Von Willebrand Factor and the Development of Renal and Vascular Complications in Diabetes

  • Coen D. A. Stehouwer


Both in IDDM [1–4] and in NIDDM [5–10], the presence of microalbuminuria or clinical proteinuria identifies a group of patients at very high risk of developing severe vascular complications, ie, proliferative retinopathy, renal insufficiency, and cardiovascular disease. Several hypotheses have been advanced to explain why an increased urinary albumin excretion rate should be associated with an excess of extrarenal complications [1, 11–13]. This chapter will discuss the role of von Willebrandfactor (vWF), a haemostatic glycoprotein synthesised by endothelial cells and megakaryocytes.


Endothelial Dysfunction Platelet Adhesion Urinary Albumin Excretion Endothelial Injury Insulin Resistance Syndrome 
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  1. 1.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 1989; 32: 219–226.PubMedCrossRefGoogle Scholar
  2. 2.
    Parving HH, Hommel E, Mathiesen ER, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin-dependent diabetes. BMJ 1988; 296: 156–160.PubMedCrossRefGoogle Scholar
  3. 3.
    Krolewski AS, Kosinski EJ, Warram JH, et al. Magnitude and determinants of coronary artery disease in juvenile-onset insulin-dependent diabetes mellitus. Am J Cardiol 1987; 59: 750–755.PubMedCrossRefGoogle Scholar
  4. 4.
    Messent JWC, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC. Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: A twenty-three year follow-up study. Kidney Int 1992; 41: 836–839.PubMedCrossRefGoogle Scholar
  5. 5.
    Schmitz A, Vaeth M. Microalbuminuria. A major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabetic Med 1988; 5: 126–134.PubMedCrossRefGoogle Scholar
  6. 6.
    Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC. Effect of proteinuria on mortality in non-insulin-dependent diabetes mellitus. Diabetes 1988; 37: 1499–1504.PubMedCrossRefGoogle Scholar
  7. 7.
    Gall MA, Rossing P, Skott P, et al. Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European Type 2 (non-insulindependent) diabetic patients. Diabetologia 1991; 34: 655–661.PubMedCrossRefGoogle Scholar
  8. 8.
    Damsgaard EM, Froland A, Jorgensen OD, Mogensen CE. Eight-nine year mortality in known non-insulin-dependent diabetics and controls. A prospective study. Kidney Int 1992; 41: 731–735.CrossRefGoogle Scholar
  9. 9.
    Mattock MB, Morrish NJ, Viberti GC, Keen H, Fitzgerald AP, Jackson G. Prospective study of microalbuminuria as predictor of mortality in non-insulin-dependent diabetes mellitus. Diabetes 1992; 41: 736–741.PubMedCrossRefGoogle Scholar
  10. 10.
    Stehouwer CDA, Nauta JJP, Zeldenrust GC, Hackeng WHL, Donker AJM, den Ottolander GJH. Albuminuria, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet 1992; 340: 319–323.PubMedCrossRefGoogle Scholar
  11. 11.
    Viberti GC, Messent J. Hypertension and diabetes: Critical combination for micro- and macrovascular disease. Diabetes Care 1991; 11: suppl. 4: 4–7.Google Scholar
  12. 12.
    DeFronzo RA, Ferranini E. Insulin resistance: A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173–194.CrossRefGoogle Scholar
  13. 13.
    Stehouwer CDA, Donker AJM. Urinary albumin excretion and cardiovascular disease risk in diabetes mellitus: Is endothelial dysfunction the missing link? J Nephrol 1993; 6: 72–92.Google Scholar
  14. 14.
    Porta M, La SeIva M, Molinatti P, Molinatti GM. Endothelial cell function in diabetic microangiopathy. Diabetologia 1987; 30: 601–609.PubMedGoogle Scholar
  15. 15.
    Jensen T. Increased plasma level of von Willebrand factor in type 1 (insulin-dependent) diabetic patients with incipient nephropathy. BMJ 1989; 298: 27–28.PubMedCrossRefGoogle Scholar
  16. 16.
    Stehouwer CDA, Stroes ESG, Hackeng WHL, Mulder PGH, den Ottolander GJH. von Willebrand factor and development of diabetic nephropathy in insulin-dependent diabetes mellitus. Diabetes 1991; 40: 971–976 [erratum, Diabetes 1991; 40: 1746].PubMedCrossRefGoogle Scholar
  17. 17.
    Schmitz A, Ingerslev J. Haemostatic measures in Type 2 diabetic patients with microalbuminuria. Diabetic Med 1990; 7: 521–525.PubMedCrossRefGoogle Scholar
  18. 18.
    Collier A, Rumley A, Rumley AG, et al. Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria. Diabetes 1992; 41: 909–913.PubMedCrossRefGoogle Scholar
  19. 19.
    Stehouwer CDA, Zellenrath P, Polak BCP, et al. von Willebrand factor and early diabetic retinopathy: no evidence for a relationship in patients with Type 1 (insulindependent) diabetes mellitus and normal urinary albumin excretion. Diabetologia 1992; 35: 555–559.PubMedCrossRefGoogle Scholar
  20. 20.
    Meyer D, Girma JP. von Willebrand factor: Structure and function. Thromb Haemost 1993; 70: 111–118.Google Scholar
  21. 21.
    Wagner DD. The Weibel-Palade body: The storage granule for von Willebrand factor and P-selectin. Thromb Haemost 1993; 70: 105–110.PubMedGoogle Scholar
  22. 22.
    Factor VIII-related antigen and vasculitis [editorial]. Lancet 1988; i: 1203–1204.Google Scholar
  23. 23.
    Bern MM, Cassani MP, Horton J, Rand L, Davis G. Changes of fibrinolysis and factor VIII coagulant, antigen, and ristocetin cofactor in diabetes mellitus and atherosclerosis. Thromb Res 1980; 19: 831–839.PubMedCrossRefGoogle Scholar
  24. 24.
    Ross R. The pathogenesis of atherosclerosis: A perspective for the 1990s. Nature 1993; 362: 801–809.PubMedCrossRefGoogle Scholar
  25. 25.
    Kanwar YS. Biophysiology of glomerular filtration and proteinuria. Lab Invest 1984; 51: 7–21.PubMedGoogle Scholar
  26. 26.
    Diamond JR, Karnovsky MJ. Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 1988; 33: 917–924.PubMedCrossRefGoogle Scholar
  27. 27.
    Vane JR, Ånggård EE, Botting RM. Mechanisms of disease: regulatory functions of the vascular endothelium. N Engl J Med 1990; 323: 27–36.PubMedCrossRefGoogle Scholar
  28. 28.
    Nawroth PP, Handley D, Stern DM. The multiple levels of endothelial cell-coagulation factor interactions. Clin Haematol 1986; 15: 293–321.PubMedGoogle Scholar
  29. 29.
    McVeigh GE, Brennan GM, Johnston GD, et al. Impaired endothelium-dependent and independent vasodilation in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1992; 35: 771–776.PubMedGoogle Scholar
  30. 30.
    Juhan-Vague I, Vague P. Hyperinsulinemia and its effects on coagulation and fibrinolysis in cardiovascular disease. In: Francis RB (ed). Atherosclerotic Cardiovascular Disease, Hemostasis, and Endothelial Function. New York: Marcel Dekker; 1992; pp. 141–182.Google Scholar
  31. 31.
    Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992; 90: 2548–2554.PubMedCrossRefGoogle Scholar
  32. 32.
    Smits P, Kapma J, Jacobs MC, Lutterman J, Thien T. Endothelium-dependent vascular relaxation in patients with Type 1 diabetes. Diabetes 1993; 42: 148–153.PubMedCrossRefGoogle Scholar
  33. 33.
    Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: A novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351–355.PubMedCrossRefGoogle Scholar
  34. 34.
    Badimon L, Badimon JJ, Chesebro JH, Fuster V. von Willebrand factor and cardiovascular disease. Thromb Haemost 1993; 70: 111–118.PubMedGoogle Scholar
  35. 35.
    Jorgensen JOL, Pedersen SA, Ingerslev J, Moller J, Skakkebaek NE, Christiansen JS. Growth hormone (GH) therapy in GH-deficient patients, the plasma factor VIII-von Willebrand factor complex, and capillary fragility. A double-blind, placebo-controlled crossover study. Scand J Clin Lab Invest 1990; 50: 417–420.PubMedCrossRefGoogle Scholar
  36. 36.
    Ribes JA, Francis CW, Wagner DD. Fibrin induces release of von Willebrand factor from endothelial cells. J Clin Invest 1987; 79: 117–123.PubMedCrossRefGoogle Scholar
  37. 37.
    Lorenzi M. Glucose toxicity in the vascular complications of diabetes: the cellular perspective. Diabetes Metab Rev 1992; 8: 85–103.PubMedCrossRefGoogle Scholar
  38. 38.
    Hattori Y, Kasai K, Nakamura T, Emoto T, Shimodi SI. Effect of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells. Metabolism 1991; 40: 165–169.PubMedCrossRefGoogle Scholar
  39. 39.
    Lerman A, Edwards BS, Hallet JW, Heublein DM, Sandberg SM, Burnett JC. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991; 325: 997–1001.PubMedCrossRefGoogle Scholar
  40. 40.
    Benigni A, Zoja C, Corna D, et al. A specific endothelin subtype A receptor antagonist protects against injury in renal disease progression. Kidney Int 1993; 44: 440–444.PubMedCrossRefGoogle Scholar
  41. 41.
    Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 1990; 33: 306–310.PubMedCrossRefGoogle Scholar
  42. 42.
    Conlan MG, Folsom AR, Finch A, et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70: 380–385.PubMedGoogle Scholar
  43. 43.
    Niskanen L, Uusitupa M, Sarlund H, et al. Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed Type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1990; 33: 237–243.PubMedCrossRefGoogle Scholar
  44. 44.
    Haffner SM, Morales PA, Gruber MK, Hazuda HP, Stern MP. Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria. Arteriosclerosis Thromb 1993; 13: 205–210.CrossRefGoogle Scholar
  45. 45.
    Parving HH, Gall MA, Skott P, et al. Prevalence and causes of albuminuria in noninsulin-dependent diabetic patients. Kidney Int 1992; 41: 758–762.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1994

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  • Coen D. A. Stehouwer

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