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Thromb Haemost 2013; 110(04): 669-680
DOI: 10.1160/TH13-01-0075
Theme Issue Article
Schattauer GmbH

Thrombosis in central obesity and metabolic syndrome: Mechanisms and epidemiology

Pierre-Emmanuel Morange
1   Laboratoire d’Hématologie, Inserm UMR 1062, Faculté de Médecine, Université de la Méditerranée, Marseille, France
,
Marie-Christine Alessi
1   Laboratoire d’Hématologie, Inserm UMR 1062, Faculté de Médecine, Université de la Méditerranée, Marseille, France
› Author Affiliations
Further Information

Publication History

Received: 29 January 2013

Accepted after major revision: 20 April 2013

Publication Date:
01 December 2017 (online)

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summary

Central obesity is a key feature of the metabolic syndrome (metS), a multiplex risk factor for subsequent development of type 2 diabetes and cardiovascular disease. Many metabolic alterations closely related to this condition exert effects on platelets and vascular cells. A procoagulant and hypofibrinolytic state has been identified, mainly underlain by inflammation, oxidative stress, dyslipidaemia, and ectopic fat that accompany central obesity. In support of these data, central obesity independently predisposes not only to atherothrombosis but also to venous thrombosis.

Keywords

Haemostasis - metabolic syndrome - visceral obesity - thrombosis
 

  • References

  • 1 Grundy SM, Brewer HB Jr, Cleeman JI. et al. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association. Circulation 2004; 109: 433-438.
    CrossrefPubMedGoogle Scholar
  • 2 Mottillo S, Filion KB, Genest J, et a. l The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
    CrossrefPubMedGoogle Scholar
  • 3 Abbasi F, Brown BW Jr, Lamendola C. et al. Relationship between obesity, insulin resistance, and coronary heart disease risk. J Am Coll Cardiol 2002; 40: 937-943.
    CrossrefPubMedGoogle Scholar
  • 4 Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93: 359-404.
    CrossrefPubMedGoogle Scholar
  • 5 Takaya J, Iwamoto Y, Higashino H. et al. Altered intracellular calcium and phorbol 12,13-dibutyrate binding to intact platelets in young obese subjects. J Lab Clin Med 1997; 129: 245-250.
    CrossrefPubMedGoogle Scholar
  • 6 Touyz RM, Schiffrin EL. Blunted inhibition by insulin of agonist-stimulated calcium, pH and aggregatory responses in platelets from hypertensive patients. J Hypertens 1994; 12: 1255-1263.
    CrossrefPubMedGoogle Scholar
  • 7 Davì G, Guagnano MT, Ciabattoni G. et al. Platelet activation in obese women: role of inflammation and oxidant stress. J Am Med Assoc 2002; 288: 2008-2014.
    CrossrefPubMedGoogle Scholar
  • 8 Anfossi G, Russo I, Trovati M. Platelet dysfunction in central obesity. Nutr Metab Cardiovasc Dis 2009; 19: 440-449.
    CrossrefPubMedGoogle Scholar
  • 9 Arteaga RB, Chirinos JA, Soriano AO. et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 2006; 98: 70-74.
    CrossrefPubMedGoogle Scholar
  • 10 Anfossi G, Trovati M. Pathophysiology of platelet resistance to anti-aggregating agents in insulin resistance and type 2 diabetes : implications for anti-aggregating therapy. Cardiovasc Hematol Agents Med Chem 2006; 4: 111-128.
    CrossrefPubMedGoogle Scholar
  • 11 Schäfer K, Konstantinides S. Adipokines and thrombosis. Clin Exp Pharmacol Physiol 2011; 38: 864-871.
    CrossrefPubMedGoogle Scholar
  • 12 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes 2005; 54: 2430-2435.
    CrossrefPubMedGoogle Scholar
  • 13 Anfossi G, Russo I, Trovati M. Platelet resistance to the anti-aggregating agents in the insulin resistant states. Curr Diabetes Rev 2006; 2: 409-430.
    CrossrefPubMedGoogle Scholar
  • 14 Ferreira IA, Mocking AI, Feijge MA. et al. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol 2006; 26: 417-422.
    CrossrefPubMedGoogle Scholar
  • 15 Anfossi G, Mularoni EM, Burzacca S. et al. Platelet resistance to nitrates in obesity and obese NIDDM, and normal platelet sensitivity to both insulin and nitrates in lean NIDDM. Diabetes Care 1998; 21: 121-126.
    CrossrefPubMedGoogle Scholar
  • 16 Anfossi G, Russo I, Massucco P. et al. Impaired synthesis and action of antiaggregating cyclic nucleotides in platelets from obese subjects: possible role in platelet hyperactivation in obesity. Eur J Clin Invest 2004; 34: 482-489.
