Disorders of Coagulation and Hemostasis in Abdominal Obesity: Emerging Role of Fatty Liver

ABSTRACT

Abdominal obesity represents a public health concern because its prevalence is reaching epidemic proportions worldwide, and it is associated with an increased risk of cardiovascular morbidity and mortality and other pathological conditions. A large body of evidence suggests that abdominal obesity is associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombosis in these individuals. This review briefly summarizes the evidence of direct and indirect effects of the accumulation of excess lipid in visceral adipose tissue on coagulation and fibrinolysis. In addition, this article critically appraises the rapidly expanding body of experimental and clinical data that support a potential direct contribution for the accumulation of excess lipid in the liver (i.e., nonalcoholic fatty liver disease, a very frequent pathological condition in subjects with abdominal obesity) in the pathogenesis of the obesity-induced disorders of coagulation and fibrinolysis.

KEYWORDS

Abdominal obesity - blood coagulation disorders - hemostatic factors - inflammation - insulin resistance - nonalcoholic fatty liver disease

REFERENCES

• 1 Ogden C L, Carroll M D, Curtin L R, McDowell M A, Tabak C J, Flegal K M. Prevalence of overweight and obesity in the United States, 1999–2004.  JAMA. 2006;  295(13) 1549-1555
• 2 Ogden C L, Yanovski S Z, Carroll M D, Flegal K M. The epidemiology of obesity.  Gastroenterology. 2007;  132(6) 2087-2102
• 3 Zhang C, Rexrode K M, van Dam R M, Li T Y, Hu F B. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women.  Circulation. 2008;  117(13) 1658-1667
• 4 Pischon T, Boeing H, Hoffmann K et al.. General and abdominal adiposity and risk of death in Europe.  N Engl J Med. 2008;  359(20) 2105-2120
• 5 Colditz G A, Willett W C, Rotnitzky A, Manson J E. Weight gain as a risk factor for clinical diabetes mellitus in women.  Ann Intern Med. 1995;  122(7) 481-486
• 6 Marchesini G, Moscatiello S, Di Domizio S, Forlani G. Obesity-associated liver disease.  J Clin Endocrinol Metab. 2008;  93(11, suppl 1) S74-S80
• 7 Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2008;  28(1) 27-38
• 8 Van Gaal L F, Mertens I L, De Block C E. Mechanisms linking obesity with cardiovascular disease.  Nature. 2006;  444(7121) 875-880
• 9 Mertens I, Van Gaal L F. Visceral fat as a determinant of fibrinolysis and hemostasis.  Semin Vasc Med. 2005;  5(1) 48-55
• 10 Després J P, Lemieux I, Bergeron J et al.. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk.  Arterioscler Thromb Vasc Biol. 2008;  28(6) 1039-1049
• 11 Mina A, Favaloro E J, Koutts J. Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review.  Semin Thromb Hemost. 2007;  33(8) 798-809
• 12 Alessi M C, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis.  Thromb Haemost. 2008;  99(6) 995-1000
• 13 Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial thrombosis.  Semin Thromb Hemost. 2009;  35(5) 451-457
• 14 Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;  122(6) 727-735
• 15 Tavil Y, Sen N, Yazici H U, Hizal F, Abaci A, Cengel A. Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease.  Thromb Res. 2007;  120(2) 245-250
• 16 Muscari A, De Pascalis S, Cenni A et al.. Determinants of mean platelet volume (MPV) in an elderly population: relevance of body fat, blood glucose and ischaemic electrocardiographic changes.  Thromb Haemost. 2008;  99(6) 1079-1084
• 17 Davì G, Guagnano M T, Ciabattoni G et al.. Platelet activation in obese women: role of inflammation and oxidant stress.  JAMA. 2002;  288(16) 2008-2014
• 18 Samocha-Bonet D, Justo D, Rogowski O et al.. Platelet counts and platelet activation markers in obese subjects.  Mediators Inflamm. 2008;  2008 , ID 834153
• 19 De Pergola G, Pannacciulli N, C oviello M et al.. sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors.  Nutr Metab Cardiovasc Dis. 2008;  18(3) 227-232
