key: cord-0693557-y8ux76b3 authors: Katz, Jason N.; Kolappa, Kamalkumar P.; Becker, Richard C. title: Beyond Thrombosis: The Versatile Platelet in Critical Illness date: 2015-12-16 journal: Chest DOI: 10.1378/chest.10-1971 sha: 39ae1255bf578428f00dcdb5422846fc94ce1c22 doc_id: 693557 cord_uid: y8ux76b3 Sepsis, acute lung injury, and ARDS contribute substantially to the expanding burden of critical illness within our ICUs. Each of these processes is characterized by a myriad of injurious events, including apoptosis, microvascular dysfunction, abnormal coagulation, and dysregulated host immunity. Only recently have platelets—long considered merely effectors of thrombosis—been implicated in inflammatory conditions and the pathobiology of these disease processes. A growing body of evidence suggests a prominent role for maladaptive platelet activation and aggregation during sepsis and ARDS and has begun to underscore the pluripotential influence of platelets on outcomes in critical illness. Not only do platelets enhance vascular injury through thrombotic mechanisms but also appear to help orchestrate pathologic immune responses and are pivotal players in facilitating leukocyte recruitment to vulnerable tissue. These events contribute to the organ damage and poor patient outcomes that still plague the care of these high-risk individuals. An understanding of the role of platelets in critical illness also highlights the potential for both the development of risk stratification schema and the use of novel, targeted therapies that might alter the natural history of sepsis, acute lung injury, and ARDS. Future studies of adenosine, platelet polyphosphates, and the platelet transcriptome/proteome also should add considerably to our ability to unravel the mysteries of the versatile platelet. in the activation of platelets. 9 Thromboxane A 2 induces aggregation and vascular smooth muscle contraction. Stimulation of adenosine diphosphate (ADP) receptors on the platelet surface results in alterations in platelet shape and supports further platelet aggregation. The metabolically primed armamentarium of the platelet extends beyond these cell surface receptors, however. Platelets also express and release a variety of adhesion molecules, mitogenic factors, and vasoactive compounds, all of which play key roles in modulating endothelial function, aggregation, and cellular interactions. These compounds include cytoplasmic substances such as serotonin, epinephrine, norepinephrine, nitric oxide, vascular endothelial growth factor, and transforming growth factor b 8 ; the selectins, which interact with cell surface glycoconjugates to mediate adhe sion and cellular communication 10 ; and mitochondrial lysosomes, which store and release potent glycosidases, proteases, and cationic proteins. 11 Platelets also contain a granules, which release important contributors to coagulation, 9 and dense granules, which release nonprotein molecules, including ADP, calcium, and serotonin, that modulate infl ammatory and thrombotic processes ( Table 1 ) . 11 It is well known that platelets are the primary effector cells of hemostasis, and their roles in both thrombosis and vascular repair have been well established. There are four main phases governing platelet function: (1) activation, (2) adhesion, (3) aggregation, and (4) secretion. Under the influence of substances, including thrombin, collagen, epinephrine, vasopressin, platelet-activating factor, and arachidonic acid metab olites, released from sites of tissue injury, platelets are activated and undergo robust rheologic transformation ( Fig 1 ) . When components of the suben dothelial matrix then become exposed to circulating blood, platelet glycoproteins critical illness is vitally important to those clinicians and investigators who hope to improve the care of these high-risk patients. Platelets are anucleate cells of myeloid origin that continuously fl ow in a quiescent state throughout the human vasculature. 7 Derived from megakaryocytes, the circulating platelet readies itself to perform a myriad of hemostatic, infl ammatory, and reparative tasks once activated. 8 Under conditions of heightened demand, platelet production can increase by as much as 20-fold. When summoned by tissue injury and infl ammation, this amplifi ed platelet offensive can then exert its infl uence on a variety of other cells directly or through the release of highly potent intracellular constituents. Platelet recruitment and adhesion are orchestrated by a number of specialized chemokines, adhesion molecules, and receptors. In particular, platelets express cell surface receptors called integrins. Integrins make up a large family of receptors that are constitutively expressed on the surface of many cells and whose job it is to facilitate both cell-to-cell and cellto-extracellular matrix interactions. 