Some pro-inflammatory and anti-inflammatory cytokines.
The hemostatic system is composed of primary hemostasis and coagulation on the one hand, and natural regulatory anticoagulant protein mechanisms and fibrinolysis, on the other hand. Under physiological conditions, these processes are balanced. Under septic conditions, coagulopathy may followed by disseminated intravascular coagulation (DIC). Tissue factor (TF) pathway is regarded to be the core way for activation of the coagulation cascade in sepsis. TF is triggered by pro-inflammatory mediators, encompassing cytokines, C-reactive protein, and advanced glycation end products in peripheral blood cells and on microparticle molecules. Once a septic patient develops DIC, a significant increase in the susceptibility of developing organ dysfunction, morbidity, and mortality may occur. This work was basic elucidation of the idea that coagulation and its inhibitors are of major importance in coagulation-inflammation noise, similarly as in cure from sepsis.
- diagnostic criteria
Sepsis is a confounding clinical condition that emerges when a patient responds unfavorably to a disease and creates organ dysfunction as an outcome. It can influences all the intents and purposes of organ framework; however, organ involvement and the level of dysfunction will change remarkably between patients. It will end in death in extreme cases. Sepsis is these days formally distinct as a dysregulated host reflection to disease, triggering perilous organ pathology . This new definition, working with clinical measures, will ideally give a lot of grounded, increasingly predictable base to better illuminate occurrence, results, and survey. The impact of sepsis is implausibly florid, and therefore the infectious track will vary significantly among patients. So far, sepsis has not been resolved and determined crucially in several cases. Determination often depends upon the practician pattern as authoritative microbiological proof of Associate in Nursing encouraging contamination is frequently missing. Besides, endeavors to find an association in nursing enchantment remedy and sepsis have been in vain .
Management is primarily supported with resuscitation, organ backup and wipe out the dependent contagion with antibiotics ± supply control . On an increasingly affirmative note, our comprehension of sepsis has significantly amplified, and superior diagnostics are being created to help recognizable proof and focus on the potion and timing of restorative medications. In developing nations, sepsis has a consolidated recurrence of 2.5 million patients for each year and demise extent of roughly 650,000 patients consistently . This would mean, usually 19 million instances of sepsis a year, internationally, with roughly 5 million deaths . This estimation is probably going to be uncontrollably inaccurate, as there is a general absence of intensive medical specialty data on low- and middle-income countries. The absence of good essential consideration, sufficient infection control, convenient anti-microbial treatment, poor staffing levels, and satisfactory basic care arrangement represents a totally distinctive circumstance in these nations. The World Health Organization gives extra insight regarding this problem. As indicated by WHO data, three irresistible infections were among the 10 most important reasons for death worldwide in 2015: lower respiratory disorder, diarrheal disease, and tuberculosis with a consolidated mortality of 7.3 million individuals .
Most of those fatalities happen in developing countries. Similarly, most die from sepsis as infection, while not organ dysfunction cannot be touch-and-go. The death rate of sepsis is declining within the developing countries, to some extent due to the very fact that of previous acknowledgment and clinical administration nevertheless additionally on the grounds that expanded acknowledgment has considerably expanded the denominator . Sepsis might not usually be recorded because the reason for death may be attributed of various comorbidities, as an example, cancer or cardiovascular issues. Death in a septic patient may be connected to a secondary or an unrelated sequel .
2. Sepsis and coagulation
Sepsis is associated with intense and conceivably dangerous sequel of infection. Sepsis happens when host defense mediators are discharged into the circulation to battle the infection evoking fundamental inflammatory responses all through the body . About two-hundredth of patients with infection die within the emergency clinic, and extreme sepsis prompts a death rate of around four-hundredth [3, 4].
Sepsis is reliably connected with coagulation variations . These variations emerge from activation of coagulation that must be distinguished by profoundly delicate examines for hemostatic factor assays to some degree progressively extreme coagulation activation that might be recognizable by an inconspicuous fall in thrombocyte count check and subclinical prolongation of worldwide hemostatic factors characteristics to squeaky disseminated intravascular coagulation (DIC), demonstrated by plentiful microvascular occlusion in very little and medium-size veins and synchronous diffused bleeding from totally different sites [5, 6, 7]. Septic patients and intensive cases of DIC might evidence thromboembolic involvements or clinically less clear microvascular clot development, which will boost multiple organ failure [6, 8]. In several cases, intensive hemorrhage may well be the predominant presentation ; also, a lot of the time, sepsis and a DIC cause synchronous thrombosis and bleeding. Hemorrhage is owed to consumption and consequent depletion of coagulation factors and platelets, brought by progressing activation of the hemostatic system . Furthermore, this conjunction might present because the Waterhouse-Friderichsen syndrome, unremarkably highlighted throughout fulminant meningococcal septicemia, and despite numerous different microorganisms may cause this clinical circumstance .
