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Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

ABSTRACT: Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We showed that histones trigger coagulation activation in vivo, as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on intracellular inflammasome pathways involving caspase 1/11 and gasdermin D (GSDMD), nor on cell surface receptor TLR2- and TLR4-mediated host immune response, as the deficiency of these genes in mice did not protect against histone-induced coagulopathy. The incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. The neutralization of TF diminished the histone-induced coagulation. Our findings revealed lytic cell death as a novel mechanism of histone-induced coagulation activation and thrombosis.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC9224270 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

Zhang Yan Y Wu Congqing C Li Lan L Pandeya Ankit A Zhang Guoying G Cui Jian J Kirchhofer Daniel D Wood Jeremy P JP Smyth Susan S SS Wei Yinan Y Li Zhenyu Z

International journal of molecular sciences 20220618 12

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue-factor (TF)-dependent mechanism. We used a combination of various deficient mice to elucidate the molecular mechanism of histone-induced coagulation. We ...[more]

PMID: 35743244

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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.

Project description:Backgroundsepsis is a life-threatening organ dysfunction caused by an excessive host immunological response to infection. The incidence of sepsis is increasing every year, and sepsis is the primary cause of mortality in intensive care units (ICUs). DIC is a coagulopathy syndrome that causes microvascular and macrovascular thrombosis and increases the risk of bleeding due to consumptive coagulopathy. The pathophysiology of DIC in sepsis is complex, and further research is required to investigate the involved mechanisms and risk factors.Methodthis study is a prognostic analysis of a retrospective cohort. Samples were patients diagnosed with sepsis and admitted to Cipto Mangunkusumo National General Hospital from January 2016 to October 2022. Research subjects were followed until occurrence of DIC during sepsis or recovery from sepsis. The research subjects were selected from medical records using a consecutive total sampling approach. The inclusion criteria were patients aged ≥18 years old and diagnosed with sepsis according to qSOFA criteria with a score of 2. The exclusion criterion was an incomplete medical record. Bivariate and multivariate logistic regression analyses were performed to determine which independent variables contributed to the incidence of DIC and obtain the odds ratios (ORs). p < 0.05 was considered to indicate a statistically significant difference.Resultsa total of 248 patients were included after considering the inclusion and exclusion criteria. Of these, 50 (20.2%) septic patients developed DIC. In the multivariate analysis, albumin ≤2.5 g/dL (OR: 2.363; 95% CI: 1.201-4.649), respiratory infection (OR: 2.414; 95% CI: 1.046-5.571), and antibiotic treatment ≥1 h (OR: 2.181; 95% CI: 1.014-4.689) were associated with DIC development. On the basis of the ROC curve, the area under the curve (AUC) was determined to be 0.705 with 95% CI = (0.631-0.778).Conclusionin our study, the prevalence of DIC in septic patients was 20.2%. Low albumin, respiratory infection, and antibiotic treatment ≥1 h were found to be risk factors for development of DIC in septic patients.

Dataset Information

Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

Publications

Extracellular Histones Trigger Disseminated Intravascular Coagulation by Lytic Cell Death.

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