9 Perhaps the most well known and most abundant platelet integrin is the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. Following cellular activation, GP IIb/IIIa binds fi brinogen, fi brin, and other ligands, mediating adhesive events and stimulating platelet aggregation. Other integrins play key roles in adhesion, aggregation, thrombus formation, and vascular repair. In addition to the integrins, there are a number of G-protein-coupled receptors present on the platelet surface that promote platelet activation, changes in platelet rheology, and enhanced aggregation. Proteaseactivated receptor 1, for example, plays a pivotal role 15 Platelets have been shown to facilitate the leukocyte response, largely under the infl uence of P-selectin, which promotes leukocyteplatelet binding. 15, 16 Although platelets interact with most leukocyte subpopulations, it is their intimate relationship with neutrophils that seems to drive their primary role in host immunity. Endothelial-bound platelets can induce "secondary capture" of neutrophils by fi rst facilitating platelet-neutrophil interactions and then by directing subsequent neutrophil-endothelial cell contact. Neutrophils also are capable of rolling along a template of adherent platelets-an event regulated by numerous adhesive receptors and promoted by shear forces and alterations in cellular structure. 17 This rolling phenomenon is thought to be mediated largely by P-selectin, which directs leukocyte adherence and then supports leukocyte transmigration directly to the site of injury. 18 From a more clinical perspective, alterations in platelet number and function are frequently recognized in association with critical illness. In particular, the development of thrombocytopenia is commonplace, with an incidence ranging from 20% to nearly 50% across a spectrum of intensive care settings. 19, 20 When present, thrombocytopenia is independently associated with increased morbidity and mortality. 19, 20 and von Willebrand factor (vWF) mediate an intense adhesive process. Platelet aggregation fi rmly ensues, largely supported by the GP IIb/IIIa receptor, and these events are then ultimately reinforced by a potent milieu of vasoactive compounds secreted from the galvanized platelet offensive. 8 Platelets have long been considered by many to be vital participants in immune processes and, hence, potentially key instigators in a number of common infl ammatory diseases. Once activated, platelets release numerous secretory products and have been shown to express a multitude of receptors involved in the infl ammatory response ( Table 1 ). In atherosclerosis, for instance, activated platelets can release adhesive ligands such as P-selectin. P-selectin is capable of creating a phospholipid-rich platform that then facilitates the recruitment of mononuclear cells and lymphocytes to the atherosclerotic plaque. 7 Platelet activation has been associated with enhanced cytokine expression in other infl ammatory conditions, including acute coronary syndromes, coronary stent restenosis, and solid organ transplant rejection. 12, 13 Platelets also interact directly with other infl ammatory cells, helping to engineer both physiologic and pathologic immune events. Leukocytes, for instance, are known to play an important role in host defense when recruited to sites of infl ammation. 14 Although critical in helping to defend the host from invading Gawaz and colleagues 29 found that plasma from patients with sepsis increased both the adhesion and the aggregability of normal platelets to cultured endothelium. Mavrommatis et al 22 later showed that platelet activation was significantly increased in patients with sepsis compared with healthy control subjects. Others have demonstrated that sepsis results in increased P-selectin expression. 30 On the other hand, platelet function by aggregometry and fl ow cytometry was shown to be decreased in studies by Yaguchi et al, 31 and Boldt et al 32 demonstrated that aggregation decreased over time in a cohort of trauma patients who later developed sepsis. Recently, both human and murine platelets have been shown to express toll-like receptors 4 that facilitate platelet migration and deposition into tissue during sepsis. 33 It is possible that these pattern recognition receptors may represent a unique mechanism by which organ dysfunction develops in severe infection; further research, however, will be necessary to clarify this association. Acquired deficiencies in the plasma protease ADAMTS13 also may support the enhanced platelet activation that has been described in both sepsis and the systemic infl ammatory response syndrome. Nguyen and colleagues 34 reported functional decreases in ADAMTS13-the principle physiologic modulator of vWF in human plasma-among patients with sepsis. Others have demonstrated a stepwise decline in ADAMTS13 activity, which paralleled the extent of infl ammatory response in small samples of critically ill ICU patients. 