Current understanding of thrombosis and hemostasis — from bench to bedside von Willebrand factor : at the crossroads of bleeding and thrombosis

Hemostasis and thrombosis represent two sides of the same coin. Hemostasis maintains blood fluidity in the vascular system while allowing for rapid thrombus formation to prevent excessive hemorrhage after blood vessel injury. Thrombosis is a pathologic extension of the normal hemostatic mechanism, occurring when unwanted clot formation develops in certain pathological situations. The molecular mechanisms underlying both phenomena are fundamentally identical. One of the key players in both processes is the plasma glycoprotein von Willebrand factor, which perfectly illustrates this duality between hemostatic and thrombotic mechanisms. The purpose of this review is to discuss novel findings on the role of von Willebrand factor at this interface, and how some of these findings may help develop new therapeutic strategies.

[1]  C. Casari,et al.  Clearance of von Willebrand factor , 2013, Journal of thrombosis and haemostasis : JTH.

[2]  G. Gambaro,et al.  Oxidation of Met1606 in von Willebrand factor is a risk factor for thrombotic and septic complications in chronic renal failure. , 2012, The Biochemical journal.

[3]  D. Wagner,et al.  Neutrophil extracellular traps promote deep vein thrombosis in mice , 2012, Journal of thrombosis and haemostasis : JTH.

[4]  D. Wagner,et al.  Histones induce rapid and profound thrombocytopenia in mice. , 2011, Blood.

[5]  D. Lane,et al.  Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. , 2011, Blood.

[6]  Hiroshi Uji-i,et al.  Local Elongation of Endothelial Cell-anchored von Willebrand Factor Strings Precedes ADAMTS13 Protein-mediated Proteolysis* , 2011, The Journal of Biological Chemistry.

[7]  D. Tregouet,et al.  Combined analysis of three genome-wide association studies on vWF and FVIII plasma levels , 2011, BMC Medical Genetics.

[8]  K. Ghosh,et al.  Pathophysiology of acquired von Willebrand disease: a concise review , 2011, European journal of haematology.

[9]  A. Iorio,et al.  Management of Inherited von Willebrand Disease in Italy: Results from the Retrospective Study on 1234 Patients , 2011, Seminars in thrombosis and hemostasis.

[10]  R. Schneppenheim,et al.  von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein , 2011, Journal of thrombosis and haemostasis : JTH.

[11]  T. Springer,et al.  Biology and physics of von Willebrand factor concatamers , 2011, Journal of thrombosis and haemostasis : JTH.

[12]  A. Ganser,et al.  How I treat the acquired von Willebrand syndrome. , 2011, Blood.

[13]  D. Strachan,et al.  Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. , 2011, Blood.

[14]  F. Leebeek,et al.  Genetic determinants of von Willebrand factor levels and activity in relation to the risk of cardiovascular disease: a review , 2011, Journal of thrombosis and haemostasis : JTH.

[15]  D. Lillicrap,et al.  Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models. , 2011, Blood.

[16]  D. Motto,et al.  Modulation of von Willebrand Factor by ADAMTS13 , 2011 .

[17]  J. Moake,et al.  N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. , 2011, The Journal of clinical investigation.

[18]  B. Lämmle,et al.  von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. , 2011, Blood.

[19]  A. Tosetto,et al.  Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance , 2011, Thrombosis and Haemostasis.

[20]  J. Moake,et al.  Disulfide bond reduction of von Willebrand factor by ADAMTS‐13 , 2010, Journal of thrombosis and haemostasis : JTH.

[21]  P. Lenting,et al.  ADAMTS‐13: double trouble for von Willebrand factor , 2010, Journal of thrombosis and haemostasis : JTH.

[22]  D. Strachan,et al.  Effect of Genetic Variations in Syntaxin-Binding Protein-5 and Syntaxin-2 on von Willebrand Factor Concentration and Cardiovascular Risk , 2010, Circulation. Cardiovascular genetics.

[23]  Junmei Chen,et al.  Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region. , 2010, Blood.

[24]  G. Stoll,et al.  Binding of von Willebrand Factor to Collagen and Glycoprotein Ib&agr;, But Not to Glycoprotein IIb/IIIa, Contributes to Ischemic Stroke in Mice—Brief Report , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[25]  M. Slaughter Hematologic Effects of Continuous Flow Left Ventricular Assist Devices , 2010, Journal of cardiovascular translational research.

[26]  J. Hartwig,et al.  Extracellular DNA traps promote thrombosis , 2010, Proceedings of the National Academy of Sciences.

[27]  P. D. de Groot,et al.  Regulation of von Willebrand factor-platelet interactions , 2010, Thrombosis and Haemostasis.

[28]  P. Legendre,et al.  Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. , 2010, Blood.

[29]  R. Hoffmann,et al.  Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD , 2010, Journal of thrombosis and haemostasis : JTH.

[30]  Andrew D. Johnson,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 , 2010, Circulation.

[31]  S. Rutella,et al.  Formation of methionine sulfoxide by peroxynitrite at position 1606 of von Willebrand factor inhibits its cleavage by ADAMTS-13: A new prothrombotic mechanism in diseases associated with oxidative stress. , 2010, Free radical biology & medicine.

[32]  Junmei Chen,et al.  Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. , 2010, Blood.

[33]  Y. Asada,et al.  Critical role of von Willebrand factor and platelet interaction in venous thromboembolism. , 2009, Histology and histopathology.

