BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) is commonly used in Japan to treat disseminated intravascular coagulation (DIC), but its efficacy compared with other anticoagulants is unclear. We conducted a systematic review and meta-analysis to investigate this issue in DIC patients with hematological malignancies.
METHODS: We searched PubMed, Cochrane, and Scopus for prospective and retrospective studies evaluating the efficacy and safety of rhTM in DIC patients with hematological malignancies between April 2008 and April 2023. We performed a systematic review and meta-analysis evaluating recovery from DIC, hemorrhagic adverse events (AEs), and overall survival (OS).
RESULTS: We analyzed one prospective (64 patients) and seven retrospective studies (209 patients). Use of rhTM was associated with a higher rate of recovery from DIC (OR: 2.25 [1.09-4.63] and 1.98 [1.12-3.50] in prospective and retrospective studies, respectively; same order below) and fewer hemorrhagic AEs (OR: 0.83 [0.30-2.30] and 0.21 [0.08-0.57]). rhTM did not improve OS (OR: 1.06 [0.42-2.66] and 1.72 [0.87-3.39]), although the incidence of hemorrhagic death was lower in the rhTM group (0 of 94 patients).
CONCLUSIONS: Use of rhTM in patients with hematological malignancy-associated DIC is strongly expected to be effective and safe.

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.
METHODS: 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.
BACKGROUND: This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: 000049820).

Thrombin is a serine protease that catalyzes a large number of different reactions including proteolytic cleave of fibrinogen to make the fibrin clot (procoagulant activity), of the protease activated receptors (for cell signaling) and of protein C generating activated protein C (anticoagulant activity). Thrombin has an effector binding site called the anion binding exosite 1 that is allosterically coupled to the active site. In this review, we survey results from thermodynamic characterization of the allosteric coupling as well as hydrogen-deuterium exchange mass spectrometry to reveal which parts of the thrombin structure are changed upon effector binding and/or mutagenesis, and finally NMR spectroscopy to characterize the different timescales of motions elicited by the effectors. We also relate the experimental work to computational network analysis of the thrombin-thrombomodulin complex.

UNASSIGNED: Acute respiratory distress syndrome (ARDS) is a heterogeneous illness that has a high mortality rate. The role and predictive value of soluble thrombomodulin (sTM) in ARDS mortality is disputable, so the present study aimed to evaluate the association and predictive value of sTM for the in-hospital mortality of ARDS.
UNASSIGNED: PubMed, Web of Science, Embase, Cochrane Library, Chongqing VIP, WanFang, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature databases were searched for relevant literature published before October 10, 2022. Relevant observable studies were included for analysis. The Newcastle-Ottawa Scale and QUAPAS (Quality Assessment of Prognostic Accuracy Studies) were employed to appraise the quality of the included studies.
UNASSIGNED: Thirteen articles were included in the present study. The eligible studies were of moderate to high quality [Newcastle-Ottawa Scale (NOS) 5-8 scores], and the high risk of bias in the included studieson predictive value was mainly distributed in participant and analysis domains of QUAPAS. There were 1,992 patients with ARDS, and 538 died. Our meta-analysis demonstrated that nonsurvivors had more significantly increased sTM levels than did survivors [standardized mean difference (SMD) =1.473; 95% CI: 0.874-2.072; P<0.001]. Elevated sTM levels had an independent correlation with higher mortality in patients with ARDS [pooled odds ratio (OR) =2.126; 95% CI: 1.548-2.920; P<0.001]. sTM showed satisfactory performance in predicting the mortality of ARDS [summary receiver operating characteristic curve (SROC) =0.78; 95% CI: 0.64-0.89]. The pooled sensitivity was 72% (95% CI: 66-77%), and the pooled specificity was 77% (95% CI: 72-82%). Subgroup analysis showed no significant difference in the sTM levels between nonsurvivors and survivors in terms of patients with direct ARDS (SMD =0.813; 95% CI: -0.673 to 2.229; P=0.253).
UNASSIGNED: sTM is associated with hospital mortality in ARDS and shows moderate predictive performance. As a result, it is a potential candidate for predicting the mortality of ARDS. However, caution is needed when sTM is used to predict adverse outcomes in patients with direct ARDS.

One of the \'organs\' that can be affected by sepsis is the coagulation system. Coagulopathy in sepsis may take the form of sepsis-induced coagulopathy (SIC) or sepsis-associated disseminated intravascular coagulation (DIC). It is important to identify SIC early, as at this stage of coagulopathy anticoagulants may be of the greatest benefit. The most recent diagnostic scoring systems for septic coagulopathy come from the International Society on Thrombosis and Hemostasis and the Japanese Association for Acute Medicine. Recommendations regarding the management of septic coagulopathy differ between organizations. Moreover, septic coagulopathy is an area of intense research in recent years. Therefore we searched three databases to review the most recent management strategies in septic coagulopathy. The mainstream management strategies in septic coagulopathy include the causal treatment of sepsis, unfractionated heparin, low-molecular-weight heparin, antithrombin, and recombinant human thrombomodulin. The last two have been associated with the highest survival benefit. Nevertheless, the indiscriminate use of these anticoagulants should be avoided due to the lack of mortality benefit and increased risk of bleeding. The early diagnosis of SIC and monitoring of coagulation status during sepsis is crucial for the timely management and selection of the most suitable treatment at a time. New directions in septic coagulopathy include new diagnostic biomarkers, dynamic diagnostic models, genetic markers for SIC management, and new therapeutic agents. These new research avenues may potentially result in timelier SIC diagnosis and improved management of all stages of septic coagulopathy by making it more effective, safe, and personalized.

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.
METHODS: 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.

OBJECTIVE: Thrombomodulin (TM) is closely related to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE). However, current evidence on circulating TM levels in SLE patients is contradictory. We conducted this meta-analysis to more accurately assess circulating TM levels in patients with SLE and lupus nephritis (LN) and to analyze related influencing factors.
METHODS: Systematic search of relevant documents was conducted in PubMed, Embase, and The Cochrane Library databases (up to 28 February 2021). Studies on the comparison of circulating TM between SLE patients and controls were screened and evaluated for inclusion. Random-effects model analysis was applied to calculate the combined standardized mean difference (SMD) with a 95% confidence interval (CI). Heterogeneity was estimated by Q statistics and I2.
RESULTS: A total of 353 articles were identified, 14 provided adequate information for this study finally. The results illustrated that SLE patients had higher TM levels than healthy controls (SMD =0.38, 95% CI: 0.02 to 0.74, p=0.04). Circulating TM levels were increased in patients with active SLE compared to inactive SLE patients (SMD=1.12, 95% CI: 0.03 to 2.20, p=0.04). In addition, circulating TM levels of SLE patients with LN were higher than those without LN (SMD=4.55, 95% CI: 1.97 to 7.12, p=0.001).
CONCLUSIONS: The circulating TM levels in SLE patients are enhanced. In addition, circulating TM levels may be practical in reflecting the disease activity and nephritis involvement of SLE patients.

Pseudomonas (P.) aeruginosa is a Gram-negative bacteria that causes human infectionsinfections. It can cause keratitis, a severe eye infection, that develops quickly and is a major cause of ulceration of the cornea and ocular complications globally. Contact lens wear is the greatest causative reason in developed countries, but in other countries, trauma and predominates. Use of non-human models of the disease are critical and may provide promising alternative argets for therapy to bolster a lack of new antibiotics and increasing antibiotic resistance. In this regard, we have shown promising data after inhibiting high mobility group box 1 (HMGB1), using small interfering RNA (siRNA). Success has also been obtained after other means to inhinit HMGB1 and include: use of HMGB1 Box A (one of three HMGB1 domains), anti-HMGB1 antibody blockage of HMGB1 and/or its receptors, Toll like receptor (TLR) 4, treatment with thrombomodulin (TM) or vasoactive intestinal peptide (VIP) and glycyrrhizin (GLY, a triterpenoid saponin) that directly binds to HMGB1. ReducingHMGB1 levels in P. aeruginosa keratitis appears a viable treatment alternative.

Several studies have reported that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can directly infect endothelial cells, and endothelial dysfunction is often found in severe cases of coronavirus disease 2019 (COVID-19). To better understand the prognostic values of endothelial dysfunction in COVID-19-associated coagulopathy, we conducted a systematic review and meta-analysis to assess biomarkers of endothelial cells in patients with COVID-19.
A literature search was conducted on online databases for observational studies evaluating biomarkers of endothelial dysfunction and composite poor outcomes in COVID-19 patients.
A total of 1187 patients from 17 studies were included in this analysis. The estimated pooled means for von Willebrand Factor (VWF) antigen levels in COVID-19 patients was higher compared to healthy control (306.42 [95% confidence interval (CI) 291.37-321.48], p < 0.001; I2:86%), with the highest VWF antigen levels was found in deceased COVID-19 patients (448.57 [95% CI 407.20-489.93], p < 0.001; I2:0%). Meta-analysis showed that higher plasma levels of VWF antigen, tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 antigen (PAI-1) antigen, and soluble thrombomodulin (sTM) were associated with composite poor outcome in COVID-19 patients ([standardized mean difference (SMD) 0.74 [0.33-1.16], p < 0.001; I2:80.4%], [SMD 0.55 [0.19-0.92], p = 0.003; I2:6.4%], [SMD 0.33 [0.04-0.62], p = 0.025; I2:7.9%], and [SMD 0.55 [0.10-0.99], p = 0.015; I2:23.6%], respectively).
The estimated pooled means show increased levels of VWF antigen in COVID-19 patients. Several biomarkers of endothelial dysfunction, including VFW antigen, t-PA, PAI-1, and sTM, are significantly associated with increased composite poor outcomes in patients with COVID-19.
CRD42021228821.

BACKGROUND: Previous studies displayed that thrombomodulin gene polymorphisms are closely associated with venous thromboembolism (VTE), while the results are inconsistent. Therefore, we conducted a meta-analysis to accurately determine the association between thrombomodulin gene polymorphism and the risk of VTE.
METHODS: Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, EmBase, and Web of Science databases were searched, and the time to build the database was set until January 2021. The association between thrombomodulin gene polymorphism and the risk of VTE was evaluated. Meta-analysis was performed with STATA 16.0 software, and the odds ratio and its 95% confidence interval were applied to estimate the relationship between thrombomodulin gene polym\'orphism and the risk of VTE.
RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.
CONCLUSIONS: This meta-analysis will summarize the relationship between thrombomodulin genepolymorphism and VTE risk.
BACKGROUND: Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations.
UNASSIGNED: DOI 10.17605/OSF.IO/UEHJP.