    CrossrefPubMedGoogle Scholar
  • 17 Russo I, Traversa M, Bonomo K. et al. In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity 2010; 18: 788-797.
    CrossrefPubMedGoogle Scholar
  • 18 Russo I, Del Mese P, Doronzo G. et al. Platelet resistance to the antiaggregatory cyclic nucleotides in central obesity involves reduced phosphorylation of vasodilator-stimulated phosphoprotein. Clin Chem 2007; 53: 1053-1060.
    CrossrefPubMedGoogle Scholar
  • 19 Westerbacka J, Yki-Järvinen H, Turpeinen A. et al. Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity. Arterioscler Thromb Vasc Biol 2002; 22: 167-172.
    CrossrefPubMedGoogle Scholar
  • 20 Basili S, Pacini G, Guagnano MT. et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol. 2006; 48: 2531-2538.
    CrossrefPubMedGoogle Scholar
  • 21 Gerrits AJ, Koekman CA, van Haeften TW. et al. Platelet tissue factor synthesis in type 2 diabetic patients is resistant to inhibition by insulin. Diabetes 2010; 59: 1487-1495.
    CrossrefPubMedGoogle Scholar
  • 22 Englyst NA, Taube JM, Aitman TJ. et al. A novel role for CD36 in VLDL-enhanced platelet activation. Diabetes 2003; 52: 1248-1255.
    CrossrefPubMedGoogle Scholar
  • 23 Korporaal SJ, Akkerman JW. Platelet activation by low density lipoprotein and high density lipoprotein. Pathophysiol Haemost Thromb 2006; 35: 270-280.
    CrossrefPubMedGoogle Scholar
  • 24 Akkerman JW. From low-density lipoprotein to platelet activation. Int J Biochem Cell Biol 2008; 40: 2374-2378.
    CrossrefPubMedGoogle Scholar
  • 25 Patrono C, Falco A, Davì G. Isoprostane formation and inhibition in atherothrombosis. Curr Opin Pharmacol 2005; 5: 198-203.
    CrossrefPubMedGoogle Scholar
  • 26 Colas R, Sassolas A, Guichardant M. et al. LDL from obese patients with the metabolic syndrome show increased lipid peroxidation and activate platelets. Diabetologia 2011; 54: 2931-2940.
    CrossrefPubMedGoogle Scholar
  • 27 Helal O, Defoort C, Robert S. et al. Increased levels of microparticles originating from endothelial cells, platelets and erythrocytes in subjects with metabolic syndrome: relationship with oxidative stress. Nutr Metab Cardiovasc Dis 2011; 21: 665-671.
    CrossrefPubMedGoogle Scholar
  • 28 Konstantinides S, Schafer K, Loskutoff DJ. The prothrombotic effects of leptin possible implications for the risk of cardiovascular disease in obesity. Ann NY Acad Sci 2001; 947: 134-141.
    CrossrefPubMedGoogle Scholar
  • 29 Konstantinides S, Schafer K, Koschnick S. et al. Leptin-dependent platelet aggregation and arterial thrombosis suggests a mechanism for atherothrombotic disease in obesity. J Clin Invest 2001; 108: 1533-1540.
    CrossrefPubMedGoogle Scholar
  • 30 Nakata M, Yada T, Soejima N. et al. Leptin promotes aggregation of human platelets via the long form of its receptor. Diabetes 1999; 48: 426-429.
    CrossrefPubMedGoogle Scholar
  • 31 Kato H, Kashiwagi H, Shiraga M. et al. Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol 2006; 26: 224-230.
    CrossrefPubMedGoogle Scholar
  • 32 Elbatarny HS, Netherton SJ, Ovens JD. et al. Adiponectin, ghrelin, and leptin differentially influence human platelet and human vascular endothelial cell functions: implication in obesity-associated cardiovascular diseases. Eur J Pharmacol 2007; 558: 7-13.
    CrossrefPubMedGoogle Scholar
  • 33 Von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
    CrossrefPubMedGoogle Scholar
  • 34 Desideri G, Ferri C. Effects of obesity and weight loss on soluble CD40L levels. J Am Med Assoc 2003; 289: 1781-1782.
    CrossrefPubMedGoogle Scholar
  • 35 Santilli F, Basili S, Ferroni P. et al. CD40/CD40L system and vascular disease. Intern Emerg Med 2007; 2: 256-268.
