Infective Endocarditis is a microbial infection characterised by the presence of septic vegetations on the surface of the endocardium (Moreillon and Que, 2004). Infection most commonly occurs on the heart valves that has been damaged by congenital defects such as previous disease or trauma (Durack, 1995). As a result these sites have the ability to generate turbulent blood flow which in turn can cause damage to inner most lining of the blood vessels, the endothelium, which causes surface damage leading to exposure of underlying matrix protein (Ruggeri, 2009). Once exposed this highly thrombogenic surface leads to rapid platelet deposition and the formation of a fibrin network. Circulating bacteria from a transient bacteremia in turn binds to this sterile platelet fibrin nidus which allows a secondary accumulation of platelets that encase the bacteria leading to stable thrombus formation (Moreillon and Que, 2004).
Despite improvements in medical and surgical therapy, invasive staphylococcal disease causing infective endocarditis is still associated with a severe prognosis and remains a significant therapeutic challenge. Once a disease primarily affecting younger patients presenting with rheumatic heart disease, modern times see a significant increase in newer ‘at risk’ categories including patients with long term indwelling central venous catheters, patients undergoing haemodialysis and invasive intravascular procedures such as arthroplasty, immunocompromized patients and intraveneous drug abusers (Thuny et al., 2012). Treatment of infective endocarditis usually requires a multidisciplinary approach involving specialists in infectious disease, cardiologists and cardiac surgeons. Current treatment regimes consist of aggressive prolonged antibiotic therapy, frequently combined with surgery (Prendergast and Tornos, 2010, Wilson et al., 2007). Prolonged antibiotic use is often less than successful as 40% of patients relapse within 2 months of finishing clinically effective therapy. Furthermore, prolonged exposure to antibiotics leads to a greater risk of adding to the global problem of multiple antibiotic resistant strains of bacteria. Surgery is a costly and risky alternative, however necessary in up to 47% of patients (Castillo et al., 2000, Murdoch et al., 2009). In many cases surgery is not preferable due to risks associated with cardiac failure, further spread of infection leading to persistent sepsis due to surgical removal of an infected thrombus and/or life threatening embolisation (Jault et al., 1997, Heiro et al., 2000, Thuny et al., 2012, Remadi et al., 2007).
2. The Staphylococcus
3. Platelets play a critical role in thrombosis and haemostasis
Platelets are small anucleate cell fragments of the larger haematopoietic precursor cell, the megakaryocyte (Thon and Italiano, 2010) and are crucial mediators of haemostasis. Platelets have no control over gene expression as they do not possess a nucleus however they have got limited capabilities in translational protein synthesis (Lindemann et al., 2001b). The primary role of platelets in haemostasis is to police the integrity of the endothelium to prevent blood loss (Nieswandt et al., 2009). Platelets circulate close to the endothelial cell surface at high shear as individual entities that ordinarily do not interact with any other cell types. A transition from this resting state to an activated state can be rapidly initiated if platelets are exposed to an appropriate stimulus. Disruption of the endothelial cell lining due to trauma or injury to the vascular endothelium platelets rapidly accumulate at the site of injury (Gawaz et al., 2005). Recruitment is a highly controlled event that is initiated by the adhesive interaction between the exposed extracellular matrix proteins in damaged endothelium and specific membrane receptors on the platelet (Tabuchi and Kuebler, 2008). Collagen (Santoro and Zutter, 1995), vonWillebrand factor (vWf) (Ruggeri, 1999), fibronectin (Savage et al., 1998, Kasirer-Friede et al., 2007) and thrombospondin (Jurk et al., 2003) constitute the exposed matrix proteins at the site of injury. Athough plasma proteins such as fibrinogen/fibrin and vitronectin are not synthesized by endothelial cells they can bind to exposed matrix proteins and increase adhesiveness at the damaged site (Ruggeri et al., 2006, Ruggeri and Mendolicchio, 2007).
