Determining prognostic indicator for anticoagulant therapy in sepsis-induced disseminated intravascular coagulation.

BACKGROUND: There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment. METHODS: The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan's nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan-Meier analysis. RESULTS: In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22-0.45, P < 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36-0.50, P < 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score-Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71. CONCLUSION: CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.

Organ Dysfunction in Sepsis-associated Intravascular Coagulation.

Sepsis is frequently associated with disseminated intravascular coagulation (DIC) and multiple organ damage. It is widely accepted that DIC is not merely a complication but also plays a role in the development of organ dysfunction. Thrombus formation in the microvasculature leads to impaired tissue perfusion and organ damage. Activated neutrophils interacting with platelets, endothelial injury, and an imbalance of coagulation and fibrinolysis are the essence of thromboinflammation induced in sepsis-associated DIC. The above mechanisms are typically seen in sepsis-associated acute kidney injury (AKI), and the development of AKI is known to be strongly associated with the severity of sepsis. It is important to recognize the pathway of this mechanism in the context of sepsis management.

Endothelial Glycocalyx Protection in Sepsis.

The glycocalyx serves as the covering layer of the luminal surface of vascular endothelial cells, comprising proteoglycans, glycosaminoglycans, and adherent plasma proteins. This intricate structure is crucial in promoting antithrombogenicity, controlling vascular permeability, regulating vascular tone, and managing leukocyte/platelet adhesion. However, during sepsis, the glycocalyx undergoes significant degradation through inflammatory mechanisms; this process can be further facilitated by treatment for sepsis and septic shock. Therefore, it is crucial to exercise careful management to avoid damage to the glycocalyx during sepsis treatment.

Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation.

Historically, heparin has had the longest historical use as an anticoagulant and continues this day to be the primary therapeutic option for preventing thrombosis and thromboembolism in critically ill hospitalized patients. Heparin is also used to treat sepsis and sepsis-associated disseminated intravascular coagulation (DIC) in various countries. However, the efficacy and safety of heparin for this indication remains controversial, as adequately powered randomized clinical studies have not demonstrated as yet a survival benefit in sepsis and sepsis-associated DIC, despite meta-analyses and propensity analyses reporting improved outcomes without increasing bleeding risk. Further, activated protein C and recombinant thrombomodulin showed greater improvements in outcomes compared with heparin, although these effects were inconclusive. In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.

Proposal and Validation of a Clinically Relevant Modification of the Japanese Association for Acute Medicine Disseminated Intravascular Coagulation Diagnostic Criteria for Sepsis.

BACKGROUND: Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) criteria were launched nearly 20 years ago. Following the revised conceptual definition of sepsis and subsequent omission of systemic inflammatory response syndrome (SIRS) score from the latest sepsis diagnostic criteria, we omitted the SIRS score and proposed a modified version of JAAM DIC criteria, the JAAM-2 DIC criteria. OBJECTIVES: To validate and compare performance between new JAAM-2 DIC criteria and conventional JAAM DIC criteria for sepsis. METHODS: We used three datasets containing adult sepsis patients from a multicenter nationwide Japanese cohort study (J-septic DIC, FORECAST, and SPICE-ICU registries). JAAM-2 DIC criteria omitted the SIRS score and set the cutoff value at ≥3 points. Receiver operating characteristic (ROC) analyses were performed between the two DIC criteria to evaluate prognostic value. Associations between in-hospital mortality and anticoagulant therapy according to DIC status were analyzed using propensity score weighting to compare significance of the criteria in determining introduction of anticoagulants against sepsis. RESULTS: Final study cohorts of the datasets included 2,154, 1,065, and 608 sepsis patients, respectively. ROC analysis revealed that curves for both JAAM and JAAM-2 DIC criteria as predictors of in-hospital mortality were almost consistent. Survival curves for the anticoagulant and control groups in the propensity score-weighted prediction model diagnosed using the two criteria were also almost entirely consistent. CONCLUSION: JAAM-2 DIC criteria were equivalent to JAAM DIC criteria regarding prognostic and diagnostic values for initiating anticoagulation. The newly proposed JAAM-2 DIC criteria could be potentially alternative criteria for sepsis management.

Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines.

