J. Respir. Crit. Care Med. 10, 1988–1996 (2001).

    Article  Google Scholar 

  68. Scrascia, G. et al. Acute kidney injury in high-risk cardiac surgery patients: roles of inflammation and coagulation. J. Cardiovasc. Med. 18, 359–365 (2015).

    Article  Google Scholar 

  69. Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Tsuji, N. et al. Role of mitochondrial DNA in septic AKI via toll-like receptor 9. J. Am. Soc. Nephrol. 27, 2009–2020 (2016).

    Article  PubMed  CAS  Google Scholar 

  71. Zakiyanov, O. et al. Placental growth factor, pregnancy-associated plasma protein-A, soluble receptor for advanced glycation end products, extracellular newly identified receptor for receptor for advanced glycation end products binding protein and high mobility group box 1 levels in patients with acute kidney injury: a cross sectional study. BMC Nephrol. 14, 245 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Boudreau, L. H. et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood 124, 2173–2183 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Beutler, B. A. TLRs and innate immunity. Blood 113, 1399–1407 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Aslam, R. et al. Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 107, 637–641 (2006).

    Article  PubMed  CAS  Google Scholar 

  75. Andonegui, G. et al. Platelets express functional Toll-like receptor-4. Blood 106, 2417–2423 (2005).

    Article  PubMed  CAS  Google Scholar 

  76. Zhang, G. et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J. Immunol. 182, 7997–8004 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Thurman, J. M., Lucia, M. S., Ljubanovic, D. & Holers, V. M. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int. 67, 524–530 (2005).

    Article  PubMed  CAS  Google Scholar 

  78. Ricklin, D., Reis, E. S. & Lambris, J. D. Complement in disease: a defence system turning offensive. Nat. Rev. Nephrol. 12, 383–401 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Ricklin, D., Mastellos, D. C., Reis, E. S. & Lambris, J. D. The renaissance of complement therapeutics. Nat Rev Nephrol. 1, 26–47 (2018).

    Google Scholar 

  80. Hajishengallis, G., Reis, E. S., Mastellos, D. C., Ricklin, D. & Lambris, J. D. Novel mechanisms and functions of complement. Nat. Immunol. 18, 1288–1298 (2017).

    Article  PubMed  CAS  Google Scholar 

  81. Verschoor, A. & Langer, H. F. Crosstalk between platelets and the complement system in immune protection and disease. Thromb. Haemost. 110, 910–919 (2013).

    Article  PubMed  CAS  Google Scholar 

  82. Cosgrove, L. J., d’Apice, A. J., Haddad, A., Pedersen, J. & McKenzie, I. F. CR3 receptor on platelets and its role in the prostaglandin metabolic pathway. Immunol. Cell Biol. 65, 453–460 (1987).

    Article  PubMed  CAS  Google Scholar 

  83. Martel, C. et al. Requirements for membrane attack complex formation and anaphylatoxins binding to collagen-activated platelets. PLoS ONE 6, e18812 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Peerschke, E. I. & Ghebrehiwet, B. Platelet receptors for the complement component C1q: implications for hemostasis and thrombosis. Immunobiology 199, 239–249 (1998).

    Article  PubMed  CAS  Google Scholar 

  85. Peerschke, E. I. & Ghebrehiwet, B. Human blood platelets possess specific binding sites for C1q. J. Immunol. 138, 1537–1541 (1987).

    PubMed  CAS  Google Scholar 

  86. Peerschke, E. I. & Ghebrehiwet, B. Platelet membrane receptors for the complement component C1q. Semin. Hematol. 31, 320–328 (1994).

    PubMed  CAS  Google Scholar 

  87. Ando, B., Wiedmer, T., Hamilton, K. K. & Sims, P. J. Complement proteins C5b-9 initiate secretion of platelet storage granules without increased binding of fibrinogen or von Willebrand factor to newly expressed cell surface GPIIb-IIIa. J. Biol. Chem. 263, 11907–11914 (1988).

    PubMed  CAS  Google Scholar 

  88. Wiedmer, T., Esmon, C. T. & Sims, P. J. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood 68, 875–880 (1986).

    PubMed  CAS  Google Scholar 

  89. Yamamoto, T. et al. Intravital videomicroscopy of peritubular capillaries in renal ischemia. Am. J. Physiol. Renal Physiol. 282, F1105–1105 (2002).

