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Age Is Associated With the Efficacy of Anticoagulant Therapies Against Sepsis-Induced Disseminated Intravascular Coagulation.

ABSTRACT: Disseminated Intravascular Coagulation (DIC) commonly complicates sepsis and considerably worsens mortality. Recent studies suggested that anticoagulant therapies improved mortality only in specific sepsis populations, and key pathologies for selecting optimal targets needed to be identified. Anticoagulant activities were naturally altered with aging. This study aimed to evaluate age-related differences in efficacy of anticoagulant therapies in sepsis. This post hoc analysis of a nationwide multicenter cohort study was conducted in 42 intensive care units in Japan. Adult patients with septic DIC were divided into anticoagulant and control groups. Age-related changes in predicted mortality in both groups were compared using a logistic regression model including 2-way interaction terms. Patients were also stratified into 3 subsets based on age, and propensity score-adjusted Cox regression analyses were conducted to examine survival effect of anticoagulants in each subset. We included 1432 patients with septic DIC; 867 patients received anticoagulants and 565 received none. Age-related change in predicted mortality was significantly different between groups (P for interaction = 0.013), and the gap between groups was broad in the younger population. Similarly, in Cox regression analyses, anticoagulant therapies were associated with significantly lower mortality in the subsets of age ≤ 60 and 60-79 (hazard ratios = 0.461, 0.617, P = 0.007, 0.005, respectively), whereas there was no difference in survival between the groups in the subsets of age ≥ 80. The efficacy of anticoagulant therapies for septic DIC might be associated with patient age.

SUBMITTER: Takahashi K

PROVIDER: S-EPMC8293841 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sepsis is an uncontrolled inflammatory response against a systemic infection that results in elevated mortality, mainly induced by bacterial products known as endotoxins, producing endotoxemia. Disseminated intravascular coagulation (DIC) is frequently observed in septic patients and is associated with organ failure and death. Sepsis activates endothelial cells (ECs), promoting a prothrombotic phenotype contributing to DIC. Ion channel-mediated calcium permeability participates in coagulation. The transient reception potential melastatin 7 (TRPM7) non-selective divalent cation channel that also contains an α-kinase domain, which is permeable to divalent cations including Ca2+, regulates endotoxin-stimulated calcium permeability in ECs and is associated with increased mortality in septic patients. However, whether endothelial TRPM7 mediates endotoxemia-induced coagulation is not known. Therefore, our aim was to examine if TRPM7 mediates coagulation during endotoxemia. The results showed that TRPM7 regulated endotoxin-induced platelet and neutrophil adhesion to ECs, dependent on the TRPM7 ion channel activity and by the α-kinase function. Endotoxic animals showed that TRPM7 mediated neutrophil rolling on blood vessels and intravascular coagulation. TRPM7 mediated the increased expression of the adhesion proteins, von Willebrand factor (vWF), intercellular adhesion molecule 1 (ICAM-1), and P-selectin, which were also mediated by the TRPM7 α-kinase function. Notably, endotoxin-induced expression of vWF, ICAM-1 and P-selectin were required for endotoxin-induced platelet and neutrophil adhesion to ECs. Endotoxemic rats showed increased endothelial TRPM7 expression associated with a procoagulant phenotype, liver and kidney dysfunction, increased death events and an increased relative risk of death. Interestingly, circulating ECs (CECs) from septic shock patients (SSPs) showed increased TRPM7 expression associated with increased DIC scores and decreased survival times. Additionally, SSPs with a high expression of TRPM7 in CECs showed increased mortality and relative risk of death. Notably, CECs from SSPs showed significant results from the AUROC analyses for predicting mortality in SSPs that were better than the Acute Physiology and Chronic Health Evaluation II (APACHE II) and the Sequential Organ Failure Assessment (SOFA) scores. Our study demonstrates that sepsis-induced DIC is mediated by TRPM7 in ECs. TRPM7 ion channel activity and α-kinase function are required by DIC-mediated sepsis-induced organ dysfunction and its expression are associated with increased mortality during sepsis. TRPM7 appears as a new prognostic biomarker to predict mortality associated to DIC in SSPs, and as a novel target for drug development against DIC during infectious inflammatory diseases.

Project description:ObjectivesTo evaluate the utility of dielectric blood coagulometry for early sepsis-induced disseminated intravascular coagulation diagnosis.DesignSingle-center, prospective observational study.SettingPatients with sepsis or septic shock at the Tokyo Medical and Dental University Hospital of Medicine between September 2019 and September 2020.PatientsThe patients were divided into three groups according to the timing of disseminated intravascular coagulation diagnosis based on the Disseminated Intravascular Coagulation score by the Japanese Association for Acute Medicine: 1) no disseminated intravascular coagulation group, 2) late-diagnosed disseminated intravascular coagulation group: not diagnosed with disseminated intravascular coagulation on day 1 but diagnosed within 48 hours after admission, and 3) disseminated intravascular coagulation group: diagnosed with disseminated intravascular coagulation on day 1. The study evaluated 80 patients (no disseminated intravascular coagulation, 31 [38.8%]; late-diagnosed disseminated intravascular coagulation, 34 (42.5%); disseminated intravascular coagulation, 15 [18.8%]).Measurements and main resultsWe compared the clinical severity scores and mortality of the groups and assessed the correlation between the dielectric blood coagulometry-derived coagulation marker, thrombin levels, and Disseminated Intravascular Coagulation score using Spearman rank correlation. The mortality rate was 0% (0/31) in the no disseminated intravascular coagulation group, 35.3% (12/34) in the late-diagnosed disseminated intravascular coagulation group, and 33.3% (5/15) in the disseminated intravascular coagulation group. Although the Disseminated Intravascular Coagulation score on day 1 did not reflect disseminated intravascular coagulation in approximately 70% of patients who developed disseminated intravascular coagulation by day 2, dielectric clot strength measured by dielectric blood coagulometry on day 1 strongly correlated with disseminated intravascular coagulation development by day 2 (Spearman ρ = 0.824; p < 0.05) and with thrombin level on day 1 (Spearman ρ = 0.844; p < 0.05).ConclusionsDielectric blood coagulometry can be used to detect early-phase disseminated intravascular coagulation in patients with sepsis and is strongly correlated with thrombin levels. Larger studies are needed to verify our results for developing clinical applications.

Project description:IntroductionSince disseminated intravascular coagulation (DIC) was first described, it has been considered a serious disease of the coagulation system and a major challenge to clinicians. Currently, several important knowledge gaps remain. The DANish Disseminated Intravascular Coagulation (DANDIC) Cohort Study will aim to answer questions regarding the incidence and mortality of patients with DIC including time trends. The study will also identify prognostic factors that may guide personalised prevention and treatment. Furthermore, the study will describe treatment patterns and the safety and effectiveness of various treatment modalities.Methods and analysisWe will establish the DANDIC Cohort using data collected in daily clinical practice from the Central Denmark Region, which covers approximately 1.3 million residents. The study period will encompass 1 January 2011 through 1 July 2021. Potential DIC cases will be identified from the hospital laboratory database, based on coagulation biomarkers, and diagnoses will be adjudicated by medical experts. The dataset will be enriched with detailed clinical data from electronic medical charts on aetiologies, bleeding, microthrombus formation, organ failure, thrombosis, treatments and comorbidities. The dataset will also take advantage of in-hospital data with longitudinal information on laboratory records, transfusions, microbiology and treatments. It will be possible to merge this dataset with other unique Danish health registries with more than 10 years of virtually complete follow-up. The project will use state-of-the-art epidemiological and biostatistical methods.Ethics and disseminationThe project has been approved by the Danish Patient Safety Authority (31-1521-452), the Central Denmark Region (1-45-70-83-21), the Danish Data Protection Agency (1-16-02-258-21) and all the hospital chairs. Register-based studies require no ethical approval in Denmark. The results will be disseminated in international peer-reviewed journals.

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Age Is Associated With the Efficacy of Anticoagulant Therapies Against Sepsis-Induced Disseminated Intravascular Coagulation.

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