ISTH DIC Scoring System.

ISTH DIC Scoring System.

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It has been well established that angiopoietin 2 (Ang-2), a glycoprotein involved in activation of the endothelium, plays an integral role in the pathophysiology of sepsis and many other inflammatory conditions. However, the role of Ang-2 in sepsis-associated coagulopathy (SAC) specifically has not been defined. The aim of this study was to measure...

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... DIC score was calculated in all patients using the 2001 ISTH scoring algorithm for DIC subclassification into no DIC (score <3), non-overt DIC (score 3-4), and overt DIC (score !5; Table 4). 53 The score is calculated using laboratory values, including platelet count, fibrin markers, prothrombin time (PT), and fibrinogen level. ...

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... The SI and ChSI scales are open systems whose components can be changed and supplemented to address specific tasks. In particular, there are well-established methods of microcirculatory disorder assessment, such as intravascular bed microscopic examination [27] and determination of blood markers of pathological endotheliocyte activation, for instance, syndecan-1 [28,29] and angiopoietin-2 [30], as well as markers of mononuclear phagocyte activation such as sTREM1 [31] and presepsin (sCD14) [32]. In addition, the evaluation of non-coding microRNAs and extracellular vesicles in the blood is a promising method for assessing systemic inflammation, which allows for the clarification of tissue sites of activation and damage in the systemic process [33,34]. ...
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Currently, there is rationale for separating the systemic manifestations of classical inflammation from systemic inflammation (SI) itself as an independent form of the general pathological process underlying the pathogenesis of the most severe acute and chronic diseases. With this aim in view, we used integral scales of acute and chronic SI (ChSI), including the following blood plasma parameters: interleukins 6, 8, 10; tumor necrosis factor alpha; C-reactive protein; D-dimer; cortisol; troponin I; myoglobin. The presence of multiple organ dysfunction according to the SOFA score was also taken into account. The effectiveness of the scales was tested in groups of intensive care patients during different periods of acute trauma, sepsis, and septic shock. The ChSI scale was applicable under systemic autoimmune diseases, chronic purulent infections, chronic limb threatening ischemia, and end-stage renal disease of various genesis. The number of examined patients was 764 in total. The scales allowed us to verify specific phases of acute SI and identify pathogenetic risk factors of lethal outcomes, as well as the most severe variants of the chronic pathologies course. These scales are open adaptable systems (in terms of the nomenclature and choice of indicators). They are primarily intended for scientific research. However, the SI verification methodology presented in this paper may be useful for developing advanced criteria for assessing both the typical links in the pathogenesis of many diseases and the severity of the overall condition of patients for clinical practice.
... Angiotensin 2 is also known to increase endothelial permeability, and therefore, it is considered a critical factor in multiple organ dysfunction [70]. A clinical study demonstrated that higher levels of serum angiopoietin 2 were associated with decreased survival in sepsis [71], and another study has shown the association with a higher likelihood of DIC [72]. Concerning the clinical usefulness, not many studies have been done, and further study is warranted. ...
Article
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Disseminated intravascular coagulation (DIC) is not a disease criterion but a pathomechanistic process that accompanies various underlying diseases. According to the International Society on Thrombosis and Haemostasias definition, endothelial injury is an essential component in addition to systemic coagulation activation. Despite this definition, current diagnostic criteria for DIC do not include biomarkers for vascular endothelial injury. Endothelial cells are critical for hemostatic regulation because they produce various antithrombotic substances and express anticoagulant factors at the same time as facilitating coagulation, inflammatory reactions, platelet aggregation, and fibrinolysis with acute injury. Endothelial cells also exhibit various receptors, adhesion molecules, and the critical role of glycocalyx that regulates cellular interactions in thromboinflammation. For clinicians, biomarkers suitable for assessing endothelial injury are not readily available. Although we still do not have ideal biomarkers, antithrombin activity and von Willebrand factor can be candidates for the endothelium-related markers because those reflect the severity and are available in most clinical settings. Further, the dysfunction of endothelial cell in DIC arising from various underlying diseases is likely highly variable. For example, the involvement of endothelial dysfunction is significant in sepsis-induced coagulopathy, while moderate in trauma-induced coagulopathy, and variable in hematologic malignancy-associated coagulopathy. Because of the complexity of disease status associated with DIC, further research searching clinically available endothelium-related biomarkers is expected to establish individualized diagnostic criteria and potential therapeutic approaches.
... The relevance of endothelial cell-derived procoagulant substances such as von Willebrand factor and angiopoietin 2 should be examined in the future. 95 Other important factors that can induce DIC, such as DAMPs from the injured cells, are the target of research. 96 Along with the advances of the aforementioned research, the understanding of the detailed differences in pathophysiology between the underlying conditions progresses, and the diagnostic criteria specially designed for each disease are important for future development. ...
Article
Disseminated intravascular coagulation (DIC) has been understood as a consumptive coagulopathy. However, impaired hemostasis is a component of DIC that occurs in a progressive manner. The critical concept of DIC is systemic activation of coagulation with vascular endothelial damage. DIC is the dynamic coagulation/fibrinolysis disorder that can proceed from compensated to decompensated phases, and is not simply impaired hemostasis, a misunderstanding that continues to evoke confusion among clinicians. DIC is a critical step of disease progression that is important to monitor over time. Impaired microcirculation and subsequent organ failure due to pathologic microthrombi formation are the pathophysiologies in sepsis-associated DIC. Impaired hemostasis due to coagulation factor depletion from hemodilution, shock, and hyperfibrinolysis occurs in trauma-associated DIC. Overt-DIC diagnostic criteria have been used clinically for more than 20 years but may not be adequate to detect the compensated phase of DIC, and due to different underlying causes, there is no "one-size-fits-all criteria." Individualized criteria for heterogeneous conditions continue to be proposed to facilitate the diagnosis. We believe that future research will provide therapeutics using new diagnostic criteria. Finally, DIC is also classified as either acute or chronic, and acute DIC results from progressive coagulation activation over a short time and requires urgent management. In this review, we examine the advances in research for DIC.
... In addition to the fragmentation of heparan sulfate (and its fragments), heparanase is involved in the cleavage of heparan sulfate-bound cytokines and growth factors such as angiopoietin-2 (Ang-2). In various studies, a significantly higher Ang-2 concentration was measured in the serum of septic patients compared to healthy subjects [20,21]. Furthermore, increased heparan sulfate and heparanase levels in the serum of patients and mice with sepsis [22][23][24] suggests an association between heparanase activity and increased expression of Ang-2. ...
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SARS-CoV-2 was first detected in 2019 in Wuhan, China. It has been found to be the most pathogenic virus among coronaviruses and is associated with endothelial damage resulting in respiratory failure. Determine whether heparanase and heparan sulfate fragments, biomarkers of endothelial function, can assist in the risk stratification and clinical management of critically ill COVID-19 patients admitted to the intensive care unit. We investigated 53 critically ill patients with severe COVID-19 admitted between March and April 2020 to the University Hospital RWTH Aachen. Heparanase activity and serum levels of both heparanase and heparan sulfate were measured on day one (day of diagnosis) and day three in patients with COVID-19. The patients were classified into four groups according to the severity of ARDS. When compared to baseline data (day one), heparanase activity increased and the heparan sulfate serum levels decreased with increasing severity of ARDS. The heparanase activity significantly correlated with the lactate concentration on day one (r = 0.34, p = 0.024) and on day three (r = 0.43, p = 0.006). Heparanase activity and heparan sulfate levels correlate with COVID-19 disease severity and outcome. Both biomarkers might be helpful in predicting clinical course and outcomes in COVID-19 patients.
... Increased Ang-2 is predominantly associated with increased intracellular gap formation and disseminated intravascular coagulation (DIC) (5). For instance, Statz et al (6) reported that serum Ang-2 levels were related to the prognosis of patients with sepsis-associated DIC. Overall, prediction of a patient's outcome is of great importance to clinicians in their management of septic shock, and the optimal place of novel vasoactive agents in therapy for circulatory dysfunction should be established with further confidence. ...
... In the critical setting, the upregulation of angiopoietin 2 (Ang-2) is a physiologic and potentially lifesaving response and is significantly associated with the severity of disease. Ang-2 has been proven to increase in the context of sepsis (6,9,10). Ang-2 mRNA is directly or indirectly induced by infection across a broad spectrum of diseases (9,11). ...
... In a prospective study, Ang-2 expression was found to be significantly upregulated in sepsis-associated coagulopathy, and this biomarker was used to stratify patients with sepsis into non-overt DIC and overt DIC (6). Studies have also shown that Ang-2 is a promising biomarker with which to evaluate the gastrointestinal status and function in acute pancreatitis and it could serve as a useful tool for clinicians evaluating disease severity and prognosis (31,32). ...
Article
It has been reported that angiopoietin 2 (Ang-2) plays an integral role in the pathophysiology of sepsis and many other inflammatory diseases. However, the specific role of Ang-2 in septic shock has not been defined. The aim of the present study was to assess the predictive value of serum Ang-2 in patients with septic shock. Clinical data of 85 patients with septic shock and 10 healthy controls admitted to the intensive care unit with a diagnosis of septic shock were collected between January 2020 and October 2020 at Tongji Hospital (Wuhan, China). The serum levels of Ang-2 mRNA were quantified using a quantitative real-time PCR assay. Ang-2, SOFA and APACHE II scores were retrospectively analyzed in relation to 28-day mortality. The area under the receiver operating characteristic (ROC) curve (AUC) was used to discriminate the accuracy of the prediction. Mean Ang-2 mRNA levels in the patients with septic shock were significantly higher than those in the healthy controls (P<0.05), and the Ang-2 levels showed a downwards trend over time following treatment. The three indicators (AUCs, SEMs, P-values) were Ang-2 (0.82, 0.03, P<0.01), SOFA score (0.76, 0.04, P<0.01), and APACHE II score (0.73, 0.04, P<0.01). The present study confirmed that Ang-2 mRNA levels were significantly elevated in septic shock. The Ang-2 mRNA level at ICU admission in a patient with septic shock could be a predictive biomarker for mortality.
... In the CLS group, patients were more frequently diagnosed with sepsis (56 vs. 5%, P < 0.001), acute respiratory distress syndrome (6 vs. 0%, P = 0.03), acute kidney injury (58 vs. 32%, P = 0.003), and shock of any cause (41 vs. 11%, P < 0.001). Among the patients undergoing surgery prior to admission, blood loss was higher in the patients classified as CLS Our study measurements can be summarized as follows (see Fig. 2 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] vs. 19 [13][14][15][16][17][18][19][20][21][22][23][24], P < 0.001), SOFA (day 1: 6 [4][5][6][7][8][9] vs. 1[0-3] mL, P < 0.001), and APACHE II score (day 1: 12 [9][10][11][12][13][14][15][16] vs. 6 [4][5][6][7][8][9] mL, P < 0.001). ...
... Body impedance electrical analysis revealed increased extracellular water (day 1: 26 [22][23][24][25][26][27][28][29][30][31][32] vs. 21 [18][19][20][21][22][23][24] L, P < 0.001) and body water (day 1: 51 [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] vs. 47 [41][42][43][44][45][46][47][48][49][50][51][52] [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] vs. 10 [8][9][10][11][12][13][14] mmol/L, P < 0.001) were increased in the CLS group, and prothrombin time (day 1: 41 [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] vs. 34 [29][30][31][32][33][34][35][36][37][38] sec, P < 0.001) was prolonged. ...
... In sepsis, angiopoietin-2 levels correlated with severity of organ failure in critically ill children, while non-survivors showed higher angiopoietin-2 concentration [38]. Angiopoietin-2 was, furthermore, evaluated as a biomarker for sepsis and its sequelae [39,40]. Importantly, CLS patients in our study showed increased levels of angiopoietin-2. ...
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Background The concomitant occurrence of the symptoms intravascular hypovolemia, peripheral edema and hemodynamic instability is typically named Capillary Leak Syndrome (CLS) and often occurs in surgical critical ill patients. However, neither a unitary definition nor standardized diagnostic criteria exist so far. We aimed to investigate common characteristics of this phenomenon with a subsequent scoring system, determining whether CLS contributes to mortality. Methods We conducted this single-center, observational, multidisciplinary, prospective trial in two separately run surgical ICUs of a tertiary academic medical center. 200 surgical patients admitted to the ICU and 30 healthy volunteers were included. Patients were clinically diagnosed as CLS or No-CLS group (each N = 100) according to the grade of edema, intravascular hypovolemia, hemodynamic instability, and positive fluid balance by two independent attending physicians with > 10 years of experience in ICU. We performed daily measurements with non-invasive body impedance electrical analysis, ultrasound and analysis of serum biomarkers to generate objective diagnostic criteria. Receiver operating characteristics were used, while we developed machine learning models to increase diagnostic specifications for our scoring model. Results The 30-day mortility was increased among CLS patients (12 vs. 1%, P = 0.002), while showing higher SOFA-scores. Extracellular water was increased in patients with CLS with higher echogenicity of subcutaneous tissue [29(24–31) vs. 19(16–21), P < 0.001]. Biomarkers showed characteristic alterations, especially with an increased angiopoietin-2 concentration in CLS [9.9(6.2–17.3) vs. 3.7(2.6–5.6)ng/mL, P < 0.001]. We developed a score using seven parameters (echogenicity, SOFA-score, angiopoietin-2, syndecan-1, ICAM-1, lactate and interleukin-6). A Random Forest prediction model boosted its diagnostic characteristics (AUC 0.963, P < 0.001), while a two-parameter decision tree model showed good specifications (AUC 0.865). Conclusions Diagnosis of CLS in critically ill patients is feasible by objective, non-invasive parameters using the CLS-Score. A simplified two-parameter diagnostic approach can enhance clinical utility. CLS contributes to mortality and should, therefore, classified as an independent entity. Trial Registration: German Clinical Trials Registry (DRKS No. 00012713), Date of registration 10/05/2017, www.drks.de
... Platelet depletion was also reflected in the association with hemostatic markers. 22,23 The increases in INR and decrease in fibrinogen observed in patients with reduced platelet counts are reflective of the same consumptive process. 22 The relationship of platelet biomarkers to platelet count was largely dictated by platelet depletion. ...
Article
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Sepsis-associated disseminated intravascular coagulation (DIC) is related to marked hemostatic changes such as transient thrombocytopenia secondary to the endogenous activation and consumption of platelets. This study measured markers of platelet function in 103 adult ICU patients with clinically established sepsis-associated DIC to determine the biomarker association with disease severity. Patients were categorized as having no DIC, nonovert DIC, or overt DIC using the International Society of Thrombosis and Hemostasis scoring system. Plasma levels of CD40L, platelet factor 4 (PF4), platelet-derived microparticles, and microparticle-associated tissue factor were quantified. Markers of platelet activation were significantly elevated in patients with DIC compared to healthy individuals. This increase was independent of platelet count. Levels of PF4 differed based on the severity of DIC and differentiated nonsurvivors and survivors. These findings suggest that the markers of platelet activation in DIC may not be regulated by the number of circulating platelets and may be independent of the factors leading to their consumption.
... 74 Finally, higher levels of soluble Ang-2 were associated with higher likelihood of disseminated intravascular coagulation (DIC), one of the most morbid complications of sepsis. 75 Despite the undeniable importance of Ang1/Ang2 equilibrium, only a handful of studies is available focusing on altering this balance in treatment of sepsis. Various compounds stimulating Tie2 (thus mimicking the effect of Ang1) were reported to improve mortality in murine models of sepsis. ...
Article
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Sepsis accounts for nearly 700,000 deaths in Europe annually is caused by an overwhelming host response to infection resulting in organ failure. The endothelium is an active contributor to sepsis and as such represents a major target for therapy. During sepsis, endothelial cells amplify the immune response and activate the coagulation system. They are both a target and source of inflammation and serve as a link between local and systemic immune responses. In response to cytokines produced by immune cells, the endothelium expresses adhesion molecules and produces vasoactive compounds, inflammatory cytokines and chemoattractants, thus switching from an anticoagulant to procoagulant state. These responses contribute to local control of infection, but systemic activation can lead to microvascular thrombosis, capillary permeability, hypotension, tissue hypoxia, and ultimately tissue damage. This review focuses on the role of the endothelium in leucocyte adhesion and transmigration, production of reactive oxygen and nitrogen species as well as microRNAs and cytokines, formation of signaling microparticles and disseminated intravascular coagulation. We also discuss alterations in endothelial permeability and apoptosis. Finally, we review the diagnostic potential of endothelial markers and endothelial pathways as therapeutic targets for this devastating disease.
Article
The International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for disseminated intravascular coagulation (DIC) are widely used for DIC diagnosis. However, the prognostic value of the score may vary between different patient populations and settings. This systematic review investigated the association between the ISTH DIC score and mortality in sepsis patients. A literature search was conducted in PubMed and Embase. Inclusion criteria were studies including adult and pediatric patients hospitalized with sepsis, using any sepsis definition, and investigating the association between mortality and the ISTH DIC score. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 42 studies were included. A positive association between the ISTH DIC score and mortality was consistently reported, with odds ratios of death in DIC versus non-DIC patients ranging from 1.125 (95% confidence interval [CI]: 0.838–1.511) to 21.008 (95% CI: 1.408–313.405) in adults and from 1.378 (95% CI: 1.004–1.893) to 2.99 (95% CI: 0.54–16.6) in pediatric populations. However, the DIC score only had a low-moderate positive predictive value for mortality, as area under receiver-operator characteristics ranged from 0.602 (95% CI: 0.575–0.630) to 0.815 (95% CI: 0.676–0.954) in adults. Of note, only few studies adjusted for potential confounders such as age, gender, and comorbidity. The ISTH DIC score is consistently associated with sepsis-related mortality but is not a strong positive predictor for mortality. Nevertheless, the score may still have a prognostic value and its use in sepsis is encouraged.
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Plasma fibrinogen levels increase in response to infection, but they could also decrease due to degradation as in severe coagulopathy. We evaluated 60 septic patients with their CRP levels over 5.00 mg/dL. The patients were classified into three groups based on the ratio of the maximum or minimum fibrinogen concentration within day 3 to the initial concentration on day 0: down-, flat, and uptrend groups (n = 15, 30, and 15, respectively). Both down- and flat trend groups showed reduced inflammatory markers on day 3, and the degree of platelet loss (103/μL) and the mortality rate (%) were more remarkable in the downtrend group ( - 108 vs - 42 [p = 0.026] and 46.7 vs 10.0 [p = 0.027]). On day 0, in total 12 and 9 patients were diagnosed with non-overt DIC in the down- and uptrend groups, of which 5 (41.7%) and 1 (11.1%) died within 28 days after admission. In conclusion, decreasing fibrinogen levels in the ICU are associated with high mortality in patients with sepsis followed by decreasing platelet counts, even when they are diagnosed with non-overt DIC.