    CrossrefPubMedGoogle Scholar
  • 36 Cabeza N, Li Z, Schulz C. et al. Surface expression of collagen receptor Fc receptor-gamma/glycoprotein VI is enhanced on platelets in type 2 diabetes and mediates release of CD40 ligand and activation of endothelial cells. Diabetes 2004; 53: 2117-2121.
    CrossrefPubMedGoogle Scholar
  • 37 Cipollone F, Mezzetti A, Porreca E. et al. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation 2002; 106: 399-402.
    CrossrefPubMedGoogle Scholar
  • 38 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: 1169-1174.
    CrossrefPubMedGoogle Scholar
  • 39 Varo N, Libby P, Nuzzo R. et al. Elevated release of sCD40L from platelets of diabetic patients by thrombin,glucose and advanced glycation end products. Diab Vasc Dis Res 2005; 2: 81-87.
    CrossrefPubMedGoogle Scholar
  • 40 Genc H, Dogru T, Tapan S. et al. Soluble CD40 ligand, soluble P-selectin and von Willebrand factor levels in subjects with prediabetes: the impact of metabolic syndrome. Clin Biochem 2012; 45: 92-95.
    CrossrefPubMedGoogle Scholar
  • 41 Cipollone F, Chiarelli F, Davì G. et al. Enhanced soluble CD40 ligand contributes to endothelial cell dysfunction in vitro and monocyte activation in patients with diabetes mellitus: effect of improved metabolic control. Diabetologia 2005; 48: 1216-1224.
    CrossrefPubMedGoogle Scholar
  • 42 Vaidyula VR, Rao AK, Mozzoli M. et al. Effects of hyperglycemia and hyperinsulinemia on circulating tissue factor procoagulant activity and platelet CD40 ligand. Diabetes 2006; 55: 202-208.
    CrossrefPubMedGoogle Scholar
  • 43 Restituto P, Colina I, Varo JJ. et al. Adiponectin diminishes platelet aggregation and sCD40L release. Potential role in the metabolic syndrome. Am J Physiol Endocrinol Metab 2010; 298: E1072-E1077.
    CrossrefPubMedGoogle Scholar
  • 44 Neubauer H, Setiadi P, Günesdogan B. et al. Influence of glycaemic control on platelet bound CD40-CD40L system, P-selectin and soluble CD40 ligand in Type 2 diabetes. Diabet Med 2010; 27: 384-390.
    CrossrefPubMedGoogle Scholar
  • 45 Jinchuan Y, Zonggui W, Jinming C. et al. Upregulation of CD40--CD40 ligand system in patients with diabetes mellitus. Clin Chim Acta 2004; 339: 85-90.
    CrossrefPubMedGoogle Scholar
  • 46 Poggi M, Jager J, Paulmyer-Lacroix O. et al. The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 2009; 52: 1152-1163.
    CrossrefPubMedGoogle Scholar
  • 47 Freedman JE, Larson MG, Tanriverdi K. et al. Relation of platelet and leukocyte inflammatory transcripts to body mass index in the Framingham heart study. Circulation 2010; 122: 119-129.
    CrossrefPubMedGoogle Scholar
  • 48 Gerrits AJ, Gitz E, Koekman CA. et al. Induction of insulin resistance (IR) by the adipokines resistin, leptin, plasminogen activator inhibitor-1 and retinol binding protein 4 in human megakaryocytes. Haematologica 2012; 97: 1149-1157.
    CrossrefPubMedGoogle Scholar
  • 49 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: 1079-1084.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Coban E, Ozdogan M, Yazicioglu G. et al. The mean platelet volume in patients with obesity. Int J Clin Pract 2005; 59: 981-982.
    CrossrefPubMedGoogle Scholar
  • 51 Ozhan H, Aydin M, Yazici M. et al. Mean platelet volume in patients with non-alcoholic fatty liver disease. Platelets 2010; 21: 29-32.
    CrossrefPubMedGoogle Scholar
  • 52 Arslan N, Makay B. Mean platelet volume in obese adolescents with nonalcoholic fatty liver disease. J Pediatr Endocrinol Metab 2010; 23: 807-813.
    CrossrefPubMedGoogle Scholar
  • 53 Tavil Y, Sen N, Yazici HU. et al. Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease. Thromb Res 2007; 120: 245-250.
    CrossrefPubMedGoogle Scholar
  • 54 Brown AS, Hong Y, de Belder A. et al. Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. Arterioscler Thromb Vasc Biol 1997; 17: 802-807.
    CrossrefPubMedGoogle Scholar
  • 55 Carter AM, Cymbalista CM, Spector TD. et al. Heritability of clot formation, morphology, and lysis: the EuroCLOT study. Arterioscler Thromb Vasc Biol 2007; 27: 2783-2789.
