Abstract

SummaryAlthough their central role is in the prevention of bleeding, platelets probably contribute to diverse processes that extend beyond hemostasis and thrombosis. For example, platelets can recruit leukocytes and progenitor cells to sites of vascular injury and inflammation; they release proinflammatory and anti‐inflammatory and angiogenic factors and microparticles into the circulation; and they spur thrombin generation. Data from animal models suggest that these functions may contribute to atherosclerosis, sepsis, hepatitis, vascular restenosis, acute lung injury, and transplant rejection. This article represents an integrated summary of presentations given at the Fourth Annual Platelet Colloquium in January 2009. The process of and factors mediating platelet–platelet and platelet–leukocyte interactions in inflammatory and immune responses are discussed, with the roles of P‐selectin, chemokines and Src family kinases being highlighted. Also discussed are specific disorders characterized by local or systemic platelet activation, including coronary artery restenosis after percutaneous intervention, alloantibody‐mediated transplant rejection, wound healing, and heparin‐induced thrombocytopenia. Although their central role is in the prevention of bleeding, platelets probably contribute to diverse processes that extend beyond hemostasis and thrombosis. For example, platelets can recruit leukocytes and progenitor cells to sites of vascular injury and inflammation; they release proinflammatory and anti‐inflammatory and angiogenic factors and microparticles into the circulation; and they spur thrombin generation. Data from animal models suggest that these functions may contribute to atherosclerosis, sepsis, hepatitis, vascular restenosis, acute lung injury, and transplant rejection. This article represents an integrated summary of presentations given at the Fourth Annual Platelet Colloquium in January 2009. The process of and factors mediating platelet–platelet and platelet–leukocyte interactions in inflammatory and immune responses are discussed, with the roles of P‐selectin, chemokines and Src family kinases being highlighted. Also discussed are specific disorders characterized by local or systemic platelet activation, including coronary artery restenosis after percutaneous intervention, alloantibody‐mediated transplant rejection, wound healing, and heparin‐induced thrombocytopenia. Platelets play important roles in several diverse processes beyond hemostasis and thrombosis, including promoting inflammatory and immune responses, maintaining vascular integrity, and contributing to wound healing. Platelets can recruit leukocytes and progenitor cells to sites of vascular injury and thrombosis; they store, produce and release proinflammatory and anti‐inflammatory and angiogenic factors and microparticles into the circulation; and they spur thrombin generation. In experimental models, these functions have been shown to contribute to atherosclerosis, sepsis, hepatitis, vascular restenosis, acute lung injury, and transplant rejection. This article represents an integrated summary of presentations given at the Fourth Annual Platelet Colloquium, held in Washington, DC on 22–24 January 2009, which focused, in part, on current knowledge regarding the role of platelets in vascular integrity, tissue repair, and immune responses. The ability of platelets to store and release bioactive mediators allows them to play an important role in modulating the function of other cells. Platelets contain three types of storage compartments –α‐granules, dense granules, and lysosomes – whose contents are released into the circulation or translocated to the platelet surface upon platelet activation [1Quinn M. Platelet physiology.in: Quinn M Fitzgerald D Cox D Platelet Function: Assessment, Diagnosis, and Treatment. Humana Press, Inc., 2005: 1-15Crossref Google Scholar]. When stimulated by thrombin, the platelet releasate contains > 300 proteins [2Coppinger J.A. Cagney G. Toomey S. Kislinger T. Belton O. McRedmond J.P. Cahill D.J. Emili A. Fitzgerald D.J. Maguire P.B. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions.Blood. 2004; 103: 2096-104Crossref PubMed Scopus (678) Google Scholar]. A partial listing of platelet granule contents can be found in Table 1 [3Parise L.V. Smyth S.S. Coller B.S. Platelet morphology, biochemistry, and function.in: Lichtman MA Beutler E Kaushansky K Kipps TJ Seligsohn U Prchal J Williams Hematology. 7th edn. McGraw‐Hill Professional, 2005: 1357-408Google Scholar]. Fibrinogen, von Willebrand factor (VWF), platelet factor 4 (PF4), transforming growth factor‐β and platelet‐derived growth factor are among the contents of α‐granules, whereas dense granules are rich in ADP and serotonin. Although the release of cargo during exocytosis delivers many proteins into the circulation, the process also alters the composition of the platelet membrane, resulting in surface expression of P‐selectin and an increase in the number of integrin αIIbβ3 [glycoprotein (GP) IIb–IIIa] molecules. The exposure of P‐selectin is especially important for platelet–leukocyte interactions, given that this receptor mediates the initial interactions of leukocytes with activated platelets. P‐selectin also serves as a C3b‐binding protein to initiate complement activation on the platelet surface [4Del 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. 2005; 201: 871-9Crossref PubMed Scopus (317) Google Scholar].Table 1Platelet granular and secreted moleculesα‐GranulesDense bodiesPlatelet‐specific proteinsADP Platelet factor 4ATP β‐Thromboglobulin family*CalciumMultimerinSerotoninAdhesive glycoproteinsPyrophosphate FibrinogenGDP von Willebrand factorMagnesium von Willebrand factor propeptideOther secreted or released proteins FibronectinProtease nexin I Thrombospondin‐1Gas6 VitronectinAmyloid β‐protein precursor (protease nexin II)Coagulation factorsTissue factor pathway inhibitor Factor VFactor XIII Protein Sα1‐Protease inhibitor Factor XIComplement l inhibitorMitogenic factorsHigh molecular weight kininogen Platelet‐derived growth factorα2‐Macroglobulin Transforming growth factor‐βVascular permeability factor Endothelial cell growth factorInterleukin‐1β Epidermal growth factorHistidine‐rich glycoprotein Insulin‐like growth factor IChemokinesAngiogenic factorsMIP‐Iα (CCL3) Vascular endothelial growth factorRANTES (CCL5) Platelet factor 4 (inhibitor)MCP‐3 (CCL7)Fibrinolytic inhibitorsGro‐α (CXCL1) α2‐Plasmin inhibitorPlatelet factor 4 (CXCL4) Plasminogen activator inhibitor‐1ENA‐78 (CXCL5)AlbuminNAP‐2 (CXCL7)ImmunoglobulinsInterleukin‐8 (CXCL8)Granule membrane‐specific proteinsTARC (CCL17) P‐selectin (CD62P) CD63 (LAMP‐3) GMP 33Adapted from Parise et al. [3Parise L.V. Smyth S.S. Coller B.S. Platelet morphology, biochemistry, and function.in: Lichtman MA Beutler E Kaushansky K Kipps TJ Seligsohn U Prchal J Williams Hematology. 7th edn. McGraw‐Hill Professional, 2005: 1357-408Google Scholar], with permission. *Platelet basic protein, low‐affinity platelet factor 4, β‐thromboglobulin, and β‐thromboglobulin‐F. CCL, C–C motif ligand; CXCL, C–X–C motif ligand; ENA, epithelial cell‐derived neutrophil‐activating (peptide); GMP, granule membrane protein; Gro, growth‐related oncogene; LAMP, lysosome‐associated membrane protein; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NAP, neutrophil‐activating peptide; RANTES, regulated on activation, normal T‐cell expressed and secreted; TARC, thymus and activation‐regulated chemokine. Open table in a new tab Adapted from Parise et al. [3Parise L.V. Smyth S.S. Coller B.S. Platelet morphology, biochemistry, and function.in: Lichtman MA Beutler E Kaushansky K Kipps TJ Seligsohn U Prchal J Williams Hematology. 