Loss of high-molecular-weight von Willebrand factor multimers mainly affects platelet aggregation in patients with aortic stenosis

 

 Buy Article Permissions and Reprints

Summary

Severe aortic stenosis is associated with a haemostatic abnormality that resembles acquired von Willebrand syndrome type 2. It is assumed that high shear conditions render large von Willebrand factor (VWF) multimers accessible to cleavage by ADAMTS-13. However, whether loss of these large multimers affects platelet function by impairing adhesion, aggregate formation, or both has not been evaluated in clinical studies. We prospectively enrolled 47 patients with severe aortic stenosis, and studied them prior to aortic valve surgery and at a median of six months after valve replacement. We investigated levels of large VWF multimers, platelet function under high shear conditions, and residual response to suboptimal concentrations of ADP to express P-selectin. As expected, there was a significant reduction of VWF large multimers before surgery that resolved thereafter in most patients (p<0.0001). The closure time of the ADP cartridge of the PFA-100 was also corrected in most patients after the operation (p<0.0001). We used the cone and plate(let) analyser Impact-R to differentiate between adhesion and aggregation. Both adhesion (p=0.03) and ADP-inducible platelet aggregation (p=0.002) improved considerably after valve replacement. Consequently, ADP-inducible expression of P-selectin was higher after valve replacement (p=0.001). We conclude that reduced levels of large VWF multimers associated with aortic stenosis lead to impairment of both adhesion and, especially, ADP-inducible platelet aggregation.

• References

• 1 Heyde EC. Gastrointestinal bleeding in aortic stenosis. N Engl J Med 1958; 259: 196.
  PubMedGoogle Scholar
• 2 Warkentin TE, Moore JC, Morgan DG. Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand’s disease the link?. Lancet 1992; 340: 35-37.
  CrossrefPubMedGoogle Scholar
• 3 Tsai HM, Sussman II, Nagel RL. Shear stress enhances the proteolysis of von Wille-brand factor in normal plasma. Blood 1994; 83: 2171-2179.
  PubMedGoogle Scholar
• 4 Tsai HM. Shear stress and von Willebrand factor in health and disease. Semin Thromb Hemost 2003; 29: 479-488.
  Article in Thieme ConnectPubMedGoogle Scholar
• 5 Anderson RP, McGrath K, Street A. Reversal of aortic stenosis, bleeding gastrointestinal angiodysplasia, and von Willebrand syndrome by aortic valve replacement. Lancet 1996; 347: 689-690.
  PubMedGoogle Scholar
• 6 Warkentin TE, Moore JC, Morgan DG. Gastrointestinal angiodysplasia and aortic stenosis. N Engl J Med 2002; 347: 858-859.
  CrossrefPubMedGoogle Scholar
• 7 Veyradier A, Balian A, Wolf M. et al. Abnormal von Willebrand factor in bleeding angiodysplasias of the digestive tract. Gastroenterology 2001; 120: 346-353.
  CrossrefPubMedGoogle Scholar
• 8 Pareti FI, Lattuada A, Bressi C. et al. Proteolysis of von Willebrand factor and shear stress-induced platelet aggregation in patients with aortic valve stenosis. Circulation 2000; 102: 1290-1295.
  CrossrefPubMedGoogle Scholar
• 9 Vincentelli A, Susen S, Le TT. et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med 2003; 349: 343-349.
  CrossrefPubMedGoogle Scholar
• 10 Yoshida K, Tobe S, Kawata M. Acquired von Willebrand disease type IIA in patients with aortic valve stenosis. Ann Thorac Surg 2006; 81: 1114-1116.
  CrossrefPubMedGoogle Scholar
• 11 Sucker C. The Heyde syndrome: proposal for a unifying concept explaining the association of aortic valve stenosis, gastrointestinal angiodysplasia and bleeding. Int J Cardiol 2007; 115: 77-78.
  CrossrefPubMedGoogle Scholar
• 12 Warkentin TE, Moore JC, Anand SS. et al. Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev 2003; 17: 272-286.
  CrossrefPubMedGoogle Scholar
• 13 Geisen U, Heilmann C, Beyersdorf F. et al. Non-surgical bleeding in patients with ventricular assist devices could be explained by acquired von Willebrand disease. Eur J Cardiothorac Surg 2008; 33: 679-684.
  CrossrefPubMedGoogle Scholar
• 14 Reininger AJ, Heijnen HF, Schumann H. et al. Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress. Blood 2006; 107: 3537-3545.
  CrossrefPubMedGoogle Scholar
• 15 Ruggeri ZM, Orje JN, Habermann R. et al. Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood 2006; 108: 1903-1910.
  CrossrefPubMedGoogle Scholar
• 16 Budde U, Schneppenheim R, Plendl H. et al. Luminographic detection of von Willebrand factor multimers in agarose gels and on nitrocellulose membranes. Thromb Haemost 1990; 63: 312-315.
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Budde U, Pieconka A, Will K. et al. Laboratory testing for von Willebrand disease: contribution of multimer analysis to diagnosis and classification. Semin Thromb Hemost 2006; 32: 514-521.
  Article in Thieme ConnectPubMedGoogle Scholar
• 18 Jilma B. Platelet function analyzer (PFA-100): a tool to quantify congenital or acquired platelet dysfunction. J Lab Clin Med 2001; 138: 152-163.
  CrossrefPubMedGoogle Scholar
• 19 Shenkman B, Einav Y, Salomon O. et al. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19: 440-446.
  CrossrefPubMedGoogle Scholar
• 20 Panzer S, Höcker L, Koren D. Agonists-induced platelet activation varies considerably in healthy male individuals studies by flow cytometry. Ann Hematol 2006; 85: 121-125.
  CrossrefPubMedGoogle Scholar
• 21 Revel-Vilk S, Hyam E, Zelikowitz T. et al. Evaluation of Children with Suspected Bleeding Disorder Applying the Impact-R [Cone and Plate(let) Analyzer]. ASH Annual Meeting Abstracts 2007; 110: 3962.
  PubMedGoogle Scholar
• 22 Sucker C, Feindt P, Scharf RE. Aortic stenosis, von Willebrand factor, and bleeding. N Engl J Med 2003; 349: 1773.
  CrossrefPubMedGoogle Scholar
• 23 Schmid W, Steindl-Munda Petra, Mandl C. et al. Estimation of platelet function under high shear conditions to assist a rapid diagnosis of Heyde Syndrome. Platelets 2008; 19: 636-640.
  CrossrefPubMedGoogle Scholar
• 24 Panzer S, Eichelberger B, Koren D. et al. Monitoring survival and function of transfused platelets in Bernard-Soulier syndrome by flow cytometry and a cone and plate(let) analyzer (Impact-R). Transfusion 2007; 47: 103-106.
  CrossrefPubMedGoogle Scholar