    CrossrefPubMedGoogle Scholar
  • 56 Collet JP, Allali Y, Lesty C. et al. Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis. Arterioscler Thromb Vasc Biol 2006; 26: 2567-2573.
    CrossrefPubMedGoogle Scholar
  • 57 Han S, Liang CP, DeVries-Seimon T. et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell Metab 2006; 3: 257-266.
    CrossrefPubMedGoogle Scholar
  • 58 Diamant M, Nieuwland R, Pablo RF. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 2002; 106: 2442-2447.
    CrossrefPubMedGoogle Scholar
  • 59 Meerarani P, Moreno PR, Cimmino G. et al. Atherothrombosis: role of tissue factor; link between diabetes, obesity and inflammation. Indian J Exp Biol 2007; 45: 103-110.
    PubMedGoogle Scholar
  • 60 Napoleone E, DI Santo A, Amore C. et al. Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk?. J Thromb Haemost 2007; 5: 1462-1468.
    CrossrefPubMedGoogle Scholar
  • 61 Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the ATs of obese mice. Proc Natl Acad Sci USA 1998; 95: 7591-7596.
    CrossrefPubMedGoogle Scholar
  • 62 Samad F, Pandey M, Loskutoff DJ. Regulation of tissue factor gene expression in obesity. Blood 2001; 98: 3353-3358.
    CrossrefPubMedGoogle Scholar
  • 63 Kopp CW, Kopp HP, Steiner S. et al. Weight loss reduces tissue factor in morbidly obese patients. Obes Res 2003; 11: 950-956.
    CrossrefPubMedGoogle Scholar
  • 64 Sakkinen PA, Wahl P, Cushman M. et al. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in IR syndrome. Am J Epidemiol 2000; 152: 897-907.
    CrossrefPubMedGoogle Scholar
  • 65 Godsland IF, Crook D, Proudler AJ. et al. Hemostatic risk factors and insulin sensitivity, regional body fat distribution, and the metabolic syndrome. J Clin Endocrinol Metab 2005; 90: 190-197.
    CrossrefPubMedGoogle Scholar
  • 66 Bell LN, Theodorakis JL, Vuppalanchi R. et al. Serum proteomics and biomarker discovery across the spectrum of non-alcoholic fatty liver disease. Hepatology 2010; 51: 111-120.
    CrossrefPubMedGoogle Scholar
  • 67 Kotronen A, Joutsi-Korhonen L, Sevastianova K. et al. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int 2011; 31: 176-183.
    CrossrefPubMedGoogle Scholar
  • 68 Kraja AT, Province MA, Arnett D. et al. Do inflammation and procoagulation biomarkers contribute to the metabolic syndrome cluster?. Nutr Metab 2007; 4: 28.
    CrossrefPubMedGoogle Scholar
  • 69 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993; 13: 1865-1873.
    CrossrefPubMedGoogle Scholar
  • 70 Folsom AR, Conlan MG, Davis CE. et al. Relations between hemostasis variables and cardiovascular risk factors in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol 1992; 2: 481-494.
    CrossrefPubMedGoogle Scholar
  • 71 Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
    PubMedGoogle Scholar
  • 72 Yudkin JS, Kumari M, Humphries SE. et al. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?. Atherosclerosis 2000; 148: 209-214.
    CrossrefPubMedGoogle Scholar
  • 73 Carvalho de Sousa J, Bruckert E, Giral P. et al. Coagulation Factor VII and plasma triglycerides. Decreased catabolism as a possible mechanism of factor VII hyperactivity. Haemostasis 1989; 19: 125-130.
    PubMedGoogle Scholar
  • 74 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
    CrossrefPubMedGoogle Scholar
  • 75 Mineo C, Deguchi H, Griffin JH. et al. Endothelial and antithrombotic actions of HDL. Circ Res 2006; 98: 1352-1364.
    CrossrefPubMedGoogle Scholar
  • 76 Xie W, Zhai Z, Yang Y. et al. Free fatty acids inhibit TM-EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome. J Thromb Thrombolysis 2012; 34: 468-474.
    CrossrefPubMedGoogle Scholar
  • 77 Al Dieri R, de Laat B, Hemker HC. Thrombin generation: what have we learned?. Blood Rev 2012; 26: 197-203.
    CrossrefPubMedGoogle Scholar
  • 78 Sanchez C, Poggi M, Morange PE. et al. Diet modulates endogenous thrombin generation, a biological estimate of thrombosis risk, independently of the metabolic status. Arterioscler Thromb Vasc Biol 2012; 32: 2394-2404.
    CrossrefPubMedGoogle Scholar
  • 79 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207.