7th edn. McGraw‐Hill Professional, 2005: 1357-408Google Scholar], with permission. *Platelet basic protein, low‐affinity platelet factor 4, β‐thromboglobulin, and β‐thromboglobulin‐F. CCL, C–C motif ligand; CXCL, C–X–C motif ligand; ENA, epithelial cell‐derived neutrophil‐activating (peptide); GMP, granule membrane protein; Gro, growth‐related oncogene; LAMP, lysosome‐associated membrane protein; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NAP, neutrophil‐activating peptide; RANTES, regulated on activation, normal T‐cell expressed and secreted; TARC, thymus and activation‐regulated chemokine. Platelets are not only storage houses for bioactive molecules, but also generate lipid‐derived mediators such as thromboxane A2 and participate in transcellular metabolism, which results in the production of both proinflammatory and anti‐inflammatory molecules. In addition, platelets have several unique, extranuclear mechanisms for translating mRNA into protein in a ‘signal‐dependent manner’, and can produce, among other proteins, interleukin‐1β and tissue factor, which may link hemostasis and inflammation [5Weyrich A.S. Schwertz H. Kraiss L.W. Zimmerman G.A. Protein synthesis by platelets: historical and new perspectives.J Thromb Haemost. 2009; 7: 241-6Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar]. Analogously to the interactions of leukocytes with inflamed endothelium, leukocytes can roll on a template of adherent platelets, firmly adhere, and then transmigrate through the adherent platelets [6Ley K. Laudanna C. Cybulsky M.I. Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated.Nat Rev Immunol. 2007; 7: 678-89Crossref PubMed Scopus (3212) Google Scholar, 7Wagner D.D. Frenette P.S. The vessel wall and its interactions.Blood. 2008; 111: 5271-81Crossref PubMed Scopus (258) Google Scholar]. Although some of the receptor–ligand pairs and signaling molecules that mediate platelet–leukocyte interactions may differ from those involved in endothelial cell–leukocyte interactions (Fig. 1) [7Wagner D.D. Frenette P.S. The vessel wall and its interactions.Blood. 2008; 111: 5271-81Crossref PubMed Scopus (258) Google Scholar], many of the fundamental aspects are similar. Rolling and adhesion of leukocytes on platelets or endothelial cells are regulated by adhesive receptors, cellular geometry, and, perhaps of greatest overall relevance, shear forces generated within flowing blood [8Hammer D.A. Apte S.M. Simulation of cell rolling and adhesion on surfaces in shear flow: general results and analysis of selectin‐mediated neutrophil adhesion.Biophys J. 1992; 63: 35-57Abstract Full Text PDF PubMed Scopus (474) Google Scholar]. The selectin family of adhesive receptors mediates the initial stage of cellular rolling (Fig. 1) [9Cummings R.D. McEver R.P. C‐type lectins.in: Varki A Cummings RD Esko JD Freeze HH Stanley P Bertozzi CR Hart GW Etzler ME Essentials of Glycobiology. 2nd edn. CSH Press, 2009: 1857-1929Google Scholar]. P‐selectin plays an essential role in platelet–leukocyte contacts, whereas both P‐selectin and E‐selectin are present on endothelial cells and contribute to endothelial cell–leukocyte interactions. The third selectin, L‐selectin, is present on leukocytes. The best‐characterized leukocyte ligand for P‐selectin is P‐selectin glycoprotein ligand (PSGL)‐1, which can interact with all selectin subtypes under inflammatory conditions [10McEver R.P. Selectins: lectins that initiate cell adhesion under flow.Curr Opin Cell Biol. 2002; 14: 581-6Crossref PubMed Scopus (367) Google Scholar]. Ligation of PSGL‐1 transmits signals within the leukocyte that are necessary for adhesion mediated by leukocyte integrins [11Zarbock A. Ley K. The role of platelets in acute lung injury.Front Biosci. 2009; 14: 150-8Crossref PubMed Scopus (101) Google Scholar]. Although unnecessary for leukocyte rolling on P‐selectin, the cytoplasmic domain of PSGL‐1 is essential for activation of leukocyte β2 integrins [12Miner J.J. Xia L. Yago T. Kappelmayer J. Liu Z. Klopocki A.G. Shao B. McDaniel J.M. Setiadi H. Schmidtke D.W. McEver R.P. Separable requirements for cytoplasmic domain of PSGL‐1 in leukocyte rolling and signaling under flow.Blood. 2008; 112: 2035-45Crossref PubMed Scopus (91) Google Scholar]. Immobilized and released chemokines are also required for firm leukocyte adhesion and arrest. In reconstituted systems, immobilized chemokines trigger the arrest of leukocytes within 1 s [13Campbell J.J. Hedrick J. Zlotnik A. Siani M.A. Thompson D.A. Butcher E.C. Chemokines and the arrest of lymphocytes rolling under flow conditions.Science. 