The impact of statin therapy on plasma levels of von Willebrand factor antigen Systematic review and meta-analysis of randomised placebo-controlled trials


Amirhossein Sahebkar | Corina Serban | Sorin Ursoniu | Dimitri P. Mikhailidis | Anetta Undas | Gregory Y. H. Lip | Vera Bittner | Kausik K. Ray | Gerald F. Watts | G. Kees Hovingh | Jacek Rysz | John J. P. Kastelein | Maciej Banach | Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

First published: 20 March 2018


Increased plasma levels of von Willebrand factor antigen (vWF:Ag) are associated with high risk of coronary artery disease. The effect of statin therapy on vWF:Ag levels remains uncertain. Therefore the aim of this meta-analysis was to evaluate the effect of statin therapy on vWF:Ag Levels. A systematic multiple-database search was carried out to identify randomized controlled trials (RCTs) that investigated the effect of statins on plasma vWF:Ag levels. Random-effect meta-analysis of 21 treatment arms revealed a significant decrease in plasma vWF:Ag levels following statin therapy (SMD: −0.54, 95 %CI: −0.87, −0.21, p=0.001). In subgroup analyses, the greatest effect was observed with simvastatin (SMD: −1.54, 95 %CI: −2.92, −0.17, p=0.028) and pravastatin (SMD: −0.61, 95 %CI: −1.18, −0.04, p=0.035), but not with fluvastatin (SMD: −0.34, 95 %CI: −0.69, 0.02, p=0.065), atorvastatin (SMD: −0.23, 95 %CI: −0.57, 0.11, p=0.179) and rosuvastatin (SMD: −0.20, 95 %CI: −0.71, 0.30, p=0.431). The lowering effect of statins on plasma vWF:Ag levels was greater in the subset of studies lasting ≥ 12 weeks (SMD: −0.70, 95 %CI: −1.19, −0.22, p=0.005) compared with that of studies lasting > 12 weeks (SMD: −0.34, 95 %CI: −0.67, 0.003, p=0.052). Finally, low-intensity statin therapy was not associated with a significant reduction in vWF:Ag levels (SMD: −0.28, 95 %CI: −0.82, 0.27, p=0.320), but a significant effect was observed in high-intensity statin trials (SMD: −0.66, 95 %CI: −1.07, −0.24, p=0.002). This meta-analysis of available RCTs demonstrates a significant reduction in plasma vWF:Ag levels following statin therapy.

  1. Vischer U. von Willebrand factor, endothelial dysfunction, and cardiovascular disease. J Thromb Haemost 2006; 4: 1186-1193.
  2. Ruggeri ZM. The role of von Willebrand factor in thrombus formation. Thromb Res 2007; 120: S5-S9.
  3. Bowie E. et al. Transplantation of normal bone marrow into a pig with severe
  4.  Nishio K. et al. Binding of platelet glycoprotein Iba to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Proc Natl Acad Sci USA 2004; 101: 10578-10583.
  5. Favaloro EJ, Mohammed S. Towards improved diagnosis of von Willebrand disease: Comparative evaluations of several automated von Willebrand factor antigen and activity assays. Thromb Res 2014; 134: 1292-1300.
  6. Sonneveld MA. et al. Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis. Blood Rev 2014; 28: 167-178.
  7.  Miller C. et al. Measurement of von Willebrand factor activity: relative effects of ABO blood type and race. J Thromb Haemost 2003; 1: 2191-2197.
  8. Jenkins PV, O’Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?. Transfusion 2006; 46: 1836-1844.
  9. Zhou Z. et al. Possible race and gender divergence in association of genetic variations with plasma von Willebrand factor: a study of ARIC and 1000 genome cohorts. PloS one 2014; 9: e84810.
  10. Investigators A. The atherosclerosis risk in communit (ARIC) study: Design and objectwes. Am J Epidemiol 1989; 129: 687-702.
