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.

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).

An evaluation of circulating activated TAFI in septic DIC: a case series and review of the literature.

BACKGROUND: Administration of recombinant human soluble thrombomodulin (rTM) is often used in Japan to treat septic disseminated intravascular coagulation (DIC). Thrombin-activatable fibrinolysis inhibitor (TAFI) is a fibrinolysis inhibitor activated by the thrombin-thrombomodulin complex, however, it is unknown whether circulating activated TAFI is increased after rTM administration in patients with DIC. Furthermore, the relationship between TAFI activation and the prognosis of septic DIC is not defined yet. CASE PRESENTATION: We report a series of 8 patient's TAFI activation with septic DIC treated by rTM. We sought to investigate the effect of rTM on TAFI activation and the association of plasma activated TAFI (TAFIa/ai) levels with the prognosis of septic DIC. Using plasma samples from clinical studies conducted from May 2016-March 2017 on eight patients with septic DIC at Kagoshima University Hospital, we measured plasma levels of total TAFI, TAFIa/ai, thrombin-antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), soluble fibrin (SF), antithrombin (AT), protein C (PC), protein S (PS), and plasminogen activator inhibitor-1 (PAI-1) before and after intravenous rTM administration. Then, we evaluated the relationship of these marker levels to prognosis. The thrombin-rTM complex activated TAFI in vitro in plasma from a healthy volunteer. However, TAFIa/ai levels did not significantly increase over baseline in the septic DIC patients after intravenous rTM administration. Baseline TAFIa/ai levels in non-survivors were significantly higher than those in survivors. CONCLUSIONS: Plasma TAFIa/ai did not increase with rTM administration. Elevated baseline TAFIa/ai concentration may be a negative prognostic indicator in septic DIC. Larger studies are needed to confirm the in vivo effect of rTM on TAFI activation.

Specific detection of high mobility group box 1 degradation product with a novel ELISA.

BACKGROUND: During sepsis or sterile tissue injury, the nuclear protein high mobility group box 1 (HMGB1) can be released to the extracellular space and ultimately into systemic circulation, where it mediates systemic inflammation and remote organ failure. The proinflammatory effects of HMGB1 can be suppressed by recombinant thrombomodulin (rTM), in part through a mechanism involving thrombin-rTM-mediated degradation of HMGB1. Given that HMGB1 is proinflammatory but the HMGB1 degradation product (desHMGB1) is not, an analytical method that discriminates between these two molecules may provide a more in-depth understanding of HMGB1-induced pathogenicity as well as rTM-mediated therapeutic efficiency. METHODS: A peptide that has a shared amino-terminal structure with desHMGB1 was synthesized. C3H/lpr mice were immunized with the desHMGB1 peptide conjugate, and antibody-secreting hybridoma cells were developed using conventional methods. The reactivity and specificity of the antibodies were then analyzed using antigen-coated enzyme-linked immunosorbent assay (ELISA) as well as antibody-coated ELISA. Next, plasma desHMGB1 levels were examined in a cecal ligation and puncture (CLP)-induced septic mouse model treated with rTM. RESULTS: Through a series of screening steps, we obtained a monoclonal antibody that recognized desHMGB1 but did not recognize intact HMGB1. ELISA using this antibody specifically detected desHMGB1, which was significantly increased in CLP-induced septic mice treated with rTM compared with those treated with saline. CONCLUSIONS: In this study, we obtained a desHMGB1-specific monoclonal antibody. ELISA using the novel monoclonal antibody may be an option for the in-depth analysis of HMGB1-induced pathogenicity as well as rTM-mediated therapeutic efficiency.

Association between Preoperative Cardiac Left Ventricular Dysfunction and Perioperative Intraaortic Balloon Pump in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery.

