Highlights
- •NAFLD could be associated with atherothrombosis and thromboembolism.
- •This association seems to be independent of obesity, diabetes, and hyperlipidaemia.
- •Metabolic features of NAFLD may lead to a prothrombotic state and hypercoagulation.
- •Increased PAI-1 levels and inflammation support the prothrombotic state in NAFLD.
- •NASH-cirrhosis is associated with a high rate of systemic thrombosis and the portal system.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is an emerging and threatening pathological
condition, ranging from fatty liver (FL) to chronic steatohepatitis (NASH), liver
cirrhosis, and eventually to hepatocellular carcinoma (HCC). Recent findings suggest
that patients with NAFLD have a higher risk of cardiovascular events and thromboembolism
and that this risk is independent of metabolic diseases that are frequently associated
with NAFLD, such as diabetes, hyperlipidaemia, and obesity. The vascular involvement
of NAFLD might be considered its systemic burden, conditioning higher mortality in
patients affected by the disease. These clinical findings suggested the existence
of a prothrombotic state in NAFLD, which is partially unexplored and whose underlying
mechanisms are to date not completely understood. Here, we review the mechanisms involved
in the pathogenesis of the prothrombotic state in NAFLD across the progression from
the healthy liver through the different stages of the disease. We focused on the possible
role of several metabolic features of NAFLD possibly leading to hypercoagulation other
than endothelial and platelet activation, such as insulin-resistance, nitric oxide
production regulation, and gut microbiota homeostasis. Also, we analysed the involvement
of plasminogen activator inhibitor-1 (PAI-1) and thromboinflammation taking place
in NAFLD. Finally, we described factors striking a prothrombotic imbalance in NASH
cirrhosis, with a particular focus on the pathogenesis of portal vein thrombosis.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Thrombosis ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.Hepatology. 2018; 67: 328-357
- Nonalcoholic fatty liver disease and cardiovascular disease.World J. Gastroenterol. 2014; 20: 8407-8415
- Increased risk of portal vein thrombosis in patients with cirrhosis due to nonalcoholic steatohepatitis.Liver Transpl. 2015; 21: 1016-1021
- Increased risk of venous thromboembolism in hospitalized patients with cirrhosis due to non-alcoholic steatohepatitis.Clin. Transl. Gastroenterol. 2018; 9: 140
- Nonalcoholic fatty liver disease: what the pathologist can tell the clinician.Dig. Dis. 2012; 30: 61-68
- Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review.Clin. Gastroenterol. Hepatol. 2012; 10 (e1342): 1342-1359
- Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults.Aliment. Pharmacol. Ther. 2011; 34: 274-285
- Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches.J. Gastroenterol. Hepatol. 2013; 28: 68-76
- Metabolic syndrome—a new world-wide definition. A consensus statement from the International Diabetes Federation.Diabet. Med. 2006; 23: 469-480
- Effect of weight reduction on hepatic abnormalities in overweight patients.Gastroenterology. 1990; 99: 1408-1413
- Therapeutic effects of restricted diet and exercise in obese patients with fatty liver.J. Hepatol. 1997; 27: 103-107
- Molecular pathways in non-alcoholic fatty liver disease.Clin. Exp. Gastroenterol. 2014; 7: 221-239
- Molecular mechanisms involved in NAFLD progression.J. Mol. Med. (Berl). 2009; 87: 679-695
- Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.Hepatology. 2010; 52: 1836-1846
- Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease.World J. Gastroenterol. 2014; 20: 1768-1776
- Involvement of free radicals and oxidative stress in NAFLD/NASH.Free Radic. Res. 2013; 47: 869-880
- Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites.Hepatology. 2010; 52: 774-788
- Gut-liver axis and fibrosis in nonalcoholic fatty liver disease: an input for novel therapies.Dig. Liver Dis. 2013; 45: 543-551
- Fibrogenesis in nonalcoholic steatohepatitis.Expert Rev. Gastroenterol. Hepatol. 2011; 5: 179-187
- Venous and arterial thrombosis: is there a link?.Adv. Exp. Med. Biol. 2017; 906: 273-283
- The metabolic syndrome and the risk of arterial and venous thrombosis.Thromb. Res. 2008; 122: 727-735
- The metabolic syndrome as a risk factor for venous and arterial thrombosis.Semin. Thromb. Hemost. 2009; 35: 451-457
