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Objectives Extracorporeal membrane oxygenation is used to stabilize severe cardiocirculatory and/or respiratory failure. However, extracorporeal membrane oxygenation is associated with a coagulopathy characterized by thromboembolic and hemorrhagic complications. This study aimed to characterize the pathomechanism of the extracorporeal membrane oxygenation-associated coagulopathy and identify options to optimize its monitoring and therapy. Design Prospective observational clinical trial. Setting ICU of a university hospital. Patients Patients treated with venovenous extracorporeal membrane oxygenation (n = 10) due to acute respiratory distress syndrome and patients treated with venoarterial extracorporeal membrane oxygenation (n = 8) due to cardiocirculatory failure. One patient per group (venovenous extracorporeal membrane oxygenation or venoarterial extracorporeal membrane oxygenation) had surgery before extracorporeal membrane oxygenation. Interventions Blood was sampled before, and 1, 24, and 48 hours after extracorporeal membrane oxygenation implantation. Point-of-care tests (thrombelastometry/platelet aggregometry), conventional coagulation tests, whole blood counts, and platelet flow cytometry were performed. Measurements and main results Even before extracorporeal membrane oxygenation, plasmatic coagulation and platelet aggregation were impaired due to systemic inflammation, liver failure, anticoagulants (heparins, phenprocoumon, apixaban), and antiplatelet medication. During extracorporeal membrane oxygenation, hemodilution and contact of blood components with artificial surfaces and shear stress inside extracorporeal membrane oxygenation additionally contributed to coagulation and platelet defects. Fibrinogen levels, fibrin polymerization, platelet activation, and microparticle release were increased in venovenous extracorporeal membrane oxygenation compared to venoarterial extracorporeal membrane oxygenation patients. Point-of-care results were available faster than conventional analyses. Bleeding requiring blood product application occurred in three of 10 venovenous extracorporeal membrane oxygenation patients and in four of eight venoarterial extracorporeal membrane oxygenation patients. No thrombotic events were observed. In-hospital mortality was 30% for venovenous extracorporeal membrane oxygenation and 37.5% for venoarterial extracorporeal membrane oxygenation patients. Conclusions The extracorporeal membrane oxygenation-associated coagulopathy is a multifactorial and quickly developing syndrome. It is characterized by individual changes of coagulation parameters and platelets and is aggravated by anticoagulants. The underlying factors of the extracorporeal membrane oxygenation-associated coagulopathy differ between venovenous extracorporeal membrane oxygenation and venoarterial extracorporeal membrane oxygenation patients and are best diagnosed by a combination of point-of-care and conventional coagulation and platelet analyses. Therapy protocols for treating extracorporeal membrane oxygenation-associated coagulopathy should be further validated in large-scale prospective clinical investigations.

Background/Aims Cirrhotic patients show an increased risk of variceal bleeding upon bacterial infections. Kupffer cells (KC) constitute the first macrophage population to become activated by bacterial β-glucans and endotoxins derived from the gut. We therefore investigated whether and how KC activation increases portal pressure. Methods KC in normal and fibrotic livers from bile duct ligated (BDL) rats were activated by the β-glucan component of zymosan in vivo and during isolated rat liver perfusion. Results Activation of KC in normal livers resulted in a severalfold increase of portal pressure in vivo as well as in isolated perfused liver preparations. This increase and the accompanying 40-fold stimulation of hepatic prostaglandin F 2α /D 2 and thromboxane A 2 (TxA 2 ) production in isolated perfused livers were attenuated by KC blockade. The TxA 2 synthase inhibitor furegrelate and the TxA 2 receptor antagonist BM 13.177 reduced the increase of portal perfusion pressure supporting TxA 2 as pivotal vasoconstrictor released by activated KC. Importantly, a more pronounced vasopressor response in fibrotic livers was related to a raise in KC density and a 10-fold increase of TxA 2 production after KC activation. Conclusions KC activated by β-glucans increase portal pressure through the release of TxA 2 . This vasopressor response is augmented in BDL induced fibrosis.

The IL-10-like cytokine IL-22 is produced by activated T cells. In this study, we analyzed the role of this cytokine system in hepatic cells. Expression studies were performed by RT-PCR and quantitative PCR. Signal transduction was analyzed by Western blot experiments and ELISA. Cell proliferation was measured by MTS and [3H]thymidine incorporation assays. Hepatocyte regeneration was studied in in vitro restitution assays. Binding of IL-22 to its receptor complex expressed on human hepatic cells and primary human hepatocytes resulted in the activation of MAPKs, Akt, and STAT proteins. IL-22 stimulated cell proliferation and migration, which were both significantly inhibited by the phosphatidylinositol 3-kinase inhibitor wortmannin. IL-22 increased the mRNA expression of suppressor of cytokine signaling (SOCS)-3 and the proinflammatory cytokines IL-6, IL-8, and TNF-α. SOCS-1/3 overexpression abrogated IL-22-induced STAT activation and decreased IL-22-mediated liver cell regeneration. Hepatic IL-22 mRNA expression was detectable in different forms of human hepatitis, and hepatic IL-22 mRNA levels were increased in murine T cell-mediated hepatitis in vivo following cytomegalovirus infection, whereas no significant differences were seen in an in vivo model of ischemia-reperfusion injury. In conclusion, IL-22 promotes liver cell regeneration by increasing hepatic cell proliferation and hepatocyte migration through the activation of Akt and STAT signaling, which is abrogated by SOCS-1/3 overexpression.

Background/Aims Alterations in hepatobiliary transporters may render fatty livers more vulnerable against various toxic insults. Methods We therefore studied expression and function of key organic anion transporters and their transactivators in 8-week-old obese Zucker rats, an established model for non-alcoholic fatty liver disease. Results Compared to their heterozygous littermates, obese animals showed a significant reduction in canalicular bile salt secretion, which was paralleled by significantly diminished Oatp2 mRNA and protein levels together with reduced nuclear HNF3β, while expression of bile salt export pump, organic anion transporter (Oatp) 1 and multidrug resistance-associated protein (Mrp) 4 were unchanged. Impaired bile salt-independent bile flow in obese rats was associated with a 50% reduction of biliary secretion of the Mrp 2 model-substrates glutathione disulfide and S -(2,4-dinitrophenyl)glutathione. In line Mrp2 protein expression was reduced by 50% in obese rats. Conclusions Oatp2 and Mrp2 expression is decreased in fatty liver and may impair metabolism and biliary secretion of numerous xenobiotics. Reduction of bile salt secretion and absence of biliary GSH excretion may contribute to impaired bile flow and posthepatic disorders associated with biliary GSH depletion.