35 The burden of evidence seems to support the notion that platelet activation and aggregation increase during sepsis. The result of this accelerated platelet response, and the mechanism of resulting tissue injury, is less well defi ned. Although small studies have shown that platelets can cause microvascular obstruction and tissue hypoperfusion, impairment in cardiac contractility, 36 and endothelial dysfunction as a consequence of platelet-induced apoptosis, 37 it is likely that a number of other poorly defi ned pathologic events contribute to the untoward infl uence of platelets on septic outcomes. One such mechanism of injury during sepsis may center around the aforementioned role that platelets play in leukocyte recruitment. Although this likely represents an adaptive response to facilitate host defense, there is mounting evidence to suggest that maladaptive platelet-leukocyte interactions can result in tissue injury. 38 In a study of polymicrobial sepsis, Asaduzzaman et al 39 found that signifi cant lung injury resulted from enhanced pulmonary What has been less well established is a causal relationship between thrombocytopenia and critical care outcomes. Whether thrombocytopenia represents platelet activation and consumption as a primary pathologic event or merely serves as a marker for disease severity is unknown. This uncertainty is a consequence of the myriad of conditions known to infl uence circulating platelet numbers in heterogeneous ICU patients, rendering it diffi cult for investigators to account for all potential confounders in clinical research. Critically ill individuals may have diminished platelet production due to medication effects, bone marrow suppression, nutritional deficiencies, and infection. They also may have enhanced platelet elimination due to splenic sequestration, consumption related to disseminated intravascular coagulopathy, and thrombocytopenia as a result of hemodilution. Immunologically mediated thrombocytopenia and spurious thrombocytopenia also can introduce complexity into a patient's evaluation and ICU course. Thrombocytopenia is a poor prognostic marker and a rather powerful predictor of mortality in patients with sepsis and septic shock, 21 and the magnitude of platelet reduction seems to correlate with the severity of illness. 20, 22 In ALI and ARDS, the development of clinical thrombocytopenia and its infl uence on outcomes are poorly understood. In small patient series representing noncontemporary treatment eras, thrombocytopenia was believed to occur in as many as 50% of patients with ARDS. 18, 23 The degree of thrombocytopenia has been shown to parallel the course of progressive hypoxemic respiratory failure 24 but has been inconsistently associated with mortality. 24, 25 More recently, thrombocytopenia has been described as a prominent feature among patients with severe acute respiratory syndrome, a rapidly progressive coronavirus-associated respiratory illness resulting in a global outbreak of ALI and shock. 26 There are confl icting data about platelet function and response to stimuli in critically ill patients with sepsis. Some would suggest that the septic milieu, in part infl uenced by lipopolysaccharide and endotoxemia, promotes enhanced platelet aggregation, leading to microvascular obstruction and tissue injury. 27 Others have argued that aggregation and platelet responsiveness actually decrease in patients with sepsis, 28 whereas still others have suggested that activation may in fact be enhanced during sepsis but that signifi cant platelet degranulation only occurs in those who are most severely decompensated. 29 increased neutrophil adhesion and activation resulted from thromboxane A 2 produced by platelet-neutrophil aggregates. Efforts to deplete platelets or disrupt these aggregates resulted in reduced neutrophil migration and permeability, improved gas exchange, and better survival. Enhanced platelet activation and secretion also have been supported by several other clinical and preclinical studies of ALI. In a ventilator stressinduced model of ARDS, Yiming et al 47 demonstrated increased expression of vWF, glycoprotein Ib, and P-selectin on the endothelial surfaces of rat and mice lungs. In a bronchoscopic study of patients with lung injury, Idell and colleagues 48 found that levels of platelet-specifi c a -granule proteins were elevated in BAL fl uid from injured tissue and directly correlated with the degree of pulmonary injury. In a study of critically ill patients, investigators not only found that in vivo platelet activation was more robust among those with acute respiratory failure but also showed that marked platelet dysfunction, characterized by impaired aggregation and prolonged bleeding time, was a typical feature in these individuals. 