Sepsis is characterized by a systemic inflammatory response followed by immunosuppression of the host. Metabolic defects and mitochondrial failure are common in immunocompromised patients with sepsis. The NLRP3 inflammasome is important for establishing an inflammatory response after activation by the purinergic P2X7 receptor. Here, we study a cohort of individuals with intra-abdominal origin sepsis and show that patient monocytes have impaired NLRP3 activation by the P2X7 receptor. Furthermore, most sepsis-related deaths are among patients whose NLRP3 activation is profoundly altered. In monocytes from sepsis patients, the P2X7 receptor is associated with mitochondrial dysfunction. Furthermore, activation of the P2X7 receptor results in mitochondrial damage, which in turn inhibits NLRP3 activation by HIF-1α. We show that mortality increases in a mouse model of sepsis when the P2X7 receptor is activated in vivo. These data reveal a molecular mechanism initiated by the P2X7 receptor that contributes to NLRP3 impairment during infection.

Introduction This study aimed to ascertain the associations of thromboelastography (TEG®) and standard laboratory test (SLTs) values with the presence of bleeding in critically ill patients with known coagulopathy. Methods Three groups of coagulopathic patients with (a) hepatic failure, (b) postoperative period after prolonged cardiac surgery, and (c) complex abdominal surgery with sepsis were prospectively included in this study. On intensive care unit (ICU) admission, patients were stratified into two groups according to whether they had major bleeding (MB) (evident overt bleeding, important bleeding apparent on imaging studies, and/or need for moderate‐massive blood transfusion and hemodynamic instability). Blood samples were drawn for the SLTs (international normalized ratio [INR], activated partial thromboplastin time [aPTT], platelet count, and fibrinogen level [Clauss]) and TEG whole blood coagulation assays. Receiver operating characteristic (ROC) curves were generated to determine the efficiency of TEG and SLTs for detecting bleeding. The correlations between SLTs and TEG parameters with similar coagulation profiles were evaluated by Spearman rank‐order analysis. Results Eighty‐three patients were included, and bleeding was confirmed in 45 (54%). The fibrinogen level demonstrated the best accuracy for detecting bleeding with an area under the curve and 95% confidence intervals [AUC (95% CI)] of 0.74 (0.63‐0.85) with the best cutoff value of ≤ 2 g/L. Regarding TEG‐MA, the AUC (CI) obtained with the optimal cutoff value of ≤ 51 mm was 0.68 (0.56‐0.80). Conclusions Both conventional clotting tests and TEG values were poorly associated with bleeding in this critically ill cohort of patients with coagulopathy.

Background This study aimed to verify the reference intervals (RIs) recently established in the Danish population for platelet aggregation induced by a specific agonist of the rotational thromboelastometry (ROTEM) platelet impedance aggregometer. Our local results were also compared with those published by the manufacturer. Methods This prospective study included healthy blood donors. Subjects with a history of coagulopathy, those on antiplatelet/anticoagulant therapy, or those taking nonsteroidal anti-inflammatory drugs were excluded. Blood samples were collected for ROTEM® platelet arachidonic acid thromboelastometry (ARATEM), adenosine-di-phosphate thromboelastometry (ADPTEM), and thrombin receptor-activating peptide-6 thromboelastometry (TRAPTEM). The parameters determined were the area under the curve (AUC, ohm·min), maximum amplitude at 6 min (A6, ohm), and maximum slope (MS, ohm/min). Values are expressed as 2.5th–97.5th percentiles. Comparisons are expressed as local vs Danish and manufacturer population RIs. Number (n) and percentage (%) of local tests below (<2.5th percentile) of the Danish and manufacturer population are shown. Results Forty donors (19 male; mean, 58 [range: 56 to 60] years) were included. There were no differences between our results and those published for the Danish population. In contrast, all ARATEM and ADPTEM values were lower in the local vs manufacturer group. Conclusions Our results confirm those published for the Danish population, with respect to the ROTEM platelet aggregometer. Clinicaltrials.gov Registration Number NCT02652897

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