Skip to main content
SpringerLink
Log in

Diabetes and Thrombosis

  • Chapter
  • First Online:
Diabetes and Cardiovascular Disease

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 745 Accesses

Abstract

Subjects with diabetes mellitus have a high prevalence and rapid progression of coronary artery, peripheral vascular, and cerebral vascular disease secondary in part to (1) increased platelet reactivity; (2) increased thrombotic activity reflecting increased concentrations and activity of coagulation factors and decreased activity of antithrombotic factors; and (3) decreased fibrinolytic system capacity resulting from overexpression of plasminogen activator inhibitor type-1 (PAI-1) by hepatic, arterial, and adipose tissue in response to hyperinsulinemia, hypertriglyceridemia, and hyperglycemia. In addition, macrovascular disease appears to be accelerated by an insulin-dependent imbalance in proteo(fibrino)lytic system activity within walls of arteries predisposing to accumulation of extracellular matrix and paucity of migration of vascular smooth muscle cells during the evolution of atheroma predisposing toward the development of plaques vulnerable to rupture. Therapy designed to reduce insulin resistance decreases concentrations in blood not only of insulin but also of PAI-1. Thus, the treatment of subjects with diabetes, and particularly type 2 diabetes, should focus not only on improved metabolic control but also on reduction of insulin resistance and hyperinsulinemia. Treatment designed to address both the hormonal and metabolic abnormalities of diabetes is likely to reduce hyperactivity of platelets, decrease the intensity of the prothrombotic state, and normalize activity of the fibrinolytic system in blood and in vessel walls thereby reducing the rate of progression of macrovascular disease and its sequelae.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Geiss LS, Herman WH, Smith PJ. Mortality in non-insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko, Reiber GE, Bennet PH, editors. Diabetes in America. Washington, DC: U.S. Government Printing Office; 1995. p. 233–57, Chap 11, DHHS NIH Publ no. 95-1468.

    Google Scholar 

  2. Portuese E, Orchard T. Mortality in insulin-dependent diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko, Reiber GE, Bennet PH, editors. Diabetes in America. Washington, DC: U.S. Government Printing Office; 1995. p. 221–32, Chap 10, DHHS NIH Publ no. 95-1468.

    Google Scholar 

  3. Alexandru N, Jardin I, Popov D, Simionescu M, Garcia-Estan J, Salido GM, Rosado JA. Effect of homocysteine on calcium mobilisation and platelet function in type 2 diabetes mellitus. J Cell Mol Med. 2007;12:2015.

    Article  Google Scholar 

  4. Sasaki N, Yamashita T, Takaya T, Shinohara M, Shiraki R, Takeda M, Emoto N, Fukatsu A, Hayashi T, Ikemoto K, Nomura T, Yokoyama M, Hirata K-I, Kawashima S. Augmentation of vascular remodeling by uncoupled endothelial nitric oxide synthase in a mouse model of diabetes mellitus. Arterioscler Thromb Vasc Biol. 2008;28:1068–76.

    Article  CAS  PubMed  Google Scholar 

  5. Jeppesen J, Hansen TW, Rasmussen S, Ibsen H, Torp-Pedersen C, Madsbad S. Insulin resistance, the metabolic syndrome, and risk of incident cardiovascular disease. J Am Coll Cardiol. 2007;49:2112–9.

    Article  CAS  PubMed  Google Scholar 

  6. Sobel BE. Coronary artery disease and fibrinolysis: from the blood to the vessel wall. Thromb Haemost. 1999;82:8–13.

    Article  PubMed  Google Scholar 

  7. Schneider DJ, Sobel BE. Determinants of coronary vascular disease in patients with type II diabetes mellitus and their therapeutic implications. Clin Cardiol. 1997;20:433–40.

    Article  CAS  PubMed  Google Scholar 

  8. Uusitupa MIJ, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia. 1993;36:1175–84.

    Article  CAS  PubMed  Google Scholar 

  9. Kornowski R, Mintz GS, Kent KM, Pichard AD, Satler LF, Bucher TA, Hong MK, Popma JJ, Leon MB. Increased restenosis in diabetes mellitus after coronary interventions is due to exaggerated intimal hyperplasia. Circulation. 1997;95:1366–9.

    Article  CAS  PubMed  Google Scholar 

  10. Velican C, Velican D. The precursors of coronary atherosclerotic plaques in subjects up to 40 years old. Atherosclerosis. 1980;37:33–46.

    Article  CAS  PubMed  Google Scholar 

  11. Spurlock BO, Chandler AB. Adherent platelets and surface microthrombi of the human aorta and left coronary artery: a scanning electron microscopy feasibility study. Scanning Microsc. 1987;1:1359–65.

    CAS  PubMed  Google Scholar 

  12. Nicholls S, Tuzcu E, Kalidindi S, Wolski K, Moon K-W, Sipahi K, Schoenhagen P, Nissen S. Effect of diabetes on progression of coronary atherosclerosis and arterial remodeling. J Am Coll Cardiol. 2008;52:255–62.

    Article  CAS  PubMed  Google Scholar 

  13. Ambrose JA, Tannenbaum AM, Alexpoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorling R, Fuster V. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56–62.

    Article  CAS  PubMed  Google Scholar 

  14. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation. 1988;78:1157–66.

    Article  CAS  PubMed  Google Scholar 

  15. Davies MJ, Richardson PD, Woolf N, Kratz DR, Mann J. Risk of thrombosis in human atherosclerotic plaques role of extracellular lipid, macrophage, and smooth muscle content. Br Heart J. 1993;69:377–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92:657–71.

    Article  CAS  PubMed  Google Scholar 

  17. Dai J, Xing L, Jia H, Zhu Y, Zhang S, Hu S, Lin L, Ma L, Liu H, Xu M, Ren X, Yu H, Li L, Zou Y, Zhang S, Mintz GS, Hou J, Yu B. In vivo predictors of plaque erosion in patients with ST-segment elevation myocardial infarction: a clinical, angiographical, and intravascular optical coherence tomography study. Eur Heart J. 2018;39:2077–85.