  11. Fried LP. et al. The cardiovascular health study: Design and rationale. Ann Epidemiol 1991; 1: 263-276.
  12. Feinleib M. et al. The framingham offspring study. Design and preliminary data. Prevent Med 1975; 4: 518-525.
  13. Hofman A. et al. The Rotterdam Study: objectives and design update. Eur J Epidemiol 2007; 22: 819-829.
  14. Strachan DP. et al. Lifecourse influences on health among British adults: effects of region of residence in childhood and adulthood. Intern J Epidemiol 2007; 36: 522-531.
  15. Smith NL. et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor the CHARGE (Cohorts for heart and aging research in genome epidemiology) consortium. Circulation 2010; 121: 1382-1392.
  16. van Schie MC. et al. Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease. Blood 2011; 117: 1393-1399.
  17. Dmitrieva NI, Burg MB. Secretion of von Willebrand factor by endothelial cells links sodium to hypercoagulability and thrombosis. Proc Natl Acad Sci 2014; 111: 6485-6490.
  18. Van Kesteren P. et al. The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning. Thromb Haemost 1998; 79: 1029-1033.
  19. Bernardo A. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104: 100-106.
  20. Pinsky DJ. et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest 1996; 97: 493.
  21. Galbusera M. et al. Fluid shear stress modulates von Willebrand factor release from human vascular endothelium. Blood 1997; 90: 1558-1564.
  22. Paczuski R, Ciešlicka M. The moderate physical exercise significantly increases von Willebrand’s factor’s activity and concentration in the blood. Polish Ann Med 2013; 20: 100-105.
  23. van Mourik JA. et al. Biogenesis and exocytosis of Weibel-Palade bodies. Histo-chem Cell Biol 2002; 117: 113-122.
  24. Fish R. et al. Fluvastatin inhibits regulated secretion of endothelial cell von Willebrand factor in response to diverse secretagogues. Biochem J 2007; 405: 597-604.
  25. Ordulu E, Erdogan O. Early effects of low versus high dose atorvastatin treatment on coagulation and inflammation parameters in patients with acute coronary syndromes. Intern J Cardiol 2008; 128: 282-284.
  26. Undas A. et al. Anticoagulant effects of statins and their clinical implications. Thromb Haemost 2014; 111: 392-400.
  27. Sahebkar A. et al. Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials. Thromb Haemost 2015; 114: 546-557.
  28. Ii M, Losordo DW. Statins and the endothelium. Vasc Pharmacol 2007; 46: 1-9.
  29. Blum A, Shamburek R. The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis. Atherosclerosis 2009; 203: 325-330.
  30. Moher D. et al. Preferred reporting items for systematic reviews and meta-ana-lyses: the PRISMA statement. Br Med J 2009; 339: b2535.
  31. Collaboration C. Cochrane handbook for systematic reviews of interventions version 5.1. 0. 2011. 2013. Available at: http://handbook cochrane org. Accessed March 12, 2014.
  32. Borenstein M. et al. Comprehensive meta-analysis version 2. Englewood, NJ: Biostat; 2005: 104.
  33. Hozo SP. et al. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodology 2005; 5: 13.
  34. Sutton AJ. et al. Methods for meta-analysis in medical research. J. Wiley; 2000
  35. Stone N. et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63: 2889-2934. Erratum in J Am Coll Cardiol 2014; 63: 3024-3025.
  36. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455-463.
  37. Spiel AO. et al. Von Willebrand factor in cardiovascular disease focus on acute coronary syndromes. Circulation 2008; 117: 1449-1459.
  38. Blann A. et al. Altered levels of soluble adhesion molecules in rheumatoid arthritis, vasculitis and systemic sclerosis. Rheumatology 1995; 34: 814-819.
  39. Frankel DS. et al. Von Willebrand Factor, Type 2 Diabetes Mellitus, and Risk of Cardiovascular Disease The Framingham Offspring Study. Circulation 2008; 118: 2533-2539.
  40. Morise T. et al. Increased plasma levels of immunoreactive endothelin and von Willebrand factor in NIDDM patients. Diabetes Care 1995; 18: 87-89.