1998; 279: 381-4Crossref PubMed Scopus (844) Google Scholar, 14Grabovsky V. Feigelson S. Chen C. Bleijs D.A. Peled A. Cinamon G. Baleux F. Arenzana‐Seisdedos F. Lapidot T. Van Kooyk Y. Subsecond induction of alpha4 integrin clustering by immobilized chemokines stimulates leukocyte tethering and rolling on endothelial vascular cell adhesion molecule 1 under flow conditions.J Exp Med. 2000; 192: 495-506Crossref PubMed Scopus (288) Google Scholar], largely due to activation of G‐protein‐coupled receptors (GPCRs). Prominent among the chemokines released by platelets that influence leukocyte function and platelet–leukocyte interactions are PF4/CXCL4, RANTES (regulated on activation, normal T‐cell expressed and secreted; CCL5), and growth‐related oncogene‐α [15Koenen R.R. Von Hundelshausen P. Nesmelova I.V. Zernecke A. Liehn E.A. Sarabi A. Kramp B.K. Piccinini A.M. Paludan S.R. Kowalska M.A. Kungl A.J. Hackeng T.M. Mayo K.H. Weber C. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice.Nat Med. 2009; 15: 97-103Crossref PubMed Scopus (376) Google Scholar, 16Clemetson K.J. Clemetson J.M. Proudfoot A.E. Power C.A. Baggiolini M. Wells T.N. Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets.Blood. 2000; 96: 4046-54Crossref PubMed Google Scholar]. When leukocytes receive signals from both activated PSGL‐1 and GPCRs, the expression of transcription factors, cytokines and chemokines is increased [17Galt S.W. Lindemann S. Medd D. Allen L.L. Kraiss L.W. Harris E.S. Prescott S.M. McIntyre T.M. Weyrich A.S. Zimmerman G.A. Differential regulation of matrix metalloproteinase‐9 by monocytes adherent to collagen and platelets.Circ Res. 2001; 89: 509-16Crossref PubMed Scopus (94) Google Scholar, 18Lindemann S.W. Weyrich A.S. Zimmerman G.A. Signaling to translational control pathways: diversity in gene regulation in inflammatory and vascular cells.Trends Cardiovasc Med. 2005; 15: 9-17Crossref PubMed Scopus (32) Google Scholar, 19Weyrich A.S. McIntyre T.M. McEver R.P. Prescott S.M. Zimmerman G.A. Monocyte tethering by P‐selectin regulates monocyte chemotactic protein‐1 and tumor necrosis factor‐alpha secretion. Signal integration and NF‐kappa B translocation.J Clin Invest. 1995; 95: 2297-303Crossref PubMed Scopus (369) Google Scholar, 20Weyrich A.S. Elstad M.R. McEver R.P. McIntyre T.M. Moore K.L. Morrissey J.H. Prescott S.M. Zimmerman G.A. Activated platelets signal chemokine synthesis by human monocytes.J Clin Invest. 1996; 97: 1525-34Crossref PubMed Scopus (553) Google Scholar]. Leukocyte activation enhances the strength of the integrin bonds, leading to firm adhesion mediated by integrin αMβ2 (Mac‐1) binding to GPIb and/or other ligands, such as fibrinogen bound to integrin αIIbβ3, on the platelet surface [5Weyrich A.S. Schwertz H. Kraiss L.W. Zimmerman G.A. Protein synthesis by platelets: historical and new perspectives.J Thromb Haemost. 2009; 7: 241-6Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar]. Signaling through Src‐family kinases (SFKs) is required to sustain β2 integrin activation [21Evangelista V. Pamuklar Z. Piccoli A. Manarini S. Dell’elba G. Pecce R. Martelli N. Federico L. Rojas M. Berton G. Lowell C.A. Totani L. Smyth S.S. Src family kinases mediate neutrophil adhesion to adherent platelets.Blood. 2007; 109: 2461-9Crossref PubMed Scopus (109) Google Scholar]. An important downstream mediator of SFK‐dependent signaling may be Pyk2, which is phosphorylated in leukocytes upon adhesion to platelets and is required to sustain platelet–neutrophil adhesion in murine and human cells (Fig. 2) [21Evangelista V. Pamuklar Z. Piccoli A. Manarini S. Dell’elba G. Pecce R. Martelli N. Federico L. Rojas M. Berton G. Lowell C.A. Totani L. Smyth S.S. Src family kinases mediate neutrophil adhesion to adherent platelets.Blood. 2007; 109: 2461-9Crossref PubMed Scopus (109) Google Scholar]. As leukocytes undergo the transition from rolling to more firm adhesion, they become polarized through clustering of L‐selectin and PSGL‐1, and this promotes further leukocyte recruitment through leukocyte–leukocyte interactions [22Hidalgo A. Peired A.J. Wild M.K. Vestweber D. Frenette P.S. Complete identification of E‐selectin ligands on neutrophils reveals distinct functions of PSGL‐1, ESL‐1, and CD44.Immunity. 