    Article  PubMed  Google Scholar 

  18. Sugiyama T, Yamamoto E, Bryniarski K, Xing L, Fracassi F, Lee H, Jang IK. Coronary plaque characteristics in patients with diabetes mellitus who presented with acute coronary syndromes. J Am Heart Assoc. 2018;7:e009245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fateh-Moghadam S, Li Z, Ersel S, Reuter T, Htun P, Plockinger U, Bocksch W, Dietz R, Gawaz M. Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol. 2005;25:1299–303.

    Article  CAS  PubMed  Google Scholar 

  20. Boden G, Rao AK. Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood coagulation. Curr Diab Rep. 2007;7:223–7.

    Article  CAS  PubMed  Google Scholar 

  21. Nemerson Y. Tissue factor and hemostasis. Blood. 1988;71:1–8.

    Article  CAS  PubMed  Google Scholar 

  22. Rand MD, Lock JB, Veer CV, Gaffney DP, Mann KG. Blood clotting in minimally altered whole blood. Blood. 1996;88:3432–45.

    Article  CAS  PubMed  Google Scholar 

  23. Monroe DM, Roberts HR, Hoffman M. Platelet procoagulant complex assembly in a tissue factor-initiated system. Br J Haemotol. 1994;88:364–71.

    Article  CAS  Google Scholar 

  24. Staatz WD, Rajpara SM, Wayner EA, Carter WG, Santoro SA. The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg+2-dependent adhesion of platelets to collagen. J Cell Biol. 1989;108:1917–21.

    Article  CAS  PubMed  Google Scholar 

  25. Kroll MH, Harris TS, Moake JL, Handin RI, Schafer AI. Von Willebrand Factor binding to platelet GP Ib initiates signals for platelet activation. J Clin Invest. 1991;88:1568–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sims PJ, Ginsberg MH, Plow EF, Shattil SJ. Effect of platelet activation on the conformation of the plasma membrane glycoprotein IIb-IIIa complex. J Biol Chem. 1991;266:7345–52.

    Article  CAS  PubMed  Google Scholar 

  27. Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated by P-selectin on adherent platelets. Nature. 1992;359:848–51.

    Article  CAS  PubMed  Google Scholar 

  28. Schwartz CJ, Valente AJ, Kelley JL, Sprague EA, Edwards EH. Thrombosis and the development of atherosclerosis: Roditansky revisited. Semin Thromb Hemost. 1988;14:189–95.

    Article  CAS  PubMed  Google Scholar 

  29. Stirk CM, Kochhar A, Smith EB, Thompson WD. Presence of growth-stimulating fibrin-degradation products containing fragment E in human atherosclerotic plaques. Atherosclerosis. 1993;103:159–69.

    Article  CAS  PubMed  Google Scholar 

  30. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–9.

    Article  CAS  PubMed  Google Scholar 

  31. Scharf RE, Harker LA. Thrombosis and atherosclerosis: regulatory role of interactions among blood components and endothelium. Blut. 1987;55:131–44.

    Article  CAS  PubMed  Google Scholar 

  32. Bar-Shavit R, Hruska KA, Kahn AJ, Wilner GD. Hormone-like activity of human thrombin. Ann N Y Acad Sci. 1986;485:335–48.

    Article  CAS  PubMed  Google Scholar 

  33. Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992;89:507–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Friedman RJ, Stemerman MB, Wenz B, Moore S, Gauldie J, Gent M, Tiell ML, Spaet TH. The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle proliferation and re-endothelialization. J Clin Invest. 1977;60:1191–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fernandez-Ortiz AJ, Badimon JJ, Falk E, Fuster V, Meyer B, Mailhac A, Weng D, Shah PK, Badimon LL. Characterization of relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol. 1994;23:1562–9.

    Article  CAS  PubMed  Google Scholar 

  36. Grant PJ. Diabetes mellitus as a prothrombotic condition. J Intern Med. 2007;262:157–72.

    Article  CAS  PubMed  Google Scholar 

  37. Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost. 2008;99:995–1000.

    Article  CAS  PubMed  Google Scholar 

  38. Lim HS, Blann AD, Lip GY. Soluble CD40 ligand, soluble P-selectin, interleukin-6, and tissue factor in diabetes mellitus: relationships to cardiovascular disease and risk factor intervention. Circulation. 2004;109:2524–8.

    Article  CAS  PubMed  Google Scholar 

  39. Brown AS, Hong Y, de Belder A, Beacon H, Beeso J, Sherwood R, Edmonds M, Mrtin JF, Erusalimsky JD. Megakaryoctye ploidy and platelet changes in human diabetes and atherosclerosis. Arterioscler Thromb Vasc Biol. 1997;17:802–7.

    Article  CAS  PubMed  Google Scholar 

  40. Olufadi R, Byrne CD. Effects of VLDL and remnant particles on platelets. Pathophysiol Haemost Thromb. 2006;35:281–91.

    Article  CAS  PubMed  Google Scholar 

  41. Koga H, Sugiyama S, Kugiyama K, Fukushima H, Watanabe K, Sakamoto T, Yoshimura M, Jinnouchi H, Ogawa H. Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease. Eur Heart J. 2006;27:817–23.

    Article  CAS  PubMed  Google Scholar 

  42. Mayfield RK, Halushka PV, Wohltmann HJ, Lopes-Virella M, Chambers JK, Loadholt CB, Colwell JA. Platelet function during continuous insulin infusion treatment in insulin-dependent diabetic patients. Diabetes. 1985;34:1127–33.

    Article  CAS  PubMed  Google Scholar 

  43. Iwase E, Tawata M, Aida K, Ozaki Y, Kume S, Satoh K, Qi R, Onaya T. A cross-sectional evaluation of spontaneous platelet aggregation in relation to complications in patients with type II diabetes mellitus. Metabolism. 1998;47:699–705.

    Article  CAS  PubMed  Google Scholar 

  44. Davi G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, Patrono C. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med. 1990;322:1769–74.

    Article  CAS  PubMed  Google Scholar 

  45. Winocour PD, Watala C, Kinlough-Rathbone RL. Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipid molar ratio in isolated platelet membranes from diabetic and control subjects. Thromb Haemost. 1992;67:567–71.