    Article  Google Scholar 

  90. Stokes, K. Y. & Granger, D. N. Platelets: a critical link between inflammation and microvascular dysfunction. J. Physiol. 590, 1023–1034 (2012).

    Article  PubMed  CAS  Google Scholar 

  91. Möhle, R., Green, D., Moore, M. A., Nachman, R. L. & Rafii, S. Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc. Natl Acad. Sci. USA 94, 663–668 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Knezevic, I. I. et al. Tiam1 and Rac1 are required for platelet-activating factor-induced endothelial junctional disassembly and increase in vascular permeability. J. Biol. Chem. 284, 5381–5394 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Cloutier, N. et al. Platelets can enhance vascular permeability. Blood 120, 1334–1343 (2012).

    Article  PubMed  CAS  Google Scholar 

  94. Sutton, T. A. et al. Injury of the renal microvascular endothelium alters barrier function after ischemia. Am. J. Physiol. Renal Physiol. 285, F191–198 (2003).

    Article  PubMed  CAS  Google Scholar 

  95. Mariano, F. et al. Production of platelet-activating factor in patients with sepsis-associated acute renal failure. Nephrol. Dial. Transplant. 14, 1150–1157 (1999).

    Article  PubMed  CAS  Google Scholar 

  96. Mercado, C. P. & Kilic, F. The molecular mechanism of SERT in platelets: regulation of plasma serotonin levels. Mol. Interv. 10, 231–241 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Li, Y. et al. Sepsis-induced elevation in plasma serotonin facilitates endothelial hyperpermeability. Sci. Rep. 6, 22747 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Löwenberg, E. C., Meijers, J. C. M. & Levi, M. Platelet-vessel wall interaction in health and disease. J. Med. 68, 242–251 (2010).

    Google Scholar 

  99. Slupsky, J. R. et al. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb. Haemost. 6, 1008–1014 (1998).

    Google Scholar 

  100. Muller, F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139, 1143–1156 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Ruiz, F. A., Lea, C. R., Oldfield, E. & Docampo, R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J. Biol. Chem. 279, 44250–44257 (2004).

    Article  PubMed  CAS  Google Scholar 

  102. Hou, Y. et al. Platelets in hemostasis and thrombosis: novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J. Biomed. Res. 29, 437–444 (2015).

    PubMed Central  Google Scholar 

  103. Bevers, E. M., Comfurius, P., van Rijn, J. L., Hemker, H. C. & Zwaal, R. F. Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur. J. Biochem. 122, 429–436 (1982).

    Article  PubMed  CAS  Google Scholar 

  104. Wu, H. et al. HMGB1 contributes to kidney ischemia reperfusion injury. J. Am. Soc. Nephrol. 21, 1878–1890 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Bonventre, J. V. & Yang, L. Cellular pathophysiology of ischemic acute kidney injury. J. Clin. Invest. 121, 4210–4221 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Zuchtriegel, G. et al. Platelets guide leukocytes to their sites of extravasation. PLoS Biol. 14, e1002459 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Massberg, S. et al. Platelet-endothelial cell interactions during ischemia reperfusion, the role of P-selectin. Blood 92, 507–515 (1998).

    PubMed  CAS  Google Scholar 

  108. Massberg, S. et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood 94, 3829–3838 (1999).

    PubMed  CAS  Google Scholar 

  109. Semple, J. W., Italiano, J. E. Jr & & Freedman, J. Platelets and the immune continuum. Nat. Rev. Immunol. 11, 264–274 (2011).

    Article  PubMed  CAS  Google Scholar 

  110. Gleissner, C. A., von Hundelshausen, P. & Ley, K. Platelet chemokines in vascular disease. Arterioscler Thromb. Vasc. Biol. 11, 1920–1927 (2008).

    Article  CAS  Google Scholar 

  111. Inwald, D. P., McDowall, A., Peters, M. J., Callard, R. E. & Klein, N. J. CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation. Circ. Res. 92, 1041–1048 (2003).

    Article  PubMed  CAS  Google Scholar 

  112. Chakrabarti, S., Varghese, S., Vitseva, O., Tanriverdi, K. & Freedman, J. E. CD40 ligand influences platelet release of reactive oxygen intermediates. Arterioscler Thromb. Vasc. Biol. 25, 2428–2434 (2005).