[34]  F. Rosendaal,et al.  Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men. , 2009, Blood.

[35]  M. Laffan,et al.  Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. , 2009, Blood.

[36]  Cheng-Zhong Zhang,et al.  Mechanoenzymatic Cleavage of the Ultralarge Vascular Protein von Willebrand Factor , 2009, Science.

[37]  G. Stoll,et al.  Deficiency of von Willebrand factor protects mice from ischemic stroke. , 2009, Blood.

[38]  H. Deckmyn,et al.  Von Willebrand factor: drug and drug target. , 2009, Cardiovascular & hematological disorders drug targets.

[39]  P. Mannucci,et al.  Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. , 2009, Blood.

[40]  Z. Ruggeri Platelet Adhesion under Flow , 2009, Microcirculation.

[41]  A. Reininger Function of von Willebrand factor in haemostasis and thrombosis , 2008, Haemophilia : the official journal of the World Federation of Hemophilia.

[42]  N. Lamblin,et al.  Functional Impairment of Von Willebrand Factor in Hypertrophic Cardiomyopathy: Relation to Rest and Exercise Obstruction , 2008, Circulation.

[43]  O. Christophe,et al.  Altered thrombus formation in von Willebrand factor-deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa. , 2008, Blood.

[44]  J. Moake,et al.  Covalent regulation of ULVWF string formation and elongation on endothelial cells under flow conditions , 2008, Journal of thrombosis and haemostasis : JTH.

[45]  J. Goudemand,et al.  Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). , 2008, Blood.

[46]  P. D. de Groot,et al.  beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. , 2007, Blood.

[47]  P. Lenting,et al.  Clearance mechanisms of von Willebrand factor and factor VIII , 2007, Journal of thrombosis and haemostasis : JTH.

[48]  A Alexander-Katz,et al.  Shear-induced unfolding triggers adhesion of von Willebrand factor fibers , 2007, Proceedings of the National Academy of Sciences.

[49]  P. Legendre,et al.  Effect of von Willebrand disease type 2B and type 2M mutations on the susceptibility of von Willebrand factor to ADAMTS‐13 , 2007, Journal of thrombosis and haemostasis : JTH.

[50]  P. Hogg,et al.  Hypothesis for control of von Willebrand factor multimer size by intra‐molecular thiol‐disulphide exchange , 2007, Journal of thrombosis and haemostasis : JTH.

[51]  P. Mannucci,et al.  Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor , 2006, Journal of thrombosis and haemostasis : JTH.

[52]  R. Paschke,et al.  Impact of the Thr789Ala variant of the von Willebrand factor levels, on ristocetin co-factor and collagen binding capacity and its association with coronary heart disease in patients with diabetes mellitus type 2. , 2005, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[53]  P. D. de Groot,et al.  A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. , 2005, Blood.

[54]  P. Lenting,et al.  Cysteine‐mutations in von Willebrand factor associated with increased clearance , 2005, Journal of thrombosis and haemostasis : JTH.

[55]  A. Hofman,et al.  Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study , 2004, British journal of haematology.

[56]  S. Susen,et al.  Acquired von Willebrand syndrome in aortic stenosis. , 2003, The New England journal of medicine.

[57]  A. Folsom,et al.  Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). , 2002, The American journal of medicine.

[58]  A. Sala,et al.  Proteolysis of von Willebrand Factor and Shear Stress–Induced Platelet Aggregation in Patients With Aortic Valve Stenosis , 2000, Circulation.

[59]  A. Ahlbom,et al.  Plasma levels of tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor are significant risk markers for recurrent myocardial infarction in the Stockholm Heart Epidemiology Program (SHEEP) study. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[60]  G. Chatellier,et al.  Association between high von Willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes , 2000 .

[61]  L. Bouter,et al.  von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[62]  M. Furlan,et al.  Von Willebrand factor: molecular size and functional activity , 1996, Annals of Hematology.

[63]  J. Vandenbroucke,et al.  Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis , 1995, The Lancet.

[64]  Z. Ruggeri,et al.  Elevated platelet count as a cause of abnormal von Willebrand factor multimer distribution in plasma. , 1993, Blood.

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

[66]  C. Richard,et al.  Acquired von willebrand disease in multiple myeloma secondary to absorption of von willebrand factor by plasma cells , 1990, American journal of hematology.

[67]  A. K. Banerjee Angiodysplasia associated with hypertrophic obstructive cardiomyopathy (HOCM) , 1990, The British journal of clinical practice.

[68]  C. Rothschild,et al.  New variant of von Willebrand disease with defective binding to factor VIII. , 1989, Blood.

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

[70]  D. Deykin,et al.  Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. , 1982, The New England journal of medicine.

[71]  A. Chauhan,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins , 2007 .

[72]  R. Schneppenheim,et al.  Phenotypic and genotypic diagnosis of von Willebrand disease: a 2004 update. , 2005, Seminars in hematology.

[73]  C. Denis Molecular and Cellular Biology of von Willebrand Factor , 2002, International journal of hematology.

[74]  A. Girolami,et al.  Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. , 2002, Blood.

[75]  G. Chatellier,et al.  Association between high von willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group. , 2000, Kidney international.

[76]  Z. Ruggeri,et al.  The complex multimeric composition of factor VIII/von Willebrand factor. , 1981, Blood.