• 20 Keogh J B, Brinkworth G D, Noakes M, Belobrajdic D P, Buckley J D, Clifton P M. Effects of weight loss from a very-low-carbohydrate diet on endothelial function and markers of cardiovascular disease risk in subjects with abdominal obesity.  Am J Clin Nutr. 2008;  87(3) 567-576
• 21 Gokulakrishnan K, Deepa R, Mohan V, Gross M D. Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome—the Chennai Urban Rural Epidemiology Study.  Metabolism. 2006;  55(2) 237-242
• 22 Lee W L, Lee W J, Chen Y T 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;  55(8) 1029-1034
• 23 Angelico F, Alessandri C, Ferro D et al.. Enhanced soluble CD40L in patients with the metabolic syndrome: relationship with in vivo thrombin generation.  Diabetologia. 2006;  49(6) 1169-1174
• 24 Natal C, Restituto P, Iñigo C, Colina I, Díez J, Varo N. The proinflammatory mediator CD40 ligand is increased in the metabolic syndrome and modulated by adiponectin.  J Clin Endocrinol Metab. 2008;  93(6) 2319-2327
• 25 Russo I, Traversa M, Bonomo K et al.. In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin.  Obesity (Silver Spring). 2009;  , October 15 (Epub ahead of print)
• 26 Murakami T, Horigome H, Tanaka K et al.. Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity.  Thromb Res. 2007;  119(1) 45-53
• 27 Anfossi G, Russo I, Trovati M. Platelet dysfunction in central obesity.  Nutr Metab Cardiovasc Dis. 2009;  19(6) 440-449
• 28 Olufadi R, Byrne C D. Effects of VLDL and remnant particles on platelets.  Pathophysiol Haemost Thromb. 2006;  35(3–4) 281-291
• 29 Cigolini M, Targher G, Bergamo Andreis I A, Tonoli M, Agostino G, De Sandre G. Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men.  Arterioscler Thromb Vasc Biol. 1996;  16(3) 368-374
• 30 Shimomura I, Funahashi T, Takahashi M et al.. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity.  Nat Med. 1996;  2(7) 800-803
• 31 De Pergola G, De Mitrio V, Giorgino F et al.. Increase in both pro-thrombotic and anti-thrombotic factors in obese premenopausal women: relationship with body fat distribution.  Int J Obes Relat Metab Disord. 1997;  21(7) 527-535
• 32 Mertens I, Ballaux D, Funahashi T et al.. Inverse relationship between plasminogen activator inhibitor-I activity and adiponectin in overweight and obese women. Interrelationship with visceral adipose tissue, insulin resistance, HDL-chol and inflammation.  Thromb Haemost. 2005;  94(6) 1190-1195
• 33 Targher G, Bertolini L, Scala L, Zoppini G, Zenari L, Falezza G. 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(10) 1354-1358
• 34 Mertens I, Van der Planken M, Corthouts B, Van Gaal L F. Is visceral adipose tissue a determinant of von Willebrand factor in overweight and obese premenopausal women?.  Metabolism. 2006;  55(5) 650-655
• 35 Mertens I, Verrijken A, Michiels J J, Van der Planken M, Ruige J B, Van Gaal L F. Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome.  Int J Obes (Lond). 2006;  30(8) 1308-1314
• 36 Kopp C W, Kopp H P, Steiner S et al.. Weight loss reduces tissue factor in morbidly obese patients.  Obes Res. 2003;  11(8) 950-956
• 37 Peverill R E, Teede H J, Malan E, Kotsopoulos D, Smolich J J, McGrath B P. Relationship of waist and hip circumference with coagulation and fibrinolysis in postmenopausal women.  Clin Sci (Lond). 2007;  113(9) 383-391
• 38 Bowles L K, Cooper J A, Howarth D J, Miller G J, MacCallum P K. Associations of haemostatic variables with body mass index: a community-based study.  Blood Coagul Fibrinolysis. 2003;  14(6) 569-573
• 39 Hori Y, Gabazza E C, Yano Y et al.. Insulin resistance is associated with increased circulating level of thrombin-activatable fibrinolysis inhibitor in type 2 diabetic patients.  J Clin Endocrinol Metab. 2002;  87(2) 660-665
• 40 Guven G S, Kiliçaslan A, Oz S G et al.. Decrements in the thrombin activatable fibrinolysis inhibitor (TAFI) levels in association with orlistat treatment in obesity.  Clin Appl Thromb Hemost. 2006;  12(3) 364-368
• 41 Aubert H, Frère C, Aillaud M F, Morange P E, Juhan-Vague I, Alessi M C. Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndrome.  J Thromb Haemost. 2003;  1(4) 791-797