    Article  PubMed  CAS  Google Scholar 

  113. Henn, V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391, 591–594 (1998).

    Article  PubMed  CAS  Google Scholar 

  114. Nagasawa, M. et al. Analysis of serum soluble CD40 ligand (sCD40L) in the patients undergoing allogeneic stem cell transplantation: platelet is a major source of serum sCD40L. Eur. J. Haematol. 74, 54–60 (2004).

    Article  Google Scholar 

  115. de Ramon, L. et al. CD154-CD40 T cell co-stimulation pathway is a key mechanism in kidney ischemia-reperfusion injury. Kidney Int. 88, 538–549 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Lapchak, P. H. et al. Platelet-associated CD40/CD154 mediates remote tissue damage after mesenteric ischemia/reperfusion injury. PLoS ONE 7, e32260 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Gawaz, M. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 148, 75–85 (2000).

    Article  PubMed  CAS  Google Scholar 

  118. Lindemann, S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J. Cell Biol. 154, 485–490 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Grommes, J. et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am. J. Respir. Crit. Care Med. 185, 628–636 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Thurman, J. M., Ljubanovic, D., Edelstein, C. L., Gilkeson, G. S. & Holers, V. M. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J. Immunol. 170, 1517–1523 (2003).

    Article  PubMed  CAS  Google Scholar 

  121. Mulligan, M. S. et al. C5a-dependent up-regulation in vivo of lung vascular P-selectin. J. Immunol. 158, 1857–1861 (1997).

    PubMed  CAS  Google Scholar 

  122. Del Conde, I., Crúz, M. A., Zhang, H., López, J. A. & Afshar-Kharghan, V. Platelet activation leads to activation and propagation of the complement system. J. Exp. Med. 201, 871–879 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Ekdahl, K. N. & Nilsson, B. Phosphorylation of complement component C3 and C3 fragments by a human platelet protein kinase. Inhibition of factor I-mediated cleavage of C3b. J. Immunol. 154, 6502–6510 (1995).

    PubMed  CAS  Google Scholar 

  124. Ekdahl, K. N. & Nilsson, B. Alterations in C3 activation and binding caused by phosphorylation by a casein kinase released from activated human platelets. J. Immunol. 162, 7426–7433 (1999).

    PubMed  CAS  Google Scholar 

  125. Lapchak, P. H. et al. Platelets orchestrate remote tissue damage after mesenteric ischemia-reperfusion. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G888–G897 (2012).

    Article  PubMed  CAS  Google Scholar 

  126. Chintala, M. S., Bernardino, V. & Chiu, P. J. Cyclic GMP but not cyclic AMP prevents renal platelet accumulation after ischemia-reperfusion in anesthetized rats. J. Pharmacol. Exp. Ther. 271, 1203–1208 (1995).

    Google Scholar 

  127. Ed Rainger, G. et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets 26, 507–520 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Kelly, K. J. et al. Intercellular adhesion molecule-1–deficient mice are protected against ischemic renal injury. J. Clin. Invest. 97, 1056–1063 (1996).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Day, Y. J., Huang, L., Ye, H., Linden, J. & Okusa, M. D. Renal ischemia-reperfusion injury and adenosine 2A receptor-mediated tissue protection: role of macrophages. Am. J. Physiol. Renal Physiol. 288, F722–F731 (2005).

    Article  PubMed  CAS  Google Scholar 

  130. Kuckleburg, C. J. et al. Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation. Cardiovasc. Res. 91, 134–141 (2011).

    Article  PubMed  CAS  Google Scholar 

  131. Slaba, I. et al. Imaging the dynamic platelet-neutrophil response in sterile liver injury and repair in mice. Hepatology 62, 1593–1605 (2015).

    Article  PubMed  CAS  Google Scholar 

  132. Salter, J. W., Krieglstein, C. F., Issekutz, A. C. & Granger, D. N. Platelets modulate ischemia:reperfusion-induced leukocyte recruitment in the mesenteric circulation. Am. J. Physiol. Gastrointest. Liver Physiol. 28, G1432–1439 (2001).

    Article  Google Scholar 

  133. Zarbock, A., Singbartl, K. & Ley, K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J. Clin. Invest. 116, 3211–3219 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Schwarzenberger, C. et al. Platelets are relevant mediators of renal injury induced by primary endothelial lesions. Am. J. Physiol. Renal Physiol. 308, F1238–F1246 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Page, C. & Pitchford, S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int. Immunopharmacol. 17, 1176–1184 (2013).

