key: cord-0901496-e43rde05
authors: Shannon, Oonagh
title: The role of platelets in sepsis
date: 2020-12-20
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12465
sha: 1ec178c98845b079e1f1b378be5c8457fed5d9ba
doc_id: 901496
cord_uid: e43rde05

A State of the Art lecture titled “The role of platelets in sepsis” was presented at the ISTH congress in 2020. Sepsis is a life‐threatening organ dysfunction caused by a dysregulated and multifaceted host response to infection. Platelets play a significant role in the coordinated immune response to infection and therefore in the inflammation and coagulation dysfunction that contributes to organ damage in sepsis. Thrombocytopenia has a high incidence in sepsis, and it is a marker of poor prognosis. The genesis of thrombocytopenia is likely multifactorial, and unraveling the involved molecular mechanisms will allow development of biomarkers of platelet function in sepsis. Such platelet biomarkers can facilitate study of antiplatelet interventions as immunomodulatory treatment in sepsis. Finally, relevant new data on this topic presented during the 2020 ISTH virtual congress are reviewed.

Sepsis is a life-threatening condition that can occur as a result of an infection. The most common causative agents are gram-positive bacteria such as Staphyloccoccus aureus and Streptococcus pneumoniae, followed by gram-negative bacteria such as Escherichia coli. 1 Sepsis is a significant global health problem. The World Health Organization issued a resolution on sepsis in 2017 that urged all member states to take action to increase awareness of sepsis and invest in the development of new diagnostic and treatment strategies. It has long been established that both the pathogenicity of the infecting microorganism and the underlying inflammatory response of the infected host contribute to morbidity in infection. 2 Sepsis occurs when immune response networks fail to control the pathogen and do not maintain the inflammatory response at the local site of infection. The pathogenesis of sepsis is a highly complex syndrome that involves multiple components of the immune, coagulation, and tissue homeostasis systems over time. 3 The most recent clinical guidelines (Sepsis 3) define sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection," 4 assessed using the Sequential Organ Failure Assessment (SOFA) score. The dysregulated host response in sepsis manifests first as a systemic inflammatory response (SIRS), followed by a compensatory anti-inflammatory response (CARS) and immune suppression. 5 The overall result is life-threatening collateral damage to host tissue and organs, the etiology of which is poorly understood (Figure 1 Intensive research is ongoing to characterize sepsis at the molecular level over time. 6, 7 An important aim is to identify distinct phenotypes and stages of sepsis, based on clinical and biomarker profiles 8 or genomic profiling, 9 and to target specific immunomodulatory therapies to these patient groups.

Experimental mouse models remain essential to enhance our understanding of sepsis. The strengths and weaknesses of individual sepsis models have been reviewed elsewhere. 10, 11 Translation of therapeutic success from mouse models to human clinical trials has failed in the majority of cases, and to address this challenge, recommendations for standardization of sepsis models have been proposed. 12 Nonetheless, experimental models in rodents remain a fundamental step in enhancing our knowledge of the pathobiology of sepsis. An overview of three broad categories of experimental sepsis models is given in Figure 2 , together with factors that will influence study design and reproducibility between models. The pathogenesis and outcome of sepsis in an experimental model should be monitored at multiple levels using biomarkers of pathogen load, inflammation, coagulation dysfunction, and organ damage. Administration of the bacterial endotoxin lipopolysaccharide (LPS) is the most commonly used model for sepsis. An overwhelming systemic inflammatory response is generated to a single pathogen-associated molecular pattern (PAMP) from gramnegative bacteria. This model recapitulates some of the key features of sepsis, but it does not take into account the multifactorial nature of infection or the influence of bacteria, in particular grampositive pathogens. To investigate multiple aspects of the dynamic F I G U R E 1 Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Gram-positive bacteria, gram-negative bacteria, viruses, or fungi can cause infection at a local site resulting in activation of the immune response. Sepsis occurs when an overwhelming systemic pro-inflammatory response is generated and compensatory anti-inflammatory responses fail to rebalance the systems to homeostasis. Significant damage is mediated to host tissue, resulting in organ dysfunction that can affect in six major systems. CNS, central nervous system host-pathogen interaction during sepsis, exogenous pathogenic bacteria are administered at a local site in a susceptible mouse strain. Alternatively, endogenous infection can be achieved by surgical disruption of the gastrointestinal tract, such as cecal ligation and puncture (CLP). A polymicrobial infection is initiated, and multiple components of the interaction between the host and the host-adapted pathogens can be assessed during sepsis progression. All three experimental models have generated important insights on the role of platelets in infection, inflammation, and sepsis. Observations made in a particular model will reflect distinct aspects of sepsis, and complementary models can be applied to determine the role of platelets in diverse infections and at distinct stages of sepsis.