    CrossrefPubMedGoogle Scholar
  • 80 Sobel BE. Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcilable paradox. Circulation 1999; 99: 2496-2498.
    CrossrefPubMedGoogle Scholar
  • 81 Juhan-Vague I, Pyke SDM, Alessi MC. et al. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996; 94: 2057-2063.
    CrossrefPubMedGoogle Scholar
  • 82 Mertens I, Verrijken A, Michiels JJ. et al. Among inflammation and coagulation markers, PAI-1 is a true component of the metabolic syndrome. Int J Obes 2006; 30: 1308-1314.
    CrossrefPubMedGoogle Scholar
  • 83 Morange PE, Alessi MC, Verdier M. et al. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol 1999; 9: 1361-1365.
    CrossrefPubMedGoogle Scholar
  • 84 Alessi MC, Peiretti F, Morange P. et al. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: 860-867.
    CrossrefPubMedGoogle Scholar
  • 85 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: 800-803.
    CrossrefPubMedGoogle Scholar
  • 86 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: 173-178.
    CrossrefPubMedGoogle Scholar
  • 87 Fain JN, Madan AK, Hiler ML. et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145: 2273-2282.
    CrossrefPubMedGoogle Scholar
  • 88 Cigolini M, Targher G, Agostino G. et al. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men--role of the metabolic syndrome. Thromb Haemost 1996; 76: 69-73.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 89 Alessi MC, 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: 1262-1268.
    CrossrefPubMedGoogle Scholar
  • 90 Festa A, D’Agostino Jr R, Tracy RP. et al. IR Atherosclerosis Study. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type II diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131-1137.
    CrossrefPubMedGoogle Scholar
  • 91 Festa A, Williams K, Tracy RP. et al. Progression of plasminogen activator inhibitor-1 and fibrinogen levels in relation to incident type II diabetes. Circulation 2006; 113: 1753-1759.
    CrossrefPubMedGoogle Scholar
  • 92 Kanaya AM, Wassel Fyr C, Vittinghoff E. et al. Adipocytokines and incident diabetes mellitus in older adults: the independent effect of plasminogen activator inhibitor 1. Arch Intern Med 2006; 166: 350-356.
    CrossrefPubMedGoogle Scholar
  • 93 Meigs JB, O’Donnell CJ, Tofler GH. et al. Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes 2006; 55: 530-537.
    CrossrefPubMedGoogle Scholar
  • 94 Ingelsson E, Pencina MJ, Tofler GH. et al. Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors: the Framingham Offspring Study. Circulation 2007; 116: 984-992.
    CrossrefPubMedGoogle Scholar
  • 95 Alessi MC, Nicaud V, Scroyen I. et al. DESIR Study Group. Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort. Thromb Haemost 2011; 106: 416-422.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 96 Ma LJ, Mao SL, Taylor KL. et al. Prevention of obesity and IR in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53: 336-346.
    CrossrefPubMedGoogle Scholar
  • 97 De Taeye BM, Novitskaya T, Gleaves L. et al. Bone marrow plasminogen activator inhibitor-1 influences the development of obesity. J Biol Chem 2006; 281: 32796-32805.
    CrossrefPubMedGoogle Scholar
  • 98 Schafer K, Fujisawa K, Konstantinides S. et al. Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 2001; 15: 1840-1842.
    CrossrefPubMedGoogle Scholar
  • 99 Crandall DL, Quinet EM, El Ayachi S. et al. Modulation of adipose tissue development by pharmacologic inhibition of PAI-1. Arterioscler Thromb Vasc Biol 2006; 26: 2209-2215.
    CrossrefPubMedGoogle Scholar
  • 100 Lijnen HR, Alessi MC, Frederix L. et al. Tiplaxtinin impairs nutritionally induced obesity in mice. Thromb Haemost 2006; 96: 731-737.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 101 Lijnen HR, Alessi MC, Van Hoef B. et al. On the role of plasminogen activator inhibitor-1 in adipose tissue development and insulin resistance in mice. J Thromb Haemost 2005; 3: 1174-1179.
    CrossrefPubMedGoogle Scholar
  • 102 Liang X, Kanjanabuch T, Mao SL. et al. Plasminogen activator inhibitor-1 modulates adipocyte differentiation. Am J Physiol Endocrinol Metab 2006; 290: E103-E113.
    CrossrefPubMedGoogle Scholar
  • 103 Lopez-Alemany R, Redondo JM, Nagamine Y. et al. Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with alphavbeta3 integrin for vitronectin binding. Eur J Biochem 2003; 270: 814-821.