2007; 26: 477-89Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 23Hidalgo A. Chang J. Jang J.E. Peired A.J. Chiang E.Y. Frenette P.S. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.Nat Med. 2009; 15: 384-91Crossref PubMed Scopus (274) Google Scholar]. Given the number and variety of bioactive substances secreted by platelets (Table 1), it is unsurprising that they have been implicated in the development or severity of an array of disorders (Table 2) [11Zarbock A. Ley K. The role of platelets in acute lung injury.Front Biosci. 2009; 14: 150-8Crossref PubMed Scopus (101) Google Scholar, 24Gawaz M. Langer H. May A.E. Platelets in inflammation and atherogenesis.J Clin Invest. 2005; 115: 3378-84Crossref PubMed Scopus (1135) Google Scholar, 25Wang Y. Sakuma M. Chen Z. Ustinov V. Shi C. Croce K. Zago A.C. Lopez J. Andre P. Plow E. Simon D.I. Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac‐1 is critical for the biological response to vascular injury.Circulation. 2005; 112: 2993-3000Crossref PubMed Scopus (166) Google Scholar, 26Laschke M.W. Dold S. Menger M.D. Jeppsson B. Thorlacius H. Platelet‐dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation‐induced cholestasis.Br J Pharmacol. 2008; 153: 148-56Crossref PubMed Scopus (79) Google Scholar, 27Nishimura S. Manabe I. Nagasaki M. Seo K. Yamashita H. Hosoya Y. Ohsugi M. Tobe K. Kadowaki T. Nagai R. Sugiura S. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue.J Clin Invest. 2008; 118: 710-21PubMed Google Scholar, 28Collins C.E. Cahill M.R. Newland A.C. Rampton D.S. Platelets circulate in an activated state in inflammatory bowel disease.Gastroenterology. 1994; 106: 840-5Abstract Full Text PDF PubMed Google Scholar, 29Zeller J.A. Lindner V. Frahm K. Baron R. Deuschl G. Platelet activation and platelet–leucocyte interaction in patients with migraine. Subtype differences and influence of triptans.Cephalalgia. 2005; 25: 536-41Crossref PubMed Scopus (31) Google Scholar, 30Berrettini M. Parise P. Constantini V. Grasselli S. Nenci G.G. Platelet activation in psoriasis.Thromb Haemost. 1985; 53: 195-7Crossref PubMed Scopus (46) Google Scholar, 31Zahler S. Massoudy P. Hartl H. Hähnel C. Meisner H. Becker B.F. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass.Cardiovasc Res. 1999; 41: 722-30Crossref PubMed Scopus (141) Google Scholar, 32Milovanovic M. Nilsson E. Järemo P. Relationships between platelets and inflammatory markers in rheumatoid arthritis.Clin Chim Acta. 2004; 343: 237-40Crossref PubMed Scopus (102) Google Scholar, 33Levi M. Platelets in sepsis.Hematology. 2005; 10: 129-31Crossref PubMed Scopus (67) Google Scholar, 34Clark S.R. Ma A.C. Tavener S.A. McDonald B. Goodarzi Z. Kelly M.M. Patel K.D. Chakrabarti S. McAvoy E. Sinclair G.D. Keys E.M. Allen‐Vercoe E. Devinney R. Doig C.J. Green F.H. Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.Nat Med. 2007; 13: 463-9Crossref PubMed Scopus (1704) Google Scholar, 35Nagahama M. Nomura S. Ozaki Y. Yoshimura C. Kagawa H. Fukuhara S. Platelet activation markers and soluble adhesion molecules in patients with systemic lupus erythematosus.Autoimmunity. 2001; 33: 85-94Crossref PubMed Scopus (56) Google Scholar, 36Morrell C.N. Sun H. Swaim A.M. Baldwin III, W.M. Platelets an inflammatory force in transplantation.Am J Transplant. 2007; 7: 2447-54Crossref PubMed Scopus (70) Google Scholar]. Some of these disorders may appear obvious (thrombosis and restenosis) but others may not (psoriasis and migraine).Table 2Disorders associated with platelet activation and platelet–leukocyte interactionsAcute lung injury [11Zarbock A. Ley K. The role of platelets in acute lung injury.Front Biosci. 2009; 14: 150-8Crossref PubMed Scopus (101) Google Scholar]Interactions of platelets, leukocytes and ECs are critical to pathogenesis; key molecules include P‐selectin and the eicosanoid thromboxane A2Atherosclerosis, thrombosis, restenosis [24Gawaz M. Langer H. May A.E. Platelets in inflammation and atherogenesis.J Clin Invest. 2005; 115: 3378-84Crossref PubMed Scopus (1135) Google Scholar, 25Wang Y. Sakuma M. Chen Z. Ustinov V. Shi C. Croce K. Zago A.C. Lopez J. Andre P. Plow E. Simon D.I. Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac‐1 is critical for the biological response to vascular injury.Circulation. 2005; 112: 2993-3000Crossref PubMed Scopus (166) Google Scholar]Interactions of platelets, leukocytes and ECs trigger autocrine and paracrine activation, leading to leukocyte recruitment to the vascular wall. Platelet‐induced chronic inflammation of the vascular wall leads to atherosclerotic lesions and atherothrombosis; αMβ2 engagement of GPIbα is critical to the biological response to vessel injuryInflammatory hepatitis [26Laschke M.W. Dold S. Menger M.D. Jeppsson B. Thorlacius H. Platelet‐dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation‐induced cholestasis.Br J Pharmacol. 2008; 153: 148-56Crossref PubMed Scopus (79) Google Scholar]Bilateral ductal ligation induced intravascular platelet aggregates in the liver in mice, increased platelet adhesion in postsinusoidal venules, and massive platelet accumulation in liver sinusoids. P‐selectin mediated cholestasis‐induced platelet accumulationInflammation in obesity [27Nishimura S. Manabe I. Nagasaki M. Seo K. Yamashita H. Hosoya Y. Ohsugi M. Tobe K. Kadowaki T. Nagai R. Sugiura S. In vivo imaging in mice reveals local cell dynamics and inflammation in obese adipose tissue.J Clin Invest. 2008; 118: 710-21PubMed Google Scholar]In ob/ob mice and mice with obesity induced by a high‐fat diet, visceral adipose tissue showed increased leukocyte–EC–platelet interactions in the microcirculation, increased P‐selectin expression, formation of monocyte–platelet conjugates, and upregulated expression of adhesion molecules on macrophages and ECsInflammatory bowel disease [28Collins C.E. Cahill M.R. Newland A.C. Rampton D.S. Platelets circulate in an activated state in inflammatory bowel disease.Gastroenterology. 1994; 106: 840-5Abstract Full Text PDF PubMed Google Scholar]Patients with Crohn’s disease or ulcerative colitis showed increased platelet surface expression of P‐selectin and GP53, increased circulating platelet aggregates, incteased platelet aggregability in vitro and increased serum β‐thromboglobulin levels as compared with healthy controlsMigraine [29Zeller J.A. Lindner V. Frahm K. Baron R. Deuschl G. Platelet activation and platelet–leucocyte interaction in patients with migraine. Subtype differences and influence of triptans.Cephalalgia. 2005; 25: 536-41Crossref PubMed Scopus (31) Google Scholar]Platelet activation and leukocyte–platelet aggregation were significantly increased during migraine headaches in patients without aura vs. control volunteers in flow cytometry assays, but not in migraine patients with aura. All patients had an increased baseline level of platelet activation, and triptan drugs appeared to downregulate platelet aggregation. Possible role for release of serotonin from plateletsPsoriasis [30Berrettini M. Parise P. Constantini V. Grasselli S. Nenci G.G. Platelet activation in psoriasis.Thromb Haemost. 1985; 53: 195-7Crossref PubMed Scopus (46) Google Scholar]Spontaneous platelet hyperaggregability and plasma levels of β‐thromboglobulin were significantly increased in male patients with psoriasis vs. control subjects. Platelet regeneration time was significantly shorter in patients with the diseaseReperfusion‐induced inflammation after CPB [31Zahler S. Massoudy P. Hartl H. Hähnel C. Meisner H. Becker B.F. Acute cardiac inflammatory responses to postischemic reperfusion during cardiopulmonary bypass.Cardiovasc Res. 1999; 41: 722-30Crossref PubMed Scopus (141) Google Scholar]In 12 patients undergoing CABG, IL‐6 levels and platelet CD62 expression rose early during reperfusion after CPB. Leukocyte–platelet microaggregates also formed during surgery and persisted during reperfusionRheumatoid arthritis [32Milovanovic M. Nilsson E. Järemo P. Relationships between platelets and inflammatory markers in rheumatoid arthritis.Clin Chim Acta. 2004; 343: 237-40Crossref PubMed Scopus (102) Google Scholar]In 16 patients with active disease, platelet count and CRP and IL‐6 levels were elevated and correlated with each other, whereas neutrophil count, platelet volume and myeloperoxidase level also mirrored disease activity but did not correlate with other markersSepsis [33Levi M. Platelets in sepsis.Hematology. 