BACKGROUND: Prophylactic use of intraaortic balloon pump (IABP) reduces hospital mortality in patients with left ventricular (LV) systolic dysfunction undergoing coronary artery bypass surgery (CABG); however, its association in patients with LV diastolic dysfunction is unclear. This retrospective study investigated the association between preoperative LV function and perioperative use of IABP in patients undergoing off-pump CABG (OPCAB) at a university hospital. METHODS: 100 consecutive patients who underwent OPCAB between January 1, 2011 and August 31, 2014 were studied. Preoperative LV function was categorized into four groups based on LV systolic and diastolic function determined with preoperative transthoracic echocardiography. The use of IABP was reviewed from medical records. The Mann-Whitney test, Pearson chi-square test, or Fisher exact test were used. RESULTS: Patients were categorized into the following groups: normal LV function (n = 43), isolated LV systolic dysfunction (n = 13), isolated LV diastolic dysfunction (n = 21), and combined LV systolic and diastolic dysfunction (n = 14). Intraoperative IABP use was significantly more frequent in patients with isolated LV systolic dysfunction, isolated LV diastolic dysfunction, and combined LV systolic and diastolic dysfunction than in those with normal LV function (P < .05). Furthermore, IABP was used more frequently in patients who developed combined LV systolic and diastolic dysfunction postoperatively (P < .05). Conclusion: Not only the presence of preoperative systolic dysfunction but also LV diastolic dysfunction in the presence of normal LV systolic function were associated with increased use of IABP during and after OPCAB.

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.

Survival trends of extracorporeal membrane oxygenation support for pediatric emergency patients in regional and metropolitan areas in Japan.

BACKGROUND: To assess the performance of pediatric extracorporeal membrane oxygenation (ECMO) centers, outcomes were compared between metropolitan and other areas. METHODS: A retrospective cohort study was conducted at three regional centers on Kyushu Island and the largest center in the Tokyo metropolitan area of Japan. The clinical outcomes of patients of ≤15 years of age who received ECMO during 2010-2019 were investigated, targeting the survival and performance at discharge from intensive care units (ICUs), using medical charts. RESULTS: One hundred and fifty-five patients were analyzed (regional, n = 70; metropolitan, n = 85). Survival rates at ICU discharge were similar between the two areas (64%). In regional centers, deterioration of Pediatric Cerebral Performance Category (PCPC) scores were more frequent (65.7% vs. 49.4%; p = 0.042), but survival rates and ΔPCPC scores (PCPC at ICU discharge-PCPC before admission) improved in the second half of the study period (p = 0.005 and p = 0.046, respectively). Veno-arterial ECMO (odds ratio [OR], 3.00; p < 0.03), extracorporeal cardiopulmonary resuscitation (OR, 8.98; p < 0.01), and absence of myocarditis (OR, 5.47; p < 0.01) were independent risk factors for deterioration of the PCPC score. A sub-analysis of patients with acute myocarditis (n = 51), the main indicator for ECMO, revealed a significantly higher proportion of cases with deteriorated PCPC scores in regional centers (51.9% vs. 25.0%; p = 0.049). CONCLUSIONS: The survival rates of pediatric patients supported by ECMO in regional centers were similar to those in a metropolitan center. However, neurological outcomes must be improved, particularly in patients with acute myocarditis.

Potential roles of 1,5-anhydro-D-fructose in modulating gut microbiome in mice.

The gut microbiota has tremendous potential to affect the host's health, in part by synthesizing vitamins and generating nutrients from food that is otherwise indigestible by the host. 1,5-Anhydro-D-fructose (1,5-AF) is a monosaccharide with a wide range of bioactive potentials, including anti-oxidant, anti-inflammatory, and anti-microbial effects. Based on its potential benefits and minimal toxicity, it is anticipated that 1,5-AF will be used as a dietary supplement to support general health. However, the effects of 1,5-AF on the gut microbiota are yet to be clarified. Here, using an unbiased metagenomic approach, we profiled the bacterial taxa and functional genes in the caecal microbiota of mice fed a diet containing either 2% 1,5-AF or a reference sweetener. Supplementation with 1,5-AF altered the composition of the gut microbiota, enriching the proportion of Faecalibacterium prausnitzii. 1,5-AF also altered the metabolomic profile of the gut microbiota, enriching genes associated with nicotinamide adenine dinucleotide biosynthesis. These findings support the potential benefits of 1,5-AF, but further studies are required to clarify the impact of 1,5-AF on health and disease.

Recombinant Thrombomodulin Suppresses Histone-Induced Neutrophil Extracellular Trap Formation.

Histones, the major protein components of chromatin, are released into the extracellular space during sepsis, trauma, and ischemia-reperfusion injury, and subsequently mediate organ failure. Extracellular histones can promote endothelial damage and platelet aggregation, which can be suppressed by administration of recombinant thrombomodulin (rTM). The present study aimed to clarify whether histones can activate neutrophils to induce NET formation and whether rTM can prevent histone-induced NET formation. NET formation was analyzed in vitro by stimulating human neutrophils with histones in the absence or presence of rTM. NET formation was further analyzed in vivo by intravenous infusion of histones into rats with or without rTM. Histones induced NET release in a dose-dependent manner in vitro and NET release was induced as early as 1 h after stimulation. Histone-induced NET release was independent of NADPH oxidase. rTM suppressed histone-induced NET release in vitro as well as in vivo. The suppression might be mediated by rTM binding to histones, as suggested by analysis using a quartz crystal microbalance system. The present findings suggest that histones can activate neutrophils to form NETs and that rTM can inhibit histone-induced NET formation.

Serum histone H3 levels and platelet counts are potential markers for coagulopathy with high risk of death in septic patients: a single-center observational study.

BACKGROUND: Recent studies have suggested that anticoagulant therapy does not confer a survival benefit overall in sepsis, but might be beneficial in sepsis-associated disseminated intravascular coagulation (DIC). In particular, those with high Sequential Organ Failure Assessment (SOFA) scores might be the optimal target for anticoagulant therapy. However, both DIC and SOFA scores require the measurement of multiple markers. The purpose of this study was to explore a minimal marker set for determining coagulopathy at high risk of death in septic patients, wherein histone H3 levels were evaluated as indicators of both organ failure and coagulation activation. METHODS: We analyzed correlations among levels of serum histone H3 and other coagulation markers in 85 cases of sepsis using Spearman's rank correlation test. We then compared the utility of histone H3 to that of other coagulation markers in predicting the traditional DIC state or 28-day mortality by receiver-operating characteristics analysis. Finally, we suggested cut-off values for determining coagulopathy with high risk of death, and evaluated their prognostic utility. RESULTS: Serum histone H3 levels significantly correlated with thrombin-antithrombin complex (TAT) levels (Spearman's ρ = 0.46, p < 0.001), and weakly correlated with platelet counts (Spearman's ρ = - 0.26, p < 0.05). Compared to other coagulation markers, histone H3 levels showed better performance in predicting 28-day mortality. When combining serum histone H3 levels with platelet counts, our new scoring system showed a concordance rate of 69% with the traditional four-factor criteria of DIC established by the Japanese Association for Acute Medicine. The 28-day mortality rates of the new and the traditional criteria-positive patients were 43% and 21%, respectively. Those of the new and the traditional criteria-negative patients were 5.7% and 9.4%, respectively. CONCLUSIONS: Serum histone H3 levels and platelet counts are potential markers for determining coagulopathy with high risk of death in septic patients. Further studies are needed to clarify the utility of serum histone H3 levels in the diagnostic of coagulopathy/DIC.

Preoperative Left Ventricular Diastolic Dysfunction Is Associated with Pulmonary Edema after Carotid Endarterectomy.

This retrospective study was aimed to investigate the association between preoperative left ventricular (LV) cardiac function and the incidence of postoperative pulmonary edema (PE) in patients undergoing carotid endarterectomy (CEA). Most patients undergoing CEA for carotid artery stenosis have concomitant heart diseases, leading to hemodynamic instability that can cause postoperative cardiac complications such as cardiac heart failure. LV diastolic function has recently been recognized as an independent predictor of adverse cardiac events in patients undergoing cardiovascular surgery. We analyzed clinical data from the anesthetic and medical records of 149 consecutive patients who underwent CEA at our university hospital between March 2012 and March 2018. LV systolic and diastolic function were evaluated by ejection fraction and the ratio of LV early diastolic filling velocity to the peak velocity of mitral medial annulus (E/e'). Postoperative PE was diagnosed based on chest X-ray and arterial gas analysis by two independent physicians. Postoperative PE was developed in four patients (2.8%). Patients with postoperative PE were not related to preoperative low ventricular ejection fraction, but had a significantly higher E/e' ratio than those without PE (P = 0.01). Furthermore, there was an increasing trend of PE according to the E/e' category. Preoperative LV diastolic function evaluated by E/e' was associated with the development of postoperative PE in patients who underwent CEA. The results suggest that the evaluation of LV diastolic dysfunction could be possibly useful to predict PE in patients undergoing CEA.