    Article  PubMed  CAS  Google Scholar 

  136. Weber, C. & Springer, T. A. Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to IIb 3 and stimulated by platelet-activating factor. J. Clin. Invest. 100, 2085–2093 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Fernandes, L. S. et al. Platelet–monocyte complex formation: effect of blocking PSGL-1 alone, and in combination with αIIbβ3 and αMβ2, in coronary stenting. Thromb. Res. 111, 171–177 (2003).

    Article  PubMed  CAS  Google Scholar 

  138. Simon, D. I. et al. Platelet glycoprotein Ib is a counterreceptor for the leukocyte integrin Mac-1 (CD11b:CD18). J. Exp. Med. 192, 193–204 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Chen, C. et al. Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property. Brain Behav. Immun. 1591, 30520–30522 (2017).

    Google Scholar 

  140. Herter, J. M., Rossaint, J., Spieker, T. & Zarbock, A. Adhesion molecules involved in neutrophil recruitment during sepsis-induced acute kidney injury. J. Innate Immun. 6, 597–606 (2014).

    Article  PubMed  CAS  Google Scholar 

  141. Gerdes, N. et al. Platelet CD40 exacerbates atherosclerosis by transcellular activation of endothelial cells and leukocytes. Arterioscler Thromb. Vasc. Biol. 36, 482–490 (2016).

    Article  PubMed  CAS  Google Scholar 

  142. Lax, S. et al. Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse. Am. J. Physiol. Lung Cell. Mol. Physiol. 313, L1016–L1029 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Rainger, G. E., Buckley, C. D., Simmons, D. L. & Nash, G. B. Neutrophils sense flow-generated stress and direct their migration through alphaVbeta3-integrin. Am. J. Physiol. 276, H858–H864 (1999).

    PubMed  CAS  Google Scholar 

  144. Rainger, G. E., Buckley, C., Simmons, D. L. & Nash, G. B. Cross-talk between cell adhesion molecules regulates the migration velocity of neutrophils. Curr. Biol. 7, 316–325 (1997).

    Article  PubMed  CAS  Google Scholar 

  145. Suzuki, J. et al. Cytokine secretion from human monocytes potentiated by P-selectin-mediated cell adhesion. Int. Arch. Allergy Immunol. 160, 152–160 (2013).

    Article  PubMed  CAS  Google Scholar 

  146. Maugeri, N. et al. Polymorphonuclear leukocyte-platelet interaction: role of P-selectin in thromboxane B2 and leukotriene C4 cooperative synthesis. Thromb. Haemost. 72, 450–456 (1994).

    Article  PubMed  CAS  Google Scholar 

  147. Lammermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).

    Article  PubMed  CAS  Google Scholar 

  148. Deng, B. et al. The leukotriene B4–leukotriene B4 receptor axis promotes cisplatin-induced acute kidney injury by modulating neutrophil recruitment. Kidney Int. 92, 89–100 (2017).

    Article  PubMed  CAS  Google Scholar 

  149. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  PubMed  CAS  Google Scholar 

  150. Chow, O. A. et al. Statins enhance formation of phagocyte extracellular traps. Cell Host Microbe 8, 445–454 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Kumar, S. V. et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J. Am. Soc. Nephrol. 26, 2399–2413 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Thomas, G. M. et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119, 6335–6343 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Oklu, R., Albadawi, H., Jones, J. E., Yoo, H. J. & Watkins, M. T. Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps. J. Vasc. Surg. 58, 1627–1636 (2013).

    Article  PubMed  Google Scholar 

  154. de Boer, O. J. et al. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb. Haemost. 109, 290–297 (2013).

    Article  PubMed  CAS  Google Scholar 

  155. Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Carestia, A. et al. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J. Leukoc. Biol. 99, 153–162 (2016).

    Article  PubMed  CAS  Google Scholar 

  157. Etulain, J. et al. P-Selectin promotes neutrophil extracellular trap formation in mice. Blood 126, 242–246 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Maugeri, N. et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J. Thromb. Haemost. 12, 2074–2088 (2014).

