Thromb Haemost 2014; 112(04): 666-677
DOI: 10.1160/TH14-02-0126
Theme Issue Article
Schattauer GmbH

The role of platelets in sepsis

Sacha F. de Stoppelaar
1   Centre of Experimental and Molecular Medicine and the Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, the Netherlands
,
Cornelis van ’t Veer
1   Centre of Experimental and Molecular Medicine and the Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, the Netherlands
,
Tom van der Poll
1   Centre of Experimental and Molecular Medicine and the Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, the Netherlands
2   Division of Infectious Diseases, Academic Medical Centre, University of Amsterdam, the Netherlands
› Author Affiliations
Further Information

Publication History

Received: 12 February 2014

Accepted after major revision: 16 April 2014

Publication Date:
20 November 2017 (online)

Summary

Platelets are small circulating anucleate cells that are of crucial importance in haemostasis. Over the last decade, it has become increasingly clear that platelets play an important role in inflammation and can influence both innate and adaptive immunity. Sepsis is a potentially lethal condition caused by detrimental host response to an invading pathogen. Dysbalanced immune response and activation of the coagulation system during sepsis are fundamental events leading to sepsis complications and organ failure. Platelets, being major effector cells in both haemostasis and inflammation, are involved in sepsis pathogenesis and contribute to sepsis complications. Platelets catalyse the development of hyperinflammation, disseminated intravascular coagulation and microthrombosis, and subsequently contribute to multiple organ failure. Inappropriate accumulation and activity of platelets are key events in the development of sepsis-related complications such as acute lung injury and acute kidney injury. Platelet activation readouts could serve as biomarkers for early sepsis recognition; inhibition of platelets in septic patients seems like an important target for immune-modulating therapy and appears promising based on animal models and retrospective human studies.