The coagulation system encompasses a network of plasma proteins, endothelial cells, and platelets that collaborate to maintain vascular integrity. In response to endothelial disruption, platelet receptors are exposed to their ligands, von Willebrand factor (VWF), and collagens, resulting in adhesion and aggregation at the endothelium. Vessel damage also exposes tissue factor (TF) and a cascade of plasma serine proteases are activated to generate thrombin that cleaves fibrinogen to a fibrin clot. Thrombin is also a potent activator of endothelial cells and platelets, an example of the extensive crosstalk that exists between components of the coagulation system in health and disease. It has long been established that the coagulation system becomes activated by inflammation and is subsequently dysregulated in sepsis. 13 At the most advanced stage, disseminated intravascular coagulation (DIC) may occur. DIC results in fibrin deposition in the microvasculature and diminished fibrinolysis, which likely contributes to organ dysfunction in affected organs by impairing oxygen delivery to the tissue. 14 Coagulation dysfunction is clearly detrimental in sepsis, and anticoagulation therapy with heparins, antithrombin, or thrombomodulin may be beneficial for the treatment of DIC. 15 To achieve a successful outcome it would be important to administer anticoagulation therapy to an adequately stratified group of patients with confirmed DIC that may benefit from the intervention. During the initial immune response to an infection activation of the coagulation system may even contribute to immune defense and containment of pathogenic bacteria. Fibrin clot formation initiated in response to infection and inflammation has been reported to entrap bacteria and limit dissemination to the bloodstream and F I G U R E 2 The pathogenesis of sepsis is investigated in experimental models in mice. Sepsis can be modeled by systemic or local administration of a bacterial toxin, most commonly lipopolysaccharide (LPS), systemic or local administration of defined strains of pathogenic bacteria, or surgical manipulation to expose normally sterile sites to endogenous bacteria in the normal flora. The green boxes summarize key factors associated with the pathogen, the host and the experimental endpoint that should be considered in study design. CLP, cecal ligation and puncture model organs in a process designated "immunothrombosis." 16 The importance of fibrin formation for immune defense is implied by the fact that many successful pathogens produce virulence factors that can mediate plasmin activation and fibrinolysis at the bacterial surface, perhaps as a means to escape entrapment in a fibrin clot. 17 Further insight on the molecular mechanisms involved in dysregulation of the coagulation system in sepsis may yield biomarkers for improved stratification of patients for anticoagulation therapy or potentially identify novel therapeutic targets for organ supportive therapy.

Coagulation dysfunction contributes to the SOFA score of organ dysfunction in sepsis and the circulating platelet count is used for assessment. 15 Thrombocytopenia is a relatively common finding in critically ill patients within the intensive care unit (ICU). 18 The relative change in the platelet count over time after admission to the ICU can distinguish survivors from nonsurvivors. 19 The incidence of thrombocytopenia is particularly high in patients with sepsis, and the level of thrombocytopenia is a marker of poor prognosis associated with increased risk of bleeding, increased organ dysfunction and in some cases with an increased 28-day mortality. 20, 21, 22 Multiple mechanisms likely contribute to severe thrombocytopenia, which occurs late in the clinical progression of sepsis. Decreased platelet production, increased platelet activation and consumption in thrombi, or increased destruction may remove platelets from the circulation. It is therefore important to understand the multifaceted molecular mechanisms underlying thrombocytopenia to clarify the role of platelets and identify biomarkers of platelet function that occur earlier in the clinical progression of sepsis.

The immature platelet fraction and the mean platelet volume (MPV) are additional platelet biomarkers that can be monitored to assess platelet production. A recent systematic review concludes that an increase in circulating immature platelets is associated with severe sepsis and increased mortality. 23 This indicates that platelet production is not only maintained but also increased in sepsis.

Significant endothelial activation and dysfunction is a driving force for sepsis pathogenesis. The vascular integrity is compromised resulting in increased permeability, increased TF exposure and VWF release, downregulation of anticoagulant effectors, and an overall procoagulant status. 24 Platelets adhere and aggregate at the activated endothelium and provide a procoagulant membrane surface for additional fibrin clot formation in DIC. 25 Platelet consumption in these thrombi likely contributes to the thrombocytopenia observed in sepsis. A viscous cycle is generated since CD40L released by activated platelets stimulates further activation of the endothelium. 26 Platelet aggregates are observed in the organ microvasculature in a model of LPS-induced sepsis 27 and polymicrobial sepsis. 28 Platelet thrombi are present in the microvasculature in the liver, and this is associated with increased organ dysfunction in a model of polymicrobial sepsis 29 and a model of streptococcal sepsis. 30 

Increased platelet activation has been reported for patients with sepsis, although the sample size in these studies is often relatively small. The ex-vivo platelet population exhibits increased surfacebound thrombospondin and increased platelet-leukocyte complex formation, which correlates with organ dysfunction. 31, 32 Platelet aggregation in response to ex vivo stimulation is decreased, 33, 34 indicating that platelet activation has occurred in vivo. Upregulation of P-selectin to the activated platelet surface and platelet-monocyte complex formation is higher in patients with gram-positive sepsis than those with gram-negative sepsis, 35 suggesting that distinct platelet phenotypes may be associated with distinct pathogens.

Intriguingly, TF protein synthesis and platelet procoagulant activity is increased in a subpopulation of patients with sepsis. 36 In an elegant recent study, the platelet transcriptome and translatome were investigated in sepsis. 37 The gene encoding the αIIb subunit of the integrin complex, glycoprotein (GP) IIb/IIIa, was upregulated in human platelets and this was also confirmed for mouse platelets after CLP. It is apparent that platelet activation occurs in human sepsis and further elucidation of the distinct triggers and consequences of this activation may facilitate development of alternative and potentially more sensitive biomarkers of platelet function in inflammation and sepsis.

The role of platelets in sepsis was first investigated in terms of their 

Clawsson and coworkers first reported that platelets can directly bind to and entrap bacteria in platelet-bacteria aggregates. 44 Platelet activation and aggregation is now known to occur in response to many gram-positive bacteria, reviewed in Cox et al. 45 Importantly, multiple platelet receptors can be engaged directly by distinct bacterial proteins or indirectly using a plasma protein bridge. Recently, a common mechanism of platelet activation has been described for the significant human pathogens Staphylococcus aureus and Streptococcus pneumoniae. 46 The platelet IgG receptor FcγRIIA is critical for recognition of the IgG opsonized bacteria in collaboration with the platelet GPIIb/IIIa receptor, and release of platelet factor 4 (PF4) enhances this platelet activation. In subsequent work, it has been demonstrated that the gram-negative bacteria Escherichia coli is also recognized by platelet FcγRIIA in collaboration with GPIIb/ IIIa. 47 The evidence is clear that platelet activation occurs in response to bacteria; however, the consequences of these interactions for the platelet phenotype has not been investigated as extensively.

M protein released from Streptococcus pyogenes forms a complex with plasma fibrinogen and IgG engages the platelet GPIIb/IIIa and FcγRIIA receptors to mediate platelet activation. 48 This results in C1q acquisition and complement activation at the platelet surface and increased immune-mediated destruction of these platelets in vitro. 49 Mouse platelets lack the FcγRIIA receptor, which is a significant challenge to investigating these platelet-bacteria interactions in experimental models of sepsis. Importantly, FcγRIIA transgenic mice have been generated, and it is extremely beneficial to study bacterial sepsis and organ dysfunction in this background. 50 A recent study used FcγRIIA transgenic mice to demonstrate a dominant role for this receptor in immune complex-mediated thrombocytopenia and F I G U R E 3 Platelets in sepsis. Platelets are sentinel cells that patrol the bloodstream. Platelets can rapidly become activated in sepsis by either the pathogen, components of the activated coagulation system, or immune mediators. Activated platelets release granule proteins and extracellular vesicles (EVs), which exert immunomodulatory effects on endothelial cells and leukocytes. Activated platelets form homotypic platelet aggregates that can be stabilized by fibrin clots and build thrombi in the vasculature. Upon activation, platelets form heterotypic complexes with neutrophils or monocytes that directly influence immune cell function. DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns platelet sequestration in mouse models of systemic inflammation, including stimulation with immune complexes of IgG and LPS that are highly relevant to sepsis with gram-negative bacteria. 51 Collectively, these studies demonstrate that platelet activation and degranulation may follow thrombocytopenia, and further work should investigate this phenomenon for other bacteria and bacterial factors in in vivo experimental models.