Platelets express a vast array of membrane receptors that play a critical role in recognition of matrix proteins. The initial interaction of platelets with the injured vessel wall occurs between GPIbα and immobilised vonWillebrand factor (Chesterman and Berndt, 1986). This interaction initiates the tethering of circulating platelets to the vessel wall. Platelets typically ‘roll’ over the vWf in the direction of flow driven by shear forces experienced by the vasculature (Ruggeri, 2009). A loss of interaction between GPIb and vWf on one side of the platelet leads to the formation of another GPIb-vWf interaction on the other side of the platelet which gives rise to a rolling phenomenon. This rolling mechanism is critical to slowing down the platelet long enough for a second interaction that anchors the platelet to the damaged site. This firm adhesion can be mediated by several membrane receptors, some of which will have become activated as a result of platelet rolling and others who are expressed on the platelet surface as a result platelet activation (Jackson et al., 2009). Once firmly adhered, the platelets rearrange cytoskeletal components which results in filopodia and llamelipodia extension leading to flattening or spreading of the platelet. Platelet spreading is critical following firm adhesion as it firstly allows the platelet withstand the shear forces experienced in the vasculature and secondly it increases the platelet surface area thus covering more of the damaged site.
Following attachment, platelets undergo a series of highly controlled intracellular signalling events that lead to the release reaction where platelets release the contents of its stored intracellular granules. Alpha granules contain proteins such as P-selectin which mediates adhesion of platelets to monocytes, neutrophils and lymphocytes, resulting in the formation of platelet leukocyte complexes (Diacovo et al., 1996a, Diacovo et al., 1996b, Larsen et al., 1989). These granules also contain many chemotactic agents which lead to the recruitment of various inflammatory cells; platelet derived growth factor (PDGF) and 12-hydroxyeicosatetraenoic acid (12-HETE) which recruit neutrophils (Herd and Page, 1994, Mannaioni et al., 1997); platelet factor 4 and platelet derived histamine releasing factor (PDHRF) which recruit eosinophils in airway disease (Brindley et al., 1983, Frigas and Gleich, 1986); PDGF and transforming growth factor β (TGF-β) which recruit monocytes and macrophages and TGF-β which recruits fibroblasts (Deuel et al., 1982, Tzeng et al., 1985, Wahl et al., 1987). Platelet granules also contain several mediators of tissue damage such as oxygen free radicals and hydrolytic enzymes. Dense granules release cationic proteins that initiate vascular permeability and mediators that enhance aggregate formation such as adenosine diphosphate (ADP) and serotonin (5-HT) (Rendu and Brohard-Bohn, 2001). Bioactive amines are also secreted from platelets following activation including Thromboxane A2 (TxA2) and platelet activating factor (PAF) (McIntyre et al., 2003, Patrono et al., 2001).More recently it has been shown that platelet granules contain many antimicrobial peptides such as beta-lysin, platelet microbial protein (PMP), neutrophil activating peptide (NAP-2), released upon activation normal T-cell expressed and secreted (RANTES) and fibrinopeptides A and B (Johnson and Donaldson, 1968, Donaldson and Tew, 1977, Kameyoshi et al., 1992, Yeaman et al., 1997, Krijgsveld et al., 2000).
Once activation is complete the platelet forms a new surface for additional platelets to adhere, predominantly through GPIIb/IIIa crosslinking adjacent platelets through a fibrinogen bridge, resulting in aggregate formation. The final step sees and effective plug at the site of injury that is reinforced by the conversion of fibrinogen to fibrin through the coagulation cascade (Ruggeri et al., 2006).