Maintaining tissue perfusion in sepsis depends on vascular integrity provided by the endothelial glycocalyx, the critical layer covering the luminal surface of blood vessels. The glycocalyx is composed of proteoglycans, glycosaminoglycans, and functional plasma proteins that are critical for antithrombogenicity, regulating tone, controlling permeability, and reducing endothelial interactions with leukocytes and platelets. Degradation of the glycocalyx in sepsis is substantial due to thromboinflammation, and treatments for sepsis and septic shock may exacerbate endotheliopathy via additional glycocalyx injury. As a result, therapeutic strategies aimed at preserving glycocalyx integrity should be considered, including modifications in fluid volume resuscitation, minimizing catecholamine use, controlling hyperglycemia, and potential use of corticosteroids and anticoagulants. In this review, we explore treatment strategies aligned with the recommendations outlined in the Surviving Sepsis Campaign Guidelines 2021 with a special emphasis on evidence regarding glycocalyx protection.

Efficacy of antithrombin administration for patients with sepsis: A systematic review, meta-analysis, and meta-regression.

Aims: There have been inconsistent reports regarding the effect of antithrombin on sepsis; furthermore, there are limited reports on how dosage affects therapeutic efficacy. Thus, we aimed to perform a systematic review and meta-analysis of the use of antithrombin for sepsis and a meta-regression analysis of antithrombin dosage. Methods: We included randomized controlled trials (RCTs) and observational studies of adult patients with sepsis who received antithrombin. Outcomes included all-cause mortality and serious bleeding complications. Statistical analyses and data synthesis were performed using a random-effects model; further, meta-regression and funnel plots were used to explore heterogeneity and biases. Results: Seven RCTs and six observational studies were included. Most patients in the RCTs and observational studies had severe sepsis and septic-disseminated intravascular coagulation (DIC), respectively. A meta-analysis using RCTs showed no significant differences in mortality between the antithrombin and control groups. However, the meta-analysis of observational studies indicated a trend of decreasing mortality rates with antithrombin administration (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.68-0.92; p = 0.002). Bleeding complications were significantly higher in the antithrombin group than in the control group in both study types (OR, 1.90; 95% CI, 1.52-2.37; p < 0.01). The meta-regression analysis showed no correlation between antithrombin dosage and mortality. Conclusion: A meta-analysis of RCTs confirmed no survival benefit of antithrombin, whereas that of observational studies, which mostly focused on septic DIC, showed a significant beneficial effect on improving outcomes. Indications of antithrombin should be considered based on its beneficial and harmful effects.

2023 ISTH update of the 2022 ISTH guidelines for antithrombotic treatment in COVID-19.

Based on emerging evidence from the COVID-19 pandemic, the International Society on Thrombosis and Haemostasis (ISTH) guidelines for antithrombotic treatment in COVID-19 were published in 2022. Since then, at least 16 new randomized controlled trials have contributed additional evidence, which necessitated a modification of most of the previous recommendations. We used again the American College of Cardiology Foundation/American Heart Association methodology for assessment of level of evidence (LOE) and class of recommendation (COR). Five recommendations had the LOE upgraded to A and 2 new recommendations on antithrombotic treatment for patients with COVID-19 were added. Furthermore, a section was added to answer questions about COVID-19 vaccination and vaccine-induced immune thrombotic thrombocytopenia (VITT), for which studies have provided some evidence. We only included recommendations with LOE A or B. Panelists agreed on 19 recommendations, 4 for nonhospitalized, 5 for noncritically ill hospitalized, 3 for critically ill hospitalized, and 2 for postdischarge patients, as well as 5 for vaccination and VITT. A strong recommendation (COR 1) was given for (a) use of prophylactic dose of low-molecular-weight heparin or unfractionated heparin in noncritically ill patients hospitalized for COVID-19, (b) for select patients in this group, use of therapeutic-dose low-molecular-weight heparin/unfractionated heparin in preference to prophylactic dose, and (c) for use of antiplatelet factor 4 enzyme immunoassays for diagnosing VITT. A strong recommendation was given against (COR 3) the addition of an antiplatelet agent in hospitalized, noncritically ill patients. These international guidelines provide recommendations for countries with diverse healthcare resources and COVID-19 vaccine availability.

Four years into the pandemic, managing COVID-19 patients with acute coagulopathy: what have we learned?

Coagulopathy alongside micro- and macrovascular thrombotic events were frequent characteristics of patients presenting with acute COVID-19 during the initial stages of the pandemic. However, over the past 4 years, the incidence and manifestations of COVID-19-associated coagulopathy have changed due to immunity from natural infection and vaccination and the appearance of new SARS-CoV-2 variants. Diagnostic criteria and management strategies based on early experience and studies for COVID-19-associated coagulopathy thus require reevaluation. As many other infectious disease states are also associated with hemostatic dysfunction, the coagulopathy associated with COVID-19 may be compounded, especially throughout the winter months, in patients with diverse etiologies of COVID-19 and other infections. This commentary examines what we have learned about COVID-19-associated coagulopathy throughout the pandemic and how we might best prepare to mitigate the hemostatic consequences of emerging infection agents.

The role of thromboinflammation in acute kidney injury among patients with septic coagulopathy.

Inflammation and coagulation are critical self-defense mechanisms for mitigating infection that can nonetheless induce tissue injury and organ dysfunction. In severe cases, like sepsis, a dysregulated thromboinflammatory response may result in multiorgan dysfunction. Sepsis-associated acute kidney injury (AKI) is a significant contributor to patient morbidity and mortality. The connection between AKI and thromboinflammation is largely due to unique aspects of the renal vasculature. Specifically, the interaction between blood cells with the endothelial, glomerular, and peritubular capillary systems during thromboinflammation reduces oxygen supply to tubular epithelial cells. Previous studies have focused on tubular epithelial cell damage due to hypoxia, oxidative stress, and nephrotoxins. Although these factors are pivotal in acute tubular injury or necrosis, recent studies have demonstrated that AKI in sepsis encompasses a mixture of tubular and glomerular damage subtypes. In cases of sepsis-induced coagulopathy, thromboinflammation within the glomerulus and peritubular capillaries is an important pathogenic mechanism for AKI. Unfortunately, and despite the use of renal replacement therapy, the development of AKI in sepsis continues to be associated with high morbidity, mortality, and clinical challenges requiring alternative approaches. This review introduces the important role of thromboinflammation in AKI pathogenesis and details innovative vascular-targeting therapeutic strategies.

Thromboinflammation and microcirculation damage in heatstroke.

Rising temperatures associated with climate change have significantly increased the risk of heatstroke. Unfortunately, the trend is anticipated to persist and increasingly threaten vulnerable populations, particularly older adults. According to Japan's environment ministry, over 1000 people died from heatstroke in 2021, and 86% of deaths occurred in those above 65. Since the precise mechanism of heatstroke is not fully understood, we examined the pathophysiology by focusing on the microcirculatory derangement. Online search of published medical literature through MEDLINE and Web of Science using the term "heatstroke," "heat-related illness," "inflammation," "thrombosis," "coagulation," "fibrinolysis," "endothelial cell," and "circulation." Articles were chosen for inclusion based on their relevance to heatstroke, inflammation, and thrombosis. Reference lists were reviewed to identify additional relevant articles. Other than preexisting conditions (genetic background, age, etc.), factors such as hydration status, acclimatization, dysregulated coagulation, and inflammation are the additional major factors that promote tissue malcirculation in heatstroke. The fundamental pathophysiologic mechanisms significantly overlap with those seen in the systemic inflammatory response to sepsis, and as a result, coagulation-predominant coagulopathy develops during heat stress. Although a bleeding tendency is not common, bleeding frequently occurs in the microcirculation, causing additional injury. Sterile inflammation is mediated by proinflammatory cytokines, chemokines, and other humoral mediators in concert with cellular factors, including monocytes, neutrophils, platelets, and endothelial cells. Excess inflammation results in inflammatory cell death, including pyroptosis and necroptosis, and the release of danger signals that further propagate systemic inflammation and coagulopathy. Consequently, thromboinflammation is the critical factor that induces microcirculatory disturbance in heatstroke.

Effects of combination therapy of antithrombin and thrombomodulin for sepsis-associated disseminated intravascular coagulation: a systematic review and meta-analysis.

BACKGROUND: Disseminated intravascular coagulation (DIC) syndrome is a highly lethal condition characterized by the complication of multiple organ damage. Although the effects of combined antithrombin (AT) and recombinant thrombomodulin (rTM) on DIC syndrome have previously been examined, the results are inconsistent and inconclusive. Therefore, we conducted a systematic review on the combined administration of AT and rTM for the treatment of septic DIC to investigate the superiority of the combination therapy over either AT or rTM monotherapy using a random-effects analysis model. METHOD: We searched electronic databases, including Medline, Cochrane Central Register of Controlled Trials, Scopus, and Igaku-Chuo Zasshi (ICHU-SHI) Japanese Central Review of Medicine Web from inception to January 2022. Studies assessing the efficacy of combined AT and rTM were included. The primary outcome was all-cause mortality, and the secondary outcome was occurrence of serious bleeding complications compared to monotherapy. We presented the pooled odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI) depending on reporting results in each primary study. RESULTS: We analyzed seven enrolled clinical trials, all of which were observational studies. Combination therapy had a non-significant favorable association with lower 28-day mortality compared to monotherapy (HR 0.67 [0.43-1.05], OR 0.73 [0.45-1.18]). The I2 values were 60% and 72%, respectively, suggesting high heterogeneity. As a secondary outcome, bleeding complications were similar between the two groups (pooled OR 1.11 [0.55-2.23], I2 value 55%). CONCLUSIONS: Although the findings in this analysis could not confirm a statistically significant effect of AT and rTM combination therapy for septic DIC, it showed a promising effect in terms of improving mortality. The incidence of bleeding was low and clinically feasible. Further research is warranted to draw more conclusive results. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).

Risk stratification utilizing sequential organ failure assessment (SOFA) score, antithrombin activity, and demographic data in sepsis-associated disseminated intravascular coagulation (DIC).

Disseminated intravascular coagulation (DIC) is a frequent complication in patients with sepsis and is associated with increased mortality. Anticoagulant therapy may be appropriate for certain patients with DIC, particularly those with increased disease severity and deficiency in the physiologic anticoagulant antithrombin. We retrospectively analyzed post-marketing survey data from 1562 patients with sepsis-associated DIC and antithrombin activity of 70% or less. All the patients were treated with antithrombin concentrates. Baseline sequential organ failure assessment (SOFA) score, DIC score, and antithrombin activity were assessed. Cox multivariate regression analysis, Kaplan-Meier curve analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the performance of variables used to assess mortality. Furthermore, a decision tree was constructed to classify the risk of 28-day mortality. COX multivariate regression analysis demonstrated a significant association of age, sex, baseline SOFA score, baseline antithrombin activity, and the presence of pneumonia or skin/soft tissue infection with increased mortality. The area under the curve of SOFA score or antithrombin activity for mortality was 0.700 and 0.614, respectively. Kaplan-Meier analysis demonstrated that mortality was significantly higher in patients with SOFA score ≥ 12 and antithrombin activity < 47%. The decision tree analysis accurately classified the risk of death into high (> 40%), medium (40%-20%), and low (< 20%) categories in 86.1% of the cohort. Twenty eight-day mortality can be strongly predicted using baseline SOFA score, antithrombin activity, infection site, age, and sex as variables in the clinical decision tree for patients with sepsis-associated disseminated intravascular coagulation (DIC).

Designing the Diagnostic Criteria for Disseminated Intravascular Coagulation (DIC).

Disseminated intravascular coagulation (DIC) is a common and critical complication in various diseases. There are several diagnostic criteria, such as the International Society on Thrombosis and Haemostasis (ISTH) criteria, the Japanese Society on Thrombosis and Hemostasis (JSTH) criteria, and the Japanese Association for Acute Medicine (JAAM) criteria. Due to the strengths and drawbacks inherent in each diagnostic criterion, it has the potential to cause confusion in clinical settings. It is possible to increase the specificity by making a complex criterion but simple and easy-to-use criteria are demanded in practice. To establish pragmatic criteria using readily available biomarkers, the ISTH focused on DIC arising from sepsis and released sepsis-induced coagulopathy criteria (SIC). A similar approach will aid in constructing a practical diagnostic criterion tailored to each specific background.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (JSSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 in Japanese. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. Members of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within eachteam were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ), and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a twothirds (>66.6%) majority vote of each of the 19 committee members. A total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in additionto ratings of the strengths of the recommendation and its supporting evidence were also added to each recommendation statement.We conducted meta-analyses for 29 CQs. Thirty seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for 5 CQs.Based on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals.