Coagulation Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Previous criteria for coagulation dysfunction in critically ill children were based mainly on expert opinion. OBJECTIVE To evaluate current evidence regarding coagulation tests associated with adverse outcomes in children to inform criteria for coagulation dysfunction during critical illness. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 by using a combination of medical subject heading terms and text words to define concepts of coagulation dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION Studies were included if critically ill children with coagulation dysfunction were evaluated, if performance characteristics of assessment and/or scoring tools to screen for coagulation dysfunction were evaluated, and if outcomes related to mortality or functional status, organ-specific outcomes, or other patient-centered outcomes were assessed. DATA EXTRACTION Data were abstracted from each eligible study into a standard data extraction form, along with risk of bias assessment, by a task force member. RESULTS The systematic review supports the presence of at least 2 of the following criteria reflecting coagulation dysfunction in the absence of liver dysfunction: platelet count <100 000 cells per μL, international normalized ratio >1.5, fibrinogen level <150 mg/dL, and D-dimer value above 10 times the upper limit of normal, or above the assay’s upper limit of detection if this limit is below 10 times the upper limit of normal. LIMITATIONS The proposed criteria for coagulation dysfunction are limited by the available evidence and will require future validation. CONCLUSIONS Validation of the proposed criteria and identified scientific priorities will enhance our understanding of coagulation dysfunction in critically ill children.

Identification of the Antithrombotic Mechanism of Leonurine in Adrenalin Hydrochloride-Induced Thrombosis in Zebrafish via Regulating Oxidative Stress and Coagulation Cascade

Thrombosis is a general pathological phenomenon during severe disturbances to homeostasis, which plays an essential role in cardiovascular and cerebrovascular diseases. Leonurine (LEO), isolated from Leonurus japonicus Houtt, showes a crucial role in anticoagulation and vasodilatation. However, the properties and therapeutic mechanisms of this effect have not yet been systematically elucidated. Therefore, the antithrombotic effect of LEO was investigated in this study. Hematoxylin-Eosin staining was used to detect the thrombosis of zebrafish tail. Fluorescence probe was used to detect the reactive oxygen species. The biochemical indexes related to oxidative stress (lactate dehydrogenase, malondialdehyde, superoxide dismutase and glutathione) and vasodilator factor (endothelin-1 and nitric oxide) were analyzed by specific commercial assay kits. Besides, we detected the expression of related genes (fga, fgb, fgg, pkcα, pkcβ, vwf, f2) and proteins (PI3K, phospho-PI3K, Akt, phospho-Akt, ERK, phospho-ERK FIB) related to the anticoagulation and fibrinolytic system by quantitative reverse transcription and western blot. Beyond that, metabolomic analyses were carried out to identify the expressions of metabolites associated with the anti-thrombosis mechanism of LEO. Our in vivo experimental results showed that LEO could improve the oxidative stress injury, abnormal platelet aggregation and coagulation dysfunction induced by adrenalin hydrochloride. Moreover, LEO restored the modulation of amino acids and inositol metabolites which are reported to alleviate the thrombus formation. Collectively, LEO attenuates adrenalin hydrochloride-induced thrombosis partly via modulating oxidative stress, coagulation cascade and platelet activation and amino acid and inositol metabolites.

The Platelet Role in Severe and Fatal Forms of COVID-19.

: On December 31, 2019, the World Health Organization received a report of several pneumonia cases in Wuhan, China. The causative agent was later confirmed as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since then, the SARS-CoV-2 virus has spread throughout the world, giving rise in 2020 to the 2019 coronavirus (COVID-19) pandemic, which, according to the world map of the World Health Organization, has, until May 18, 2021, infected 163,312,429 people and caused 3,386,825 deaths throughout the world. Most critical patients progress rapidly to acute respiratory distress syndrome (ARDS) and, in underlying form, to septic shock, irreversible metabolic acidosis, blood coagulation dysfunction, or hemostatic and thrombotic anomalies have been reported as the leading causes of death due to COVID-19. The main findings in severe and fatal COVID-19 patients make it clear that platelets play a crucial role in developing severe disease cases. Platelets are the enucleated cells responsible for hemostasis and thrombi formation; thus, platelet hyperreactivity induced by pro-inflammatory microenvironments contributes to the "cytokine storm" that characterizes the more aggressive course of COVID- 19.

Bioreactance-guided fluid therapy for excision of a giant brain tumor in an infant under general anesthesia: A case report and literature review

Pediatric patients are more likely to suffer from brain tumors. Surgical resection is often the optimal treatment. Perioperative management of pediatric brain tumor resection brings great challenges to anesthesiologists, especially for fluid therapy. In this case, the infant-patient was only 69-day-old, weighed 6 kg，but she was facing a gaint brain tumor (7.9 cm × 8.1 cm × 6.7 cm) excision. The infant was at great risks such as hemorrhagic shock, cerebral edema, pulmonary edema, congestive heart failure, coagulation dysfunction, etc. However, we tried to use the parameters obtained by bioreactance-based NICOM® device (Cheetah Medical) to guide the infant’s intraoperative fluid therapy, and successfully avoided these complications and achieved a good prognosis.

Thromboembolism and Bleeding in COVID-19

Coronavirus disease 2019 (COVID-19) is characterized by a coagulation dysfunction which has different underlying mechanisms and factors. Patients with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection have an increased risk for thromboembolic and bleeding complications. Incidences are high, and mainly consist of venous thromboembolism (VTE), which significantly contributes to morbidity and mortality in affected patients. Thromboprophylaxis is recommended in all hospitalized COVID-19 patients. Therapeutic doses of antithrombotic agents are only beneficial in noncritically ill patients, and usual care thromboprophylaxis is sufficient in critically ill patients at the ICU. Regarding screening for VTE, high quality evidence is warranted to investigate the significance of asymptomatic DVT in the ICU setting and its influence on PE and mortality.

Induction of soluble platelet activation markers and FXIII deficiency promote COVID-19 severity

Coagulation dysfunction and thromboembolism emerge as strong comorbidity factors in severe COVID-19 patients. However, the underlying pathomechanisms are largely undefined. Here, we sought to identify the potential molecular mechanisms of SARS-CoV-2 mediated coagulopathy and thromboembolism. A broader investigation was conducted including hospitalized COVID-19 patients with (severe cases that required intensive care) or without pneumonia (moderate cases). Phenotypic and molecular characterizations were performed employing basic coagulation tests, flow cytometry-based multiplex assays, and ELISA. The investigations revealed induction of plasma P-selectin and CD40 ligand (sCD40L) in moderate COVID-19 cases which were significantly abolished with the progression of COVID-19 severity. Moreover, a profound reduction in plasma tissue factor pathway inhibitor (TFPI) and FXIII were identified particularly in the severe COVID-19. Further analysis revealed a profound induction of fibrinogen in both moderate and severe patients. Interestingly, an elevated plasminogen activator inhibitor-1 more prominently in moderate, and tissue plasminogen activator (tPA) particularly in severe COVID-19 cases were observed. Particularly, the levels of fibrinogen and tPA directly correlated with the severity of COVID-19. In summary, SARS-CoV-2 infection induces the levels of platelet activation markers soluble P-selectin and sCD40L in hospitalized COVID-19 patients. Furthermore, an attenuated level of TFPI indicates TF pathway activation and, acquired FXIII deficiency likely plays a key role in thrombus instability and promotes thromboembolism in severe cases. The progression of COVID-19 severity could be limited with anti-platelet in combination with recombinantTFPI treatment. Furthermore, thromboembolic events in severe COVID-19 patients could be minimized if treated with recombinantFXIII in combination with LMW heparin.

Coagulation Dysfunction in Acute Respiratory Distress Syndrome and Its Potential Impact in Inflammatory Subphenotypes

The Acute Respiratory Distress Syndrome (ARDS) has caused innumerable deaths worldwide since its initial description over five decades ago. Population-based estimates of ARDS vary from 1 to 86 cases per 100,000, with the highest rates reported in Australia and the United States. This syndrome is characterised by a breakdown of the pulmonary alveolo-epithelial barrier with subsequent severe hypoxaemia and disturbances in pulmonary mechanics. The underlying pathophysiology of this syndrome is a severe inflammatory reaction and associated local and systemic coagulation dysfunction that leads to pulmonary and systemic damage, ultimately causing death in up to 40% of patients. Since inflammation and coagulation are inextricably linked throughout evolution, it is biological folly to assess the two systems in isolation when investigating the underlying molecular mechanisms of coagulation dysfunction in ARDS. Although the body possesses potent endogenous systems to regulate coagulation, these become dysregulated and no longer optimally functional during the acute phase of ARDS, further perpetuating coagulation, inflammation and cell damage. The inflammatory ARDS subphenotypes address inflammatory differences but neglect the equally important coagulation pathway. A holistic understanding of this syndrome and its subphenotypes will improve our understanding of underlying mechanisms that then drive translation into diagnostic testing, treatments, and improve patient outcomes.

Exploring the Mechanism of Coagulation Dysfunction in a Sepsis Model though Gene Expression Profiles

Objective. Sepsis is a life-threatening condition, and the mechanism of coagulation dysfunction in sepsis remains unknown. We aimed to investigate the mechanism of coagulation dysfunction in sepsis.Methods. Standard methods were used to establish the sepsis models and generate gene expression profiles. Bioinformatics analysis was carried out by GO and KEGG enrichment analysis, construction of PPIs and screening of seed genes. Finally, seed genes were used to rebuild the disease-related pathways.Results. Our experiments revealed an inflammatory response and coagulation dysfunction in both animal and cell models. After determining the DEGs, GO and KEGG functional analysis showed that there is a significant correlation between the inflammatory response and DNA damage. PPI network analysis screened 9 seed genes related to cell mitosis and platelet-derived growth factor receptor signaling pathways. Some of the seed genes were relevant to COVID-19.Conclusions. This study explored the molecular mechanism of coagulation dysfunction in sepsis models by bioinformatics analysis. This may have guiding significance in reducing the risk of complications in patients with sepsis and improving the effectiveness of treatment.

Delayed Cerebellar Injury is Affected by Multiple Organ Dysfunction Syndrome Caused by Heat Stroke, a Retrospective Cohort Study

Objective Nervous dysfunction is the main manifestation of heat stroke (HS). Here we investigated the clinical signs for HS-induced nerve injuries. Methods Retrospective data were collected on 119 patients who got HS from 2016 to 2020. Patients were divided into 4 groups, including the cerebellar injury group, the other nerve injuries group, non-cerebellar injury group and non-nerve injury group. The age, body temperature (Tc), degree of consciousness disorder, liver and kidney function, blood coagulation function, blood routine and cardiac indicators within 24 h after HS were summarized. Moreover, we performed regression analyses to identify risk factors for nervous dysfunction. The Activity of Daily Living (ADL) score was assessed 3 months after HS to evaluate the prognosis of HS. Results Compared with other groups, the cerebellar injury group had shorter Tc recovering time, lower GSC scales, longer coma time and more hypotension, gastrointestinal bleeding, multiple organ dysfunction syndrome (MODS) and metabolic acidosis significantly. The cerebellar injury group had higher myocardial enzymogram and indexes of liver and kidney dysfunction, immune and coagulation dysfunction significantly. Risk factors associated with HS-induced cerebellar injury are Tc, recovery time of Tc, NSE, GCS scale, lymphocyte count, HLA-DR/CD14, coagulation dysfunction, cardiac injury, metabolic acidosis and MODS. The ADL scale of the cerebellar injury group and the other nerve injury group were significantly lower than other groups. Conclusions Patients with severe coma and MODS are more prone to cerebellar injury after HS and the HS-induced nerve injury leaded to a worse prognosis.