    Article  PubMed  CAS  Google Scholar 

  160. Rossaint, J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 123, 2573–2584 (2014).

    Article  PubMed  CAS  Google Scholar 

  161. Whitaker, R. M. et al. Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury. Kidney Int. 88, 1336–1344 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Jansen, M. P. B. et al. Mitochondrial DNA is released in urine of Sirs patients with acute kidney injury and correlates with severity of renal dysfunction. Shock (2017).

  163. Okubo, K. et al. Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury. Nat. Med. 24, 232–238 (2018).

    Article  PubMed  CAS  Google Scholar 

  164. Agah, R., Plow, E. F. & Topol, E. J. in Platelets Second Edition (ed. Michelson, A.) 1145–1163 (Elsevier, 2006).

  165. Taylor, F. B. et al. 7E3 F(ab’)2, a monoclonal antibody to the platelet GPIIb/IIIa receptor, protects against microangiopathic hemolytic anemia and microvascular thrombotic renal failure in baboons treated with C4b binding protein and a sublethal infusion of Escherichia coli. Blood 89, 4078–4084 (1997).

    PubMed  CAS  Google Scholar 

  166. Guan, W. et al. Protective effects of tirofiban on ischemia/reperfusion-induced renal injury in vivo and in vitro. Eur. J. Pharmacol. 761, 144–152 (2015).

    Article  PubMed  CAS  Google Scholar 

  167. Cattaneo, M. in Platelets Second Edition (ed. Michelson, A.) 1127–1144 (Elsevier, 2006).

  168. Mederle, K., Meurer, M., Castrop, H. & Höcherl, K. Inhibition of COX-1 attenuates the formation of thromboxane A2and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice. Am. J. Physiol. Renal Physiol. 309, F332–F340 (2015).

    Article  PubMed  CAS  Google Scholar 

  169. Ikeda, Y., Sudo, T. & Kimura, Y. in Platelets Second Edition (ed. Michelson, A.) 1181–1191 (Elsevier, 2006).

  170. Ragab, D., Abdallah, D. M. & El-Abhar, H. S. Cilostazol renoprotective effect: modulation of PPAR-gamma, NGAL, KIM-1 and IL-18 underlies its novel effect in a model of ischemia-reperfusion. PLoS ONE 9, e95313 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Abdelrahman, M., Sivarajah, A. & Thiemermann, C. Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock. Cardiovasc. Res. 65, 772–781 (2005).

    Article  PubMed  CAS  Google Scholar 

  172. Bischoff, A., Bucher, M., Gekle, M. & Sauvant, C. Differential effect of COX1 and COX2 inhibitors on renal outcomes following ischemic acute kidney injury. Am. J. Nephrol. 40, 1–11 (2014).

    Article  PubMed  CAS  Google Scholar 

  173. Badr, K. F., Kelley, V. E., Rennke, H. G. & Brenner, B. M. Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure. Kidney Int. 30, 74–480 (1986).

    Article  Google Scholar 

  174. Awrty, E. A. & Loscalzo, J. in Platelets Second Edition (ed. Michelson, A.) 1099–1125 (Elsevier, 2006).

  175. Mangano, D. T. et al. Aspirin and mortality from coronary bypass surgery. N Engl. J. Med. 347, 1309–1317 (2002).

    Article  PubMed  CAS  Google Scholar 

  176. Cao, L., Silvestry, S., Zhao, N., Diehl, J. & Sun, J. Effects of preoperative aspirin on cardiocerebral and renal complications in non-emergent cardiac surgery patients: a sub-group and cohort study. PLoS ONE 7, e30094 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Hur, M. et al. Preoperative aspirin use and acute kidney injury after cardiac surgery: a propensity-score matched observational study. PLoS ONE 12, e0177201 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Garg, A. X. et al. Perioperative aspirin and clonidine and risk of acute kidney injury: a randomized clinical trial. JAMA 312, 2254–2264 (2014).

    Article  PubMed  CAS  Google Scholar 

  179. Devereaux, P. J. et al. Aspirin in patients undergoing noncardiac surgery. N. Engl. J. Med. 370, 1494–1503 (2014).

    Article  PubMed  CAS  Google Scholar 

  180. Karrowni, W. et al. Blood transfusion and the risk of acute kidney injury among patients with acute coronary syndrome undergoing percutaneous coronary intervention. Circ. Cardiovasc. Interv. 9, e003279 (2016).

    Article  PubMed  Google Scholar 

  181. Karkouti, K. Transfusion and risk of acute kidney injury in cardiac surgery. Br. J. Anaesth. 109 (Suppl. 1), i29–i38 (2012).

    Article  PubMed  Google Scholar 

  182. Stenberg, P. E., McEver, R. P., Shuman, M. A., Jacques, Y. V. & Bainton, D. F. A. Platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation J. Cell Biol. 101, 880–886 (1985).

    Article  PubMed  CAS  Google Scholar 

  183. Zizzi, H. C. et al. Quantification of P-selectin expression after renal ischemia and reperfusion. J. Pediatr. Surg. 32, 1010–1013 (1997).

    Article  PubMed  CAS  Google Scholar 

  184. Johnston, G. I., Cook, R. G. & McEver, R. P. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation. Cell 56, 1033–1044 (1989).

    Article  PubMed  CAS  Google Scholar 

  185. Singbartl, K., Green, S. A. & Ley, K. Blocking P-selectin protects from ischemia reperfusion. Faseb J. 14, 48–54 (2000).

    Article  PubMed  CAS  Google Scholar 

  186. Singbartl, K., Forlow, S. B. & Ley, K. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure. FASEB J. 15, 2337–2344 (2001).

    Article  PubMed  CAS  Google Scholar 

  187. Linden, M. D. & Furman, M. I. in Cardiovascular Biomarkers Pathophysiology and Disease Management (ed. Morrow, G. A.), 487–493 (Humana Press, 2005).

  188. McEver, R. P. in Platelets Second Edition (ed. Michelson, A.) 231–249 (Elsevier, 2006).

  189. Koo, D. D., Welsh, K. I., Roake, J. A., Morris, P. J. & Fuggle, S. V. Ischemia/reperfusion injury in human kidney transplantation: an immunhistochemical analysis of changes after reperfusion. Am. J. Pathol. 153, 557–566 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Patrono, C. Biosynthesis and pharmacological modulation of thromboxane in humans. Circulation 81, 12–15; discussion 122–123 (1990).

    Google Scholar 

  191. Lopez, L. R. et al. Platelet thromboxane (11-dehydro-Thromboxane B2) and aspirin response in patients with diabetes and coronary artery disease. World J. Diabetes 5, 115–127 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Klausner, J. M. et al. Vasodilating prostaglandins attenuate ischemic renal injury only if thromboxane is inhibited. Ann. Surg. 209, 219–224 (1989).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. Ujike-Omori, H. et al. The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study. Clin. Exp. Nephrol. 19, 1024–1036 (2015).

    Article  PubMed  CAS  Google Scholar 

  194. Aukrust, P. et al. Elevated Circulating Levels of C-C chemokines in patients with congestive heart failure. Circulation 97, 1136–1143 (1998).

    Article  PubMed  CAS  Google Scholar 

  195. Yu, T. M. et al. RANTES mediates kidney ischemia reperfusion injury through a possible role of HIF-1alpha and LncRNA PRINS. Sci. Rep. 6, 18424 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Levine, S. P. & Wohl, H. Human platelet factor 4: purification and characterization by affinity chromatography. Purification of human platelet factor. J. Biol. Chem. 251, 324–328 (1976).

    PubMed  CAS  Google Scholar 

  197. Kowalska, M. A., Rauova, L. & Poncz, M. Role of the platelet chemokine platelet factor 4 (PF4) in hemostasis and thrombosis. Thromb. Res. 4, 292–296 (2010).

    Article  CAS  Google Scholar 

  198. Lapchak, P. H. et al. The role of platelet factor 4 in local and remote tissue damage in a mouse model of mesenteric ischemia/reperfusion injury. PLoS ONE 7, e39934 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

J.J.T.H.R. is supported by The Netherlands Organisation for Health Research and Development (Clinical Fellowship grant #40-00703-97-12480) and by the Dutch Kidney Foundation (grant #KJP10.017).

Reviewer information

Nature Reviews Nephrology thanks B. Kerlin, A. Zarbock and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands

    Marcel P. B. Jansen, Sandrine Florquin & Joris J. T. H. Roelofs

Authors
  1. Marcel P. B. Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandrine Florquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joris J. T. H. Roelofs
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.P.B.J. researched data for the article and wrote the manuscript. M.P.B.J. and J.J.T.H.R. substantially contributed to the discussion of the content. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Joris J. T. H. Roelofs.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Thrombin

A serine protease that plays a key part in the coagulation cascade. Thrombin is generated from prothrombin by proteolytic cleavage that is mediated by blood coagulation factor X. This activation also releases prothrombin fragment 1.2, which can be used clinically as a coagulation marker.