    Article  CAS  PubMed  Google Scholar 

  46. Ishii H, Umeda F, Nawata H. Platelet function in diabetes mellitus. Diabetes Metab Rev. 1992;8:53–66.

    Article  CAS  PubMed  Google Scholar 

  47. Hendra T, Betteridge DJ. Platelet function, platelet prostanoids and vascular prostacyclin in diabetes. Prostaglandins Leukot Essent Fat Acids. 1989;35:197–212.

    Article  CAS  Google Scholar 

  48. Menys VS, Bhatnagar D, Mackness MI, Durrington PN. Spontaneous platelet aggregation in whole blood is increased in non-insulin-dependent diabetes mellitus and in female but not male patients with primary dyslipidemia. Atherosclerosis. 1995;112:115–22.

    Article  CAS  PubMed  Google Scholar 

  49. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C. Platelet function profiles in patients with type 2 diabetes and coronary artery disease on combined aspirin and clopidogrel treatment. Diabetes. 2005;54:2430–5.

    Article  CAS  PubMed  Google Scholar 

  50. Vaidyula VR, Boden G, Rao AK. Platelet and monocyte activation by hyperglycemia and hyperinsulinemia in healthy subjects. Platelets. 2006;17:577–85.

    Article  CAS  PubMed  Google Scholar 

  51. Calverley DC, Hacker MR, Loda KA, Brass E, Buchanan TA, Tsao-Wei DD, Groshen S. Increased platelet Fc receptor expression as a potential contributing cause of platelet hypersensitivity to collagen in diabetes mellitus. Br J Haematol. 2003;121:139–42.

    Article  CAS  PubMed  Google Scholar 

  52. Calverley DC, Baldermann LV, Moran K, Chen NN, McFann K. Platelet FcgammaRIIA expression is associated with the alpha2 integrin C807T gene polymorphism in type 2 diabetes. Platelets. 2006;17:78–83.

    Article  CAS  PubMed  Google Scholar 

  53. Schneider DJ, McMahon SR, Chava S, Taatjes-Sommer HS, Meagher S, Ehle GL, Brummel-Ziedins KE. FcγRIIa: a new cardiovascular risk marker. J Am Coll Cardiol. 2018;72:237–8.

    Article  PubMed  Google Scholar 

  54. Schneider DJ, McMahon SR, Ehle GL, Chava S, Taatjes-Sommer HS, Meagher S. Assessment of cardiovascular risk by the combination of clinical risk scores plus platelet expression of FcγRIIa. Am J Cardiol. 2020;125:670–2.

    Article  PubMed  Google Scholar 

  55. Cabeza N, Li Z, Schulz C, Kremmer E, Massberg S, Bultmann A, Gawaz M. 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;53:2117–21.

    Article  CAS  PubMed  Google Scholar 

  56. Arthur JF, Jandeleit-Dahm K, Andrews RK. Platelet hyperreactivity in diabetes: focus on GPVI signaling-are useful drugs already available? Diabetes. 2017;66:7–13.

    Article  CAS  PubMed  Google Scholar 

  57. Sugimoto H, Franks DJ, Lecavalier L, Chiasson JL, Hamet P. Therapeutic modulation of growth-promoting activity in platelets from diabetics. Diabetes. 1987;36:667–72.

    Article  CAS  PubMed  Google Scholar 

  58. Koschinsky T, Bunting CR, Rutter R, Gries FA. Vascular growth factors and the development of macrovascular disease in diabetes mellitus. Diabetes Metab. 1987;13:318–25.

    CAS  Google Scholar 

  59. Winocour PD, Bryszewska M, Watala C, Rand ML, Epand RM, Kinlough-Rathbone RL, Packham MA, Mustard JF. Reduced membrane fluidity in platelets from diabetic patients. Diabetes. 1990;39:241–4.

    Article  CAS  PubMed  Google Scholar 

  60. Rao AK, Goldberg RE, Walsh PN. Platelet coagulation activity in diabetes mellitus. Evidence for relationship between platelet coagulant hyperactivity and platelet volume. J Lab Clin Med. 1984;103:82–92.

    CAS  PubMed  Google Scholar 

  61. Lupu C, Calb M, Ionescu M, Lupu F. Enhanced prothrombin and intrinsic factor X activation on blood platelets from diabetic patients. Thromb Haemost. 1993;70:579–83.

    Article  CAS  PubMed  Google Scholar 

  62. Tschoepe D, Roesen P, Kaufmann L, Schauseil S, Kehrel B, Ostermann H, Gries FA. Evidence for abnormal platelet glycoprotein expression in diabetes mellitus. Eur J Clin Investig. 1990;20:166–70.

    Article  CAS  Google Scholar 

  63. Romano M, Pomilio M, Vigneri S, Falco A, Chiesa PL, Chiarelli F, Davi G. Endothelial perturbation in children and adolescents with type 1 diabetes: association with markers of the inflammatory reaction. Diabetes Care. 2001;24:1674–8.

    Article  CAS  PubMed  Google Scholar 

  64. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003;23(1):17. (abstract).

    Article  CAS  PubMed  Google Scholar 

  65. Bastyr EJ III, Lu J, Stowe R, Green A, Vinik AI. Low molecular weight GTP-binding proteins are altered in platelet hyperaggragation in IDDM. Oncogene. 2003;8:515–8.

    Google Scholar 

  66. Livingstone C, McLellan AR, McGregor MA, Wilson A, Connell JM, Small M, Milligan G, Paterson KR, Houslay MD. Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects. Biochim Biophys Acta. 1991;1096:127–33.

    Article  CAS  PubMed  Google Scholar 

  67. Ishii H, Umeda F, Hashimoto T, Nawata H. Changes in phosphoinositide turnover, Ca2+ mobilization, and protein phosphorylation in platelets from NIDDM patients. Diabetes. 1990;39:1561–8.