4. The growing role of platelets in infection and immunity
Platelets are poorly recognised for their role in infection and immunity even though just like professional phagocytes (neutrophils, macrophages and dendritic cells) platelets are derived from the same haematopoietic stem cell, undergo chemotaxis (Clemetson et al., 2000), phagocytose foreign particles (Youssefian et al., 2002), and secrete a multitude of products including inflammatory mediators (Kameyoshi et al., 1992), cytokines (Lindemann et al., 2001a, Antczak et al., 2010) and antimicrobial peptides (Tang et al., 2002, Mercier et al., 2004), all while directing and recruiting several members of the innate immune system to the infected area (Cox et al., 2011, Semple and Freedman, 2010). In addition, toll like receptors (TLR) which are a family of pattern recognition receptors expressed by several professional phagocytes recognise conserved molecular motifs expressed on different classes of infectious agent (Janeway and Medzhitov, 2002, Armant and Fenton, 2002). To date at least 13 TLRs have been described in various immune and nonimmune cells in both human and mice. Recently human platelet have been shown to express TLR1,2,4,6,8 and 9, reinforcing their role as primitive immune cells in host defence (Cognasse et al., 2005, Shiraki et al., 2004, Aslam et al., 2006, Zhang et al., 2009, Garraud and Cognasse, 2010, Andonegui et al., 2005, Keane et al., 2010). More recent studies have also demonstrated that TLRs are also responsible for lipopolysaccharide (LPS)-induced thrombocytopenia (Andonegui et al., 2005, Aslam et al., 2006).
5. Mechanisms of interaction
Bacteria can interact with platelet in two ways, they can either support platelet adhesion or they can induce platelet aggregation. Platelet adhesion to immobilised bacteria is a measure of the strength of the interaction, whereas platelet aggregation induced by bacteria is a measure of the quality of the interaction. In contrast to typical platelet aggregation induced by physiological agonists such as adenosine diphosphate (ADP), collagen or thrombin, bacteria induce an all or nothing response. This means that the bacteria either induce a maximal aggregation or they don’t induce platelet aggregation at all, there is no intermediate response. Another unique feature of bacteria induced platelet aggregation is a distinct pause in time before aggregation takes place. This is typically called the lag time. Increasing the concentration of bacteria shortens the lag time but never eliminates it. The average lag time to platelet aggregation following addition of Staphylococci is between 5-12 minutes. This is in contrast to the lag time observed upon the addition of typical platelet agonists ADP or thrombin which have a lag time less than 10 seconds.
There are 3 main interactions between bacteria and platelets. In the first interaction bacteria express proteins that can directly interact with a surface receptor on the platelet. In this case the bacterial protein express ligand mimetic domains that act as agonists on the platelet receptor thus triggering an intracellular signal that culminates in platelet activation. In the second interaction bacterial proteins bind a plasma protein that is a natural ligand for a platelet receptor. For example, bacteria can bind antibody which in turn bridges the bacteria to the antibody receptor (FcγRIIa) expressed on the platelet. Once engaged the receptor results in the generation of an intracellular signal leading to platelet activation. Finally bacteria may have the ability to secrete products or toxins that in turn activate platelets. Engagement of the product or toxin with a platelet receptor results in activation. These different mechanisms of interaction may help explain the lag time to platelet aggregation. For example, the lag time could be representative of the time taken to trigger a response or bind a plasma protein. A major challenge in studying platelet bacterial interactions is that most bacteria can interact with platelets using multiple mechanisms. This makes it incredibly difficult to identify either the platelet receptors or the bacterial proteins involved in triggering thrombus formation. Moreover not only are the interactions species specific but strain specific as well.
6. Staphylococci interactions with platelets
6.1. Indirect interaction (Released products)
Lipoteichoic acid (LTA) is an essential component of the cell wall of
6.2. Indirect interaction (Cell wall proteins)
There are numerous cell wall proteins expressed on the surface of
More recent studies demonstrated that multiple cell wall proteins expressed on
A critical part of
As discussed in chapter 2 serine rich proteins expressed by viridans streptococci play a critical role in inducing platelet aggregation.
While all of these studies are critical to our understanding of the molecular mechanisms involved in aggregate formation, one must be aware of the relevance of these findings to physiological conditions experienced in the vasculature. For example, almost all of the studies carried out to date have been carried out under non-physiological stirring or using static adhesion assays, neither of which are representative of the conditions experienced in the vasculature. Many reports in the literature in recent times have clearly demonstrated that the local fluid environment in the circulation critically affects the molecular pathways of cell-cell interactions (Varki, 1994). To address this several attempts have been made to create an environment more representative of conditions experienced in the circulation. Rheology is a useful technique that can be employed to shear cells at physiological rates. Using a cone and plate viscometer, Pawar et al. demonstrated that when
6.3. Direct interaction (Cell wall proteins)
A growing concern about studies to date is the apparent lack of contrast with conditions experienced physiologically.
