Proteolysis of von Willebrand Factor and Shear Stress–Induced Platelet Aggregation in Patients With Aortic Valve Stenosis

BackgroundExcessive bleeding may complicate congenital cardiac defects. To explain the pathogenesis of this abnormality, we evaluated selected parameters of primary hemostasis in patients with aortic valve stenosis before and after corrective surgery. Methods and ResultsWe examined shear-induced platelet aggregation with the filter aggregometer test and von Willebrand factor (vWF) structure by evaluating the multimeric distribution and extent of subunit proteolysis. The platelet count was reduced before corrective surgery, and shear-induced platelet aggregation was impaired. Moreover, vWF multimers of higher molecular mass were decreased, and proteolytic subunit fragments were increased. After correction of the cardiac defect, all of these parameters returned to normal. ConclusionsAlterations of vWF and platelet function may contribute to the bleeding diathesis in patients with aortic valve stenosis. Improvement after corrective surgery suggests that the passage of blood through a stenosed aortic valve may result in shear forces that induce vWF interaction with platelets in the circulation and, in turn, trigger platelet clearance, vWF degradation, and the impairment of primary hemostasis.

[1]  S. Berkowitz,et al.  Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. , 1992, Blood.

[2]  D. Morgan,et al.  Aortic stenosis and bleeding gastrointestinal angiodysplasia: is acquired von Willebrand's disease the link? , 1992, The Lancet.

[3]  P K Paulsen,et al.  Turbulent stresses downstream of three mechanical aortic valve prostheses in human beings. , 1994, The Journal of thoracic and cardiovascular surgery.

[4]  F Rodeghiero,et al.  Epidemiological investigation of the prevalence of von Willebrand's disease. , 1987, Blood.

[5]  Z. Ruggeri,et al.  Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). , 1986, The Journal of clinical investigation.

[6]  B. Lämmle,et al.  Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. , 1996, Blood.

[7]  R. Montgomery,et al.  Loss of the largest von Willebrand factor multimers from the plasma of patients with congenital cardiac defects. , 1986, Blood.

[8]  H. Tsai Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. , 1996, Blood.

[9]  J. Levin,et al.  A Critical Reappraisal of the Bleeding Time* , 1990, Seminars in thrombosis and hemostasis.

[10]  P. Mannucci,et al.  Treatment of von Willebrand disease , 1998, Thrombosis and haemostasis.

[11]  S. Goto,et al.  Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. , 1998, The Journal of clinical investigation.

[12]  P. Mannucci,et al.  Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis. , 1993, Blood.

[13]  P. Mannucci,et al.  Transfusion Requirements Are Correlated with the Degree of Proteolysis of von Willebrand Factor during Orthotopic Liver Transplantation , 1997, Thrombosis and Haemostasis.

[14]  E. Giuliani,et al.  The association of unexplained gastrointestinal bleeding with calcific aortic stenosis. , 1987, The Annals of thoracic surgery.

[15]  P. Mannucci,et al.  Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. , 1980, The New England journal of medicine.

[16]  D. Ginsburg,et al.  Von Willebrand disease. , 2008, Pediatric clinics of North America.

[17]  D. MacLeod,et al.  PERSISTENT GASTROINTESTINAL BLEEDING DUE TO ANGIODYSPLASIA OF THE GUT IN VON WILLEBRAND'S DISEASE , 1976, The Lancet.

[18]  P. Mannucci,et al.  Correction of the bleeding time in treated patients with severe von willebrand disease is not solely dependent on the normal multimeric structure of plasma von willebrand factor , 1987, American journal of hematology.

[19]  P. Mannucci,et al.  Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. , 1992, Blood.

[20]  B. Lämmle,et al.  Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. , 1997, Blood.

[21]  P. Mannucci Treatment of von Willebrand Disease. , 1998, Hematology.

[22]  T. Barbui,et al.  Proteolysis of von Willebrand factor is decreased in acute promyelocytic leukaemia by treatment with all‐trans‐retinoic acid , 1996, British journal of haematology.

[23]  P. Mannucci,et al.  Evaluation of the Abnormal Platelet Function in von Willebrand Disease by the Blood Filtration Test , 1996, Thrombosis and Haemostasis.

[24]  D. D. Mcgavi THE ANONYMOUS WHITE TABLET. , 1965, Lancet.

[25]  K. Titani,et al.  Epitope mapping of the von Willebrand factor subunit distinguishes fragments present in normal and type IIA von Willebrand disease from those generated by plasmin. , 1987, The Journal of clinical investigation.

[26]  J. Moake,et al.  Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. , 1986, The Journal of clinical investigation.

[27]  R. Greenstein,et al.  Colonic vascular ectasias and aortic stenosis: coincidence or causal relationship? , 1986, American journal of surgery.

[28]  Joseph Loscalzo,et al.  Thrombosis and Hemorrhage , 2002 .

[29]  Brian Savage,et al.  Specific Synergy of Multiple Substrate–Receptor Interactions in Platelet Thrombus Formation under Flow , 1998, Cell.

[30]  A. Federici,et al.  Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand's disease subtypes. , 1982, Blood.

[31]  M. Cappell,et al.  Cessation of recurrent bleeding from gastrointestinal angiodysplasias after aortic valve replacement. , 1986, Annals of internal medicine.

[32]  J. Moake,et al.  Shear-induced platelet aggregation requires von Willebrand factor and platelet membrane glycoproteins Ib and IIb-IIIa. , 1987, Blood.

[33]  Z. Ruggeri,et al.  Variant von Willebrand's disease: characterization of two subtypes by analysis of multimeric composition of factor VIII/von Willebrand factor in plasma and platelets. , 1980, The Journal of clinical investigation.

[34]  R. Marchant,et al.  Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. , 1996, Blood.

[35]  E. Salzman,et al.  Changes in von Willebrand factor during cardiac surgery: effect of desmopressin acetate. , 1988, Blood.

[36]  R. D. Wade,et al.  Amino acid sequence of human von Willebrand factor. , 1986, Biochemistry.

[37]  I. Nilsson,et al.  Platelet aggregation induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in Type IIB von Willebrand's disease. , 1983, The New England journal of medicine.

[38]  M. Boisseau,et al.  Technical and Biological Conditions Influencing the Functional APC Resitance Test , 1996, Thrombosis and Haemostasis.

[39]  J. Ware,et al.  Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand factor. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. O'brien,et al.  Shear stress activation of platelet glycoprotein IIb/IIIa plus von Willebrand factor causes aggregation: filter blockage and the long bleeding time in von Willebrand's disease. , 2016, Blood.

[41]  A. Tosetto,et al.  The bleeding time in normal subjects is mainly determined by platelet von Willebrand factor and is independent from blood group. , 1992, Thrombosis research.

[42]  Y. Ikeda,et al.  Characterization of the Unique Mechanism Mediating the Shear-dependent Binding of Soluble von Willebrand Factor to Platelets (*) , 1995, The Journal of Biological Chemistry.

[43]  Z. Ruggeri,et al.  Proteolysis of von Willebrand factor in therapeutic plasma concentrates. , 1994, Blood.

[44]  Z. Ruggeri,et al.  Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the constituent subunit. , 1991, The Journal of clinical investigation.

[45]  F. Fabris,et al.  Glycocalicin in the diagnosis and management of immune thrombocytopenia , 1998, European journal of haematology.