Thromb Haemost 2008; 99(06): 995-1000
DOI: 10.1160/TH07-11-0682
Review Article
Schattauer GmbH

Metabolic syndrome, haemostasis and thrombosis

Marie-Christine Alessi
1   Laboratoire d’Hématologie, Faculté de Médecine, Université de la Méditerranée, Inserm UMR 626, Marseille, France
,
Irène Juhan-Vague
1   Laboratoire d’Hématologie, Faculté de Médecine, Université de la Méditerranée, Inserm UMR 626, Marseille, France
› Author Affiliations
Further Information

Publication History

Received 16 November 2007

Accepted after major revision 25 April 2008

Publication Date:
28 November 2017 (online)

Summary

The metabolic syndrome (metS), a concurrence of abdominal fat, disturbed glucose and insulin metabolism, dyslipidemia, and hypertension has been strongly associated not only with subsequent development of type 2 diabetes but also with athero-thrombosis. The physiopathology of this association is complex. The metS affects the thrombogenicity of circulating blood. Apart from its effect on platelets, a procoagulant and hypofibrinolytic state has been identified; mainly the result of the inflammatory state, dyslipidemia, and liver fat accumulation that accompany the MetS. Among haemostasis disturbances, the strong rise in the inhibitor of plasminogen activator type 1 plasma level is the most documented abnormality implicating the participation of the oxidative stress and inflammatory state developed during the metS. Endothelial dysfunction is also a central feature. Moreover, secretion products of fat tissues (adipokines) are now thought to have direct modulating effects on the vascular and the circulating cells. In support of these data, the metS, may predispose not only to atherosclerosis but also to venous thrombosis.

This review article is the last contribution to the March 2008 Theme issue in connection with the GTH congress in Wiesbaden, Germany.


