Highlights
- •Cirrhosis is associated with thrombosis in portal and systemic circulation.
- •Cirrhosis display a concomitant increase of factor VIII and LPS from E. Coli.
- •LPS contributes to release factor VIII from endothelial cells.
Background & Aims
Patients with cirrhosis display enhanced blood levels of factor VIII, which may result
in harmful activation of the clotting system; however, the underlying mechanism is
unknown.
Methods
We performed a cross-sectional study in patients with cirrhosis (n = 61) and matched controls (n = 61) comparing blood levels of factor VIII, von Willebrand factor (vWf), lipopolysaccharide
(LPS) and positivity for Escherichia coli DNA. Furthermore, we performed an in vitro study to investigate if LPS, in a concentration range similar to that found in the
peripheral circulation of cirrhotic patients, was able to elicit factor VIII secretion
from human umbilical vein endothelial cells (HUVEC).
Results
Patients with cirrhosis displayed higher serum levels of LPS (55.8 [42.2–79.9] vs. 23.0 [7.0–34.0] pg/ml, p <0.001), factor VIII (172.0 [130.0–278.0] vs. 39.0 [26.0–47.0] U/dl, p <0.0001), vWf (265.0 [185.0–366.0] vs. 57.0 [48.0–65.0] U/dl, p <0.001) and positivity for Escherichia coli DNA (88% vs. 3%, p <0.001, n = 34) compared to controls. Serum LPS correlated significantly with factor VIII (r = 0.80, p <0.001) and vWf (r = 0.63, p <0.001). Only LPS (beta-coefficient = 0.70, p <0.0001) independently predicted factor VIII levels. The in vitro study showed that LPS provoked factor VIII and vWf release from HUVEC via formation
and secretion of Weibel-Palade bodies, a phenomenon blunted by pre-treating HUVEC
with an inhibitor of Toll-like receptor 4.
Conclusions
The study provides the first evidence that LPS derived from gut microbiota increases
the systemic levels of factor VIII via stimulating its release by endothelial cells.
Lay summary: Cirrhosis is associated with thrombosis in portal and systemic circulation. Enhanced
levels of factor VIII have been suggested to play a role but the underlying mechanism
is still unclear. Here we show that patients with cirrhosis display a concomitant
increase of factor VIII and lipopolysaccharide (LPS) from Escherichia coli and suggest that LPS contributes to the release of factor VIII from endothelial cells.
Graphical abstract
Graphical Abstract
Keywords
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References
Author names in bold designate shared co-first authorship
- The coagulopathy of chronic liver disease.N Engl J Med. 2011; 365: 147-156
- Bleeding and thrombosis in cirrhotic patients: what really matters?.Dig Liver Dis. 2012; 44: 275-279
- Clotting activation and hyperfibrinolysis in cirrhosis: implication for bleeding and thrombosis.Semin Thromb Hemost. 2013; 39: 426-433
- Portal vein thrombosis and chronic liver disease progression: The closer you look the more you see.Hepatology. 2016; 63: 342-343
- Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism.Am J Gastroenterol. 2006; 101: 1524-1528
- Venous thromboembolism in cirrhosis: a review of the literature.Can J Gastroenterol. 2012; 26: 905-908
- An imbalance of pro- vs. anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111
- Evidence that low protein C contributes to the procoagulant imbalance in cirrhosis.J Hepatol. 2013; 59: 265-270
- Evaluation of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis.J Lab Clin Med. 2005; 146: 238-243
- Factor VIII expression in liver disease.Thromb Haemost. 2004; 91: 267-275
- Factor VIII is synthesized in human endothelial cells, packaged in Weibel-Palade bodies and secreted bound to ULVWF strings.PLoS One. 2015; 10: e0140740
- Patterns of expression of factor VIII and von Willebrand factor by endothelial cell subsets in vivo.Blood. 2016; 128: 104-109
- High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.Hepatology. 1996; 23: 1377-1383
- The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story.J Thromb Haemost. 2013; 1: 192-201
- Systemic clotting activation by low-grade endotoxaemia in liver cirrhosis: a potential role for endothelial procoagulant activation.Ital J Gastroenterol Hepatol. 1997; 29: 434-440
- Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway.J Immunol. 2009; 182: 7997-8004
- Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease.J Am Heart Assoc. 2014; 3: e001072
- Role of NOX2 in mediating doxorubicin-induced senescence in human endothelial progenitor cells.Mech Ageing Dev. 2016; 159: 37-43
- Axitinib affects cell viability and migration of a primary foetal lung adenocarcinoma culture.Cancer Invest. 2014; 32: 13-21
- New insights into the steen solution properties: breakthrough in antioxidant effects via NOX2 downregulation.Oxid Med Cell Longev. 2014; 2014: 242180
- Transection of the oesophagus for bleeding oesophageal varices.Br J Surg. 1973; 60: 646-649
- Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.Hepatology. 2006; 44: 53-61
- The role of intestinal endotoxin in liver injury: a long and evolving history.Hepatology. 2010; 52: 1829-1835
- Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia.World J Hepatol. 2015; 7: 425-442
- Ongoing prothrombotic state in the portal circulation of cirrhotic patients.Thromb Haemost. 1997; 77: 44-47
- Linking gut microbiota and inflammation to obesity and insulin resistance.Physiology. 2016; 31: 283-293
- Endotoxemia as a trigger of thrombosis in cirrhosis.Haematologica. 2016; 101: e162-e163
- Low-grade endotoxemia and platelet activation in cirrhosis.Hepatology. 2017; 65: 571-581
- Portal vein thrombosis in cirrhosis is not associated with intestinal barrier disruption or increased platelet aggregability.Clin Res Hepatol Gastroenterol. 2016; 40: 722-729
Article info
Publication history
Published online: July 14, 2017
Accepted:
July 7,
2017
Received in revised form:
July 5,
2017
Received:
February 15,
2017
Identification
Copyright
© 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