7. Final thoughts and future directions
Infective endocarditis is notoriously difficult to treat as antibiotics are incapable of penetrating the growing thrombus to reach the encased microorganisms. As a result of this the in-hospital mortality rate can be as high as 36% (Botelho-Nevers et al., 2009). Even with treatment, 40% of patients with infective endocarditis relapse within 2 months of finishing clinically effective therapy (Netzer et al., 2002). Furthermore, approximately 25% of patients with infective endocarditis eventually require surgery, usually within 2 years after completing therapy (Olaison and Pettersson, 2003). These statistics reflect the poor delivery and penetration of antibiotic into the growing thrombus. The costs associated with hospitalization (of which the average stay in hospital is 30 days), surgery and prolonged antibiotic treatment is extremely high placing a severe burden on already over-stretched healthcare systems though out the world. The danger of
Potential drug targets identified from studies over the years suggest that blocking the interaction between IgG and platelet FcγRIIa may indeed prevent platelet receptor clustering and thus inhibit thrombus formation. Blockade of the platelet FcγRIIa receptor has distinct advantages over other anti-platelet agents as inhibitors of FcγRIIa do not affect the platelet response to other agonist and therefore does not compromise essential platelet functions.
Andonegui G Kerfoot S. M Mcnagny K Ebbert K. V Patel K. D Kubes P 2005Platelets express functional Toll-like receptor-4. Blood, 106 2417 23
Andrews R. K Gardiner E. E Shen Y Berndt M. C 2003Structure-activity relationships of snake toxins targeting platelet receptors, glycoprotein Ib-IX-V and glycoprotein VI. Curr Med Chem Cardiovasc Hematol Agents, 1 143 9
Antczak A. J Singh N Gay S. R Worth R. G 2010IgG-complex stimulated platelets: a source of sCD40L and RANTES in initiation of inflammatory cascade. Cell Immunol, 263 129 33
Armant M. A Fenton M. J 2002Toll-like receptors: a family of pattern-recognition receptors in mammals. Genome Biol,3, REVIEWS3011.
Arvand M Bhakdi S Dahlback B Preissner K. T 1990Staphylococcus aureus alpha-toxin attack on human platelets promotes assembly of the prothrombinase complex. J Biol Chem, 265 14377 81
Aslam R Speck E. R Kim M Crow A. R Bang K. W Nestel F. P Ni H Lazarus A. H Freedman J Semple J. W 2006Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood, 107 637 41
Bayer A. S Ramos M. D Menzies B. E Yeaman M. R Shen A. J Cheung A. L 1997Hyperproduction of alpha-toxin by Staphylococcus aureus results in paradoxically reduced virulence in experimental endocarditis: a host defense role for platelet microbicidal proteins. Infect Immun, 65 4652 60
Bernheimer A. W 1965Staphylococcal alpha toxin. Ann N Y Acad Sci, 128 112 23
Blair P Rex S Vitseva O Beaulieu L Tanriverdi K Chakrabarti S Hayashi C Genco C. A Iafrati M Freedman J. E 2009Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res, 104 346 54
Botelho-nevers E Thuny F Casalta J. P Richet H Gouriet F Collart F Riberi A Habib G Raoult D 2009Dramatic reduction in infective endocarditis-related mortality with a management-based approach. Arch Intern Med, 169 1290 8
Brindley L. L Sweet J. M Goetzl E. J 1983Stimulation of histamine release from human basophils by human platelet factor 4. J Clin Invest, 72 1218 23