 
  • References

  • 1 Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369: 840-851.
  • 2 Hotchkiss RS. et al. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013; 13: 260-268.
  • 3 Levi M, van der Poll T. Inflammation and coagulation. Crit Care Med 2010; 38 (02) Suppl S26-34.
  • 4 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.
  • 5 Semple JW. et al. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
  • 6 Schouten M. et al. Inflammation, endothelium, and coagulation in sepsis. J Leukocyte Biol 2008; 83: 536-545.
  • 7 Vieira-de-Abreu A. et al. Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 2012; 34: 5-30.
  • 8 Yeaman MR. Platelets in defense against bacterial pathogens. Cell Mol Life Sci 2010; 67: 525-544.
  • 9 Morrell CN. et al. Emerging roles for platelets as immune and inflammatory cells. Blood. 2014 Epub ahead of print.
  • 10 Gawaz M. et al. Platelet function in septic multiple organ dysfunction syndrome. Intensive Care Med 1997; 23: 379-385.
  • 11 Russwurm S. et al. Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock 2002; 17: 263-268.
  • 12 Sakamaki F. et al. Soluble form of P-selectin in plasma is elevated in acute lung injury. Am J Resp Crit Care Med 1995; 151: 1821-1826.
  • 13 Washington AV. et al. TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans. J Clin Invest 2009; 119: 1489-1501.
  • 14 de Stoppelaar SF. et al. Protease activated receptor 4 limits bacterial growth and lung pathology during late stage Streptococcus pneumoniae induced pneumonia in mice. Thromb Haemost 2013; 110: 582-592.
  • 15 Washington AV. et al. A TREM family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes and platelets. Blood 2004; 104: 1042-1047.
  • 16 Adamzik M. et al. Whole blood impedance aggregometry as a biomarker for the diagnosis and prognosis of severe sepsis. Crit Care 2012; 16: R204.
  • 17 Lundahl TH. et al. Impaired platelet function correlates with multi-organ dysfunction. A study of patients with sepsis. Platelets 1998; 9: 223-225.
  • 18 Yaguchi A. et al. Platelet function in sepsis. J Thromb Haemost 2004; 2: 2096-2102.
  • 19 Levi M, Schultz M. Coagulopathy and platelet disorders in critically ill patients. Minerva Anestesiol 2010; 76: 851-859.
  • 20 Akca S. et al. Time course of platelet counts in critically ill patients. Crit Care Med 2002; 30: 753-756.
  • 21 Moreau D. et al. Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest 2007; 131: 1735-1741.
  • 22 Katz JN. et al. Beyond thrombosis: the versatile platelet in critical illness. Chest 2011; 139: 658-668.
  • 23 De Blasi RA. et al. Immature platelet fraction in predicting sepsis in critically ill patients. Intensive Care Med 2012; 39: 636-643.
  • 24 Ogura H. et al. Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma 2001; 50: 801-809.
  • 25 Janiszewski M. et al. Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: A novel vascular redox pathway. Crit Care Med 2004; 32: 818-825.
  • 26 Thery C. et al. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002; 2: 569-579.
  • 27 Flaumenhaft R. et al. Megakaryocyte-derived microparticles: direct visualization and distinction from platelet-derived microparticles. Blood 2009; 113: 1112-1121.
  • 28 Reid VL, Webster NR. Role of microparticles in sepsis. Br J Anaesth 2012; 109: 503-513.
  • 29 Del Conde I. et al. Platelet activation leads to activation and propagation of the complement system. J Exp Med 2005; 201: 871-879.
  • 30 Azevedo LC. et al. Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care 2007; 11: R120.
  • 31 Kuckleburg CJ. et al. Endothelial cell apoptosis induced by bacteria-activated platelets requires caspase-8 and -9 and generation of reactive oxygen species. Thromb Haemost 2008; 99: 363-372.
  • 32 Burnier L. et al. Cell-derived microparticles in haemostasis and vascular medicine. Thromb Haemost 2009; 101: 439-451.
  • 33 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-264.
  • 34 Linden MD. Platelet physiology. Methods Mol Biol 2013; 992: 13-30.
  • 35 Markiewski MM. et al. Complexity of complement activation in sepsis. J Cell Mol Med 2008; 12: 2245-2254.
  • 36 Peerschke EI. et al. Platelet activation by C1q results in the induction of alpha IIb/beta 3 integrins (GPIIb-IIIa) and the expression of P-selectin and procoagulant activity. J Exp Med 1993; 178: 579-587.
  • 37 Arman M. et al. Amplification of bacteria-induced platelet activation is triggered by FcgammaRIIA, integrin alphaIIbbeta3 and platelet factor 4. Blood. 2014 Epub ahead of print.
  • 38 Cox D. et al. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost 2011; 9: 1097-1107.
  • 39 Kerrigan SW, Cox D. Platelet-bacterial interactions. Cellular and molecular life sciences : CMLS 2010; 67: 513-523.
  • 40 Panigrahi S. et al. Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circulation Res 2013; 112: 103-112.
  • 41 Andonegui G. et al. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417-2423.
  • 42 Shiraki R. et al. Expression of Toll-like receptors on human platelets. Thrombosis Res 2004; 113: 379-385.