49 A careful review of several currently used evidencebased therapies for ALI and ARDS provides additional insight into the potential pathologic role of platelet-mediated events. A host of clinical studies have helped to defi ne contemporary treatment strategies for this critical illness, and several of these therapies share, in part, an ability to modify mechanisms of platelet activation and aggregation. Perhaps the most well-validated strategy to reduce mortality is the use of low-tidal-volume ventilation, 2 and, in fact, the use of injurious high-tidal-volume ventilation has been shown to upregulate both vWF and P-selectin expression. 47 Using lung-protective positive pressure ventilation, however, is associated with decreased ADP-and collagen-mediated platelet aggregation. 50 Nitric oxide, another therapy often used in ARDS/ALI despite limited data to support its routine use, has been shown to decrease platelet aggregation by reduc ing fi brinogen binding to the GP IIb/IIIa receptor. 51 As well, the controversial use of corticosteroids in ARDS 52 has been associated with decreased platelet activation and activity in some experimental models. 53, 54 Although not suggesting that these therapies improved lung injury through their platelet-modifying effects alone, these data do support a biologic plausibility that should be considered when studying the impact of dysregulated platelet activity on patient outcomes ( Fig 2 ) . Although there is growing evidence to suggest a pathologic role for platelets in a number of infl ammatory infiltration of platelet-bound neutrophils. Other investigators have demonstrated that inhibition of platelet-associated neutrophil recruitment can mitigate all forms of end-organ damage, helping to establish a causal relationship between plateletneutrophil interactions and the pathologic injury seen in severe sepsis. 40, 41 It has been proposed that platelets recruit neutrophils to sites of tissue injury and infl ammation, resulting in subsequent damage through a variety of mechanisms. Platelet-neutrophil aggregates may become trapped within narrow sites of organ microvasculature, leading to regional ischemia. Kirschenbaum and colleagues, 42 for instance, showed that formation of these aggregates had a pronounced effect on altering blood rheology in patients with sepsis, a process that the investigators believed contributed significantly to impairments in perfusion. Platelets also may adhere directly to infl amed endothelial cells and promote secondary capture of toxic circulating leukocytes. This mechanism has been supported by several small studies in which targeted inhibition of platelet-specifi c ligands on neutrophils reliably attenuated sepsis-associated endothelial injury. 29, 43 Circulating platelet-neutrophil complexes and plateletstimulated neutrophil extracellular trap formation also can be seen in the patient with sepsis. These neutrophil extracellular traps are believed to represent a subset of activated neutrophils with enhanced ability to adhere, phagocytose, and produce injurious superoxide. 43 Finally, other data suggest that lymphotoxicity and lymphoid cell apoptosis may result from sepsis-induced alterations in platelet mRNA profi les. 44 Dysregulated hemostasis and enhanced infl ammation are hallmark pathophysiologic events associated with both ALI and ARDS. Postmortem series of patients with ARDS have shown that platelet deposition within the damaged pulmonary microvasculature is commonplace. 45 Ultrastructural examinations of lungs from patients with ARDS have consistently shown platelet accumulation and platelet-fi brin deposition occurring within pulmonary arteries, arterioles, and capillaries as well as within both the pulmonary interstitial and the alveolar compartments of affected individuals. 46 As in sepsis, platelet-neutrophil interactions seem to play a dominant role in tissue injury seen during ARDS. In a murine model of acid-induced lung injury, Zarbock and colleagues 41 demonstrated that tially reduced in animals who were treated with aspirin. 57 Among healthy volunteers, however, there is little compelling evidence to support an antiinfl ammatory effect of aspirin, 58 and studies among patients with both acute and chronic infl ammatory conditions have yielded mixed results. In patients with chronic, stable angina, for instance, aspirin signifi cantly lowered CRP and infl ammatory cytokine levels. 59 Conversely, in other patients with chronic ischemic heart disease, recent myocardial infarction, and acute coronary syndromes, aspirin failed to reliably reduce CRP. 60, 61 In peripheral arterial disease as well, markers of platelet-mediated infl ammation were not signifi cantly decreased with aspirin therapy. 62 There is also confl icting evidence regarding the potential of aspirin to mitigate pathologic infl ammatory interactions between platelets and leukocytes. 62, 63 Clopidogrel: Clopidogrel (Plavix), an irreversible antagonist of the G-protein-coupled platelet ADP receptor (P2Y12), has been shown to have a greater infl uence on cardiovascular risk reduction among patients at heightened inflammatory states. In a post hoc analysis of the Clopidogrel for the Reduction of Events during Observation trial, a study of prolonged clopidogrel therapy following percutaneous coronary intervention (PCI), there was a signifi cant (44%) rela tive risk reduction in the combined end point of death, myocardial infarction, or stroke at conditions, including sepsis and ALI, there are far fewer data to support targeted antiplatelet strategies as therapeutic options for managing affl icted patients. Such a strategy, however, is not without historical merit. For years now, the cardiovascular community has been espousing the benefi ts of antiplatelet agents for reducing infl ammation in both acute and chronic atherosclerotic diseases. With this as a platform for novel investigation, there is now burgeoning interest in platelets as therapeutic targets for patients with critical illness. Aspirin: Within a subset of patients enrolled in the Physicians' Health Study, a randomized trial of aspirin vs b -carotene for the primary prevention of cardiovascular disease, the use of aspirin was associated with a signifi cant reduction in the risk of myocardial infarction predominantly among patients with the highest C-reactive protein (CRP) values. 55 This fi nding was among the fi rst pieces of clinical evidence to suggest a possible antiinfl ammatory role for commonly used antiplatelet therapies. Aspirin also has been shown to have inhibitory effects on the activity of nuclear factor k b , a transcription factor that is required for the expression of genes encoding a variety of infl ammatory molecules. 56 In a mouse model of atherosclerosis, the normally enhanced nuclear factor k b activity was substan- Figure 2 . A, Infl uence of platelet and platelet-neutrophil interactions on the pathophysiology of sepsis and, B, ALI. In sepsis, platelets may be stimulated by tissue injury, hypoxia, cytokines, LPS, and endotoxemia, leading to microvascular obstruction, cellular necrosis/apoptosis, and an enhanced leukocyte response. In ALI, platelets and platelet-neutrophil complexes can similarly be found within the pulmonary vasculature, airways, interstitial, and alveolar compartments. ALI 5 acute lung injury; LPS 5 lipopolysaccharide. © 2011 American College of Chest Physicians by Kimberly Henricks on March 2, 2011 chestjournal.chestpubs.org Downloaded from requiring surgery. When adjusted for differences in baseline characteristics and disease severity, however, antiplatelet therapy use was associated with substantially reduced mortality in both groups. In a single-center study of hospitalized patients with community-acquired pneumonia, 20% of whom had received antiplatelet agents for the secondary prevention of cardiovascular disease, Winning et al 77 found antiplatelet drug use to be associated with a reduction in length of stay and the need for ICU care. Later, in a retrospective study conducted in a mixed medical-surgical ICU, these same investigators found that preexistent treatment with antiplatelet agents reduced the odds ratio for mortality by nearly fi vefold. 78 Even in patients with signs of active bleeding, including life-threatening intracranial hemorrhage and transfusion-dependent anemia, there still was a strong association between antiplatelet drugs and improved outcomes. This association was most robust among those patients with the greatest disease severity. 78 Although limited by the retrospective nature of these analyses and modest design challenges, these data still speak to the potential role of platelets as therapeutic targets among heterogeneous critical care populations. The impact of antiplatelet agents on circulating platelets and markers of infl ammation during systemic infection has yet to be clarifi ed, despite increasing study in both animal and human models. In early studies of antiplatelet drugs in endotoxemic pigs, pretreatment was found to have minimal effects on the pathogenesis of Escherichia coli -induced shock. Despite platelet targeting, clinical sepsis ensued in these animals, with concomitant decreases in levels of platelets along with activation of both the coagulation and fi brinolytic systems. 79 Clopidogrel also had no demonstrable effect on hemostatic or infl ammatory responses of pigs infused with E coli endotoxin. 80 However, when specifi cally using clopidogrel in other animal models of sepsis, several investigators have reported that not only is platelet activation reduced but also clinical thrombocytopenia is attenuated, clot formation is decreased, cytokine upregulation is mitigated, and neutrophil recruitment may be minimized. 68, 81 Antiplatelet Agents in ALI and ARDS Even fewer data exist regarding antiplatelet strategies in critically ill patients with lung injury. Targeted platelet depletion or disruption of plateletneutrophil interactions in murine models of ARDS resulted in reduced neutrophil migration and permeability, improved alveolar gas exchange, and increased survival. 41 Aspirin use in an experimental 12 months for those patients in the highest tertile of high-sensitivity CRP levels. 64 Likewise, shorter-term cardiovascular events were reduced following PCI in those patients pretreated with clopidogrel who had elevated baseline CRP values. 65 Unlike aspirin therapy, however, clopidogrel administration has been shown to reduce the secretion of adhesive ligands and to block the formation of plateletleukocyte conjugates, with resulting decreases in leukocyte activity. In patients treated with PCI, clopidogrel reduced ADP-and thrombin receptor-activating peptide-induced expression of the platelet P-selectin. 66 Evangelista and colleagues 67 showed that clopidogrel use had a potent inhibitory effect on platelet-dependent production of reactive oxygen species in neutrophils, as well as monocyte expression of tissue factor. Klinkhardt et al 68 found that more-prolonged clopidogrel pretreatment could signifi cantly reduce the volume of both platelet-monocyte and plateletneutrophil aggregates following ADP stimulation, effects that correlated directly with substantial reductions in P-selectin expression. Similarly, clopidogrel therapy has been shown to reduce platelet-neutrophil and platelet-monocyte conjugates in patients across a spectrum of vascular diseases. 62, 69 Other Antiplatelet Agents: Confl icting data have come from studies of the GP IIb/IIIa receptor antagonists in infl ammatory conditions. Modest levels of receptor blockade actually have been associated with increases in platelet-mediated proinfl ammatory effects, along with enhanced expression of P-selectin, 70 and increased release of soluble CD40 ligand. 71 Furthermore, although the synthetic small-molecule GP IIb/IIIa inhibitor eptifi batide (Integrilin) signifi cantly reduced levels of CRP at 24 h compared with placebo in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy trial, levels subsequently increased beyond baseline 30 h following infusion. 72 On the other hand, abciximab (ReoPro), a chimeric Fab fragment of a monoclonal antibody with high affi nity for the GP IIb/IIIa receptor, was found to suppress the usual rise in levels of circulating infl ammatory markers following percutaneous transluminal coronary angioplasty. 73 Finally, among small populations of patients treated with tirofi ban (Aggrastat), data have been largely inconclusive. 74, 75 In general, there has been limited study of antiplatelet therapeutic strategies in critical care populations. Lösche and colleagues 76 found that antiplatelet drugs were associated with a slight reduction in mortality among patients with nonsurgical critical illness and a slightly increased mortality rate among those disease. 86 A more-integrated understanding of platelet biology undoubtedly will allow for improved clarifi cation of the adaptive and maladaptive infl uences of platelets in critical illness. The potential for identifying molecular signatures of pathologic platelet activity also could provide an ambitious platform for studying patient variation in disease response, establishing novel risk stratifi cation tools, and developing future therapeutic targets. As critical care investigators and practitioners, we only recently have begun to understand the true versatility of the human platelet. A more concerted, multidisciplinary effort to unravel the mysteries of the platelet during critical illness clearly will be important if we hope to minimize the devastating impact of sepsis, ALI, and ARDS on an ever-expanding patient population. transfusion-related ALI model did not prevent neutrophil seques tration; however, the neutrophils that infi ltrated the pulmonary parenchyma were rendered incapable of causing lung toxicity. 82 Further study clearly is needed to build on these preliminary data in order to clarify the intriguing potential of therapeutic platelet targeting in lung injury populations. The role of platelets in the pathophysiology of critical illness continues to be elucidated, particularly with respect to lung injury where our understanding is woefully incomplete. No longer are these anucleate cells considered merely executors of the thrombotic process but, instead, are clearly key contributors to the host immune response. Although initially adaptive, unregulated platelet activation during sepsis, ALI, and ARDS leads to organ hypoperfusion, pathologic tissue injury, and poor patient outcomes. Whether modulation of this platelet response will improve the high morbidity and mortality associated with these diseases remains to be seen. Small, nonrandomized clinical studies of antiplatelet strategies have yielded mixed results but should prompt additional investigation. Following on the heels of these early discoveries, future study may further capitalize on the relationship between platelets and platelet receptors in human critical illness. Building on circumstantial evidence from trials of contemporary antiplatelet therapies, some investigators have begun to focus greater attention on the role of adenosine and its myriad of receptors on the pathobiology of infl ammation. During conditions of high metabolic stress, as seen in acute tissue injury and sepsis for instance, extracellular adenosine concentrations often are markedly increased. 83 Adenosine is believed to play an important role in preventing neutrophil infi ltration into vulnerable tissue, 84 and a growing body of data suggests a possible role for adenosine in modulating adaptive immune response to critical illness. Likewise, increased attention has and should be directed toward the infl uence of platelet polyphosphates as both proinfl ammatory and procoagulant mediators during acute illness. Recent investigation has shown that polyphosphates help to trigger fi brin formation and facilitate capillary leakage, which is commonplace among ICU patients. The polyphosphates also seem to play a role in preserving cellular integrity and modulating neutrophil response during infl ammation. 85 With advances in high-throughput experimental technologies, researchers are now beginning to characterize the full complement of transcripts and functionally relevant proteins that contribute to the versatility and complexity of platelets in human Epidemiology of acute lung injury and acute respiratory distress syndrome Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome The epidemiology of sepsis in the United States from 1979 through 2000 Treating patients with severe sepsis Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care Infl uence of rheologic changes and platelet-neutrophil interactions on cell fi ltration in sepsis Platelets in sepsis Amicus or adversary: platelets in lung biology, acute injury, and infl ammation Platelet function in septic multiple organ dysfunction syndrome Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis Platelet aggregation is impaired at the level of cyclo-oxygenase and thromboxane synthetase in severe sepsis Platelet function in critically ill patients Platelets express functional Toll-like receptor-4 Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis Infl ammationassociated ADAMTS13 defi ciency promotes formation of ultra-large von Willebrand factor Plateletderived exosomes from septic shock patients induce myocardial dysfunction Endothelial cell apoptosis induced by bacteria-activated platelets requires caspase-8 and -9 and generation of reactive oxygen species Neutrophils in development of multiple organ failure in sepsis Platelets support pulmonary recruitment of neutrophils in abdominal sepsis Platelet-dependent accumulation of leukocytes in sinusoids mediates hepatocellular damage in bile duct ligation-induced cholestasis Complete reversal of acidinduced acute lung injury by blocking of platelet-neutrophil aggregation Importance of platelets and fibrinogen in neutrophil-endothelial cell interactions in septic shock Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing Sepsis alters the megakaryocyte-platelet transcriptional axis resulting in granzyme B-mediated lymphotoxicity Intravascular coagulation associated with the adult respiratory distress syndrome Structural alterations of lung parenchyma in the adult respiratory distress syndrome Platelets enhance endothelial adhesiveness in high tidal volume ventilation Plateletneutrophil-interactions: linking hemostasis and infl ammation The role of selectins in infl ammation and disease The platelet release reaction: granules' constituents, secretion and functions Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction Platelet functions beyond hemostasis Regulation of leukocyte transmigration: cell surface interactions and signaling events Platelet, but not endothelial, P-selectin is critical for neutrophil-mediated acute postischemic renal failure The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte-endothelial and leukocyte-platelet interaction Simulation of cell rolling and adhesion on surfaces in shear fl ow: general results and analysis of selectin-mediated neutrophil adhesion Getting to the site of infl ammation: the leukocyte adhesion cascade updated Thrombocy topenia in the intensive care unit Thrombocytopenia and prognosis in intensive care Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome Coagulation system and platelets are fully activated in uncomplicated sepsis The risk factors, incidence, and prognosis of ARDS following septicemia Adult respiratory distress syndrome. Prognosis after onset Adult respiratory distress syndrome. Sequence and importance of development of multiple organ failure. The Prostaglandin E1 Study Group The severe acute respiratory syndrome An investigation into the effects of bacterial lipopolysaccharide on human platelets Endotoxinmediated inhibition of human platelet aggregation Platelet-specifi c alphagranule proteins and thrombospondin in bronchoalveolar lavage in the adult respiratory distress syndrome Platelet function in acute respiratory failure Hemostatic alterations in patients with obstructive sleep apnea and the implications for cardiovascular disease Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis Methylprednisolone prevention of increased lung vascular permeability following endotoxemia in sheep Glucocorticoids prevent NF-kappaB activation by inhibiting the early release of platelet-activating factor in response to lipopolysaccharide Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factoralpha secretion. Signal integration and NF-kappa B translocation Effect of low-dose aspirin on vascular infl ammation, plaque stability, and atherogenesis in low-density lipoprotein receptordefi cient mice Effects of aspirin (325 mg/day) on serum high-sensitivity C-reactive protein, cytokines, and adhesion molecules in healthy volunteers Increased proinfl ammatory cytokines in patients with chronic stable angina and their reduction by aspirin Relationship between effects of statins, aspirin and angiotensin II modulators on high-sensitive C-reactive protein levels COX-2 inhibitor, lowers C-reactive protein and interleukin-6 levels in patients with acute coronary syndromes Clopidogrel but not aspirin reduces P-selectin expression and formation of platelet-leukocyte aggregates in patients with atherosclerotic vascular disease Aspirin treatment does not attenuate platelet or leukocyte activation as monitored by whole blood fl ow cytometry Levels of hs-CRP prior to PCI predict long-term risk and the benefi t of clopidogrel therapy: a CREDO substudy Effect of clopidogrel added to aspirin before percutaneous coronary intervention on the risk associated with C-reactive protein Effect of clopidogrel pretreatment on infl ammatory marker expression in patients undergoing percutaneous coronary intervention Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation but not abciximab, reduces platelet leukocyte conjugates and P-selectin expression in a human ex vivo in vitro model Clopidogrel inhibits platelet-leukocyte interactions and thrombin receptor agonist peptide-induced platelet activation in patients with an acute coronary syndrome Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation Eptifibatide blocks C-reactive protein increase after coronary angioplasty Abciximab suppresses the rise in levels of circulating infl ammatory markers after percutaneous coronary revascularization Effect of tirofi ban on C-reactive protein in non-ST-elevation myocardial infarction Effects of tirofi ban on acute systemic infl ammatory response in elective percutaneous coronary interventions Antiplatelet drugs reduce mortality in surgical and non-surgical patients Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms Antiplatelet drugs and outcome in mixed admissions to an intensive care unit Coagulation and fi brinolytic reactions in experimental porcine septic shock: pretreatment with different antiplatelet factors Early endotoxin-mediated haemostatic and infl ammatory responses in the clopidogrel-treated pig Benefi cial effect of clopidogrel in a mouse model of polymicrobial sepsis Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury Platelet polyphosphates are proinfl ammatory and procoagulant mediators in vivo Platelet genomics and proteomics in human health and disease High adenosine plasma concentration as a prognostic index for outcome in patients with septic shock Adenosine: an endogenous modulator of innate immune system with therapeutic potential Financial/nonfi nancial disclosures: The authors have reported to CHEST the following confl icts of interest: Dr Katz has received research support from the Medicines Company. Dr Becker has received research support from AstraZeneca, Bayer Pharmaceuticals, Regado Biosciences Inc, and Schering-Plough Research Institute and has been an advisory board member for Merck, Eli Lilly, and Daiichi. Dr Kolappa has reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Brian Jensen, MD, for his critical review and editorial assistance with this manuscript.