Castillo J. C Anguita M. P Ramirez A Siles J. R Torres F Mesa D Franco M Munoz I Concha M Valles F 2000Long term outcome of infective endocarditis in patients who were not drug addicts: a 10 year study. Heart, 83 525 30
Chesterman C. N Berndt M. C 1986Platelet and vessel wall interaction and the genesis of atherosclerosis. Clin Haematol, 15 323 53
Clemetson K. J Clemetson J. M Proudfoot A. E Power C. A Baggiolini M Wells T. N 2000Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood, 96 4046 54
Cognasse F Hamzeh H Chavarin P Acquart S Genin C Garraud O 2005Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol, 83 196 8
Cox D Kerrigan S. W Watson S. P 2011Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost, 9 1097 107
Deuel T. F Senior R. M Huang J. S Griffin G. L 1982Chemotaxis of monocytes and neutrophils to platelet-derived growth factor. J Clin Invest, 69 1046 9
lymphocyte delivery to high endothelial venules. Diacovo T. G Puri K. D Warnock R. A Springer T. A Von Andrian U. H 1996a Platelet-mediated Science, 273 252 5
Diacovo T. G Roth S. J Buccola J. M Bainton D. F Springer T. A 1996bNeutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood, 88 146 57
Donaldson D. M Tew J. G 1977beta-Lysin of platelet origin. Bacteriol Rev, 41 501 13
Durack D. T 1995Prevention of infective endocarditis. N Engl J Med, 332 38 44
Fitzgerald J. R Loughman A Keane F Brennan M Knobel M Higgins J Visai L Speziale P Cox D Foster T. J 2006Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcgammaRIIa receptor. Mol Microbiol, 59 212 30
Foster T. J 2009Colonization and infection of the human host by staphylococci: adhesion, survival and immune evasion. Vet Dermatol, 20 456 70
Frigas E Gleich G. J 1986The eosinophil and the pathophysiology of asthma. J Allergy Clin Immunol, 77 527 37
Garraud O Cognasse F 2010Platelet Toll-like receptor expression: the link between "danger" ligands and inflammation. Inflamm Allergy Drug Targets, 9 322 33
Gawaz M Langer H May A. E 2005Platelets in inflammation and atherogenesis. J Clin Invest, 115 3378 84
George N. P Wei Q Shin P. K Konstantopoulos K Ross J. M 2006Staphylococcus aureus adhesion via Spa, ClfA, and SdrCDE to immobilized platelets demonstrates shear-dependent behavior. Arterioscler Thromb Vasc Biol, 26 2394 400
Des Prez, R. M. Hawiger J Steckley S Hammond D Cheng C Timmons S Glick A. D 1979Staphylococci-induced human platelet injury mediated by protein A and immunoglobulin G Fc fragment receptor. J Clin Invest, 64 931 7
Heiro M Nikoskelainen J Engblom E Kotilainen E Marttila R Kotilainen P 2000Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland. Arch Intern Med, 160 2781 7
Herd C. M Page C. P 1994Pulmonary immune cells in health and disease: platelets. Eur Respir J, 7 1145 60
Jackson S. P Nesbitt W. S Westein E 2009Dynamics of platelet thrombus formation. J Thromb Haemost,7 Suppl 1 17 20
Jr. & Medzhitov, R. Janeway C. A 2002Innate immune recognition. Annu Rev Immunol, 20 197 216
Jault F Gandjbakhch I Rama A Nectoux M Bors V Vaissier E Nataf P Pavie A Cabrol C 1997Active native valve endocarditis: determinants of operative death and late mortality. Ann Thorac Surg, 63 1737 41
Johnson F. B Donaldson D. M 1968Purification of staphylocidal beta-lysin from rabbit serum. J Bacteriol, 96 589 95
Jurk K Clemetson K. J De Groot P. G Brodde M. F Steiner M Savion N Varon D Sixma J. J Van Aken H Kehrel B. E 2003Thrombospondin-1 mediates platelet adhesion at high shear via glycoprotein Ib (GPIb): an alternative/backup mechanism to von Willebrand factor. FASEB J, 17 1490 2