• 42 Mills J D, Mansfield M W, Grant P J. Factor XIII-circulating levels and the Val34Leu polymorphism in the healthy male relatives of patients with severe coronary artery disease.  Thromb Haemost. 2002;  87(3) 409-414
• 43 Targher G, Bonadonna R C, Alberiche M, Zenere M B, Muggeo M, Bonora E. Relation between soluble adhesion molecules and insulin sensitivity in type 2 diabetic individuals: role of adipose tissue.  Diabetes Care. 2001;  24(11) 1961-1966
• 44 Arteaga R B, Chirinos J A, Soriano A O et al.. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome.  Am J Cardiol. 2006;  98(1) 70-74
• 45 Morange P E, Renucci J F, Charles M A et al.. Plasma levels of free and total TFPI, relationship with cardiovascular risk factors and endothelial cell markers.  Thromb Haemost. 2001;  85(6) 999-1003
• 46 Bowles L K, Cooper J A, Howarth D J, Miller G J, MacCallum P K. Associations of haemostatic variables with body mass index: a community-based study.  Blood Coagul Fibrinolysis. 2003;  14(6) 569-573
• 47 Solá E, Navarro S, Medina P et al.. Activated protein C levels in obesity and weight loss influence.  Thromb Res. 2009;  123(5) 697-700
• 48 de Alwis N M, Day C P. Non-alcoholic fatty liver disease: the mist gradually clears.  J Hepatol. 2008;  48(suppl 1) S104-S112
• 49 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome.  Semin Thromb Hemost. 2009;  35(3) 277-287
• 50 Yoneda M, Mawatari H, Fujita K et al.. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH.  J Gastroenterol. 2007;  42(7) 573-582
• 51 Wieckowska A, Papouchado B G, Li Z, Lopez R, Zein N N, Feldstein A E. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis.  Am J Gastroenterol. 2008;  103(6) 1372-1379
• 52 Thuy S, Ladurner R, Volynets V et al.. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake.  J Nutr. 2008;  138(8) 1452-1455
• 53 Targher G, Bertolini L, Rodella S et al.. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men.  Obesity (Silver Spring). 2008;  16(6) 1394-1399
• 54 Greco D, Kotronen A, Westerbacka J et al.. Gene expression in human NAFLD.  Am J Physiol Gastrointest Liver Physiol. 2008;  294(5) G1281-G1287
• 55 Westerbacka J, Kolak M, Kiviluoto T et al.. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects.  Diabetes. 2007;  56(11) 2759-2765
• 56 Badman M K, Flier J S. The adipocyte as an active participant in energy balance and metabolism.  Gastroenterology. 2007;  132(6) 2103-2115
• 57 Shoelson S E, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance.  Gastroenterology. 2007;  132(6) 2169-2180
• 58 Shoelson S E, Lee J, Goldfine A B. Inflammation and insulin resistance.  J Clin Invest. 2006;  116(7) 1793-1801
• 59 Fontana L, Eagon J C, Trujillo M E, Scherer P E, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans.  Diabetes. 2007;  56(4) 1010-1013
• 60 Cartier A, Lemieux I, Alméras N, Tremblay A, Bergeron J, Després J P. Visceral obesity and plasma glucose-insulin homeostasis: contributions of interleukin-6 and tumor necrosis factor-alpha in men.  J Clin Endocrinol Metab. 2008;  93(5) 1931-1938
• 61 Ribeiro P S, Cortez-Pinto H, Solá S et al.. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients.  Am J Gastroenterol. 2004;  99(9) 1708-1717
• 62 Kolak M, Westerbacka J, Velagapudi V R et al.. Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity.  Diabetes. 2007;  56(8) 1960-1968
• 63 Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis.  N Engl J Med. 2000;  343(20) 1467-1476
• 64 Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis.  Trends Mol Med. 2008;  14(2) 72-81
• 65 Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?.  Diabetologia. 2008;  51(11) 1947-1953
• 66 Bastelica D, Morange P, Berthet B et al.. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits.  Arterioscler Thromb Vasc Biol. 2002;  22(1) 173-178
• 67 Alessi M C, Bastelica D, Mavri A et al.. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation.  Arterioscler Thromb Vasc Biol. 2003;  23(7) 1262-1268