    CrossrefPubMedGoogle Scholar
  • 104 Crandall DL, Busler DE, McHendry-Rinde B. et al. Autocrine regulation of human preadipocyte migration by plasminogen activator inhibitor-1. J Clin Endocrinol Metab 2000; 85: 2609-2614.
    CrossrefPubMedGoogle Scholar
  • 105 Bernot D, Stalin J, Stocker P. et al. Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase. J Cell Sci 2011; 124: 1224-1230.
    CrossrefPubMedGoogle Scholar
  • 106 Lijnen HR, Maquoi E, Morange P. et al. Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23: 78-84.
    CrossrefPubMedGoogle Scholar
  • 107 Scroyen I, Christiaens V, Lijnen HR. No functional role of plasminogen activator inhibitor-1 in murine adipogenesis or adipocyte differentiation. J Thromb Haemost 2007; 5: 139-145.
    CrossrefPubMedGoogle Scholar
  • 108 Devy L, Blacher S, Grignet-Debrus C. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16: 147-154.
    CrossrefPubMedGoogle Scholar
  • 109 Baron AD, Steinberg H, Brechtel G. et al. Skeletal muscle blood flow independently modulates insulin-mediated glucose uptake. Am J Physiol 1994; 266: E248-E253.
    PubMedGoogle Scholar
  • 110 Coggins M, Lindner J, Rattigan S. et al. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 2001; 50: 2682-2690.
    CrossrefPubMedGoogle Scholar
  • 111 Baron AD, Tarshoby M, Hook G. et al. Interaction between insulin sensitivity and muscle perfusion on glucose uptake in human skeletal muscle, evidence for capillary recruitment. Diabetes 2000; 49: 768-774.
    CrossrefPubMedGoogle Scholar
  • 112 Lteif A, Vaishnava P, Baron AD. et al. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes 2007; 56: 728-734.
    CrossrefPubMedGoogle Scholar
  • 113 Kim JA, Montagnani M, Koh KK. et al. Reciprocal relationships between IR and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888-1904.
    CrossrefPubMedGoogle Scholar
  • 114 Montagnani M, Golovchenko I, Kim I. et al. Inhibition of phosphatidylinositol 3-kinase enhances mitogenic actions of insulin in endothelial cells. J Biol Chem 2002; 277: 1794-1799.
    CrossrefPubMedGoogle Scholar
  • 115 Rask-Madsen C, Li Q, Freund B. et al. Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice. Cell Metab 2010; 11: 379-389.
    CrossrefPubMedGoogle Scholar
  • 116 Arteaga RB, Chirinos JA, Soriano AO. et al. Endothelial microparticles and platelet and leukocyte activation in patients with the metabolic syndrome. Am J Cardiol 2006; 98: 70-74.
    CrossrefPubMedGoogle Scholar
  • 117 Meigs JB, Mittleman MA, Nathan DM. et al. Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. J Am Med Assoc 2000; 283: 221-228.
    CrossrefPubMedGoogle Scholar
  • 118 Ziccardi P, Nappo F, Giugliano G. et al. Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 2002; 105: 804-849.
    CrossrefPubMedGoogle Scholar
  • 119 Picchi A, Gao X, Belmadani S. et al. Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 2006; 99: 69-77.
    CrossrefPubMedGoogle Scholar
  • 120 Valle Jimenez M, Estepa RM, Camacho RM. et al. Endothelial dysfunction is related to insulin resistance and inflammatory biomarker levels in obese prepubertal children. Eur J Endocrinol 2007; 156: 497-502.
    CrossrefPubMedGoogle Scholar
  • 121 Dong XC, Copps KD, Guo S. et al. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 2008; 8: 65-76.
    CrossrefPubMedGoogle Scholar
  • 122 Abid MR, Shih SC, Otu HH. et al. A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression. J Biol Chem 2006; 281: 35544-35553.
    CrossrefPubMedGoogle Scholar
  • 123 Lakka HM, Laaksonen DE, Lakka TA. et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc 2002; 288: 2709-2716.
    CrossrefPubMedGoogle Scholar
  • 124 Hu G, Qiao Q, Tuomilehto J. et al. DECODE Study Group. Prevalence of the metabolic syndrome and its relation to all-cause and cardiovascular mortality in nondiabetic European men and women. Arch Intern Med 2004; 164: 1066-1076.
    CrossrefPubMedGoogle Scholar
  • 125 Meigs JB, Wilson PW, Nathan DM. et al. Prevalence and characteristics of the metabolic syndrome in the San Antonio. Heart and Framingham Offspring Studies. Diabetes 2003; 52: 2160-2167.
    CrossrefPubMedGoogle Scholar
  • 126 Freeman MS, Mansfield MW, Barrett JH. et al. Insulin resistance: an atherothrombotic syndrome. The Leeds family study. Thromb Haemost 2003; 89: 161-168.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 127 Mottillo S, Filion KB, Genest J. et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-1132.
    CrossrefPubMedGoogle Scholar
  • 128 Arnlöv J, Ingelsson E, Sundström J. et al. Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men. Circulation 2010; 121: 230-236.
    CrossrefPubMedGoogle Scholar
  • 129 Coutinho T, Goel K, Corrêa de Sá D. et al. Central obesity and survival in subjects with coronary artery disease: a systematic review of the literature and collaborative analysis with individual subject data. J Am Coll Cardiol 2011; 57: 1877-1886.
    CrossrefPubMedGoogle Scholar
  • 130 Chrysant SG, Chrysant GS. New insights into the true nature of the obesity paradox and the lower cardiovascular risk. J Am Soc Hypertens 2013; 7: 85-94.
    CrossrefPubMedGoogle Scholar
  • 131 Goel K, Thomas RJ, Squires RW. et al. Combined effect of cardiorespiratory fitness and adiposity on mortality in patients with coronary artery disease. Am Heart J 2011; 161: 590-597.
    CrossrefPubMedGoogle Scholar
  • 132 Bayturan O, Tuzcu EM, Lavoie A. et al. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Arch Intern Med 2010; 170: 478-484.
    CrossrefPubMedGoogle Scholar
  • 133 Mente A, Yusuf S, Islam S. et al. Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries. J Am Coll Cardiol 2010; 55: 2390-2398.
    CrossrefPubMedGoogle Scholar
  • 134 Malone PC, Agutter PS. The aetiology of deep venous thrombosis. Quart J Med 2006; 99: 581-593.
    CrossrefPubMedGoogle Scholar
  • 135 Lisman T, de Groot PG, Meijers JC. et al. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105: 1102-1105.
    CrossrefPubMedGoogle Scholar
  • 136 Meltzer ME, Lisman T, de Groot PG. et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116: 113-121.
    CrossrefPubMedGoogle Scholar
  • 137 Vanschoonbeek K, Feijge MA, Van Kampen RJ. et al. Initiating and potentiating role of platelets in tissue factor-induced thrombin generation in the presence of plasma: subject-dependent variation in thrombogram characteristics. J Thromb Haemost 2004; 2: 476-484.
    CrossrefPubMedGoogle Scholar
  • 138 Cabeza N, Li Z, Schulz C. et al. Surface expression of collagen receptor Fc receptor-gamma/glycoprotein VI is enhanced on platelets in type 2 diabetes and mediates release of CD40 ligand and activation of endothelial cells. Diabetes 2004; 53: 2117-2121.
    CrossrefPubMedGoogle Scholar
  • 139 Bezemer ID, Bare LA, Doggen CJ. et al. Gene variants associated with deep vein thrombosis. J Am Med Assoc 2008; 299: 1306-1314.
    CrossrefPubMedGoogle Scholar
  • 140 Watson HG, Chee YL. Aspirin and other antiplatelet drugs in the prevention of venous thromboembolism. Blood Rev 2008; 22: 107-116.
    CrossrefPubMedGoogle Scholar
  • 141 Mazzoccoli G, Grilli M, Ferrandino F. et al. Arterial endothelial dysfunction and idiopathic deep venous thrombosis. J Biol Regul Homeost Agents 2011; 25: 565-573.
    PubMedGoogle Scholar
  • 142 Ten Cate H. Thrombin generation in clinical conditions. Thromb Res 2012; 129: 367-370.
    CrossrefPubMedGoogle Scholar
  • 143 Vayá A, Mira Y, Ferrando F. et al. Hyperlipidaemia and venous thromboembolism in patients lacking thrombophilic risk factors. Br J Haematol 2002; 118: 255-259.
    CrossrefPubMedGoogle Scholar
  • 144 Gonzalez-Ordonez AJ, Fernandez-Carreira JM, Fernandez-Alvarez CR. et al. The concentrations of soluble vascular cell adhesion molecule-1 and lipids are independently associated with venous thromboembolism. Haematologica 2003; 88: 1035-1043.
    PubMedGoogle Scholar
  • 145 Doggen CJ, Smith NL, Lemaitre RN. et al. Serum lipid levels and the risk of venous thrombosis. Arterioscler Thromb Vasc Biol 2004; 24: 1970-1975.
    CrossrefPubMedGoogle Scholar
  • 146 Deguchi H, Pecheniuk NM, Elias DJ. et al. High-density lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation 2005; 112: 893-899.