Kameyoshi Y Dorschner A Mallet A. I Christophers E Schroder J. M 1992Cytokine RANTES released by thrombin-stimulated platelets is a potent attractant for human eosinophils. J Exp Med, 176 587 92
Kasirer-friede A Kahn M. L Shattil S. J 2007Platelet integrins and immunoreceptors. Immunol Rev, 218 247 64
Kawai T Akira S 2010The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol, 11 373 84
Keane C Tilley D Cunningham A Smolenski A Kadioglu A Cox D Jenkinson H. F Kerrigan S. W 2010Invasive Streptococcus pneumoniae trigger platelet activation via Toll-like receptor 2. J Thromb Haemost, 8 2757 65
Kerrigan S. W Clarke N Loughman A Meade G Foster T. J Cox D 2008Molecular basis for Staphylococcus aureus-mediated platelet aggregate formation under arterial shear in vitro. Arterioscler Thromb Vasc Biol, 28 335 40
Kerrigan S. W Jakubovics N. S Keane C Maguire P Wynne K Jenkinson H. F Cox D 2007Role of Streptococcus gordonii surface proteins SspA/SspB and Hsa in platelet function. Infect Immun, 75 5740 7
Krijgsveld J Zaat S. A Meeldijk J Van Veelen P. A Fang G Poolman B Brandt E Ehlert J. E Kuijpers A. J Engbers G. H Feijen J Dankert J 2000Thrombocidins, microbicidal proteins from human blood platelets, are C-terminal deletion products of CXC chemokines. J Biol Chem, 275 20374 81
Larsen E Celi A Gilbert G. E Furie B. C Erban J. K Bonfanti R Wagner D. D Furie B 1989Padgem protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell, 59 305 12
Lindemann S Tolley N. D Dixon D. A Mcintyre T. M Prescott S. M Zimmerman G. A Weyrich A. S 2001aActivated platelets mediate inflammatory signaling by regulated interleukin 1beta synthesis. J Cell Biol, 154 485 90
Lindemann S Tolley N. D Eyre J. R Kraiss L. W Mahoney T. M Weyrich A. S 2001bIntegrins regulate the intracellular distribution of eukaryotic initiation factor 4E in platelets. A checkpoint for translational control. J Biol Chem, 276 33947 51
Lotz S Starke A Ziemann C Morath S Hartung T Solbach W Laskay T 2006Beta-lactam antibiotic-induced release of lipoteichoic acid from Staphylococcus aureus leads to activation of neutrophil granulocytes. Ann Clin Microbiol Antimicrob,5, 15.
Loughman A Fitzgerald J. R Brennan M. P Higgins J Downer R Cox D Foster T. J 2005Roles for fibrinogen, immunoglobulin and complement in platelet activation promoted by Staphylococcus aureus clumping factor A. Mol Microbiol, 57 804 18
Di Bello, M. G. & Masini, E. Mannaioni P. F 1997Platelets and inflammation: role of platelet-derived growth factor, adhesion molecules and histamine. Inflamm Res, 46 4 18
Mcintyre T. M Prescott S. M Weyrich A. S Zimmerman G. A 2003Cell-cell interactions: leukocyte-endothelial interactions. Curr Opin Hematol, 10 150 8
Meenan N. A Visai L Valtulina V Schwarz-linek U Norris N. C Gurusiddappa S Hook M Speziale P Potts J. R 2007The tandem beta-zipper model defines high affinity fibronectin-binding repeats within Staphylococcus aureus FnBPA. J Biol Chem, 282 25893 902
Mercier R. C Dietz R. M Mazzola J. L Bayer A. S Yeaman M. R 2004Beneficial influence of platelets on antibiotic efficacy in an in vitro model of Staphylococcus aureus-induced endocarditis. Antimicrob Agents Chemother, 48 2551 7
Miajlovic H Loughman A Brennan M Cox D Foster T. J 2007Both complement- and fibrinogen-dependent mechanisms contribute to platelet aggregation mediated by Staphylococcus aureus clumping factor B. Infect Immun, 75 3335 43