2005; 10: 129-31Crossref PubMed Scopus (67) Google Scholar, 34Clark S.R. Ma A.C. Tavener S.A. McDonald B. Goodarzi Z. Kelly M.M. Patel K.D. Chakrabarti S. McAvoy E. Sinclair G.D. Keys E.M. Allen‐Vercoe E. Devinney R. Doig C.J. Green F.H. Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.Nat Med. 2007; 13: 463-9Crossref PubMed Scopus (1704) Google Scholar]Disseminated intravascular platelet activation can occur in cases of systemic inflammation, such as the response to sepsis, contributing to microvascular failure and thus organ dysfunction. Platelets can also be directly involved in the inflammatory response – platelet TLR‐4 binding to ligands on adherent neutrophils leads to robust neutrophil activation and formation of neutrophil extracellular traps, which retain their integrity under flow conditions and ensnare bacteria within vesselsSLE [35Nagahama M. Nomura S. Ozaki Y. Yoshimura C. Kagawa H. Fukuhara S. Platelet activation markers and soluble adhesion molecules in patients with systemic lupus erythematosus.Autoimmunity. 2001; 33: 85-94Crossref PubMed Scopus (56) Google Scholar]Patients with SLE had higher levels of platelet microparticles, CD62P expression, annexin V, IL‐1β, IL‐4, IL‐6, GM‐CSF, and TNF‐α, and soluble factors (serum IL‐2R, thrombomodulin, HLA‐1, β2‐microglobulin, VCAM‐1, PECAM‐1, P‐selectin, E‐selectin) vs. control patients. Levels of IL‐4, IL‐6, β2‐microglobulin, IL‐2R, VCAM‐1, P‐selectin and E‐selectin were particularly high in SLE patients with elevated thrombomodulin levels, as were levels of CD62P expression, annexin V, and microparticlesTransplant rejection [36Morrell C.N. Sun H. Swaim A.M. Baldwin III, W.M. Platelets an inflammatory force in transplantation.Am J Transplant. 2007; 7: 2447-54Crossref PubMed Scopus (70) Google Scholar]Platelet interactions with dendritic cells, T cells and B cells can contribute to vasculopathy in transplants. Activated platelets secrete chemokines to recruit helper and cytotoxic T cells; activated T cells then stimulate platelets, through CD40–CD154 interactions, to secrete more chemokines, thereby recruiting more T cells. P‐selectin/PSGL‐1 stimulation enhances platelet–T‐cell interactions. Antibody production stimulated through increased helper T‐cell function can activate complement, creating another activation loop when platelets express receptors for antibodies and complementCABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; CRP, C‐reactive protein; EC, endothelial cell; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; GP, glycoprotein; HLA, human leukocyte antigen; IL, interleukin; IL‐2R, interkeukin‐2 receptor; PECAM, platelet–endothelial cell adhesion molecule; PSGL, P‐selectin glycoprotein ligand; SLE, systemic lupus erythematosus; TLR, toll‐like receptor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule. Open table in a new tab CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; CRP, C‐reactive protein; EC, endothelial cell; GM‐CSF, granulocyte–macrophage colony‐stimulating factor; GP, glycoprotein; HLA, human leukocyte antigen; IL, interleukin; IL‐2R, interkeukin‐2 receptor; PECAM, platelet–endothelial cell adhesion molecule; PSGL, P‐selectin glycoprotein ligand; SLE, systemic lupus erythematosus; TLR, toll‐like receptor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule. The contribution of platelets to arterial injury and restenosis has been extensively studied in experimental models, and the information gained from these investigations provides a framework with which to understand the possible role of platelets in other inflammatory conditions. In a murine model of angioplasty wire‐induced femoral artery injury, endothelial denudation is followed by a stereotypical response that includes platelet deposition, leukocyte recruitment, and altered arterial composition (Fig. 1). This response ultimately leads to development of intimal hyperplasia, the clinical correlate of which is restenosis [25Wang Y. Sakuma M. Ch