- Non-alcoholic fatty liver disease (NAFLD) and 10-year risk of cardiovascular diseases.Clin. Res. Hepatol. Gastroenterol. 2017; 41: 31-38
- Fact Sheet on Cardiovascular Diseases.2017
- Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis.Nat. Rev. Gastroenterol. Hepatol. 2013; 10: 330-344
- Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis.J. Hepatol. 2016; 65: 589-600
- Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis.Sci. Rep. 2016; 6: 33386
- Increased risk of cerebrovascular accident related to non-alcoholic fatty liver disease: a meta-analysis.Oncotarget. 2018; 9: 2752-2760
- Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.Hepatology. 2006; 43: 682-689
- The relationship between nonalcoholic fatty liver disease and the severity of coronary artery disease in patients with metabolic syndrome.Turk. Kardiyol. Dern. Ars. 2008; 36: 376-381
- Evaluation of ultrasonographic fatty liver and severity of coronary atherosclerosis, and obesity in patients undergoing coronary angiography.Anadolu Kardiyol. Derg. 2009; 9: 273-279
- Association between non-alcoholic fatty liver disease and coronary artery disease severity.Chin. Med. J. 2011; 124: 867-872
- The association between impaired collateral circulation and non-alcoholic fatty liver in patients with severe coronary artery disease.J. Cardiol. 2012; 60: 210-214
- Non-alcoholic fatty liver disease is associated with stroke severity and progression of brainstem infarctions.Eur. J. Neurol. 2018; 25: 577-e534
- Evaluation of vulnerable coronary plaques and non-alcoholic fatty liver disease (NAFLD) by 64-detector multislice computed tomography (MSCT).Circ. J. 2008; 72: 618-625
- Presence of coronary plaques in patients with nonalcoholic fatty liver disease.Radiology. 2010; 254: 393-400
- High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial.Radiology. 2015; 274: 693-701
- Clinical significance of hepatic steatosis according to coronary plaque morphology: assessment using controlled attenuation parameter.J. Gastroenterol. 2019; 54: 271-280
- Carotid plaque compared with intima-media thickness as a predictor of coronary and cerebrovascular disease.Curr. Cardiol. Rep. 2009; 11: 21-27
- Association between nonalcoholic fatty liver disease and carotid atherosclerosis: a meta-analysis.Int. J. Clin. Exp. Med. 2015; 8: 7673-7678
- Nonalcoholic fatty liver disease is associated with subclinical atherosclerosis independent of obesity and metabolic syndrome in Asian Indians.Atherosclerosis. 2012; 223: 507-511
- Associations between liver histology and carotid intima-media thickness in patients with nonalcoholic fatty liver disease.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2687-2688
- Quantification of coronary artery calcium using ultrafast computed tomography.J. Am. Coll. Cardiol. 1990; 15: 827-832
- Association of hepatic steatosis with subclinical atherosclerosis: systematic review and meta-analysis.Hepatol. Commun. 2018; 2: 873-883
- Association of non-alcoholic fatty liver disease with impaired endothelial function by flow-mediated dilation: a meta-analysis.Hepatol. Res. 2016; 46: E165-E173
- Reactive hyperemia index (RHI) and cognitive performance indexes are associated with histologic markers of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD): a case control study.Cardiovasc. Diabetol. 2018; 17: 28
- Increased arterial stiffness in nonalcoholic fatty liver disease: a systematic review and meta-analysis.Eur. J. Gastroenterol. Hepatol. 2017; 29: e28-e35
- Fatty liver index is associated to pulse wave velocity in healthy subjects: data from the Brisighella Heart Study.Eur. J. Int. Med. 2018; 53: 29-33
- Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients.Diabetes Care. 2007; 30: 2119-2121
- Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease.World J. Gastroenterol. 2007; 13: 1579-1584
- A systematic review: burden and severity of subclinical cardiovascular disease among those with nonalcoholic fatty liver; should we care?.Atherosclerosis. 2013; 230: 258-267
- Non-alcoholic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million European adults.BMJ. 2019; 367: l5367
- Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology. 2016; 64: 73-84
- Portal vein thrombosis in cirrhosis.J. Clin. Gastroenterol. 2017; 51: 579-585
- The risk of venous thromboembolism in patients with cirrhosis. A systematic review and meta-analysis.Thromb. Haemost. 2017; 117: 139-148
- Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism.Am. J. Gastroenterol. 2006; 101 (quiz 1680): 1524-1528