The consequences of platelet activation for the bacteria are likely to be strain and species dependent. Activated platelets release bactericidal antimicrobial peptides, but not all bacteria are susceptible. 52 Platelet FcγRIIA is important for uptake and killing of IgG opsonized E coli. 53 Platelets can also exert PF4 and IgG-dependent bactericidal effects on E coli 54 and S aureus; however, S pneumoniae is not susceptible to this bactericidal mechanism. 55 S pyogenes is not killed by activated platelets in platelet-bacteria aggregates formed in vitro 56 and depletion of platelets before infection with S pyogenes is associated with decreased bacterial survival and dissemination, implying that platelets enhance streptococcal survival in this model. 57 In experimental mouse models of bacterial infection, the formation of platelet-bacteria aggregates is important for removing some bacterial species from the circulation in a sophisticated collaboration with complement C3, and tissue resident immune cells of the spleen and liver. 58, 59, 60 In experimental models of sepsis following lung infection, depletion of platelets before initiation of infection leads to increased bacterial growth at the local site of infection and an overall increased mortality. 61 Collectively, these studies demonstrate that platelets employ multiple bactericidal effects that contribute to immune defense. The anucleate platelet is not expected to migrate; however, a recent study applied state-of-the-art imaging techniques to demonstrate active platelet migration to sites of infection and subsequent aggregation with the infiltrating bacteria. 80 This results in immunomodulation, whereby neutrophil recruitment, phagocytosis, and NET formation are enhanced. PNC formation is not always beneficial for neutrophil function and pathogen-dependent phenotypes should be investigated. The M protein released from S pyogenes stimulates PNC formation in the absence of NET formation. 81 Fibrinogen is enriched in these PNCs, and neutrophils are functionally impaired, exhibiting decreased chemotactic ability as compared with thrombin-stimulated PNCs.

Platelets can avidly form PMCs; however, the impact on monocyte function has not been fully elucidated. Engagement of platelets can enhance monocyte adhesion to the activated endothelium, 71 | 33 SHANNON stimulate cytokine release, 82 and procoagulant activity. 83, 84 As previously described, ICU patients with sepsis exhibit thrombocytopenia.

Intriguingly, it has been demonstrated that these patients with thrombocytopenia exhibit increased systemic cytokine levels, in particular interleukin (IL)-8 and IL-10 and increased plasma markers of endothelial dysfunction. 85 This provides important evidence of an immunomodulatory role for platelets in the pathogenesis of sepsis in human patients.

Antiplatelet therapy in sepsis has been proposed to combat the contribution of platelets to organ dysfunction based on results from experimental models in mice and retrospective studies of human patients with sepsis. For example, administration of clopidogrel F I G U R E 4 The immunomodulatory effects of platelets on neutrophils and monocytes. Activated platelets upregulate surface receptors that mediate direct binding to neutrophils (A) and monocytes (B). Platelet activation is an important modulator of neutrophil and monocyte function during the immune response to infection and the pathogenesis of inflammatory disease. Activated platelets at the endothelium produce chemokines and provide an adhesive surface for both neutrophils and monocytes. Neutrophils in complex with platelets release their granule contents, exhibit increased phagocytosis, and increased neutrophil extracellular trap (NET) formation. Monocytes in complex with platelets upregulate procoagulant tissue factor (TF) to the surface and increase synthesis of key inflammatory mediators and cytokines before induction of sepsis decreases plasma markers of liver damage in a mouse model. 86 Pharmacological blockade of platelet production in response to thrombopoeitin decreases organ damage in the lungs and liver in mouse models of sepsis. 87 A retrospective study of critically ill patients indicates that antiplatelet therapy at the time of sepsis is associated with reduced mortality, 88 while in another study antiplatelet therapy was not associated with reduced mortality. 89 Since platelets exhibit a plethora of functions in inflammation and thrombosis at distinct stages of infection and sepsis, the correct timing of antiplatelet therapy needs to be carefully considered.

Enhanced understanding of the platelet phenotype in sepsis should facilitate identification of biomarkers for identification of patients with sepsis that will benefit from antiplatelet therapy and potentially reveal novel antiplatelet and anti-inflammatory targets.

Abstracts presented at the 2020 ISTH congress reported important insights on the pathogenesis of endothelial dysfunction and DIC in sepsis and the potential role of platelets in COVID-19. However, these valuable contributions are not the focus of this review and will not be discussed herein. A number of abstracts presented significant advances on the role of platelets in sepsis both in patient material and in experimental models.