Miajlovic H Zapotoczna M Geoghegan J. A Kerrigan S. W Speziale P Foster T. J 2010Direct interaction of iron-regulated surface determinant IsdB of Staphylococcus aureus with the GPIIb/IIIa receptor on platelets. Microbiology, 156 920 8
Morath S Von Aulock S Hartung T 2005Structure/function relationships of lipoteichoic acids. J Endotoxin Res, 11 348 56
Moreillon P Que Y. A 2004Infective endocarditis. Lancet, 363 139 49
Jr., Bayer, A. S., Karchmer, A. W., Olaison, L., Pappas, P. A., Moreillon, P., Chambers, S. T., Chu, V. H., Falco, V., Holland, D. J., Jones, P., Klein, J. L., Raymond, N. J., Read, K. M., Tripodi, M. F., Utili, R., Wang, A., Woods, C. W. & Cabell, C. H. Murdoch D. R Corey G. R Hoen B Miro J. M Fowler V. G 2009Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study. Arch Intern Med, 169 463 73
Netzer R. O Altwegg S. C Zollinger E Tauber M Carrel T Seiler C 2002Infective endocarditis: determinants of long term outcome. Heart, 88 61 6
Nieswandt B Varga-szabo D Elvers M 2009Integrins in platelet activation. J Thromb Haemost,7 Suppl 1 206 9
D. O Brien L Kerrigan S. W Kaw G Hogan M Penades J Litt D Fitzgerald D. J Foster T. J Cox 2002Multiple mechanisms for the activation of human platelet aggregation by Staphylococcus aureus: roles for the clumping factors ClfA and ClfB, the serine-aspartate repeat protein SdrE and protein A. Mol Microbiol, 44 1033 44
T. J. O Seaghdha M Van Schooten C. J Kerrigan S. W Emsley J Silverman G. J Cox D Lenting P. J Foster 2006Staphylococcus aureus protein A binding to von Willebrand factor A1 domain is mediated by conserved IgG binding regions. FEBS J, 273 4831 41
Olaison L Pettersson G 2003Current best practices and guidelines. Indications for surgical intervention in infective endocarditis. Cardiol Clin, 21 235 51vii.
Garcia Rodriguez, L. A. Patrono C Patrignani P 2001Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs. J Clin Invest, 108 7 13
Patti J. M Allen B. L Mcgavin M. J Hook M 1994MSCRAMM-mediated adherence of microorganisms to host tissues. Annu Rev Microbiol, 48 585 617
Pawar P Shin P. K Mousa S. A Ross J. M Konstantopoulos K 2004Fluid shear regulates the kinetics and receptor specificity of Staphylococcus aureus binding to activated platelets. J Immunol, 173 1258 65
Ian Douglas, C. W. Plummer C Wu H Kerrigan S. W Meade G Cox D 2005A serine-rich glycoprotein of Streptococcus sanguis mediates adhesion to platelets via GPIb. Br J Haematol, 129 101 9
Prendergast B. D Tornos P 2010Surgery for infective endocarditis: who and when? Circulation, 121 1141 52
Raibaud S Schwarz-linek U Kim J. H Jenkins H. T Baines E. R Gurusiddappa S Hook M Potts J. R 2005Borrelia burgdorferi binds fibronectin through a tandem beta-zipper, a common mechanism of fibronectin binding in staphylococci, streptococci, and spirochetes. J Biol Chem, 280 18803 9
Jr., Moller, J. E., Skov, R. L., Larsen, C. T., Hansen, T. F., Mard, S., Smit, J., Andersen, P. S. & Bruun, N. E. Rasmussen R. V Host U Arpi M Hassager C Johansen H. K Korup E Schonheyder H. C Berning J Gill S Rosenvinge F. S Fowler V. G 2011Prevalence of infective endocarditis in patients with Staphylococcus aureus bacteraemia: the value of screening with echocardiography. Eur J Echocardiogr, 12 414 20
Remadi J. P Habib G Nadji G Brahim A Thuny F Casalta J. P Peltier M Tribouilloy C 2007Predictors of death and impact of surgery in Staphylococcus aureus infective endocarditis. Ann Thorac Surg, 83 1295 302
Rendu F Brohard-bohn B 2001The platelet release reaction: granules’ constituents, secretion and functions. Platelets, 12 261 73
Ruggeri Z. M 1999Structure and function of von Willebrand factor. Thromb Haemost, 82 576 84
Ruggeri Z. M 2009Platelet adhesion under flow. Microcirculation, 16 58 83
Ruggeri Z. M Mendolicchio G. L 2007Adhesion mechanisms in platelet function. Circ Res, 100 1673 85
Ruggeri Z. M Orje J. N Habermann R Federici A. B Reininger A. J 2006Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood, 108 1903 10
Santoro S. A Zutter M. M 1995The alpha 2 beta 1 integrin: a collagen receptor on platelets and other cells. Thromb Haemost, 74 813 21
Savage B Almus-jacobs F Ruggeri Z. M 1998Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell, 94 657 66
Semple J. W Freedman J 2010Platelets and innate immunity. Cell Mol Life Sci, 67 499 511
Sheu J. R Hsiao G Lee C Chang W Lee L. W Su C. H Lin C. H 2000aAntiplatelet activity of Staphylococcus aureus lipoteichoic acid is mediated through a cyclic AMP pathway. Thromb Res, 99 249 58
Sheu J. R Lee C. R Lin C. H Hsiao G Ko W. C Chen Y. C Yen M. H 2000bMechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets. Thromb Haemost, 83 777 84
Shiraki R Inoue N Kawasaki S Takei A Kadotani M Ohnishi Y Ejiri J Kobayashi S Hirata K Kawashima S Yokoyama M 2004Expression of Toll-like receptors on human platelets. Thromb Res, 113 379 85
Siboo I. R Chambers H. F Sullam P. M 2005Role of SraP, a Serine-Rich Surface Protein of Staphylococcus aureus, in binding to human platelets. Infect Immun, 73 2273 80
Siegel I Cohen S 1964Action of Staphylococcal Toxin on Human Platelets. J Infect Dis, 114 488 502
Tabuchi A Kuebler W. M 2008Endothelium-platelet interactions in inflammatory lung disease. Vascul Pharmacol, 49 141 50
Tang Y. Q Yeaman M. R Selsted M. E 2002Antimicrobial peptides from human platelets. Infect Immun, 70 6524 33
Thon J. N Italiano J. E 2010Platelet formation. Semin Hematol, 47 220 6
Thuny F Grisoli D Collart F Habib G Raoult D 2012Management of infective endocarditis: challenges and perspectives. Lancet, 379 965 75
Tzeng D. Y Deuel T. F Huang J. S Baehner R. L 1985Platelet-derived growth factor promotes human peripheral monocyte activation. Blood, 66 179 83
Varki A 1994Selectin ligands. Proc Natl Acad Sci U S A, 91 7390 7
Wahl S. M Hunt D. A Wakefield L. M Mccartney-francis N Wahl L. M Roberts A. B Sporn M. B 1987Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A, 84 5788 92
Ward J. R Bingle L Judge H. M Brown S. B Storey R. F Whyte M. K Dower S. K Buttle D. J Sabroe I 2005Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb Haemost, 94 831 8
Wilson W Taubert K. A Gewitz M Lockhart P. B Baddour L. M Levison M Bolger A Cabell C. H Takahashi M Baltimore R. S Newburger J. W Strom B. L Tani L. Y Gerber M Bonow R. O Pallasch T Shulman S. T Rowley A. H Burns J. C Ferrieri P Gardner T Goff D Durack D. T 2007Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc,138, 739-45, 747-60.
Yeaman M. R Tang Y. Q Shen A. J Bayer A. S Selsted M. E 1997Purification and in vitro activities of rabbit platelet microbicidal proteins. Infect Immun, 65 1023 31
Youssefian T Drouin A Masse J. M Guichard J Cramer E. M 2002Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood, 99 4021 9
Zhang G Han J Welch E. J Ye R. D Voyno-yasenetskaya T. A Malik A. B Du X Li Z 2009Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol, 182 7997 8004