On how thrombosis drives progression of liver and lung disease

Liver disease can be acute or chronic and can be accompanied by a severe loss of liver function. Ultimately, liver function can deteriorate to such an extent that a liver transplant will be required. The course of serious liver diseases is different for each individual because there are several factors that influence the speed of the disease process. This thesis focuses on the development of thrombosis, or a dangerous blood clot, as a complication of liver disease, but also as a factor that can contribute to the worsening of the disease. Thrombosis can develop anywhere in the body, but we now know that this can also happen in the liver itself. This can then lead to an accelerated disease process because the supply of oxygen and nutrients is cut off in the smaller liver blood vessels. Thrombosis within the liver is likely caused by damage to the liver and the inflammatory response resulting from this damage. The liver also produces many of the proteins involved in the development of thrombosis. The coagulation balance is disturbed in patients with liver disease and these changes in the blood coagulation system are likely to contribute to thrombosis in the liver. Liver failure thus appears to be able to accelerate itself through a tendency to develop thrombosis in the liver. However, we do not know exactly what changes in the coagulation system are behind this, in whom they will occur and, above all, what we can do about it. This thesis has helped unravel some of these mechanisms. We also describe how similar changes in the blood coagulation system can increase the risk of thrombosis in a number of other diseases and procedures, such as lung transplantation. We provide advice from which others can develop therapies. This could be, for example, a new anticoagulant therapy that can slow down the disease process by preventing thrombosis

Thromboelastography does not predict outcome in different etiologies of cirrhosis

Background: New laboratory tests that measure global hemostasis indicate generally preserved hemostatic function in patients with cirrhosis. It is not known whether normal hemostatic function is maintained across various subsets of patients. Objectives: In the present study, we investigated clot generation and clot lysis kinetics in a large group of patients with different etiologies of disease. Patients/Methods: Blood samples of 270 patients with cirrhosis were studied using thromboelastography (TEG), which measures the dynamic and physical properties of clot formation and lysis in whole blood. TEG parameters of different subsets of the patient population were compared. Correlations with routine laboratory tests as well as clinical outcomes were explored. Results: Overall, TEG parameters were normal and similar between underlying disease etiologies. A proportion of subjects showed hypocoagulable features, with the exception of patients with cholestatic cirrhosis in whom TEG readings showed hypercoagulable features. In all groups, K-time, α-Angle, and MA correlated well with platelet counts and fibrinogen plasma levels. After a mean follow-up of 2 years and 11 months, 31 patients had experienced a bleeding event, 8 had developed thrombosis, and 173 patients (64%) had undergone liver transplantation and/or had died. TEG baseline parameters were similar between patients subdivided according to outcome. Conclusions: TEG parameters reflected generally preserved function of the hemostatic system in patients with cirrhosis, with hypo- and hypercoagulable features in subsets of patients with specific underlying disease etiologies. Abnormalities in TEG parameters did however not predict bleeding, thrombosis, or risk of liver transplantation and/or death

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

The Platelet and Platelet Function Testing in Liver Disease

Patients who have liver disease commonly present with alterations in platelet number and function. Recent data have questioned the contribution of these changes to bleeding complications in these patients. Modern tests of platelet function revealed compensatory mechanisms for the decreased platelet number and function, the most prominent compensatory mechanism being substantially elevated levels of the adhesive protein von Willebrand's factor. Consequently, standard diagnostic tests of platelet functions seem to be of little use to predict bleeding complication in patients who have liver disease. This article outlines the role of platelet abnormalities and possibilities for platelet function testing in patients who have liver disease

TAFI deficiency promotes liver damage in murine models of liver failure through defective down-regulation of hepatic inflammation

<p>Emerging evidence indicates that various haemostatic components can regulate the progression of liver disease. Thrombin-activatable fibrinolysis inhibitor (TAFI) possesses anti-inflammatory properties besides its anti-fibrinolytic function. Here, we investigated the contribution of TAFI to the progression of disease in murine models of chronic and acute liver failure. Chronic carbon tetrachloride (CCL4) administration induced liver damage and fibrosis both in TAFI knockout (TAFI(-/-)) mice and wild-type controls. Smooth muscle actin-alpha (alpha-SMA) content of liver tissue was significantly increased after 1 and 3 weeks, and pro-collagen alpha 1 expression was significantly increased after 3 and 6 weeks in TAFI(-/-) mice. TAFI(-/-) mice showed significantly elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) after 3 weeks of CCL4. Neutrophil influx was significantly increased in TAFI(-/-) mice after 6 weeks of CCL4. No difference in hepatic fibrin deposition between TAFI(-/-) and wild-types was observed. After acetaminophen intoxication, necrosis was significantly increased in TAFI(-/-) mice at 24 hours (h) after injection. AST and ALT levels were decreased at 2 and 6 h after acetaminophen injection in TAFI(-/-) mice, but were significantly higher in the TAFI(-/-) mice at 24 h. Similarly, hepatic fibrin deposition was decreased at 6 h in TAFI(-/-) mice, but was comparable to wild-types at 24 h after injection. In conclusion, TAFI deficiency results in accelerated fibrogenesis and increased liver damage in murine models of chronic and acute liver disease, which may be related to increased inflammation.</p>

American Gut: an Open Platform for Citizen Science Microbiome Research.

Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education. IMPORTANCE We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating n = 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples

American Gut:an Open Platform for Citizen Science Microbiome Research

Although much work has linked the human microbiome to specific phenotypes and lifestyle variables, data from different projects have been challenging to integrate and the extent of microbial and molecular diversity in human stool remains unknown. Using standardized protocols from the Earth Microbiome Project and sample contributions from over 10,000 citizen-scientists, together with an open research network, we compare human microbiome specimens primarily from the United States, United Kingdom, and Australia to one another and to environmental samples. Our results show an unexpected range of beta-diversity in human stool microbiomes compared to environmental samples; demonstrate the utility of procedures for removing the effects of overgrowth during room-temperature shipping for revealing phenotype correlations; uncover new molecules and kinds of molecular communities in the human stool metabolome; and examine emergent associations among the microbiome, metabolome, and the diversity of plants that are consumed (rather than relying on reductive categorical variables such as veganism, which have little or no explanatory power). We also demonstrate the utility of the living data resource and cross-cohort comparison to confirm existing associations between the microbiome and psychiatric illness and to reveal the extent of microbiome change within one individual during surgery, providing a paradigm for open microbiome research and education. IMPORTANCE We show that a citizen science, self-selected cohort shipping samples through the mail at room temperature recaptures many known microbiome results from clinically collected cohorts and reveals new ones. Of particular interest is integrating n = 1 study data with the population data, showing that the extent of microbiome change after events such as surgery can exceed differences between distinct environmental biomes, and the effect of diverse plants in the diet, which we confirm with untargeted metabolomics on hundreds of samples