    CrossrefPubMedGoogle Scholar
  • 147 Ageno W, Becattini C, Brighton T. et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.
    CrossrefPubMedGoogle Scholar
  • 148 Van Schouwenburg IM, Mahmoodi BK, Gansevoort RT. et al. Lipid levels do not influence the risk of venous thromboembolism. Results of a population-based cohort study. Thromb Haemost 2012; 108: 923-929.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 149 Van Schouwenburg IM, Mahmoodi BK, Veeger NJ. et al. Insulin resistance and risk of venous thromboembolism: results of a population-based cohort study. J Thromb Haemost 2012; 10: 1012-1018.
    CrossrefPubMedGoogle Scholar
  • 150 Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism. Results from the Copenhagen city heart study. Circulation 2010; 121: 1896-1903.
    CrossrefPubMedGoogle Scholar
  • 151 Fronek A, Criqui MH, Denenberg J, Langer RD. Common femoral vein dimensions and hemodynamics including valsalva response as a function of sex, age, and ethnicity in a population study. J Vasc Surg 2001; 33: 1050-1056.
    CrossrefPubMedGoogle Scholar
  • 152 Sugerman H, Windsor A, Bessos M. et al. Intra-abdominal pressure, sagittal abdominal diameter and obesity comorbidity. J Intern Med 1997; 241: 71-79.
    CrossrefPubMedGoogle Scholar
  • 153 Willenberg T, Schumacher A, Amann-Vesti B. et al. Impact of obesity on venous hemodynamics of the lower limbs. J Vasc Surg 2010; 52: 664-668.
    CrossrefPubMedGoogle Scholar
  • 154 Mazzoccoli G, Copetti M, Dagostino MP. et al. Epicardial adipose tissue and idiopathic deep venous thrombosis: an association study. Atherosclerosis 2012; 223: 378-383.
    CrossrefPubMedGoogle Scholar
  • 155 Vayá A, Martínez-Triguero ML, España F. et al. The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population. Metab Syndr Relat Disord 2011; 9: 197-201.
    CrossrefPubMedGoogle Scholar
  • 156 Hansson PO, Eriksson H, Welin L. et al. Smoking and abdominal obesity: risk factors for venous thromboembolism among middle-aged men: "the study of men born in 1913". Arch Intern Med 1999; 159: 1886-1890.
    CrossrefPubMedGoogle Scholar
  • 157 Ray JG, Lonn E, Yi Q. et al HOPE-2 investigators. Venous thromboembolism in association with features of the metabolic syndrome. Quart J Med 2007; 100: 679-684.
    CrossrefPubMedGoogle Scholar
  • 158 Ogren M, Eriksson H, Bergqvist D. et al. Subcutaneous fat accumulation and BMI associated with risk for pulmonary embolism in patients with proximal deep vein thrombosis: a population study based on 23 796 consecutive autopsies. J Intern Med 2005; 258: 166-171.
    CrossrefPubMedGoogle Scholar
  • 159 Ageno W, Prandoni P, Romualdi E. et al. The metabolic syndrome and the risk of venous thrombosis : a case-control study. J Thromb Haemost 2006; 4: 1914-1918.
    CrossrefPubMedGoogle Scholar
  • 160 Di Minno MN, Tufano A, Guida A. et al. Abnormally high prevalence of major components of the metabolic syndrome in subjects with early-onset idiopathic venous thromboembolism. Thromb Res 2011; 127: 193-197.
    CrossrefPubMedGoogle Scholar
  • 161 Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial thrombosis. Semin Thromb Hemost 2009; 35: 451-457.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 162 Ambrosetti M, Ageno W, Salerno M. et al. Metabolic syndrome as a risk factor for deep vein thrombosis after acute cardiac conditions. Thromb Res 2007; 120: 815-818.
    CrossrefPubMedGoogle Scholar
  • 163 Ay C, Tengler T, Vormittag R. et al. Venous thromboembolism-a manifestation of the metabolic syndrome. Haematologica 2007; 92: 374-380.
    CrossrefPubMedGoogle Scholar
  • 164 Gandhi R, Razak F, Tso P. et al. Metabolic syndrome and the incidence of symptomatic deep vein thrombosis following total knee arthroplasty. J Rheumatol 2009; 36: 2298-2301.
    CrossrefPubMedGoogle Scholar
  • 165 Steffen LM, Cushman M, Peacock JM. et al. Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. J Thromb Haemost 2009; 7: 746-751.
    CrossrefPubMedGoogle Scholar
  • 166 Borch KH, Braekkan SK, Mathiesen EB. et al. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the Tromsø study. J Thromb Haemost 2009; 7: 739-745.
    CrossrefPubMedGoogle Scholar