The incidence of thrombocytopenia in patients with sepsis in the ICU was investigated by Russell and coworkers in a large multicenter patient cohort. 90 Platelet counts were monitored on admission to the ICU and followed for 5 days. On admission, 37% of patients were thrombocytopenic, and this had risen to 52% by day 3. Significantly, patients with thrombocytopenia had an increased 28-day mortality.

In a single-center cohort of ICU patients with sepsis, the platelet count and MPV, on addition of platelet agonists ex vivo, was investigated on inclusion in the study. 91 The MPV post-arachidonic acid stimulation was found to be significantly different between survivors and nonsurvivors.

In a single-center cohort of ICU patients, Hoppensteadt and In particular, GPVI-dependent signaling failed to occur, and the ability to recover this response over time was associated with increased survival. Collectively, these two studies confirm the relevance of mapping distinct platelet phenotypes in patients with sepsis.

Although platelet function was not under investigation in the work from Abrams and coworkers, 94 the work is an excellent example of how we can move forward to determine distinct biomarkers that can be used to identify patients with sepsis for tailored treatments.

The ability of plasma from ICU patients to induce NET formation on addition to isolated healthy neutrophils ex vivo was used to stratify patients into absent, mild, moderate, and strong NET formation.

Strong NET formation was associated with sepsis and predicted DIC and mortality. In a complementary mouse model of sepsis, similar results were obtained and anti-IL-8 therapy reduced NET formation and organ damage in this model. 94 Megakaryocytes are the precursor cells to platelets. Krauel and coworkers 95 report that LPS circulates in the blood and penetrates to the bone marrow of mice in a CLP model of sepsis.

IL-6 mRNA was upregulated in megakaryocytes from these mice.

This reveals an intriguing immunomodulatory role for megakaryocytes. Furthermore, the immunomodulatory role of platelets is highlighted in the abstract from Parra-Izquierdo and coworkers, 96 which describes the pathways involved in toll-like receptor 2/6 engagement on platelets and subsequently profiles the platelet activation responses that occur.

Platelets have emerged as important immune cells in the host defense to infection and consequently in the dysregulated response in sepsis. Activated platelets drive central events that contribute to organ dysfunction in experimental models of sepsis; however, additional insight is required both from experimental models and from patient cohorts. Future work should focus on clarifying molecular mechanisms underlying platelet phenotypes in distinct infections, distinct stages in the progression to sepsis, and organ-specific pathogenesis. Multiple parallel immune defense networks collaborate in the dysregulated responses in sepsis. It is increasingly clear that multicomponent biomarker profiles can characterize sepsis response in individual patients. Further, it is likely that in the future, platelet-derived biomarkers will be used to identify patients that might benefit from antiplatelet therapies.

All figures were created with Biorender, https://biore nder.com/

The authors declare no conflicts of interest.

https://orcid.org/0000-0001-8291-8189

The epidemiology of sepsis in the United States from 1979 through 2000

The damage-response framework of microbial pathogenesis

Severe sepsis and septic shock

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy

The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer?

The immunopathology of sepsis and potential therapeutic targets

Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis

van der Poll T, MARS consortium. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

Animal models of sepsis: setting the stage

Current gaps in sepsis immunology: new opportunities for translational research

Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis

Coagulation and sepsis

Sepsis, thrombosis and organ dysfunction

Scientific and Standardization Committee on DIC, and the Scientific and Standardization Committee on Perioperative and Critical Care of the International Society on Thrombosis and Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation

Blood coagulation in immunothrombosis-at the frontline of intravascular immunity

Fibrin and fibrinolysis in infection and host defense

How do we approach thrombocytopenia in critically ill patients?

Time course of platelet counts in critically ill patients

Thrombocytopenia in adult patients with sepsis: incidence, risk factors, and its association with clinical outcome

Thrombocytopenia and outcome in critically ill patients with bloodstream infection

Thrombocytopenia in septic shock patients-a prospective observational study of incidence, risk factors and correlation with clinical outcome

Immature platelets as a predictor of disease severity and mortality in sepsis and septic shock: a systematic review

Endothelial barrier dysfunction in septic shock

Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis

CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells

Complement-dependent accumulation and degradation of platelets in the lung and liver induced by injection of lipopolysaccharides

Impaired microvascular perfusion in sepsis requires activated coagulation and P-selectin-mediated platelet adhesion in capillaries

Hepatic platelet and leukocyte adherence during endotoxemia

The dynamics of platelet activation during the progression of streptococcal sepsis

Platelet activation and interaction with leucocytes in patients with sepsis or multiple organ failure

Platelet function in septic multiple organ dysfunction syndrome

Platelet function in sepsis

Whole blood impedance aggregometry as a biomarker for the diagnosis and prognosis of severe sepsis

Higher platelet reactivity and platelet-monocyte complex formation in gram-positive sepsis compared to Gramnegative sepsis

The septic milieu triggers expression of spliced tissue factor mRNA in human platelets

Sepsis alters the transcriptional and translational landscape of human and murine platelets

Nouvelle cuisine: platelets served with inflammation

Platelet secretion in inflammatory and infectious diseases

Platelets in inflammation and infection

The era of thromboinflammation: platelets are dynamic sensors and effector cells during infectious diseases

Platelets and infection-an emerging role of platelets in viral infection

Potential role of platelets in COVID-19: implications for thrombosis

Platelet interaction with bacteria. II. Fate of the bacteria

Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation

Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4

Human platelet activation by Escherichia coli: roles for FcγRIIA and integrin αIIbβ3

Severe streptococcal infection is associated with M protein-induced platelet activation and thrombus formation

Complement activation occurs at the surface of platelets activated by streptococcal M1 protein and this results in phagocytosis of platelets

The role of the human Fc receptor Fc gamma RIIA in the immune clearance of platelets: a transgenic mouse model

Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration

Antimicrobial peptides from human platelets

Human platelets efficiently kill IgG-opsonized E. coli

Platelets kill bacteria by bridging innate and adaptive immunity via platelet factor 4 and FcγRIIA

Activated platelets kill Staphylococcus aureus, but not Streptococcus pneumoniae-the role of FcγRIIa and platelet factor 4/heparinantibodies

Platelet activation by Streptococcus pyogenes leads to entrapment in platelet aggregates, from which bacteria subsequently escape

Platelets promote bacterial dissemination in a mouse model of streptococcal sepsis

A platelet-mediated system for shuttling bloodborne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3

Dual-track clearance of circulating bacteria balances rapid restoration of blood sterility with induction of adaptive immunity

Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance

Thrombocytopenia impairs host defense in gram-negative pneumonia-derived sepsis in mice

Platelets express functional toll-like receptor-4

Platelet toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo

Platelets interact with bacterial pathogens

Toll-like receptor 4 ligand can differentially modulate the release of cytokines by human platelets

LPS stimulation of purified human platelets is partly dependent on plasma soluble CD14 to secrete their main secreted product, soluble-CD40-ligand

Functional significance of the platelet immune receptors GPVI and CLEC-2

Platelet glycoprotein VI aids in local immunity during pneumonia-derived sepsis caused by gram-negative bacteria

Inflammation drives thrombosis after Salmonella infection via CLEC-2 on platelets

The podoplanin-CLEC-2 axis inhibits inflammation in sepsis

Platelets in leucocyte recruitment and function

Neutrophil extracellular traps kill bacteria

Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood

Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis

Extracellular DNA traps promote thrombosis

Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice

Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis

Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis

Inhibition of immunothrombosis does not affect pathogen capture and does not promote bacterial dissemination in a mouse model of sepsis

Migrating platelets are mechano-scavengers that collect and bundle bacteria

Platelet-dependent neutrophil function is dysregulated by M protein from Streptococcus pyogenes

Granzyme A in human platelets regulates the synthesis of proinflammatory cytokines by monocytes in aging

Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression

Platelet P-selectin triggers rapid surface exposure of tissue factor in monocytes

Molecular Diagnosis and Risk Stratification of Sepsis Consortium. Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients

Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis

Blockade of thrombopoietin reduces organ damage in experimental endotoxemia and polymicrobial sepsis

Do aspirin and other antiplatelet drugs reduce the mortality in critically ill patients? Thrombosis

Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: a historical cohort study

Thrombocytopenia in adult ICU patients with sepsis

Prognostic Value of Platelet-Derived Parameters in Septic Patients: A Prospective Study Res Pract Thromb Haemost

Biomarkers of Platelet Activation and their Prognostic Value in Patients in Sepsis

Acquired GPVI Deficiency Is a Biomarker for Early Diagnosis and Prognostic Assessment of Patients with

A Novel Neutrophil Extracellular Traps (NETs) Assay Predicts DIC and Stratifies Patients with Sepsis for Anti-IL-8

Megakaryocytes Are Reprogrammed by Lipopolysaccharide Exposure during

Toll-Like Receptor 2 Ligands Promote and Enhance Platelet Activation Res Pract Thromb Haemost

How to cite this article: Shannon O. The role of platelets in sepsis