- High prevalence of nonalcoholic fatty liver in patients with idiopathic venous thromboembolism.World J. Gastroenterol. 2010; 16: 6119-6122
- Hypercoagulation and thrombophilia in nonalcoholic fatty liver disease: mechanisms, human evidence, therapeutic implications, and preventive implications.Semin. Liver Dis. 2012; 32: 39-48
- AISF position paper on nonalcoholic fatty liver disease (NAFLD): updates and future directions.Dig. Liver Dis. 2017; 49: 471-483
- The metabolic syndrome.Endocr. Rev. 2008; 29: 777-822
- Consequences of comorbid sleep apnea in the metabolic syndrome--implications for cardiovascular risk.Sleep. 2010; 33: 1193-1199
- LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature.Expert. Rev. Clin. Pharmacol. 2018; 11: 959-970
- Hypercoagulability in the metabolic syndrome.Curr. Opin. Pharmacol. 2005; 5: 155-159
- Platelet activation in obesity and metabolic syndrome.Obes. Rev. 2012; 13: 27-42
- Altered clot kinetics in patients with non-alcoholic fatty liver disease.Ann. Hepatol. 2009; 8: 331-338
- Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.J. Clin. Invest. 2005; 115: 1343-1351
- Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease.Metabolism. 2016; 65: 1049-1061
- Influence of blood lipids on global coagulation test results.Ann. Lab Med. 2015; 35: 15-21
- Coagulation factor VII and the risk of coronary heart disease in healthy men.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1539-1544
- Lipolysis of triglyceride-rich lipoproteins activates coagulant factor XII: a study in familial lipoprotein-lipase deficiency.Atherosclerosis. 1992; 95: 119-125
- Nitric oxide synthases: regulation and function.Eur. Heart J. 2012; 33 (837a-837d): 829-837
- Non alcoholic fatty liver disease and eNOS dysfunction in humans.BMC Gastroenterol. 2017; 17: 35
- Regulation of obesity and insulin resistance by nitric oxide.Free Radic. Biol. Med. 2014; 73: 383-399
- Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis.Mol. Cell. Biol. 2003; 23: 5726-5737
- Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation.J. Biol. Chem. 2000; 275: 6123-6128
- Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action.J. Clin. Invest. 1998; 102: 1403-1412
- Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients.Clin. Exp. Med. 2016; 16: 193-202
- Tumor necrosis factor-alpha inhibits endothelial nitric-oxide synthase gene promoter activity in bovine aortic endothelial cells.J. Biol. Chem. 2004; 279: 963-969
- Tumor necrosis factor-alpha downregulates endothelial nitric oxide synthase mRNA stability via translation elongation factor 1-alpha 1.Circ. Res. 2008; 103: 591-597
- Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.Circ. Res. 1993; 73: 205-209
- Nitric oxide synthases: structure, function and inhibition.Biochem. J. 2001; 357: 593-615
- Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia—effects of selective inducible nitric oxide synthase inhibition.Thromb. Haemost. 2007; 97: 304-309
- Ceramides in insulin resistance and lipotoxicity.Prog. Lipid Res. 2006; 45: 42-72
- Ceramide as a mediator of non-alcoholic fatty liver disease and associated atherosclerosis.PLoS One. 2015; 10e0126910
- Mechanistic interplay between ceramide and insulin resistance.Sci. Rep. 2017; 7: 41231
- Role of ceramides in nonalcoholic fatty liver disease.Trends Endocrinol. Metab. 2012; 23: 365-371
- Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex.Diabetes. 2012; 61: 1848-1859
- Impact of sphingomyelin levels on coronary heart disease and left ventricular systolic function in humans.Nutr. Metab. (Lond.). 2011; 8: 25
- Association of plasma sphingomyelin levels and incident coronary heart disease events in an adult population: multi-ethnic study of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 628-633
- Selective reduction in the sphingomyelin content of atherogenic lipoproteins inhibits their retention in murine aortas and the subsequent development of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2114-2120
- Inhibition of sphingomyelin synthesis reduces atherogenesis in apolipoprotein E-knockout mice.Circulation. 2004; 110: 3465-3471
- Abnormal glucose tolerance in young male patients with nonalcoholic fatty liver disease.Liver Int. 2009; 29: 525-529
- Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia.Am. Heart J. 2004; 147: 803-807
- Is diabetes mellitus an independent risk factor for venous thromboembolism?: a population-based case-control study.Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1399-1405