  • 43 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
  • 44 Medzhitov R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell 1998; 2: 253-258.
  • 45 Semeraro F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118: 1952-1961.
  • 46 McDonald B. et al. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12: 324-333.
  • 47 Blair P. et al. Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circulation Res 2009; 104: 346-354.
  • 48 Keane C. et al. Invasive Streptococcus pneumoniae trigger platelet activation via Toll-like receptor 2. J Thromb Haemost 2010; 8: 2757-2765.
  • 49 Montrucchio G. et al. Mechanisms of the priming effect of low doses of lipopolysaccharides on leukocyte-dependent platelet aggregation in whole blood. Thromb Haemost 2003; 90: 872-881.
  • 50 Zhang G. et al. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol 2009; 182: 7997-8004.
  • 51 Coppinger JA, Maguire PB. Insights into the platelet releasate. Curr Pharm Design 2007; 13: 2640-2646.
  • 52 Wijten P. et al. High precision platelet releasate definition by quantitative reversed protein profiling--brief report. Arterioscl Thromb Vasc Biol 2013; 33: 1635-1638.
  • 53 White GC, Rompietti R. Platelet secretion: indiscriminately spewed forth or highly orchestrated?. J Thromb Haemost 2007; 5: 2006-2008.
  • 54 Wong HR. et al. Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit Care 2012; 16: R213.
  • 55 Hamzeh-Cognasse H. et al. Contribution of activated platelets to plasma IL-27 levels. Crit Care 2013; 17: 411.
  • 56 Lindemann S. et al. Activated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490.
  • 57 Rondina MT. et al. The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. J Thromb Haemost 2011; 9: 748-758.
  • 58 Hu JY. et al. Altered proteomic pattern in platelets of rats with sepsis. Blood Cells Mol Dis 2012; 48: 30-35.
  • 59 Cecchetti L. et al. Megakaryocytes differentially sort mRNAs for matrix metalloproteinases and their inhibitors into platelets: a mechanism for regulating synthetic events. Blood 2011; 118: 1903-1911.
  • 60 Freishtat RJ. et al. Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity. Am J Resp Crit Care Med 2009; 179: 467-473.
  • 61 Ple H. et al. Alteration of the platelet transcriptome in chronic kidney disease. Thromb Haemost 2012; 108: 605-615.
  • 62 Etulain J. et al. Acidosis downregulates platelet haemostatic functions and promotes neutrophil proinflammatory responses mediated by platelets. Thromb Haemost 2012; 107: 99-110.
  • 63 Burstein SA. Cytokines, platelet production and hemostasis. Platelets 1997; 8: 93-104.
  • 64 Boman HG. Peptide antibiotics and their role in innate immunity. Ann Rev Immunol 1995; 13: 61-92.
  • 65 Trier DA. et al. Platelet antistaphylococcal responses occur through P2X1 and P2Y12 receptor-induced activation and kinocidin release. Infect Immun 2008; 76: 5706-5713.
  • 66 Drago L. et al. Antimicrobial activity of pure platelet-rich plasma against micro-organisms isolated from oral cavity. BMC Microbiol 2013; 13: 47.
  • 67 Kraemer BF. et al. Novel anti-bacterial activities of beta-defensin 1 in human platelets: suppression of pathogen growth and signaling of neutrophil extracellular trap formation. PLoS Pathogens 2011; 7: e1002355.
  • 68 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
  • 69 Slupsky JR. et al. Activated platelets induce tissue factor expression on human umbilical vein endothelial cells by ligation of CD40. Thromb Haemost 1998; 80: 1008-1014.
  • 70 May AE. et al. Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106: 2111-2117.
  • 71 Brown GT, McIntyre TM. Lipopolysaccharide Signaling without a Nucleus: Kinase Cascades Stimulate Platelet Shedding of Proinflammatory IL-1 beta-Rich Microparticles. J Immunol 2011; 186: 5489-5496.
  • 72 Cognasse F. et al. Donor platelets stored for at least 3 days can elicit activation marker expression by the recipient’s blood mononuclear cells: an in vitro study. Transfusion 2009; 49: 91-98.
  • 73 Diacovo TG. et al. Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood 1996; 88: 146-157.
  • 74 Ploppa A. et al. Mechanisms of leukocyte distribution during sepsis: an experimental study on the interdependence of cell activation, shear stress and endothelial injury. Crit Care 2010; 14: R201.
  • 75 Gawaz M. et al. Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure. Eur J Clin Invest 1995; 25: 843-851.
  • 76 Peters MJ. et al. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Br J Haematol 1999; 106: 391-399.
  • 77 Assinger A. et al. Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. J Thromb Haemost 2011; 9: 799-809.
  • 78 Haselmayer P. et al. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 2007; 110: 1029-1035.
  • 79 Weber B. et al. TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance. PLoS Pathogens 2014; 10: e1003900.
  • 80 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
  • 81 Xiang B. et al. Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway. Nat Commun 2013; 4: 2657.
  • 82 Kitchens CS. Thrombocytopenia and thrombosis in disseminated intravascular coagulation (DIC). Hematology 2009; 240-246.
  • 83 Levi M. et al. Plasma and plasma components in the management of disseminated intravascular coagulation. Best Pract Res Clin Haematol 2006; 19: 127-142.
  • 84 Goerge T. et al. Inflammation induces hemorrhage in thrombocytopenia. Blood 2008; 111: 4958-4964.
  • 85 Loria GD. et al. Platelets support a protective immune response to LCMV by preventing splenic necrosis. Blood 2013; 121: 940-950.
  • 86 Secor D. et al. Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries. Intensive Care Med 2010; 36: 1928-1934.
  • 87 Shibazaki M. et al. Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides. Infect Immun 1999; 67: 5186-5191.
  • 88 Singer G. et al. Platelet recruitment in the murine hepatic microvasculature during experimental sepsis: role of neutrophils. Microcircul 2006; 13: 89-97.
  • 89 Brown KA. et al. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157-169.
  • 90 Coopersmith CM. et al. Inhibition of intestinal epithelial apoptosis and survival in a murine model of pneumonia-induced sepsis. J Am Med Assoc 2002; 287: 1716-1721.
  • 91 Haimovitz-Friedman A. et al. Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 1997; 186: 1831-1841.
  • 92 Sharron M. et al. Platelets induce apoptosis during sepsis in a contact-dependent manner that is inhibited by GPIIb/IIIa blockade. PLoS One 2012; 7: e41549.
  • 93 Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med 2004; 351: 159-169.
  • 94 Singbartl K. et al. Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure. FASEB J 2001; 15: 2337-2344.
  • 95 Singbartl K, Ley K. Leukocyte recruitment and acute renal failure. J Molecular Med 2004; 82: 91-101.
  • 96 Tokes-Fuzesi M. et al. Microparticles and acute renal dysfunction in septic patients. J Crit Care 2013; 28: 141-147.
  • 97 Matthay MA. et al. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731-2740.
  • 98 Grommes J. et al. Disruption of platelet-derived chemokine heteromers prevents neutrophil extravasation in acute lung injury. Am J Resp Crit Care Med 2012; 185: 628-636.
  • 99 Idell S. et al. Platelet-specific alpha-granule proteins and thrombospondin in bronchoalveolar lavage in the adult respiratory distress syndrome. Chest 1989; 96: 1125-1132.
  • 100 Hamburger SA, McEver RP. GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood 1990; 75: 550-554.
  • 101 Asaduzzaman M. et al. Platelets support pulmonary recruitment of neutrophils in abdominal sepsis. Crit Care Med 2009; 37: 1389-1396.
  • 102 Rahman M. et al. Platelet-derived CD40L (CD154) mediates neutrophil up-regulation of Mac-1 and recruitment in septic lung injury. Ann Surg 2009; 250: 783-790.
  • 103 Zarbock A, Ley K. The role of platelets in acute lung injury (ALI). Front Biosci 2009; 14: 150-158.
  • 104 Zarbock A. et al. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest 2006; 116: 3211-3219.
  • 105 Rahman M. et al. Metalloproteinases regulate CD40L shedding from platelets and pulmonary recruitment of neutrophils in abdominal sepsis. Inflamm Res 2012; 61: 571-579.
  • 106 Pu Q. et al. Beneficial effect of glycoprotein IIb/IIIa inhibitor (AZ-1) on endothelium in Escherichia coli endotoxin-induced shock. Crit Care Med 2001; 29: 1181-1188.
  • 107 Taylor FB. 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 1997; 89: 4078-4084.
  • 108 Evangelista V. et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost 2005; 94: 568-577.
  • 109 Seidel M. et al. Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost 2009; 7: 1030-1032.
  • 110 Lipcsey M. et al. Early endotoxin-mediated haemostatic and inflammatory responses in the clopidogrel-treated pig. Platelets 2005; 16: 408-414.
  • 111 Derhaschnig U. et al. Effects of aspirin and NO-aspirin (NCX 4016) on platelet function and coagulation in human endotoxemia. Platelets 2010; 21: 320-328.
  • 112 Eisen DP. et al. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med 2012; 40: 1761-1767.
  • 113 Erlich JM. et al. Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study. Chest 2011; 139: 289-295.
  • 114 Kor DJ. et al. Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med 2011; 39: 2393-2400.
  • 115 Winning J. et al. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med 2010; 38: 32-37.
  • 116 Winning J. et al. Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets 2009; 20: 50-57.
  • 117 Valerio-Rojas JC. et al. Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: a historical cohort study. Crit Care Res Pract 2013; 2013: 782573.
  • 118 Gross AK. et al. Clopidogrel treatment and the incidence and severity of community acquired pneumonia in a cohort study and meta-analysis of antiplatelet therapy in pneumonia and critical illness. J Thromb Thrombol 2013; 35: 147-154.
  • 119 Storey RF. et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets. 2013 Epub ahead of print.
  • 120 Baughman RP. et al. Thrombocytopenia in the intensive care unit. Chest 1993; 104: 1243-1247.
  • 121 Boldt J. et al. Platelet function in critically ill patients. Chest 1994; 106: 899-903.