3. Recurrence of clinically relevant coagulopathy in sepsis
Clinically vital hemostatic changes might happen in up to 70% of septic patients. Furthermore, concerning 35% of patients with sepsis can fulfill the standard criteria for DIC [12, 13]. Most septic patients can create thrombocytopenia (platelet count less than 150 × 109/l) [14, 15]. Usually, blood thrombocyte count reduces within the initial 4 days following admission to the emergency clinic . The seriousness of sepsis relates uniquely to the decline in platelet count . Basic causes of thrombocytopenia in sepsis are diminished platelet production, upgraded consumption, or sequestration in the spleen. Diminished generation of megakaryocytes in the bone marrow may appear to be indiscernible with the elevated levels of platelet production-stimulating pro-inflammatory mediators, for instance, tumor necrosis factor (TNF)-α and interleukin (IL)-6, and raised values of thrombopoietin in patients with sepsis, which presumptively ought to trigger megakaryopoiesis . However, in a very sizable proportion of septic patients, hemophagocytosis happens, involving dynamic phagocytosis of thrombocyte progenitors and other diverse hematopoietic cells by mononuclear cells, clearly fetching by raising the concentration of macrophage stimulating factor (M-CSF) in sepsis . Thrombocyte utilization is outwardly likewise critical in sepsis, due to thrombocyte activation optional to ongoing advancement of thrombin.
Platelet activation, excessive utilization, and devastation occur at the endothelial surface because of the rule of endothelial cell-platelet interplay in sepsis, even though the degree may differ between completely different vascular beds of assorted organs . Elongation time of hemostatic analyses, like prothrombin clotting time (PT) or the kaolin-cephalin clotting time (KCCT), is noticeable in 15–30% of septic patients . Hemostatic changes involve high fibrin split products items (in quite 95% of patients) [22, 23] and scanty values of natural regulatory anticoagulant proteins, for instance, anti-thrombin and protein C (90% of septic patients) [23, 24].
4. Tracks prompting coagulation adjustments in sepsis
In the recent three decades, the tracks engaged in hemostatic disorder of sepsis are explained for a significant part . Unmistakably different components in the coagulation system act at the same time toward a prohemostatic state. Obviously the most significant variables that intercede with this derangement of the coagulation system during sepsis are cytokines. Abundant proof shows a broad crosstalk among inflammation and coagulation, where alongside inflammation-induced prompted coagulation activation, and coagulation likewise especially impacted inflammatory activity. Notably, comprehensive hemostatic activation and inflammation in sepsis may show with organ-specific observations that are applicable for the particular organ failure ensuing from serious sepsis . The most vital instigator of thrombin generation in sepsis is the transmembrane tissue factor. Investigations of endotoxemia or cytokinemia have exhibited a focal job of the TF/FVIIa combination within the inception of thrombin generation . Repeal of the TF/factor VII (a) pathway by appointed mediations at TF or FVIIa activity realized a total repeal of thrombin generation in experimental scopes [27, 28]. To boot, in serious gram-negative sepsis, ex vivo transmembrane tissue factor expression on monocytes of patients was exhibited . This supported the appraisal of movement of TF from mononuclear cells to activated thrombocytes in associate degree ex vivo insertion setup, it completely was anticipated that this “bloodborne” TF shifts between cells via microparticles .
Thrombocytes have a focal activity within the progression of hemostatic variations in sepsis. Thrombocytes could activate straightforwardly by pro-inflammatory cytokine mediators, such as platelet-activating factor . The produced thrombin can then potentiate platelets. Activation of blood platelets might likewise elicit fibrin makeup by elective mechanism. The manifestation of P-selectin on the thrombocyte surface membrane does not simply intervene in the adherence of thrombocytes to leukocytes and endothelial cells; it additionally promotes the aspect of TF on monocytes . In typical conditions, activation of coagulation is controlled by three significant physiological, medicinal, anticoagulant pathways: the antithrombin, the activated protein C, and the tissue factor pathway inhibitor (TFPI). In sepsis, each of the three pathways is considerably affected . Owing to a combination of reduced synthesis, continuous utilization, and proteolytic degradation (e.g., by neutrophil elastase), the levels of each of the three coagulation inhibitors are low. Additionally, noteworthy downregulation of thrombomodulin and endothelial protein C receptor (EPCR) in inflammatory conditions will create an impair diversion of protein C (autoprothrombin IIA) and activated protein C. Eventually, at the time of the massive activation of hemostasis in sepsis, endogenous fibrinolysis is commonly crushed. Afterward, during the acute release of plasminogen activators (tissue-plasminogen activator (t-PA)) and urokinase-plasminogen activator (u-PA) from capacity destinations in vascular endothelial cell structure throughout inflammatory conditions, the augmentation in plasminogen activation and subsequent placement subject production is worked by a upheld increase in plasminogen activator inhibitor-1 (PAI-1) . Apparently, researchers have indicated that a purposeful transformation within the PAI-1 sequence, the 4G/5G polymorphism, not simply influenced the level of PAI-1; but, this was in addition connected to the clinical consequences of gram-negative bacterial sepsis. Patients with the 4G/4G genotype had basically higher PAI-1 levels associated with nursing and distended mortality . Completely different studies indicated that the PAI-1 polymorphism distended the risk of making septic shock from meningococcal contamination .
5. Endothelial activation and its impact on coagulation throughout inflammation
Vascular endothelial lining assume a central role altogether element that result in inflammation-induced activation of coagulation. Throughout severe infection, the endothelium is vitalized by pathogens or indirectly through inflammatory mediators and therefore the major restrictive antithrombotic properties become inactivated [25, 37]. Pro-inflammatory cytokines containing interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6 trigger TF inside endothelial cells, which might be shed to some extent as soluble TF . Shedding of soluble TF could clarify why it has been onerous to distinguish endothelial TF by assay in animal studies . It remains questionable whether or not endothelial cells contribute to TF production in sepsis. Taking out the TF gene selectively in endothelial cells did not constrict the level of activated coagulation estimated as a thrombin-ATIII complex when mice were tested with lipopolysaccharide (LPS) . The equivalent pro-inflammatory cytokines seem to downregulate the anticoagulant receptors thrombomodulin (TM) and EPCR, furthermore cellular glycosaminoglycans .
Endothelial cells are likewise able to release adhesion particles and growth factors that will not simply advance the inflammatory response nonetheless to boot increment the coagulation response. Combining between platelets and endothelial cells, likewise as platelets and neutrophils, is considerably connected to the beginning of inflammation. In endothelial cells, the Weibel-Palade body secretes von Willebrand factor (VWF) and P-selectin, that backup thrombocyte rolling. Inflamed endothelium bolsters blood leukocyte rolling, and activated platelets in reality with leukocytes. Furthermore, endothelial cells discharge various mediators of the inflammatory response . Such a mediator incorporates CD40 ligand, lipoxygenases, prostaglandins, etc. Of potential pro-coagulant significance are microparticles that are discharged on activation and apoptosis of cells and that arise from virtually any blood cell . Microparticles have indicated procoagulant activity via activation of TF or totally different chemicals in varied disease states, together with meningococcal sepsis . Microparticles have been shown to have a few other biological properties that improve the cardiovascular system. In sepsis, microparticles manage unique inflammatory responses in an organ-specific manner and may assume a job in the appropriation of proteins like APC .
6. Inflammation and hemostatic disorders in sepsis
Like essentially all fundamental inflammation impacts of infection, the disturbance of the hemostatic protocol in sepsis is coordinated by many cytokines. Most star pro-inflammatory cytokines are shown to start out the hemostatic activation in vitro. In sepsis, elevated rates of cytokines are often found within the circulation of septic patients and analyses illness or checking endotoxemia may lead to a transient increment in plasma cytokines levels . Tumor necrosis factor (TNF) is the main acolyte that gets discovered, pursued by a rise in serum levels of some interleukins (IL), of which IL-6 and IL-1 are conspicuous. Meanwhile, anti-inflammatory plasma cytokines (like IL-10) may have a brake job in the invigoration of coagulation. As TNF is the essential cytokine to become perceptible in the blood circulation onto bacteremia and this cytokine has powerful procoagulant impacts, it was first thought that hemostatic activation in sepsis was intervened by TNF. However, in a very few preliminary trials numerous procedures to inhibit TNF action, it was demonstrated that endotoxin exhortation of TNF cytokine may be altogether repealed, though activation of blood coagulation was not influenced, nonetheless that the impacts on blood coagulation inhibitors and fibrinolysis perceived to be controlled by TNF cytokine . Strangely, it was exhibited in consequent investigations that techniques that block IL-6 cause a total inhibition of endotoxin-induced activation of coagulation . Additionally, surveys in malignant patients treated with recombinant IL-6 indicated that following the infusion of this cytokine, noticeable thrombin generation happened . Subsequently, these outcomes propose that IL-6 as opposed to TNF cytokine is critical as an inducer for cytokine-triggered blood hemostatic activation. Although IL-1 is associated in nursing intense agonist of TF expression in vitro, its role has not been utterly explained in vivo. An IL-1 receptor adversary principally hindered the procoagulant response in trial sepsis ideals and paused thrombin generation in patients . Moreover, the greater part of the modifications in hemostasis happen well prior to IL-1 getting detected in the blood circulation, leaving a potential function of IL-1 in the coagulopathy of sepsis an agitated issue. Blood coagulation factors and anticoagulant regulatory proteins do not just assume a role in hemostatic activation; they additionally communicate with specific cell receptors prompting the activation of signaling pathways. Particularly, protease interplays that regulate inflammatory operations may well be significant in sepsis. The vital pathway whereby coagulation compartments manage inflammation is by official to protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors; moreover, four distinct sets (PAR 1–4) have been perceived . A typical aspect of PARs is that they fill in as their own ligand. Proteolytic spilt by an activated blood coagulation factor prompts exposure to a neo-amino terminus that is able to activate a same receptor (and likely boarded receptors), prompting transmembrane signaling. PAR-1, PAR-3, and PAR-4 are receptors that are activated by thrombin, whereas PAR-2 is activated by the TF/FVIIa complex, factor Xa, and trypsin enzyme. PAR-1 is in addition a receptor for the TF/FVIIa complex in conjunction with factor Xa. It has become obvious that there is a major crosstalk between blood coagulation inhibitors and inflammatory arbiters additionally. Antithrombin III can render as an organizer of inflammation, for example, by direct link to inflammatory cells, during this approach diminishing cytokine and chemokine receptor manifestation . Likewise, there is plenty of proof that the protein C (PC) order critically regulates inflammatory action . APC has been manifested to constrict endotoxin-induced production of TNF-α, IL-1β, IL-6, and IL-8 cytokines by monocytes/macrophages . APC additionally prevents cytokine discharge and blood leukocyte activation in experimental bacteremia in vivo . The hindrance of the PC shunt by a monoclonal antibody exasperates the inflammatory response, as appeared by promoting levels of pro-inflammatory cytokines and dilated blood leukocyte activation and tissue injury . Mice with a various PC inadequacy due to focused disturbance of the PC gene have not just a vigorous hemostatic response to experimental endotoxemia but conjointly display high contrasts in inflammatory responses (e.g., excess value of plasma pro-inflammatory cytokines) (Table 1) .
|Tumor necrosis factor (TNF-α)|
|Transforming growth factor (TGF-β)|
|Interleukin 1 receptor antagonist|
|Soluble TNF receptors|
7. Role of neutrophil in coagulation in sepsis
In sepsis, the early cytokine storm shows up at intervals of 30–90 minutes during lipopolysaccharide (LPS) layer exposure. The following stage comprises the activation of neutrophils and nitrous oxide, further cytokine discharge, and the formation of kinins, complement protein products, lipid mediators [55, 56], and the tissue response to disease is started by expression of cellular adhesion particles. Neutrophils are basic cell arbiters not just discharging proteolytic catalysts, but additionally producing responsive oxygen species, including myeloperoxidase (MPO), neutrophil elastase, and cathepsin G. Neutrophils discharge also neutrophil extracellular traps that instantiate extracellular chromatin threads with strong cytotoxic effects, containing both histones and granular proteins, which have bactericidal properties . Also, neutrophil extracellular traps have prothrombotic properties, including activation of platelets, energizing of thrombin generation, and downregulation of anticoagulant pathways by the upgrade of APC resistance .
8. Diagnostic challenges of coagulopathy in sepsis
There are some totally different reasons for coagulation changes in septic patients. The reduced thrombocyte count is perpetually present in patients with serious sepsis; however, thrombocytopenia could likewise occur as a result of alternative conditions, for instance, immune thrombocytopenia (ITP), heparin-induced thrombocytopenia (HIT), thrombotic microangiopathies, or drug-evoked bone marrow distress . It is critical to satisfactory pinpoint these different reasons for thrombocytopenia, as they may require specific administration projections . Laboratory researches can be valuable in distinctive coagulopathy in sepsis from completely different alternative hemostatic conditions, such as vitamin K (vit K) bleeding or hepatic impairment. As these troubles might be observed simultaneously with sepsis-associated coagulopathy, dispersing is not in every case simple [60, 61].
As indicated by the contemporary pondering sepsis-associated coagulopathy, the evaluation of soluble fibrin in plasma has the mark of being significant . Commonly, the affectability of measuring soluble fibrin for sepsis-associated coagulopathy is more optimal than the specificity. Some clinical assays have noted that at specific concentrations of soluble fibrin, sepsis-associated coagulopathy is highly tolerable . Fibrin split products (FSPs) could be examined by specific Enzyme-Linked Immunosorbent Assay (ELISA) or by latex agglutination, enabling speed and bedside placement in very critical cases. None of the most accessible experiences for FDPs recognizes fragmentation products of cross-linked fibrin or fibrinogen degradation, which may contribute to faultily unusual results . The specificity of elevated plasma levels of fibrin split products (FSPs) is subsequently unobtrusive, and a progression of other clinical circumstances, for example, trauma or injury, recent surgery, inflammation, or venous thromboembolism, may cause raised FDPs. More sophisticated tests specifically focus on the measurement of neo-antigens on fragmented cross-linked fibrin. Commonly, these measures respond with an epitope attached to plasmin-degraded cross-linked γ-chain, bringing about fragment D-dimer. These tests preferably identify the fragmentation of fibrin from fibrinogen (factor I) or fibrinogen degradation products (FDPs) . Continuous coagulation activation brings exhaustion of coagulation factors in septic patients. Additionally, diminished synthesis, for example, brought by deranged hepatic function or vitamin K deficiency, and lack of coagulation factors, because of massive hemorrhage, might be significant. Estimation of plasma fibrinogen levels has been generally advanced as an accommodating tool for pinpointing coagulation anomalies in sepsis; yet in reality, this is not very supportive much of the time [10, 64]. Fibrinogen acts as an acute phase reactant, and regardless of impressive turnover, plasma concentrations can be well within normal values.
Thrombelastography is progressively utilized in critically sick patients with a hypercoagulable state, incorporating those with DIC [65, 66]. Procoagulant just as anticoagulant states in DIC as shown with thrombelastography was illustrated to have a better correlation with clinically significant organ dysfunction and survival despite the fact that its preference over usual coagulation tests has not yet been affirmed [67, 68, 69, 70, 71, 72]. The precise utilization of thrombelastography for the conclusion of DIC has not been thoroughly assessed, despite the fact that supporters accept that the examiner might find it useful for evaluating the condition of coagulation in patients with critical sickness [73, 74]. In light of review investigations of databases from fundamentally sick patients, composite scores for the conclusion of sepsis-associated coagulopathy have been conceived by the International Society on Thrombosis and Hemostasis (ISTH) . The system is in view of promptly accessible laboratory tests, that is, thrombocyte function, PT, D-dimer, and plasma fibrinogen levels. An analysis of DIC is perfect with a score of five or more excess points. PT manifested in seconds in the scoring order may be substituted by the INR, making symmetry among focuses and standardization simpler . Approval investigations have demonstrated a high analytic precision of the scoring system [77, 78]. As a decision made a decision by this composite score is firmly connected with survival rates in climatically sick patients . Joining predictive intensive care estimation systems, for example, Acute Physiology and chronic Health Evaluation (APACHE-II), with the DIC score is seemingly an intense technique to anticipate the prognosis in septic patients. Comparable composite scores are structured and examined in Japan . The most applicable paradoxes between the ISTH and Japanese scores are a higher sensitivity and a higher extent of patients with hemato-oncological diseases that are determined to possess DIC by the Japanese systems [81, 82].
This work was basic elucidation of the idea that coagulation and its inhibitors are of major importance in coagulation-inflammation noise, similarly as in survival from sepsis. Further studies are warranted to explore the groundwork for the outcome of diagnostic rule victimization, many markers of inflammation and infection, and DIC score as parameters in assessing the severity of sepsis-associated coagulopathy in a clinical setting.
Angus DC, van der Poll T. Severe sepsis and septic shock. The New England Journal of Medicine. 2013; 369(9):840-851
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. The New England Journal of Medicine. 2003; 348(16):1546-1554
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Critical Care Medicine. 2001; 29(7):1303-1310
van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nature Reviews. Immunology. 2017; 17(7):407-420
Levi M, van der Poll T. Coagulation and sepsis. Thrombosis Research. 2017; 149:38-44
Levi M. The coagulant response in sepsis. Clinics in Chest Medicine. 2008; 29(4):627-642
Gando S, Levi M, Toh CH. Disseminated intravascular coagulation. Nature Reviews Disease Primers. 2016; 2:16037
Levi M, ten Cate H. Disseminated intravascular coagulation. The New England Journal of Medicine. 1999; 341(8):586-592
Miller DL, Welty-Wolf K, Carraway MS, Ezban M, Ghio A, Suliman H, et al. Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. American Journal of Respiratory Cell and Molecular Biology. 2002; 26(6):650-658
Levi M, ten Cate H, van der Poll T. Disseminated intravascular coagulation: State of the art. Thrombosis and Haemostasis. 1999; 82:695-705
Ratnoff OD, Nebehay WG. Multiple coagulative defects in a patient with the Waterhouse-Friderichsen syndrome. Annals of Internal Medicine. 1962; 56:627
Wheeler AP, Bernard GR. Treating patients with severe sepsis. The New England Journal of Medicine. 1999; 340(3):207-214
Levi M, de Jonge E, van der Poll T. Sepsis and disseminated intravascular coagulation. Journal of Thrombosis and Thrombolysis. 2003; 16(1-2):43-47
Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E, Wilmer A, et al. Thrombocytopenia and prognosis in intensive care. Critical Care Medicine. 2000; 28(6):1871-1876
Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG. Thrombocytopenia in patients in the medical intensive care unit: Bleeding prevalence, transfusion requirements, and outcome. Critical Care Medicine. 2002; 30(8):1765-1771
Akca S, Haji Michael P, de Medonca A, Suter PM, Levi M, The VJL. Time course of platelet counts in critically ill patients. Critical Care Medicine. 2002; 30:753-756
Mavrommatis AC, Theodoridis T, Orfanidou A, Roussos C, Christopoulou-Kokkinou V, Zakynthinos S. Coagulation system and platelets are fully activated in uncomplicated sepsis. Critical Care Medicine. 2000; 28(2):451-457
Folman CC, Linthorst GE, van Mourik J, van Willigen G, de Jonge E, Levi M, et al. Platelets release thrombopoietin (Tpo) upon activation: Another regulatory loop in thrombocytopoiesis? Thrombosis and Haemostasis. 2000; 83(6):923-930
Francois B, Trimoreau F, Vignon P, Fixe P, Praloran V, Gastinne H. Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. The American Journal of Medicine. 1997; 103(2):114-120
Warkentin TE, Aird WC, Rand JH. Platelet-endothelial interactions: Sepsis, HIT, and antiphospholipid syndrome. Hematology. The Education Program of the American Society of Hematology. 2003; 1:497-519
MacLeod JB, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. The Journal of Trauma. 2003; 55(1):39-44
Shorr AF, Thomas SJ, Alkins SA, Fitzpatrick TM, Ling GS. D-dimer correlates with proinflammatory cytokine levels and outcomes in critically ill patients. Chest. 2002; 121(4):1262-1268
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. The New England Journal of Medicine. 2001; 344(10):699-709
Gando S, Nanzaki S, Sasaki S, Kemmotsu O. Significant correlations between tissue factor and thrombin markers in trauma and septic patients with disseminated intravascular coagulation. Thrombosis and Haemostasis. 1998; 79(6):1111-1115
Aird WC. Vascular bed-specific hemostasis: Role of endothelium in sepsis pathogenesis. Critical Care Medicine. 2001; 29(7 Suppl):S28-S34
Levi M, van der Poll T. Inflammation and coagulation. Critical Care Medicine. 2010; 38(2 Suppl):S26-S34
Taylor FB Jr, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, et al. Lethal E. coliseptic shock is prevented by blocking tissue factor with monoclonal antibody. Circulatory Shock. 1991; 33(3):127-134
Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR, et al. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. Journal of Clinical Investigation. 1994; 93(1):114-120
Osterud B, Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: Related to an unfavourable prognosis. Thrombosis and Haemostasis. 1983; 49(1):5-7
Rauch U, Bonderman D, Bohrmann B, Badimon JJ, Himber J, Riederer MA, et al. Transfer of tissue factor from leukocytes to platelets is mediated by CD15 and tissue factor. Blood. 2000; 96(1):170-175
Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM. The platelet activating factor signaling system and its regulators in syndromes of inflammation and thrombosis. Critical Care Medicine. 2002; 30(5 Suppl):S294-S301
Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. The Journal of Pharmacology and Experimental Therapeutics. 2002; 300(3):729-735
Levi M, van der Poll T. Coagulation in patients with severe sepsis. Seminars in Thrombosis and Hemostasis. 2015; 41(1):9-15
Biemond BJ, Levi M, ten Cate H, van dP, Buller HR, Hack CE, et al. Plasminogen activator and plasminogen activator inhibitor I release during experimental endotoxaemia in chimpanzees: Effect of interventions in the cytokine and coagulation cascades. Clinical Science. 1995; 88(5):587-594
Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA, de GR, et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet. 1999; 354(9178):556-560
Westendorp RG, Hottenga JJ, Slagboom PE. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet. 1999; 354(9178):561-563
Wiel E, Vallet B, ten Cate H. The endothelium in intensive care. Critical Care Clinics. 2005; 21:403-416
Keller TT, Mairuhu ATA, Kruif MD, et al. Infections and endothelial cells. Cardiovascular Research. 2003; 60:40-48
Szotowski B, Antoniak S, Poller W, et al. Procoagulant soluble tissue factor is released from endothelial cells in response to inflammatory cytokines. Circulation Research. 2005; 96:1233-1239
Osterud B, Bjorklid E. The tissue factor pathway in disseminated intravascular coagulation. Seminars in Thrombosis and Hemostasis. 2001; 27:605-617
Pawlinski R, Wang JG, Owens AP III, et al. Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood. 2010; 116:806-814
Wagner DD. New links between inflammation and thrombosis. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005; 25:1321-1324
Diamant M, Tushuizen ME, Sturk A, et al. Cellular microparticles: New players in the field of vascular disease? European Journal of Clinical Investigation. 2004; 34:392-401
Meziani F, Delabranche X, Asfar P, et al. Benchto-bedside review: Circulating microparticles—A new player in sepsis? Critical Care. 2010; 14:236
van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer S, Eerenberg AJ, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. The Journal of Experimental Medicine. 1994; 179(4):1253-1259
Stouthard JM, Levi M, Hack CE, Veenhof CH, Romijn HA, Sauerwein HP, et al. Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thrombosis and Haemostasis. 1996; 76(5):738-742
Boermeester MA, van Leeuwen P, Coyle SM, Wolbink GJ, Hack CE, Lowry SF, et al. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Archives of Surgery. 1995; 130(7):739-748
Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000; 407(6801):258-264
Kaneider NC, Forster E, Mosheimer B, Sturn DH, Wiedermann CJ. Syndecan-4-dependent signaling in the inhibition of endotoxin-induced endothelial adherence of neutrophils by antithrombin. Thrombosis and Haemostasis. 2003; 90(6):1150-1157
Esmon CT. New mechanisms for vascular control of inflammation mediated by natural anticoagulant proteins. The Journal of Experimental Medicine. 2002; 196(5):561-564
Yuksel M, Okajima K, Uchiba M, Horiuchi S, Okabe H. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thrombosis and Haemostasis. 2002; 88(2):267-273
Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood. 1996; 87(2):642-647
Taylor FB Jr, Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang AC, Laszik Z, et al. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000; 95(5):1680-1686
Levi M, Dorffler-Melly J, Reitsma PH, Buller HR, Florquin S, van der Poll T, et al. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein C deficient mice. Blood. 2003; 101:4823-4827
Cohen J. The immunopathogenesis of sepsis. Nature. 2002; 420:885-891
Cross AS, Opal SM. A new paradigm for the treatment of sepsis: Is it time to consider combination therapy? Archives of Internal Medicine. 2003; 138:502-505
Xu J, Zhang X, Pelayo R, et al. Extracellular histones are major mediators of death in sepsis. Nature Medicine. 2009; 15:1318-1321
Ammollo CT, Semeraro F, Xu J, et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin dependent protein C activation. Journal of Thrombosis and Haemostasis. 2011; 9:1795-1803
Baughman RP, Lower EE, Flessa HC, Tollerud DJ. Thrombocytopenia in the intensive care unit. Chest. 1993; 104(4):1243-1247
Levi M, de Jonge E, Meijers J. The diagnosis of disseminated intravascular coagulation. Blood Reviews. 2002; 16(4):217-223
Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Journal of Haematology. 2009; 145(1):24-33
Dempfle CE, Pfitzner SA, Dollman M, Huck K, Stehle G, Heene DL. Comparison of immunological and functional assays for measurement of soluble fibrin. Thrombosis and Haemostasis. 1995; 74(2):673-679
Horan JT, Francis CW. Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation. Seminars in Thrombosis and Hemostasis. 2001; 27(6):657-666
Prisco D, Paniccia R, Bonechi F, Francalanci I, Abbate R, Gensini GF. Evaluation of new methods for the selective measurement of fibrin and fibrinogen degradation products. Thrombosis Research. 1989; 56(4):547-551
Shorr AF, Trotta RF, Alkins SA, Hanzel GS, Diehl LF. D-dimer assay predicts mortality in critically ill patients without disseminated intravascular coagulation or venous thromboembolic disease. Intensive Care Medicine. 1999; 25(2):207-210
Levi M, Meijers JC. DIC: Which laboratory tests are most useful. Blood Reviews. 2011; 25(1):33-37
Dempfle CE, Borggrefe M. Point of care coagulation tests in critically ill patients. Seminars in Thrombosis and Hemostasis. 2008; 34(5):445-450
Levi M, Hunt BJ. A critical appraisal of point-of-care coagulation testing in critically ill patients. Journal of Thrombosis and Haemostasis. 2015; 13(11):1960-1967
Johansson PI, Stensballe J, Vindelov N, Perner A, Espersen K. Hypocoagulability, as evaluated by thrombelastography, at admission to the ICU is associated with increased 30-day mortality. Blood Coagulation & Fibrinolysis. 2010; 21(2):168-174
Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. The Journal of Trauma. 2009; 67(2):266-275
Collins PW, Macchiavello LI, Lewis SJ, Macartney NJ, Saayman AG, Luddington R, et al. Global tests of haemostasis in critically ill patients with severe sepsis syndrome compared to controls. British Journal of Haematology. 2006; 135(2):220-227
Muller MC, Meijers JC, Vroom MB, Juffermans NP. Utility of thromboelastography and/or thromboelastometry in adults with sepsis: A systematic review. Critical Care. 2014; 18(1):R30
Brenner T, Schmidt K, Delang M, Mehrabi A, Bruckner T, Lichtenstern C, et al. Viscoelastic and aggregometric point-of-care testing in patients with septic shock–Cross-links between inflammation and haemostasis. Acta Anaesthesiologica Scandinavica. 2012; 56(10):1277-1290
Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM. Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: A prospective cohort study. Critical Care. 2009; 13(2):R42
Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thrombosis and Haemostasis. 2001; 86(5):1327-1330
Kim HK, Hong KH, Toh CH. Application of the international normalized ratio in the scoring system for disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis. 2010; 8(5):1116-1118
Bakhtiari K, Meijers JC, de Jonge E, Levi M. Prospective validation of the international society of thrombosis and haemostasis scoring system for disseminated intravascular coagulation. Critical Care Medicine. 2004; 32:2416-2421
Toh CH, Hoots WK. The scoring system of the scientific and standardisation committee on disseminated intravascular coagulation of the International Society on thrombosis and haemostasis: A five-year overview. Journal of Thrombosis and Haemostasis. 2007; 5:604-606
Dhainaut JF, Yan SB, Joyce DE, Pettila V, Basson BR, Brandt JT, et al. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. Journal of Thrombosis and Haemostasis. 2004; 2:1924-1933
Wada H, Gabazza EC, Asakura H, Koike K, Okamoto K, Maruyama I, et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): Diagnostic criteria of the International Society of Thrombosis and Hemostasis and of the Japanese Ministry of Health and Welfare for overt DIC. American Journal of Hematology. 2003; 74(1):17-22
Wada H, Thachil J, Di NM, Mathew P, Kurosawa S, Gando S, et al. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. Journal of Thrombosis and Haemostasis. 2013; 11:761-767
Levi M. Settling the score for disseminated intravascular coagulation. Critical Care Medicine. 2005; 33(10):2417-2418