α-Granules

The most abundant storage platelet granules (50–80 granules per platelet) containing membrane-bound proteins such as P-selectin and soluble proteins such as platelet factor 4 (PF4) that are either expressed on the platelet surface or released into the extracellular space following platelet activation.

Glycocalyx

A layer of proteoglycans that line the luminal endothelial surface, providing a physical barrier that prevents the adhesion and subsequent activation of platelets by endothelial components.

Prostacyclin

(PGI2). A prostaglandin member of the eicosanoid family of lipid molecules that is released from the endothelium. PGI2 release inhibits platelet activation and has a role in the maintenance of a nonthrombotic barrier between the vessel wall and the blood. PGI2 is also an effective vasodilator.

Ectonucleoside triphosphate diphosphohydrolase 1

(NTPDase 1). A membrane-anchored glycoprotein with ecto-apyrase activity that rapidly hydrolyses ATP and ADP into AMP.

Weibel–Palade bodies

Endothelial-specific secretory granules that contain a variety of bioactive molecules that play a part in inflammation and haemostasis and are released by exocytosis upon endothelial activation.

Extrinsic coagulation pathway

A branch of the coagulation pathway that begins with initiation of the coagulation cascade in response to tissue factor exposure (for example, as a result of tissue injury), leading to thrombin generation.

Danger-associated molecular patterns

(DAMPs). Molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response.

Opsonization

A process in which particles (such as bacteria) are marked for immune cell destruction through phagocytosis.

Haemoconcentration

A decrease in plasma volume that causes an increase in the concentration of circulating blood cells. Haemoconcentration facilitates the inflammatory process by allowing increased endothelial cell–leukocyte contact.

Caecal ligation and puncture

A method used in animal models to induce polymicrobial sepsis for studying the progression and characteristics of human sepsis.

Chimeric mice

Mice composed of cells with distinct genotypes.

Intravital imaging

A form of microscopy that allows the capture of images of biological processes in vivo at a high resolution.

Leukotrienes

A family of eicosanoid inflammatory mediators (such as leukotriene B4) that are produced in leukocytes by oxidation of arachidonic acid and the essential fatty acid eicosapentaenoic acid by the enzyme arachidonate 5-lipoxygenase.

Systemic inflammatory response syndrome

(SIRS). An excessive immune response triggered by a non-infectious agent as a result of trauma, burn or acute pancreatitis.

Reactive oxygen species

(ROS). Highly reactive chemical species containing oxygen, which have important roles in processes such as cell signalling, homeostasis and defence against pathogens.

Histone citrullination

An epigenetic post-translational modification in which arginine is converted to citrulline on histones, thereby affecting chromatin structure.

Phosphodiesterase inhibitors

A class of platelet activation inhibitors that interfere with the breakdown of intracellular cyclic nucleotides (cGMP and cAMP) by reversible binding to phosphodiesterases, thereby increasing their concentration.

Thienopyridines

A class of small-molecule inhibitors that irreversibly bind to the ADP-binding pocket of P2Y purinoreceptor 12 (P2Y12) on platelets.

Thrombotic microangiopathy

A pathology that results in thrombosis in capillaries and arterioles owing to an endothelial injury.

Prostanoid

A type of biologically active lipid that forms a subclass of the eicosanoid family. Prostanoids are formed from the metabolism of arachidonic acid by the action of cyclooxygenase (COX) enzymes and include prostaglandin E2 (PGE2), thromboxanes (such as thromboxane A2 (TxA2)), prostacyclin (PGI2), prostaglandin F2A (PGF2A) and prostaglandin D2 (PGD2), each of which is involved in some aspect of the inflammatory response.

Propensity score

A statistical matching technique that attempts to estimate the effect of an intervention by accounting for the covariates that predict receiving the treatment.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jansen, M.P.B., Florquin, S. & Roelofs, J.J.T.H. The role of platelets in acute kidney injury. Nat Rev Nephrol 14, 457–471 (2018). https://doi.org/10.1038/s41581-018-0015-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-018-0015-5

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing