Research ArticlePreserved hemostatic status in patients with non-alcoholic fatty liver disease
Graphical abstract
Introduction
Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease (CVD). Increasing evidence suggests that the higher incidence of cardiovascular disease (CVD) morbidity and mortality in patients with NAFLD is independent of conventional cardiometabolic risk factors (such as obesity, insulin resistance, and diabetes mellitus) [1], [2], [3]. However, the exact mechanisms linking NAFLD to increased risk of CVD are incompletely understood and likely reflect multiple co-existing pathways [3]. Furthermore, rates of venous thromboembolism (VTE) and portal vein thrombosis (PVT) appear also increased in patients with NAFLD [4], [5]. Recent studies have suggested a role for a hypercoagulable state in the increased risk of thrombosis in patients with NAFLD. Increased plasma levels of various pro-thrombotic factors (e.g., fibrinogen, factor VIII, and plasminogen activator inhibitor 1 (PAI-1)) have been described in patients with NAFLD [6], [7], [8], [9]. Furthermore, studies have shown hypercoagulable features in patients with NAFLD detected with either thromboelastography (TEG) [10] or thrombin generation testing [11]. Platelet hyperactivity has also been implicated as a contributor of the increased risk of cardiovascular disease in patients with the metabolic syndrome [12], [13], [14], but its role in NAFLD remains unclear [3].
Nevertheless, results on the hemostatic status in NAFLD are inconsistent [3]. Furthermore, most studies have reported plasma levels of individual hemostatic proteins rather than functional tests of hemostasis. In addition, no study has profiled all components of the hemostatic system simultaneously, and patients with cirrhosis were excluded from most of these studies. The hemostatic status across the spectrum of NAFLD stages thus remains unclear. Whether the hemostatic status might explain the increased risk of thrombosis in these patients also remains to be firmly established. We, therefore, determined an in-depth hemostatic profile by performing functional hemostatic tests of platelets, coagulation, fibrinolysis, and fibrin clot structure in a cohort of well-defined patients with NAFLD. Furthermore, we compared the hemostatic status of patients with NASH-related cirrhosis to that of patients with alcoholic-(ASH) related cirrhosis. This is the first study that comprehensively investigated all components of the hemostatic system (i.e., platelets, coagulation, and fibrinolysis) using both biomarkers and functional tests in patients with various histological severities of NAFLD.
Section snippets
Patients
All subjects (healthy controls, patients with various severity of NAFLD, and patients with ASH cirrhosis) were enrolled through the NASH Clinic at the Virginia Commonwealth University (Richmond, VA). The study protocol was IRB-approved and written informed consent was obtained from each subject before inclusion in the study. NAFLD was defined by the evidence of hepatic steatosis on liver biopsy and the absence of causes for secondary hepatic fat accumulation (such as significant alcohol
Patient characteristics
Patient characteristics are reported in Table 1. Sixty-eighth patients with biopsy-proven NAFLD (simple steatosis n = 24, NASH n = 22, and NASH cirrhosis n = 22), thirty lean controls (BMI <25 kg/m2), thirty overweight controls (BMI >25 kg/m2), and fifteen patients with alcoholic (ASH) cirrhosis were included. None of the patients were diagnosed with another form of liver disease (e.g., hepatitis B, hepatitis C, autoimmune hepatitis, hereditary haemochromatosis etc.). The NAS score increased from
Discussion
The combined results of this study show that the overall hemostatic status is comparable between patients with NAFLD and controls. Our study, therefore, suggests that the role for hyperactive hemostasis in the increased risk of thrombosis in patients with NAFLD is probably limited. Furthermore, since there were no differences in the coagulation status between patients with NASH- or ASH-related cirrhosis, there is probably also a limited role for hemostasis in the increased thrombotic risk in
Financial support
This work is supported by grants RO1 DK 81410, RO1 AA 020758 from the NIDDK.
Conflict of interest
The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Authors’ contributions
Wilma Potze, Mohammad S. Siddiqui, Sherry L. Boyett, Jelle Adelmeijer, Kalyani Daita, Arun J. Sanyal, Ton Lisman: conceived and designed the experiments; Wilma Potze, Mohammad S. Siddiqui, Jelle Adelmeijer, Kalyani Daita: performed the experiments; Wilma Potze, Mohammad S. Siddiqui, Sherry L. Boyett, Jelle Adelmeijer, Kalyani Daita, Arun J. Sanyal, Ton Lisman: analysed and interpreted data; Wilma Potze, Mohammad S. Siddiqui, Sherry L. Boyett, Arun J. Sanyal: included patients in the study;
Acknowledgements
We thank D.J. Groeneveld from the Department of Surgery, University Medical Center Groningen, The Netherlands, and J. Farnsworth from the Flow Cytometry Department, Virginia Commonwealth University, Richmond, VA, USA, for their help with the flow cytometry analysis in this study.
References (43)
- et al.
Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease
Atherosclerosis
(2010) - et al.
Altered clot kinetics in patients with non-alcoholic fatty liver disease
Ann Hepatol
(2009) - et al.
Procoagulant imbalance in patients with non-alcoholic fatty liver disease
J Hepatol
(2014) - et al.
Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease
Thromb Res
(2007) - et al.
The presence of metabolic syndrome is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease
Metabolism
(2006) - et al.
The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology
Gastroenterology
(2012) - et al.
No evidence for increased platelet activation in patients with hepatitis B- or C-related cirrhosis and hepatocellular carcinoma
Thromb Res
(2015) - et al.
Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography
J Hepatol
(2012) - et al.
The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure
Blood
(2000) - et al.
Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk
Lancet
(2003)
Ex vivo addition of fibrinogen concentrate improves the fibrin network structure in plasma samples taken during liver transplantation
J Thromb Haemost
Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen
J Thromb Haemost
Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis
Blood
Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives
Blood
Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests
J Hepatol
Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy
J Thromb Haemost
Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease
J Hepatol
An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis
Gastroenterology
Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients
Diabetes Care
Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease
N Engl J Med
Vascular disease in patients with nonalcoholic fatty liver disease
Semin Thromb Hemost
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