  41. De Meyer SF. et al. von Willebrand Factor An Emerging Target in Stroke Therapy. Stroke 2012; 43: 599-606.
  42. Fuster V. et al. Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease. Arterioscl Thromb Vasc Biol 1985; 5: 67-73.
  43. Methia N. et al. Localized reduction of atherosclerosis in von Willebrand factor-deficient mice. Blood 2001; 98: 1424-1428.
  44. Montoro-García S. et al. Potential value of targeting von Willebrand factor in atherosclerotic cardiovascular disease. Expert Opin Therap Targets 2014; 18: 43-53.
  45. Sonneveld MA. et al. Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis. Blood Rev 2014; 28: 167-178.
  46. Johnsen JM. et al. Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood 2013; 122: 590-597.
  47. Caponnetto P. et al. Circulating endothelial coagulative activation markers after smoking cessation: a 12 month observational study. Eur J Clin Invest 2011; 41: 616-626.
  48. Abou-Raya A. et al. Statins as immunomodulators in systemic sclerosis. Ann NY Acad Sci 2007; 1110: 670-680.
  49. Almquist T. et al. Effects of lipid-lowering treatment on platelet reactivity and platelet-leukocyte aggregation in diabetic patients without and with chronic kidney disease: a randomized trial. Nephrol Dialys Transplant 2012; 27: 3540-3546.
  50. Ambrosi P. et al. Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients. Thromb Haemost 2000; 83: 46-48.
  51. Barreto A. et al. Rosuvastatin and vascular dysfunction markers in pulmonary arterial hypertension: a placebo-controlled study. Brazil J Med Biol Res 2008; 41: 657-663.
  52. Blann AD. et al. Influence of pravastatin on lipoproteins, and on endothelial, platelet, and inflammatory markers in subjects with peripheral artery disease. Am J Cardiol 2001; 88: 89-92.
  53. Casey RG. et al. Two-week treatment with pravastatin improves ventriculo-vascular haemodynamic interactions in young men with type 1 diabetes. Diabet Vasc Dis Res 2007; 4: 53-61.
  54. Hjelstuen A. et al. Effect of lifestyle and/or statin treatment on soluble markers of atherosclerosis in hypertensives. Scand Cardiovasc J 2007; 41: 313-320.
  55. Konduracka E. et al. Effect of atorvastatin on endothelial function and inflammation in long-duration type 1 diabetic patients without coronary heart disease and arterial hypertension. Diabet Obes Metabol 2008; 10: 719-725.
  56. Krysiak R, Okopien B. Effect of simvastatin on hemostasis in patients with isolated hypertriglyceridemia. Pharmacology 2012; 92: 187-190.
  57. Krysiak R. et al. The effect of ezetimibe and simvastatin on hemostasis in patients with isolated hypercholesterolemia. Fundam Clin Pharmacol 2012; 26: 424-431.
  58. Liu M. et al. Atorvastatin improves endothelial function and cardiac performance in patients with dilated cardiomyopathy: the role of inflammation. Car-diovasc Drugs Ther 2009; 23: 369-376.
  59. Lynch JR. et al. Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage results of a pilot randomized clinical trial. Stroke 2005; 36: 2024-2026.
  60. McCarey DW. et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind,randomisedplacebo-controlledtrial. Lancet 2004; 363: 2015-2021.
  61. Sadik HY. et al. Lack of effect of 8 weeks atorvastatin on microvascular endothe-lial function in patients with systemic sclerosis. Rheumatology 2010; 49: 990-996.
  62. Tan KC. et al. Effects of fluvastatin on prothrombotic and fibrinolytic factors in type 2 diabetes mellitus. Am J Cardiol 1999; 84: 934-937.
  63. Tehrani S. et al. Impaired endothelium-dependent skin microvascular function during high-dose atorvastatin treatment in patients with type 1 diabetes. Diabet Vasc Dis Res 2013; 10: 483-488
  64. Van De Ree M. et al. Decrease of hemostatic cardiovascular risk factors by aggressive vs. conventional atorvastatin treatment in patients with Type 2 diabetes mellitus. J Thromb Haemost 2003; 1: 1753-1757.