    Article  CAS  PubMed  Google Scholar 

  68. Schaeffer G, Wascher TC, Kostner GM, Graier WF. Alterations in platelet Ca2+ signalling in diabetic patients is due to increased formation of superoxide anions and reduced nitric oxide production. Diabetologia. 1999;42:167–76.

    Article  CAS  PubMed  Google Scholar 

  69. Tschoepe D, Roesen P, Esser J, Schwippert B, Nieuwenhuis K, Kehrel B, Gries FA. Large platelets circulate in an activated state in diabetes mellitus. Semin Thromb Hemost. 1991;17:433–8.

    Article  CAS  PubMed  Google Scholar 

  70. Tschoepe D, Driesch E, Schwippert B, Nieuwenhuis K, Gries FA. Exposure of adhesion molecules on activated platelets in patients with newly diagnosed IDDM is not normalized by near-normoglycemia. Diabetes. 1995;44:890–4.

    Article  CAS  PubMed  Google Scholar 

  71. Torr-Brown SR, Sobel BE. Plasminogen activator inhibitor is elevated in plasma and diminished in platelets in patients with diabetes mellitus. Thromb Res. 1994;75:473–7.

    Article  CAS  PubMed  Google Scholar 

  72. Colwell JA. Vascular thrombosis in type II diabetes mellitus. Diabetes. 1993;42:8–11.

    Article  CAS  PubMed  Google Scholar 

  73. Kinlough-Rathbone RL, Packham MA, Mustard JF. Vessel injury, platelet adherence, and platelet survival. Arteriosclerosis. 1983;3:529–46.

    Article  CAS  PubMed  Google Scholar 

  74. Winocour PD, Richardson M, Kinlough-Rathbone RL. Continued platelet interaction with de-endothelialized aortae of spontaneously diabetic BB Wistar rats is associated with slow re-endothelialization and extensive intimal hyperplasia. Int J Exp Pathol. 1993;74:603–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Winocour PD, Watala C, Perry DW, Kinlough-Rathbone RL. Reduced fluidity and increased glycation of membrane proteins of platelets from diabetic subjects are not associated with increased platelet adherence to glycated collagen. J Lab Clin Med. 1992;120:921–8.

    CAS  PubMed  Google Scholar 

  76. Oskarsson HJ, Hofmeyer TG. Platelets from patients with diabetes mellitus have impaired ability to mediate vasodilatation. J Am Coll Cardiol. 1996;27:1464–70.

    Article  CAS  PubMed  Google Scholar 

  77. Tschoepe D, Roesen P, Gries FA. Increase in the cytosolic concentration of calcium in platelets of diabetics type II. Thromb Res. 1991;62:421–38.

    Article  Google Scholar 

  78. Ishi H, Umeda F, Hashimoto T, Nawata H. Changes in phosphoinositide turnover, Ca2+ mobilization, and protein phosphorylation in platelets from NIDDM patients. Diabetes. 1990;39:1561–8.

    Article  Google Scholar 

  79. Keating FK, Sobel BE, Schneider DJ. Effects of increased concentrations of glucose on platelet reactivity in healthy subjects and in patients with and without diabetes. Am J Cardiol. 2003;92:1362–5.

    Article  CAS  PubMed  Google Scholar 

  80. Malmberg K, Norhammar A, Wedel H, Ryden L. Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation. 1999;99:2626–32.

    Article  CAS  PubMed  Google Scholar 

  81. Fava S, Aquilina O, Azzopardi J, Agius Muscat H, Fenech FF. The prognostic value of blood glucose in diabetic patients with acute myocardial infarction. Diabet Med. 1996;13:80–3.

    Article  CAS  PubMed  Google Scholar 

  82. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol. 2002;40:1748–54.

    Article  CAS  PubMed  Google Scholar 

  83. Trovati M, Anfossi G, Massucco P, Mattiello L, Costamagna C, Piretto V, Mularoni E, Cavalot F, Bosia A, Ghigo D. Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3′,5′-cyclic monophosphate and adenosine-3′,5′-cyclic monophosphate. Diabetes. 1997;46:742–9.

    Article  CAS  PubMed  Google Scholar 

  84. Ferreira IA, Mocking AI, Feijge MA, Gorter G, van Haeften TW, Heemskerk JW, Akkerman JW. Platelet inhibition by insulin is absent in type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2006;26:417–22.

    Article  CAS  PubMed  Google Scholar 

  85. Marina V, Bruno GA, Trucco F, Zumpano E, Tagliabue M, Di Bisceglie C, Pescarmona G. Platelet cNOS activity is reduced in patients with IDDM and NIDDM. Thromb Haemost. 1998;79:520–2.

    Article  Google Scholar 

  86. 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;4:111–28.

    Article  CAS  PubMed  Google Scholar 

  87. Khan SU, Ul Abideen Asad Z, Khan MU, Talluri S, Ali F, Shahzeb Khan M, Lone AN, Mookadam F, Krasuski RA, Kaluski E. Aspirin for primary prevention of cardiovascular outcomes in diabetes mellitus: an updated systematic review and meta-analysis. Eur J Prev Cardiol. 2020;27:2034.

    Article  PubMed  Google Scholar 

  88. Winocour PD, Kinlough-Rathbone RL, Mustard JF. Pathways responsible for platelet hypersensitivity in rats with diabetes. II. Spontaneous diabetes in BB Wistar rats. J Lab Clin Med. 1986;109:154–8.

    Google Scholar 

  89. Yan Y, Phillips DR. Aspirin response and failure in diabetic patients with cardiovascular disease. Curr Opin Pharmacol. 2005;5:190–7.

    Article  CAS  PubMed  Google Scholar 

  90. Takahashi S, Ushida M, Komine R, Shimizu A, Uchida T, Ishihara H, Shibano T, Watanabe G, Ikeda Y, Murata M. Increased basal platelet activity, plasma adiponectin levels, and diabetes mellitus are associated with poor platelet responsiveness to in vitro effect of aspirin. Thromb Res. 2007;119:517–24.

    Article  CAS  PubMed  Google Scholar 

  91. DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA, Bailon O, Singla A, Gurbel PA. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes. 2007;56:3014–9.