 
  • References

  • 1 Grundy SM, Brewer Jr HB, 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.
  • 2 Abbasi F, Brown Jr BW, Lamendola C. et al. Relationship between obesity, insulin resistance, and coronary heart disease risk. J Am Coll Cardiol 2002; 40: 937-943.
  • 3 Trovati M, Anfossi G. Insulin, insulin resistance and platelet function: similarities with insulin effects on cultured vascular smooth muscle cells. Diabetologia 1998; 41: 609-622.
  • 4 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.
  • 5 Davi 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.
  • 6 Trovati M, Anfossi G. Influence of insulin and of insulin resistance on platelet and vascular smooth muscle cell function. J Diabetes Complications 2002; 16: 35-40.
  • 7 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.
  • 8 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.
  • 9 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.
  • 10 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.
  • 11 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.
  • 12 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.
  • 13 Englyst NA, Taube JM, Aitman TJ. et al. A novel role for CD36 in VLDL-enhanced platelet activation. Diabetes 2003; 52: 1248-1255.
  • 14 Korporaal SJ, Akkerman JW. Platelet activation by low density lipoprotein and high density lipoprotein. Pathophysiol Haemost Thromb 2006; 35: 270-280.
  • 15 Haffner SM, Miettinen H Mykkanen. et al. Leptin concentrations and insulin sensitivity in normoglycemic men. Int J Obes Relat Metab Disord 1997; 21: 393-399.
  • 16 Beltowski J. Leptin and atherosclerosis. Atherosclerosis 2006; 189: 47-60.
  • 17 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.
  • 18 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.
  • 19 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.
  • 20 Ozata M, Avcu F, Durmus O. et al. Leptin does not play a major role in platelet aggregation in obesity and leptin deficiency. Obes Res 2001; 9: 627-630.
  • 21 Canavan B, Salem RO, Schurgin S. et al. Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation. J Clin Endocrinol Metab 2005; 90: 5779-5785.
  • 22 Giandomenico G, Dellas C, Czekay RP. et al. The leptin receptor system of human platelets. J Thromb Haemost 2005; 3: 1042-1049.
  • 23 Corsonello A, Perticone F, Malara A. et al. Leptindependent platelet aggregation in healthy, overweight and obese subjects. Int J Obes Relat Metab Disord 2003; 27: 566-573.
  • 24 Gualillo O, González-Juanatey JR, Lago F. The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives. Trends Cardiovasc Med 2007; 17: 275-283.
  • 25 Kato H, Kashiwagi H, Shiraga M. et al. Adiponectin acts as an endogenous antithrombotic factor. Arterioscler Thromb Vasc Biol 2006; 26: 224-230.
  • 26 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.
  • 27 Von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res 2007; 100: 27-40.
  • 28 Nicolucci A, De Berardis G, Sacco M. et al. AHA/ ADA vs. ESC/EASD recommendations on aspirin as a primary prevention strategy in people with diabetes: how the same data generate divergent conclusions. Eur Heart J 2007; 28: 1925-1927.
  • 29 Angiolillo DJ, Shoemaker SB, Desai B. et al. Randomized comparison of a high clopidogrel maintenance dose in patients with diabetes mellitus and coronary artery disease: results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) study. Circulation 2007; 115: 708-716.
  • 30 Tamminen M, Lassila R, Westerbacka J. et al. Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects. Int J Obes Relat Metab Disord 2003; 27: 907-911.
  • 31 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.
  • 32 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.
  • 33 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.
  • 34 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.
  • 35 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.
  • 36 Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the adipose tissues of obese mice. Proc Natl Acad Sci USA 1998; 95: 7591-7596.
  • 37 Samad F, Pandey M, Loskutoff DJ. Regulation of tissue factor gene expression in obesity. Blood 2001; 98: 3353-3358.
  • 38 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.
  • 39 Sakkinen PA, Wahl P, Cushman M. et al. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000; 152: 897-907.
  • 40 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.
  • 41 Kraja AT, Province MA, Arnett D. et al. Do inflammation and procoagulation biomarkers contribute to the metabolic syndrome cluster?. Nutr Metab (Lond) 2007; 4: 28.
  • 42 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.
  • 43 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.
  • 44 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.
  • 45 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.
  • 46 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.
  • 47 Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med 2007; 262: 157-172.
  • 48 Mineo C, Deguchi H, Griffin JH. et al. Endothelial and antithrombotic actions of HDL. Circ Res 2006; 98: 1352-1364.
  • 49 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome : links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26: 2200-2207.
  • 50 Eren M, Painter CA, Atkinson JB. et al. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation 2002; 106: 491-496.
  • 51 Sobel BE. Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcilable paradox. Circulation 1999; 99: 2496-2498.
  • 52 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.
  • 53 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.
  • 54 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.
  • 55 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.
  • 56 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.
  • 57 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.
  • 58 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.
  • 59 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.
  • 60 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.
  • 61 Festa A, D’Agostino Jr R, Tracy RP. et al. Insulin Resistance 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.
  • 62 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.
  • 63 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.
  • 64 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.
  • 65 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.
  • 66 Ma LJ, Mao SL, Taylor KL. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53: 336-46.
  • 67 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.
  • 68 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.
  • 69 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.
  • 70 Lijnen HR, Alessi MC, Frederix L. et al. Tiplaxtinin impairs nutritionally induced obesity in mice. Thromb Haemost 2006; 96: 731-737.
  • 71 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.
  • 72 Liang X, Kanjanabuch T, Mao SL. et al. Plasminogen activator inhibitor-1 modulates adipocyte differentiation. Am J Physiol Endocrinol Metab 2006; 290: E103-E113.
  • 73 Lebrun P, Baron V, Hauck CR. et al. Cell adhesion and focal adhesion kinase regulate insulin receptor substrate-1 expression. J Biol Chem 2000; 275: 38371-38377.
  • 74 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.
  • 75 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.
  • 76 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.
  • 77 Schalkwijk CG, Stehouwer CD. PAI-1 inhibition in obesity and the metabolic syndrome: a promising therapeutic strategy. Thromb Haemost 2006; 96: 698-699.
  • 78 Baron AD, Steinberg H, Brechtel G. et al. Skeletal muscle blood flow independently modulates insulinmediated glucose uptake. Am J Physiol 1994; 266: E248-253.
  • 79 Coggins M, Lindner J, Rattigan S. et al. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 2001; 0: 2682-2690.
  • 80 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.
  • 81 Lteif A, Vaishnava P, Baron AD. et al. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes 2007; 56: 728-734.
  • 82 Kim JA, Montagnani M, Koh KK. et al. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006; 113: 1888-1904.
  • 83 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.
  • 84 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.
  • 85 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.
  • 86 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.
  • 87 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.
  • 88 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.
  • 89 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.
  • 90 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.
  • 91 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.
  • 92 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.
  • 93 Freeman MS, Mansfield MW, Barrett JH. et al. Insulin resistance: an atherothrombotic syndrome. The Leeds family study. Thromb Haemost 2003; 89: 161-168.
  • 94 Malone PC, Agutter PS. The aetiology of deep venous thrombosis. QJM 2006; 99: 581-593.
  • 95 Prandoni P. Links between arterial and venous disease. J Intern Med 2007; 262: 341-350.
  • 96 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.
  • 97 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.
  • 98 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.
  • 99 Deguchi H, Pecheniuk NM, Elias DJ. et al. Highdensity lipoprotein deficiency and dyslipoproteinemia associated with venous thrombosis in men. Circulation 2005; 112: 893-899.
  • 100 Ageno W, Becattini C, Brighton T. et al. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation 2008; 117: 93-102.
  • 101 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.
  • 102 Ray JG, Lonn E, Yi Q. et al. HOPE-2 investigators. Venous thromboembolism in association with features of the metabolic syndrome. QJM 2007; 100: 679-684.
  • 103 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.
  • 104 Ay C, Tengler T, Vormittag R. et al. Venous thromboembolism-a manifestation of the metabolic syndrome. Haematologica 2007; 92: 374-380.