- Diabetes increases the risk of deep-vein thrombosis and pulmonary embolism. A population-based cohort study.Thromb. Haemost. 2015; 114: 812-818
- Hyperglycemia is associated with enhanced thrombin formation, platelet activation, and fibrin clot resistance to lysis in patients with acute coronary syndrome.Diabetes Care. 2008; 31: 1590-1595
- Platelet dysfunction in type 2 diabetes.Diabetes Care. 2001; 24: 1476-1485
- Platelet-dependent thrombin generation in patients with diabetes mellitus: effects of glycemic control on coagulability in diabetes.J. Am. Coll. Cardiol. 1996; 27: 560-566
- Coagulation activation in diabetes mellitus: the role of hyperglycaemia and therapeutic prospects.Diabetologia. 1993; 36: 1119-1125
- Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE.Circulation. 1997; 96: 2262-2271
- Platelet tissue factor synthesis in type 2 diabetic patients is resistant to inhibition by insulin.Diabetes. 2010; 59: 1487-1495
- The role of advanced glycation end products in diabetic vascular complications.Diabetes Metab. J. 2018; 42: 188-195
- Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes.J. Clin. Invest. 1991; 87: 432-438
- Advanced glycation end products: a molecular target for vascular complications in diabetes.Mol. Med. 2015; 21: S32-S40
- Regulation of vascular endothelial growth factor expression by advanced glycation end products.J. Biol. Chem. 2001; 276: 43836-43841
- Role of advanced glycation end products (AGEs) in thrombogenic abnormalities in diabetes.Curr. Neurovasc. Res. 2006; 3: 73-77
- Advanced glycation end products and oxidative stress in type 2 diabetes mellitus.Biomolecules. 2015; 5: 194-222
- Role of oxidative stress in atherosclerosis.Am. J. Cardiol. 2003; 91: 7A-11A
- Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 12511-12516
- Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults.Sci. Rep. 2016; 6: 19076
- Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk.Cell. 2016; 165: 111-124
- Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies.J. Am. Heart Assoc. 2017; 6
- Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies.J. Cell. Mol. Med. 2018; 22: 185-194
- The fibrinolytic system-more than fibrinolysis?.Transfus. Med. Rev. 2015; 29: 102-109
- Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.Lancet. 1987; 2: 3-9
- Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis.Stroke. 2008; 39: 1456-1463
- Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis.Thromb. J. 2018; 16: 12
- Relationship of metabolic syndrome and fibrinolytic dysfunction to cardiovascular disease.Circulation. 2003; 108: 420-425
- Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries.Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6998-7002
- Plasminogen activator inhibitor type 1 and tissue inhibitor of metalloproteinases-2 increase after arterial injury in rats.Circ. Res. 1997; 80: 490-496
- Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice.Circulation. 2001; 103: 576-583
- Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery.Blood. 2000; 96: 4212-4215
- Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease.Atherosclerosis. 2010; 209: 585-591
- Hemostatic alterations in fatty liver disease.Blood Coagul. Fibrinolysis. 2010; 21: 325-327
- Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.Hepatology. 2014; 59: 121-129
- Plasma PAI-1 levels are increased in patients with nonalcoholic steatohepatitis.Diabetes Care. 2007; 30: e31-e32
- Endotoxin and plasminogen activator inhibitor-1 serum levels associated with nonalcoholic steatohepatitis in children.J. Pediatr. Gastroenterol. Nutr. 2010; 50: 645-649
- Analysis of adipokine concentrations in paediatric non-alcoholic fatty liver disease.Pediatr. Obes. 2012; 7: 471-479
- Association between plasminogen activator inhibitor-1 and severity of liver injury and cardiovascular risk in children with non-alcoholic fatty liver disease.Pediatr. Obes. 2018; 13: 23-29
- Plasminogen activator inhibitor-1 is independently associated with non-alcoholic fatty liver disease whereas leptin and adiponectin vary between genders.J. Gastroenterol. Hepatol. 2015; 30: 329-336
- Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1262-1268
- TM5441, a plasminogen activator inhibitor-1 inhibitor, protects against high fat diet-induced non-alcoholic fatty liver disease.Oncotarget. 2017; 8: 89746-89760
- Inhibition of plasminogen activator inhibitor 1 attenuates hepatic steatosis but does not prevent progressive nonalcoholic steatohepatitis in mice.Hepatol. Commun. 2018; 2: 1479-1492
- The interactions between inflammation and coagulation.Br. J. Haematol. 2005; 131: 417-430
- Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue.Diabet. Med. 2005; 22: 1354-1358
- Elevated factor VIII levels and the risk of thrombosis.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 731-738
- Changes in the levels of endothelium-derived coagulation parameters in nonalcoholic fatty liver disease.Blood Coagul. Fibrinolysis. 2014; 25: 151-155
- Procoagulant imbalance in patients with non-alcoholic fatty liver disease.J. Hepatol. 2014; 61: 148-154
- The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story.J. Thromb. Haemost. 2013; 11: 192-201
- Inflammation, von Willebrand factor, and ADAMTS13.Blood. 2018; 132: 141-147
- Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients.Hepatology. 2001; 34: 1158-1163
- Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2.J. Hepatol. 2006; 44: 1167-1174
- Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.Blood. 2004; 104: 100-106
- Inflammatory cytokines inhibit ADAMTS13 synthesis in hepatic stellate cells and endothelial cells.J. Thromb. Haemost. 2008; 6: 1233-1235
- The factor VIII acute phase response requires the participation of NFkappaB and C/EBP.Thromb. Haemost. 2000; 84: 216-222
- Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease.Liver Int. 2011; 31: 176-183
- Serum pentraxin 3 fragment as a noninvasive marker of nonalcoholic fatty liver disease in obese children and adolescents.Horm. Res. Paediatr. 2016; 86: 11-20
- The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease.Liver Int. 2020; 40: 1079-1088
- PSGL-1 regulates platelet P-selectin-mediated endothelial activation and shedding of P-selectin from activated platelets.Thromb. Haemost. 2007; 98: 806-812
- Platelets, inflammation and atherosclerosis.J. Thromb. Haemost. 2007; 5: 203-211
- Activated platelets and atherosclerosis.Expert. Rev. Cardiovasc. Ther. 2010; 8: 1297-1307
- CC chemokine ligand-5 (CCL5/RANTES) and CC chemokine ligand-18 (CCL18/PARC) are specific markers of refractory unstable angina pectoris and are transiently raised during severe ischemic symptoms.Circulation. 2007; 116: 1931-1941
- RANTES: a versatile and controversial chemokine.Trends Immunol. 2001; 22: 83-87
- Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis.Sci. Rep. 2018; 8: 7499
- Hepatic steatosis causes induction of the chemokine RANTES in the absence of significant hepatic inflammation.Int. J. Clin. Exp. Pathol. 2010; 3: 675-680
- Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress.Transl. Res. 2017; 180 (e104): 103-117
- The emerging role of NETs in venous thrombosis and Immunothrombosis.Front. Immunol. 2016; 7: 236
- Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis.Hepatology. 2018; 68: 1347-1360
- Long-term follow-up of patients with NAFLD and elevated liver enzymes.Hepatology. 2006; 44: 865-873
- Platelet production and destruction in liver cirrhosis.J. Hepatol. 2011; 54: 894-900
- A role of autoantibody-mediated platelet destruction in thrombocytopenia in patients with cirrhosis.Hepatology. 2003; 37: 1267-1276
- Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction?.J. Hepatol. 2011; 55: 1415-1427
- Venous thromboembolism in cirrhosis: a review of the literature.Can. J. Gastroenterol. 2012; 26: 905-908
- New insights into the coagulopathy of liver disease and liver transplantation.World J. Gastroenterol. 2006; 12: 7725-7736
- Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity.Hepatology. 2006; 44: 53-61
- Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.Blood. 2001; 98: 2730-2735
- Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.Gut. 2011; 60: 1133-1138
- Activation of blood platelets in chronic hepatitis and liver cirrhosis P-selectin expression on blood platelets and secretory activity of beta-thromboglobulin and platelet factor-4.Hepato-Gastroenterol. 2001; 48: 818-822
- Platelet activation in patients with alcoholic liver disease.Tokai J. Exp. Clin. Med. 2005; 30: 41-48
- Monocyte-platelet aggregates and platelet micro-particles in patients with post-hepatitic liver cirrhosis.Thromb. Res. 2010; 125: e228-e233
- Low-grade endotoxemia and platelet activation in cirrhosis.Hepatology. 2017; 65: 571-581
- Thrombin generation in patients with cirrhosis: the role of platelets.Hepatology. 2006; 44: 440-445
- Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management.Hepatology. 2006; 44: 1039-1046
- Hypercoagulability in cirrhosis: causes and consequences.J. Thromb. Haemost. 2011; 9: 1713-1723
- The rebalanced hemostasis system in end-stage liver disease and its impact on liver transplantation.Int. Anesthesiol. Clin. 2017; 55: 107-120
- Deep vein thrombosis and pulmonary embolism in cirrhosis patients.Dig. Dis. Sci. 2008; 53: 3012-3017
- Serum albumin is inversely associated with portal vein thrombosis in cirrhosis.Hepatol. Commun. 2019; 3: 504-512
- Deficiency of natural anticoagulant proteins C, S, and antithrombin in portal vein thrombosis: a secondary phenomenon?.Gut. 2000; 46: 534-539
- Thrombotic risk factors in patients with liver cirrhosis: correlation with MELD scoring system and portal vein thrombosis development.J. Hepatol. 2009; 51: 682-689
- Protein-C in patients with alcoholic cirrhosis and other liver-diseases.J. Hepatol. 1992; 14: 163-167
- Antithrombin III metabolism in patients with liver disease.J. Clin. Pathol. 1984; 37: 523-530
- An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis.Gastroenterology. 2009; 137: 2105-2111
- Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests.Hepatology. 2005; 41: 553-558
- Coagulation proteins influencing global coagulation assays in cirrhosis: hypercoagulability in cirrhosis assessed by thrombomodulin-induced thrombin generation assay.Biomed. Res. Int. 2013; 2013: 856754
- AGA clinical practice update: coagulation in cirrhosis.Gastroenterology. 2019; 157 (e31): 34-43
- Hepatocellular carcinoma in non-alcoholic fatty liver disease: epidemiology, pathogenesis, and prevention.J. Clin. Transl. Hepatol. 2013; 1: 131-137
- Incidence, risk factors and consequences of portal vein and systemic thromboses in hepatocellular carcinoma.Thromb. Res. 2008; 122: 299-306
- Portal vein thrombosis in liver cirrhosis: incidence, management, and outcome.BMC Gastroenterol. 2017; 17: 112
- The mechanisms of cancer-associated thrombosis.Thromb. Res. 2015; 135: S8-S11
- Diagnosis, Development, and Treatment of Portal Vein Thrombosis in Patients With and Without Cirrhosis, Gastroenterology.156. 2019: 1582-1599 (e1581)
- Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study.Liver Int. 2018; 38: 94-101
- Pathophysiology of portal hypertension.Clin. Liver Dis. 2014; 18 (281-+)
- Altered Doppler flow patterns in cirrhosis patients: an overview.Ultrasonography. 2016; 35: 3-12
- Nonalcoholic fatty liver disease: portal hypertension due to outflow block in patients without cirrhosis.Radiology. 2015; 274: 597-604
- Origins of portal hypertension in nonalcoholic fatty liver disease.Dig. Dis. Sci. 2018; 63: 563-576
- Increased NAD(P)H fluorescence with decreased blood flow in the steatotic liver of the obese Zucker rat.Microvasc. Res. 2003; 66: 15-21
- The effect of graded steatosis on flow in the hepatic parenchymal microcirculation.Transplantation. 1999; 68: 780-784
- Effects of diffuse fatty infiltration of the liver on portal vein flow hemodynamics.J. Clin. Ultrasound. 2008; 36: 134-140
- Impairment of hepatic microcirculation in fatty liver.Microcirculation. 2003; 10: 447-456
- Relationship of steatosis grade and zonal location to histological features of steatohepatitis in adult patients with non-alcoholic fatty liver disease.J. Hepatol. 2008; 48: 829-834
- Perspectives on NASH histology: cellular ballooning.Ann. Hepatol. 2017; 16: 182-184
- Liver sinusoidal endothelial cells: physiology and role in liver diseases.J. Hepatol. 2017; 66: 212-227
- Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids.J. Clin. Investig. 1997; 100: 2923-2930
- Morphological mechanisms for regulating blood flow through hepatic sinusoids.Liver. 2000; 20: 3-7
- Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.Circ. Res. 2007; 100: 158-173
- Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol. Rev. 2008; 88: 125-172
- Sinusoidal communication in liver fibrosis and regeneration.J. Hepatol. 2016; 65: 608-617
- Reduction of the increased portal vascular-resistance of the isolated perfused cirrhotic rat-liver by vasodilators.J. Hepatol. 1985; 1: 325-337
- Kupffer cells in non-alcoholic fatty liver disease: the emerging view.J. Hepatol. 2009; 51: 212-223
- Fibrin fuels fatty liver disease.J. Thromb. Haemost. 2018; 16: 3-5
Article info
Publication history
Published online: December 11, 2020
Accepted:
December 7,
2020
Received in revised form:
November 17,
2020
Received:
October 7,
2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