    Article  CAS  PubMed  Google Scholar 

  92. Angiolillo DJ, Bernardo E, Sabaté M, Jimenez-Quevedo P, Costa MA, Palazuelos J, Hernández-Antolin R, Moreno R, Escaned J, Alfonso F, Bañuelos C, Guzman LA, Bass TA, Macaya C, Fernandez-Ortiz A. Impact of platelet reactivity on cardiovascular outcomes in patients with type 2 diabetes mellitus and coronary artery disease. J Am Coll Cardiol. 2007;50:1541–7.

    Article  PubMed  Google Scholar 

  93. Serebruany V, Pokov I, Kuliczkowski W, Chesebro J, Badimon J. Baseline platelet activity and response after clopidogrel in 257 diabetics among 822 patients with coronary artery disease. Thromb Haemost. 2008;100:76–82.

    Article  CAS  PubMed  Google Scholar 

  94. Angiolillo DJ, Shoemaker SB, Desai B, Yuan H, Charlton RK, Bernardo E, Zenni MM, Guzman LA, Bass TA, Costa MA. 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;115:708–16.

    Article  CAS  PubMed  Google Scholar 

  95. Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Ramirez C, Sabate M, Jimenez-Quevedo P, Hernandez R, Moreno R, Escaned J, Alfonso F, Banuelos C, Costa MA, Bass TA, Macaya C. Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes. 2006;55:780–4.

    Article  CAS  PubMed  Google Scholar 

  96. Franchi F, James SK, Ghukasyan Lakic T, Budaj AJ, Cornel JH, Katus HA, Keltai M, Kontny F, Lewis BS, Storey RF, Himmelmann A, Wallentin L, Angiolillo DJ, PLATO Investigators. Impact of diabetes mellitus and chronic kidney disease on cardiovascular outcomes and platelet P2Y12 receptor antagonist effects in patients with acute coronary syndromes: insights from the PLATO trial. J Am Heart Assoc. 2019;8:e011139.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.

    Article  CAS  PubMed  Google Scholar 

  98. Scharfstein JS, Abendschein DR, Eisenberg PR, George D, Cannon CP, Becker RC, Sobel BE, Cupples A, Braunwald D. Loscalzo J for the TIMI-5 Investigators. Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. Am J Cardiol. 1996;78:503–10.

    Article  CAS  PubMed  Google Scholar 

  99. Jones RL. Fibrinopeptide-A in diabetes mellitus. Relation to levels of blood glucose, fibrinogen disappearance, and hemodynamic changes. Diabetes. 1985;34:836–43.

    Article  CAS  Google Scholar 

  100. Librenti MC, D’Angelo A, Micossi P, Garimberti B, Mannucci PM, Pozza G. Beta-thromboglobulin and fibrinopeptide A in diabetes mellitus as markers of vascular damage. Acta Diabetol Lat. 1985;22:39–45.

    Article  CAS  PubMed  Google Scholar 

  101. Marongiu F, Conti M, Mameli G, Sorano GG, Cossu E, Cirillo R, Balestrieri A. Is the imbalance between thrombin and plasmin activity in diabetes related to the behaviour of antiplasmin activity. Thromb Res. 1990;58:91–9.

    Article  CAS  PubMed  Google Scholar 

  102. Pszota HM, Kugler RK, Szigeti G. Fibrinopeptide-A as thrombotic risk marker in diabetic and atherosclerotic coronary vasculopathy. J Med. 1992;23:93–100.

    PubMed  Google Scholar 

  103. Morishita E, Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Yamazaki M, Aoshima K, Hashimoto T, Matsuda T. Hypercoagulability and high lipoprotein (a) levels in patients with type II diabetes mellitus. Atherosclerosis. 1996;120:7–14.

    Article  CAS  PubMed  Google Scholar 

  104. Myrup B, Rossing P, Jensen T, Gram J, Kluft C, Jespersen J. Procoagulant activity and intimal dysfunction in IDDM. Diabetologia. 1995;38:73–8.

    Article  CAS  PubMed  Google Scholar 

  105. Kannel WB, D’Agostino RB, Wilson PW, Belanger AJ, Gagnon DR. Diabetes, fibrinogen, and risk of cardiovascular disease: the Framingham experience. Am Heart J. 1990;120:672–6.

    Article  CAS  PubMed  Google Scholar 

  106. Lufkin EG, Fass DN, O’Fallon WM, Bowie EJW. Increased von Willebrand factor in diabetes mellitus. Metabolism. 1979;28:63–6.

    Article  CAS  PubMed  Google Scholar 

  107. Kannel WB, Wolf PA, Wilson PWF, D’Agostino RB. Fibrinogen and risk of cardiovascular disease. JAMA. 1987;258:1183–6.

    Article  CAS  PubMed  Google Scholar 

  108. Knobl P, Schernthaner G, Schnack C, Pietschmann P, Proidl S, Prager R, Vukovich T. Haemostatic abnormalities persist despite glycaemic improvement by insulin therapy in lean type 2 diabetic patients. Thromb Haemost. 1994;71:692–7.

    Article  CAS  PubMed  Google Scholar 

  109. Eliasson M, Roder ME, Dinesen B, Evrin PE, Lindahl B. Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. Diabetes Care. 1997;20:1252–5.

    Article  CAS  PubMed  Google Scholar 

  110. Warram JH, Martin BC, Krolewski AS, Soeldner JS, Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med. 1990;113:909–15.

    Article  CAS  PubMed  Google Scholar 

  111. Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D. Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia. 1987;30:698–702.

    Article  CAS  PubMed  Google Scholar 

  112. Nagi DK, Hendra TJ, Ryle AJ, Cooper TM, Temple RC, Clark PMS, Schneider AE, Hales CN, Yudkin JS. The relationships of concentrations of insulin, intact proinsulin and 32-33 split proinsulin with cardiovascular risk factors in type 2 (non-insulin-dependent) diabetic subjects. Diabetologia. 1990;33:532–7.

    Article  CAS  PubMed  Google Scholar 

  113. Marongiu F, Mascia F, Mameli G, Cirillo R, Balestrieri A. Prothrombin fragment F 1 + 2 levels are high in NIDDM patients independently of the Hb A1 c. Thromb Haemost. 1995;74:805–6.

    Article  CAS  PubMed  Google Scholar 

  114. Mansfield MW, Heywood DM, Grant PJ. Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM. Circulation. 1996;94:2171–6.

    Article  CAS  PubMed  Google Scholar 

  115. Boden G, Vaidyula VR, Homko C, Cheung P, Rao AK. Circulating tissue factor procoagulant activity and thrombin generation in patients with type 2 diabetes: effects of insulin and glucose. J Clin Endocrinol Metab. 2007;92:4352–8.

    Article  CAS  PubMed  Google Scholar 

  116. Jude B, Watel A, Fontaine O, Fontaine P, Cosson A. Distinctive features of procoagulant response of monocytes from diabetic patients. Haemostasis. 1989;19:95–73.

    Google Scholar 

  117. Ceriello A, Russo PD, Zucotti C, Florio A, Nazzaro S, Pietrantuono C, Rosato GB. Decreased antithrombin III activity in diabetes may be due to non-enzymatic glycosylation: a preliminary report. Thromb Haemost. 1983;50:633–4.

    Article  CAS  PubMed  Google Scholar 

  118. Brownlee M, Vlassara H, Cerami A. Inhibition of heparin-catalyzed human antithrombin III activity by nonenzymatic glycosylation. Diabetes. 1984;33:532–5.

    Article  CAS  PubMed  Google Scholar 

  119. Ceriello A, Giugliano D, Quatraro A, Stante A, Consoli G, Dello Russo P, D’Omoferio R. Daily rapid blood glucose variations may condition antithrombin III biologic activity but not its plasma concentration in insulin-dependent diabetes: a possible role for labile on-enzymatic glycation. Diabetes Metab. 1987;13:16–9.

    CAS  Google Scholar 

  120. Ceriello A, Quatraro A, Dello Russo P, Marchi E, Barbanti M, Millani MR, Giugliano D. Protein C deficiency in insulin dependent diabetes: a hyperglycemia-related phenomenon. Thromb Haemost. 1990;65:104–7.

    Google Scholar 

  121. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.

    Article  Google Scholar 

  122. Bhatt DL, Eikelboom JW, Connolly SJ, Steg PG, Anand SS, Verma S, Branch KRH, Probstfield J, Bosch J, Shestakovska O, Szarek M, Maggioni AP, Widimský P, Avezum A, Diaz R, Lewis BS, Berkowitz SD, Fox KAA, Ryden L, Yusuf S. COMPASS steering committee and investigators. role of combination antiplatelet and anticoagulation therapy in diabetes mellitus and cardiovascular disease: insights from the COMPASS trial. Circulation. 2020;141:1841–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pomero F, Dentali F, Mumoli N, Salomone P, Tangianu F, Desideri G, Mastroiacovo D. The continuous challenge of antithrombotic strategies in diabetes: focus on direct oral anticoagulants. Acta Diabetol. 2019;56:1247–58.

    Article  CAS  PubMed  Google Scholar 

  124. Auwerx J, Bouillon R, Collen D, Geboers J. Tissue-type plasminogen activator antigen and plasminogen activator inhibitor in diabetes mellitus. Arteriosclerosis. 1988;8:68–72.

    Article  CAS  PubMed  Google Scholar 

  125. McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes. 1994;43:104–9.

    Article  CAS  PubMed  Google Scholar 

  126. Soares AL, Sousa MO, Dusse LM, Fernandes AP, Lasmar MC, Novelli BA, Lages Gde F, Carvalho MG. Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers. Blood Coagul Fibrinolysis. 2007;18:395–9.

    Article  CAS  PubMed  Google Scholar 

  127. The BARI 2D Investigators. Baseline characteristics of patients with diabetes and coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Am Heart J. 2008;156:1–9.

    Google Scholar 

  128. Vague P, Juhan-Vague I, Aillaud MF, Badier C, Viard R, Alessi MC, Collen D. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism. 1986;35:250–3.

    Article  CAS  PubMed  Google Scholar 

  129. Juhan-Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationships between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabetes Metab. 1987;13:331.

    CAS  Google Scholar 

  130. Keber I, Keber D. Increased plasminogen activator inhibitor activity in survivors of myocardial infarction is associated with metabolic risk factors of atherosclerosis. Haemostasis. 1992;22:187.

    CAS  PubMed  Google Scholar 

  131. Corsetti JP, Ryan D, Moss AJ, Rainwater DL, Zareba W, Sparks CE. Plasminogen activator inhibitor-1 polymorphism (4G/5G) predicts recurrence in nonhyperlipidemic postinfarction patients. Arterioscler Thromb Vasc Biol. 2008;28:548–54.

    Article  CAS  PubMed  Google Scholar 

  132. Heidgaard PE, Sidelmann JJ, Hindsberger C, Olivarius Nde F, Henriksen JE, Gram J. Relationship of glucose concentrations with PAI-1 and t-PA in subjects with normal glucose tolerance. Diabet Med. 2006;23:887–93.

    Article  Google Scholar 

  133. Nordt TK, Schneider DJ, Sobel BE. Augmentation of the synthesis of plasminogen activator inhibitor type-1 by precursors of insulin: a potential risk factor for vascular disease. Circulation. 1994;89:321–30.

    Article  CAS  PubMed  Google Scholar 

  134. Calles-Escandon J, Mirza S, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor type-1 (PAI-1) in blood in normal human subjects. Diabetes. 1998;47:290–3.

    Article  CAS  PubMed  Google Scholar 

  135. Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfeld RL, Polonsky KS. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:2108–16.

    CAS  PubMed  Google Scholar 

  136. Jansson JH, Johansson B, Boman K, Nilsson TK. Hypo-fibrinolysis in patients with hypertension and elevated cholesterol. J Intern Med. 1991;229:309–16.

    Article  CAS  PubMed  Google Scholar 

  137. Sampson M, Kong C, Patel A, Unwin R, Jacobs HS. Ambulatory blood pressure profiles and plasminogen activator inhibitor (PAI-1) activity in lean women with and without the polycytic ovary syndrome. Clin Endocrinol. 1996;45:623–9.

    Article  CAS  Google Scholar 

  138. Velazquez EM, Mendoza SG, Wang P, Glueck CJ. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein (a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metab Clin Exp. 1997;46:454–7.

    Article  CAS  PubMed  Google Scholar 

  139. Farrehi PM, Ozaki CK, Carmeliet P, Fay WP. Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation. 1998;97:1002–8.

    Article  CAS  PubMed  Google Scholar 

  140. Schneider DJ, Sobel BE. Synergistic augmentation of expression of PAI-1 induced by insulin, VLDL, and fatty acids. Coron Artery Dis. 1996;7:813–7.

    Article  CAS  PubMed  Google Scholar 

  141. Brazionis L, Rowley K, Jenkins A, Itsiopoulos C, O’Dea K. Plasminogen activator inhibitor-1 activity in type 2 diabetes: a different relationship with coronary heart disease and diabetic retinopathy. Arterioscler Thromb Vasc Biol. 2008;28:786–91.

    Article  CAS  PubMed  Google Scholar 

  142. Pandolfi A, Giaccari A, Cilli C, Alberta MM, Morviducci L, De Filippis EA, Buongiorno A, Pellegrini G, Capani F, Consoli A. Acute hyperglycemia and acute hyperinsulinemia decrease plasma fibrinolytic activity and increase plasminogen activator inhibitor type 1 in the rat. Acta Diabetol. 2001;38(2):71–6.

    Article  CAS  PubMed  Google Scholar 

  143. Chen Y, Billadello JJ, Schneider DJ. Identification and localization of a fatty acid response region in human plasminogen activator inhibitor-1 gene. Arterioscler Thromb Vasc Biol. 2000;20:2696–701.

    Article  CAS  PubMed  Google Scholar 

  144. Chen Y, Sobel BE, Schneider DJ. Effect of fatty acid chain length and thioesterification on the augmentation of expression of plasminogen activator inhibitor-1. Nutr Metab Cardiovasc Dis. 2002;12:325–30.

    CAS  PubMed  Google Scholar 

  145. Chen Y, Schneider DJ. The independence of signaling pathways mediating increased expression of plasminogen activator inhibitor type 1 in HepG2 cells exposed to free fatty acids or triglycerides. Int J Exp Diab Res. 2002;3:109–19.

    Article  Google Scholar 

  146. Alessi M-C, Bastelica D, Mavri A, Morange P, Berthet B, Grino M, et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol. 2003;23:1262–8.

    Article  CAS  PubMed  Google Scholar 

  147. Nordt TK, Klassen KJ, Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb. 1993;13:1822.

    Article  CAS  PubMed  Google Scholar 

  148. Chen YQ, Su M, Walia RR, Hao Q, Covington JW, Vaughan DE. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem. 1998;273:8225–31.

    Article  CAS  PubMed  Google Scholar 

  149. Sobel BE, Neimane D, Mack WJ, Hodis HN, Buchanan TA. The ratio of plasminogen activator inhibitor type-1 activity to the concentration of plasminogen activator inhibitor type-1 protein in diabetes: adding insult to injury. Coron Artery Dis. 2002;13:275–81.

    Article  PubMed  Google Scholar 

  150. Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med. 1996;2:568–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lundgren CH, Sawa H, Brown SL, Nordt T, Sobel BE, Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes: a potential pathogenetic link between obesity and cardiovascular disease. Circulation. 1996;93:106–10.

    Article  CAS  PubMed  Google Scholar 

  152. Calles-Escandon J, Ballor D, Harvey-Berino J, Ades P, Tracy R, Sobel BE. Amelioration of the inhibition of fibrinolysis in obese elderly subjects by moderate caloric restriction. Am J Clin Nutr. 1996;64:7–11.

    Article  CAS  PubMed  Google Scholar 

  153. Schneider DJ, Absher PM, Ricci MA. The dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells. Circulation. 1997;96:2868–76.

    Article  CAS  PubMed  Google Scholar 

  154. Sobel BE, Woodcock-Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type-1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation. 1998;97:2213–21.

    Article  CAS  PubMed  Google Scholar 

  155. Pandolfi A, Iacoviello L, Capani F, Vitalonna E, Donati MB, Consoli A. Glucose and insulin independently reduce the fibrinolytic potential of human vascular smooth muscle cells in culture. Diabetologia. 1996;39:1425–31.

    Article  CAS  PubMed  Google Scholar 

  156. Nordt TK, Peter K, Bode C, Sobel BE. Differential regulation by troglitazone of plasminogen activator inhibitor type 1 in human hepatic and vascular cells. J Clin Endocrinol Metab. 2000;85:1563–8.

    CAS  PubMed  Google Scholar 

  157. Carmassi F, Morale M, Ferrini L, Dell’Omo G, Ferdeghini M, Pedrinelli R, De Negri F. Local insulin infusion stimulates expression of plasminogen activator inhibitor-1 and tissue-type plasminogen activator in normal subjects. Am J Med. 1999;107(4):344–50.

    Article  CAS  PubMed  Google Scholar 

  158. Lund SS, Tarnow L, Stehouwer CD, Schalkwijk CG, Teerlink T, Gram J, Winther K, Frandsen M, Smidt UM, Pedersen O, Parving HH, Vaag AA. Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol. 2008;158:631–41.

    Article  CAS  PubMed  Google Scholar 

  159. Igarashi M, Hirata A, Yamaguchi H, Jimbu Y, Tominaga M. Pioglitazone reduces atherogenic outcomes in type 2 diabetic patients. J Atheroscler Thromb. 2008;15:34–40.

    Article  CAS  PubMed  Google Scholar 

  160. Hoo RL, Chow WS, Yau MH, Xu A, Tso AW, Tse HF, Fong CH, Tam S, Chan L, Lam KS. Adiponectin mediates the suppressive effect of rosiglitazone on plasminogen activator inhibitor-1 production. Arterioscler Thromb Vasc Biol. 2007;27:2777–82.

    Article  CAS  PubMed  Google Scholar 

  161. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.

    Article  CAS  PubMed  Google Scholar 

  162. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298:1180–8.

    Article  CAS  PubMed  Google Scholar 

  163. Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA. 2007;298:1189–95.

    Article  CAS  PubMed  Google Scholar 

  164. American Diabetes Association. Intense blood glucose control yields no significant effect on cardiovascular disease reduction. n.d.. Accessed 12 Jun 2008.

    Google Scholar 

  165. ACCORD Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  Google Scholar 

  166. Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, Komajda M. McMurray JJV for the RECORD Study Group. Rosiglitazone evaluated for cardiovascular outcomes – an interim analysis. N Engl J Med. 2007;357:28–38.

    Article  CAS  PubMed  Google Scholar 

  167. Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578–81.

    Article  PubMed  Google Scholar 

  168. Mulrow CD, Cornell JE, Localio AR. Rosiglitazone: a thunderstorm from scarce and fragile data. Ann Intern Med. 2007;147:585–7.

    Article  PubMed  Google Scholar 

  169. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomized controlled trial. Lancet. 2005;366:1279–89.

    Article  CAS  PubMed  Google Scholar 

  170. Eliasson M, Asplund K, Evrin PE. Regular leisure time physical activity predicts high activity of tissue plasminogen activator: the northern Sweden MONICA study. Int J Epidemiol. 1996;25:1182–8.

    Article  CAS  PubMed  Google Scholar 

  171. Nordt TK, Kornas K, Peter K, Fujii S, Sobel BE, Kubler W, Bode C. Attenuation by gemfibrozil of expression of plasminogen activator inhibitor type 1 induced by insulin and its precursors. Circulation. 1997;95:677–83.

    Article  CAS  PubMed  Google Scholar 

  172. Broijersen A, Eriksson M, Wiman B, Angelin B, Hjemdahl P. Gemfibrozil treatment of combined hyperlipoproteinemia. No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels. Arterioscler Thromb Vasc Biol. 1996;16:511–6.

    Article  CAS  PubMed  Google Scholar 

  173. Asplund-Carlson A. Effects of gemfibrozil therapy on glucose tolerance, insulin sensitivity and plasma plasminogen activator inhibitor activity in hypertriglyceridemia. J Cardiovasc Risk. 1996;3:385–90.

    Article  CAS  PubMed  Google Scholar 

  174. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins. Implications for cardiovascular event reduction. JAMA. 1998;279:1643–50.

    Article  CAS  PubMed  Google Scholar 

  175. Sobel BE, Taatjes DJ, Schneider DJ. Intramural plasminogen activator inhibitor type-1 and coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:1979–89.

    Article  CAS  PubMed  Google Scholar 

  176. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–50.

    Article  CAS  PubMed  Google Scholar 

  177. Lang IM, Moser KM, Schleef RR. Elevated expression of urokinase-like plasminogen activator and plasminogen activator inhibitor type 1 during the vascular remodeling associated with pulmonary thromboembolism. Arterioscler Thromb Vasc Biol. 1998;18:808–15.

    Article  CAS  PubMed  Google Scholar 

  178. Schneider DJ, Ricci MA, Taatjes DJ, Baumann PQ, Reese JC, Leavitt BJ, Absher PM, Sobel BE. Changes in arterial expression of fibrinolytic system proteins in atherogenesis. Arterioscler Thromb Vasc Biol. 1997;17:3294–301.

    Article  CAS  PubMed  Google Scholar 

  179. Carmeliet P, Moons L, Lijnen R, Janssens S, Lupu F, Collen D, Gerard RD. Inhibitory role of plasminogen inhibitor-1 in arterial wound healing and neointimal formation: a gene targeting and gene transfer study in mice. Circulation. 1997;96:3180–91.

    Article  CAS  PubMed  Google Scholar 

  180. Sobel BE. Potentiation of vasculopathy by insulin: implications from an NHLBI Clinical Alert. Circulation. 1996;93:1613–5.

    Article  CAS  PubMed  Google Scholar 

  181. Carrozza JP, Kuntz RE, Fishman RF, Baim DS. Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus. Ann Intern Med. 1993;118:344–9.

    Article  PubMed  Google Scholar 

  182. Chen Y, Kelm RJ Jr, Budd RC, Sobel BE, Schneider DJ. Inhibition of apoptosis and caspace-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem. 2004;92:178–88.

    Article  CAS  PubMed  Google Scholar 

  183. Schneider DJ, Chen Y, Sobel BE. The effect of plasminogen activator inhibitor type 1 on apoptosis. Thromb Haemost. 2008;100:1037.

    Article  CAS  PubMed  Google Scholar 

  184. Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 1998;83:1818–20.

    Article  CAS  PubMed  Google Scholar 

  185. Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 2001;86:3452–6.

    Article  CAS  PubMed  Google Scholar 

  186. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, Gantz I, Terra SG, Masiukiewicz U, Cannon CP. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6:e204511.

    Article  Google Scholar 

  187. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss D, Køber L, Petrie MC, McMurray JJV. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7:776–85.

    Article  CAS  PubMed  Google Scholar 

  188. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383–93.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cardiovascular Unit, Department of Medicine, Cardiovascular Research Institute, College of Medicine, The University of Vermont, Burlington, VT, USA

    David J. Schneider

  2. Colchester Research Facility, Cardiovascular Research Institute, University of Vermont, Colchester, VT, USA

    David J. Schneider

Authors
  1. David J. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David J. Schneider .

Editor information

Editors and Affiliations

  1. Steward St. Elizabeth’s Medical Center, Tufts University Medical School, Brighton, MA, USA

    Michael Johnstone

  2. Beth Israel Deaconess Medical Center / Harvard Medical School, Boston, MA, USA

    Aristidis Veves

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Schneider, D.J. (2023). Diabetes and Thrombosis. In: Johnstone, M., Veves, A. (eds) Diabetes and Cardiovascular Disease. Contemporary Cardiology. Humana, Cham. https://doi.org/10.1007/978-3-031-13177-6_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-031-13177-6_5

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-031-13176-9

  • Online ISBN: 978-3-031-13177-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation