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Biology and normal function of von Willebrand factor

Margaret E Rick, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Von Willebrand factor (VWF) is a large multimeric glycoprotein that performs two critical functions in hemostasis: it acts as a bridging molecule at sites of vascular injury for normal platelet adhesion, and under high shear conditions, it promotes platelet aggregation. VWF also acts as a carrier for factor VIII in the circulation, maintaining the normal level of factor VIII by increasing the half-life of factor VIII fivefold [1,2]. A bleeding disorder called von Willebrand disease (VWD) occurs when VWF is deficient or qualitatively abnormal. VWD is the most common of the inherited bleeding disorders, with an estimated prevalence in the general population of 1 percent by laboratory testing [3]. Symptomatic VWD is less common, approximately 0.01 percent, as estimated in hemostasis clinics [4]. Although it is primarily a congenital disorder, there are also acquired forms of the disease.

Evaluation of patients with these disorders has improved our understanding of the functions of VWF and the pathophysiology of VWD. This has taken on greater importance as the role of VWF in thrombotic diseases, such as thrombotic thrombocytopenic purpura and other forms of VWF-mediated thrombosis, is being increasingly recognized [5-11] and the use of new therapies for inhibiting VWF interactions is being explored [12].

The biology and normal functions of VWF will be reviewed here. The classification, pathophysiology, diagnosis, and treatment of VWD are discussed separately. (See "Classification and pathophysiology of von Willebrand disease" and "Clinical presentation and diagnosis of von Willebrand disease" and "Treatment of von Willebrand disease".)


The gene for VWF is located on the short arm of chromosome 12 and is composed of 178 kilobases (kb) and 52 exons [13-16]; the VWF mRNA contains approximately 9 kb. A pseudogene is present on chromosome 22 that includes exons 23-34 of the VWF gene; these exons correspond to regions of the authentic gene that encode domains A1, A2, and A3 (see 'Domain structure' below) [17].

Synthesis — Von Willebrand factor is synthesized in endothelial cells [18] and megakaryocytes as a primary translation product of 2813 amino acids; it subsequently undergoes considerable processing, including dimerization and multimerization to very large forms [19]. The primary translation product contains a signal peptide of 22 amino acids followed by a propeptide of 741 residues, also known as VWF propeptide (von Willebrand antigen II) [20,21], and a mature subunit of 2050 amino acids [22].


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Literature review current through: Sep 2016. | This topic last updated: Jun 11, 2015.
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  1. Brinkhous KM, Sandberg H, Garris JB, et al. Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci U S A 1985; 82:8752.
  2. De Meyer SF, Deckmyn H, Vanhoorelbeke K. von Willebrand factor to the rescue. Blood 2009; 113:5049.
  3. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69:454.
  4. Sadler JE, Mannucci PM, Berntorp E, et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost 2000; 84:160.
  5. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339:1578.
  6. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339:1585.
  7. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347:589.
  8. Diener JL, Daniel Lagassé HA, Duerschmied D, et al. Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779. J Thromb Haemost 2009; 7:1155.
  9. Smith NL, Rice KM, Bovill EG, et al. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood 2011; 117:6007.
  10. De Meyer SF, Savchenko AS, Haas MS, et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120:5217.
  11. Gandhi C, Motto DG, Jensen M, et al. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood 2012; 120:5224.
  12. De Meyer SF, Stoll G, Wagner DD, Kleinschnitz C. von Willebrand factor: an emerging target in stroke therapy. Stroke 2012; 43:599.
  13. Ginsburg D, Handin RI, Bonthron DT, et al. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228:1401.
  14. Lynch DC, Zimmerman TS, Collins CJ, et al. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. Cell 1985; 41:49.
  15. Sadler JE, Shelton-Inloes BB, Sorace JM, et al. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A 1985; 82:6394.
  16. Verweij CL, de Vries CJ, Distel B, et al. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res 1985; 13:4699.
  17. Patracchini P, Calzolari E, Aiello V, et al. Sublocalization of von Willebrand factor pseudogene to 22q11.22-q11.23 by in situ hybridization in a 46,X,t(X;22)(pter;q11.21) translocation. Hum Genet 1989; 83:264.
  18. Hollestelle MJ, Thinnes T, Crain K, et al. Tissue distribution of factor VIII gene expression in vivo--a closer look. Thromb Haemost 2001; 86:855.
  19. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6:217.
  20. Montgomery RR, Zimmerman TS. von Willebrand's disease antigen II. A new plasma and platelet antigen deficient in severe von Willebrand's disease. J Clin Invest 1978; 61:1498.
  21. Fay PJ, Kawai Y, Wagner DD, et al. Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II. Science 1986; 232:995.
  22. Titani K, Kumar S, Takio K, et al. Amino acid sequence of human von Willebrand factor. Biochemistry 1986; 25:3171.
  23. Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM, et al. Topology and order of formation of interchain disulfide bonds in von Willebrand factor. Blood 1987; 69:27.
  24. Carew JA, Browning PJ, Lynch DC. Sulfation of von Willebrand factor. Blood 1990; 76:2530.
  25. Lynch DC, Williams R, Zimmerman TS, et al. Biosynthesis of the subunits of factor VIIIR by bovine aortic endothelial cells. Proc Natl Acad Sci U S A 1983; 80:2738.
  26. Verweij CL, Hart M, Pannekoek H. Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. EMBO J 1987; 6:2885.
  27. Wagner DD, Mayadas T, Marder VJ. Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor. J Cell Biol 1986; 102:1320.
  28. Mayadas TN, Wagner DD. In vitro multimerization of von Willebrand factor is triggered by low pH. Importance of the propolypeptide and free sulfhydryls. J Biol Chem 1989; 264:13497.
  29. Harrison RL, McKee PA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood 1984; 63:657.
  30. Baumgartner-Parzer SM, Wagner L, Reining G, et al. Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells. J Endocrinol 1997; 154:231.
  31. Mahieu B, Jacobs N, Mahieu S, et al. Haemostatic changes and acquired activated protein C resistance in normal pregnancy. Blood Coagul Fibrinolysis 2007; 18:685.
  32. Wagner DD, Olmsted JB, Marder VJ. Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells. J Cell Biol 1982; 95:355.
  33. Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood 2000; 96:1808.
  34. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112:957.
  35. McEver RP, Beckstead JH, Moore KL, et al. GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies. J Clin Invest 1989; 84:92.
  36. Bonfanti R, Furie BC, Furie B, Wagner DD. PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. Blood 1989; 73:1109.
  37. Vischer UM, Wagner DD. CD63 is a component of Weibel-Palade bodies of human endothelial cells. Blood 1993; 82:1184.
  38. Fiedler U, Scharpfenecker M, Koidl S, et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004; 103:4150.
  39. Huang RH, Wang Y, Roth R, et al. Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor. Proc Natl Acad Sci U S A 2008; 105:482.
  40. Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost 2013; 11:581.
  41. Cramer EM, Meyer D, le Menn R, Breton-Gorius J. Eccentric localization of von Willebrand factor in an internal structure of platelet alpha-granule resembling that of Weibel-Palade bodies. Blood 1985; 66:710.
  42. Mourik MJ, Valentijn JA, Voorberg J, et al. von Willebrand factor remodeling during exocytosis from vascular endothelial cells. J Thromb Haemost 2013; 11:2009.
  43. Padilla A, Moake JL, Bernardo A, et al. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 2004; 103:2150.
  44. De Ceunynck K, Rocha S, Feys HB, et al. Local elongation of endothelial cell-anchored von Willebrand factor strings precedes ADAMTS13 protein-mediated proteolysis. J Biol Chem 2011; 286:36361.
  45. Valentijn KM, Sadler JE, Valentijn JA, et al. Functional architecture of Weibel-Palade bodies. Blood 2011; 117:5033.
  46. Rickles FR, Hoyer LW, Rick ME, Ahr DJ. The effects of epinephrine infusion in patients with von Willebrand's disease. J Clin Invest 1976; 57:1618.
  47. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio A. 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases. Lancet 1977; 1:869.
  48. Rusu L, Andreeva A, Visintine DJ, et al. G protein-dependent basal and evoked endothelial cell vWF secretion. Blood 2014; 123:442.
  49. Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308:8.
  50. Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1:682.
  51. Nachman RL, Jaffe EA. Subcellular platelet factor VIII antigen and von Willebrand factor. J Exp Med 1975; 141:1101.
  52. Keightley AM, Lam YM, Brady JN, et al. Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter. Blood 1999; 93:4277.
  53. Levy G, Ginsburg D. Getting at the variable expressivity of von Willebrand disease. Thromb Haemost 2001; 86:144.
  54. Campos M, Sun W, Yu F, et al. Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort. Blood 2011; 117:5224.
  55. Mohlke KL, Nichols WC, Westrick RJ, et al. A novel modifier gene for plasma von Willebrand factor level maps to distal mouse chromosome 11. Proc Natl Acad Sci U S A 1996; 93:15352.
  56. Mohlke KL, Purkayastha AA, Westrick RJ, et al. Mvwf, a dominant modifier of murine von Willebrand factor, results from altered lineage-specific expression of a glycosyltransferase. Cell 1999; 96:111.
  57. Gill JC, Endres-Brooks J, Bauer PJ, et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69:1691.
  58. Brown SA, Collins PW, Bowen DJ. Heterogeneous detection of A-antigen on von Willebrand factor derived from platelets, endothelial cells and plasma. Thromb Haemost 2002; 87:990.
  59. O'Donnell J, Boulton FE, Manning RA, Laffan MA. Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels. Arterioscler Thromb Vasc Biol 2002; 22:335.
  60. Bowen DJ. An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13. J Thromb Haemost 2003; 1:33.
  61. O'Donnell JS, McKinnon TA, Crawley JT, et al. Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis. Blood 2005; 106:1988.
  62. Jenkins PV, O'Donnell JS. ABO blood group determines plasma von Willebrand factor levels: a biologic function after all? Transfusion 2006; 46:1836.
  63. Davies JA, Collins PW, Hathaway LS, Bowen DJ. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Blood 2007; 109:2840.
  64. Gallinaro L, Cattini MG, Sztukowska M, et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111:3540.
  65. Castaman G, Tosetto A, Eikenboom JC, Rodeghiero F. Blood group significantly influences von Willebrand factor increase and half-life after desmopressin in von Willebrand disease Vicenza. J Thromb Haemost 2010; 8:2078.
  66. Klarmann D, Eggert C, Geisen C, et al. Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents. Transfusion 2010; 50:1571.
  67. Fernandez MF, Ginsberg MH, Ruggeri ZM, et al. Multimeric structure of platelet factor VIII/von Willebrand factor: the presence of larger multimers and their reassociation with thrombin-stimulated platelets. Blood 1982; 60:1132.
  68. Zhou W, Inada M, Lee TP, et al. ADAMTS13 is expressed in hepatic stellate cells. Lab Invest 2005; 85:780.
  69. Liu L, Choi H, Bernardo A, et al. Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. J Thromb Haemost 2005; 3:2536.
  70. Turner N, Nolasco L, Tao Z, et al. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost 2006; 4:1396.
  71. Shang D, Zheng XW, Niiya M, Zheng XL. Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts. Blood 2006; 108:2207.
  72. Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87:4223.
  73. Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87:4235.
  74. Dong JF, Moake JL, Nolasco L, et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100:4033.
  75. Reiter RA, Knöbl P, Varadi K, Turecek PL. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101:946.
  76. Bowen DJ, Collins PW. Insights into von Willebrand factor proteolysis: clinical implications. Br J Haematol 2006; 133:457.
  77. Wu JJ, Fujikawa K, McMullen BA, Chung DW. Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor. Proc Natl Acad Sci U S A 2006; 103:18470.
  78. Pruss CM, Notley CR, Hegadorn CA, et al. ADAMTS13 cleavage efficiency is altered by mutagenic and, to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor. Br J Haematol 2008; 143:552.
  79. Shim K, Anderson PJ, Tuley EA, et al. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008; 111:651.
  80. Crawley JT, de Groot R, Xiang Y, et al. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 2011; 118:3212.
  81. Turner NA, Nolasco L, Ruggeri ZM, Moake JL. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 2009; 114:5102.
  82. Cao W, Krishnaswamy S, Camire RM, et al. Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13. Proc Natl Acad Sci U S A 2008; 105:7416.
  83. Cao W, Sabatino DE, Altynova E, et al. Light chain of factor VIII is sufficient for accelerating cleavage of von Willebrand factor by ADAMTS13 metalloprotease. J Biol Chem 2012; 287:32459.
  84. Rayes J, Roumenina LT, Dimitrov JD, et al. The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status. Blood 2014; 123:121.
  85. Fujikawa K, Suzuki H, McMullen B, Chung D. Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family. Blood 2001; 98:1662.
  86. Plaimauer B, Zimmermann K, Völkel D, et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 2002; 100:3626.
  87. Zheng X, Chung D, Takayama TK, et al. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276:41059.
  88. Chauhan AK, Motto DG, Lamb CB, et al. Systemic antithrombotic effects of ADAMTS13. J Exp Med 2006; 203:767.
  89. Feys HB, Roodt J, Vandeputte N, et al. Inhibition of von Willebrand factor-platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons. Blood 2012; 120:3611.
  90. Callewaert F, Roodt J, Ulrichts H, et al. Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura. Blood 2012; 120:3603.
  91. Bernardo A, Ball C, Nolasco L, 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.
  92. Xie L, Chesterman CN, Hogg PJ. Control of von Willebrand factor multimer size by thrombospondin-1. J Exp Med 2001; 193:1341.
  93. Pimanda JE, Ganderton T, Maekawa A, et al. Role of thrombospondin-1 in control of von Willebrand factor multimer size in mice. J Biol Chem 2004; 279:21439.
  94. Hoyer LW, Shainoff JR. Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers. Blood 1980; 55:1056.
  95. Perret BA, Furlan M, Beck EA. Studies on factor VIII-related protein. II. Estimation of molecular size differences between factor VIII oligomers. Biochim Biophys Acta 1979; 578:164.
  96. Fowler WE, Fretto LJ, Hamilton KK, et al. Substructure of human von Willebrand factor. J Clin Invest 1985; 76:1491.
  97. Siedlecki CA, Lestini BJ, Kottke-Marchant KK, et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88:2939.
  98. Vicente V, Houghten RA, Ruggeri ZM. Identification of a site in the alpha chain of platelet glycoprotein Ib that participates in von Willebrand factor binding. J Biol Chem 1990; 265:274.
  99. Sadler JE. The molecular biology of human von Willebrand factor. In: Coagulation and Bleeding Disorders: The Role of Factor VIII and Von Willebrand Factor, Zimmerman TS, Ruggeri ZM (Eds), Dekker, New York 1989. p.117.
  100. Zhou YF, Eng ET, Zhu J, et al. Sequence and structure relationships within von Willebrand factor. Blood 2012; 120:449.
  101. Cruz MA, Yuan H, Lee JR, et al. Interaction of the von Willebrand factor (vWF) with collagen. Localization of the primary collagen-binding site by analysis of recombinant vWF a domain polypeptides. J Biol Chem 1995; 270:10822.
  102. Koppelman SJ, van Hoeij M, Vink T, et al. Requirements of von Willebrand factor to protect factor VIII from inactivation by activated protein C. Blood 1996; 87:2292.
  103. Foster PA, Fulcher CA, Marti T, et al. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262:8443.
  104. Sugimoto M, Mohri H, McClintock RA, Ruggeri ZM. Identification of discontinuous von Willebrand factor sequences involved in complex formation with botrocetin. A model for the regulation of von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1991; 266:18172.
  105. Jenkins PV, Pasi KJ, Perkins SJ. Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand's disease. Blood 1998; 91:2032.
  106. Miura S, Li CQ, Cao Z, et al. Interaction of von Willebrand factor domain A1 with platelet glycoprotein Ibalpha-(1-289). Slow intrinsic binding kinetics mediate rapid platelet adhesion. J Biol Chem 2000; 275:7539.
  107. Zhou YF, Springer TA. Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor. Blood 2014; 123:1785.
  108. Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 7:308.
  109. Koedam JA, Meijers JC, Sixma JJ, Bouma BN. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. J Clin Invest 1988; 82:1236.
  110. Fay PJ, Coumans JV, Walker FJ. von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation. J Biol Chem 1991; 266:2172.
  111. Chow TW, Turner NA, Chintagumpala M, et al. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol 1998; 57:293.
  112. McGrath RT, McRae E, Smith OP, O'Donnell JS. Platelet von Willebrand factor--structure, function and biological importance. Br J Haematol 2010; 148:834.
  113. Nichols TC, Samama CM, Bellinger DA, et al. Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras. Proc Natl Acad Sci U S A 1995; 92:2455.
  114. Bonnefoy A, Yamamoto H, Thys C, et al. Shielding the front-strand beta 3 of the von Willebrand factor A1 domain inhibits its binding to platelet glycoprotein Ibalpha. Blood 2003; 101:1375.
  115. Savage B, Saldívar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84:289.
  116. Fredrickson BJ, Dong JF, McIntire LV, López JA. Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex. Blood 1998; 92:3684.
  117. Savage B, Shattil SJ, Ruggeri ZM. Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin alpha IIb beta 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor. J Biol Chem 1992; 267:11300.
  118. Da Q, Behymer M, Correa JI, et al. Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress. Blood 2014; 123:2715.
  119. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67:395.
  120. Hulstein JJ, Lenting PJ, de Laat B, et al. beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Blood 2007; 110:1483.
  121. de Laat B, de Groot PG, Derksen RH, et al. Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men. Blood 2009; 114:3656.
  122. Zhang W, Deng W, Zhou L, et al. Identification of a juxtamembrane mechanosensitive domain in the platelet mechanosensor glycoprotein Ib-IX complex. Blood 2015; 125:562.
  123. Fujimoto T, Ohara S, Hawiger J. Thrombin-induced exposure and prostacyclin inhibition of the receptor for factor VIII/von Willebrand factor on human platelets. J Clin Invest 1982; 69:1212.
  124. Timmons S, Kloczewiak M, Hawiger J. ADP-dependent common receptor mechanism for binding of von Willebrand factor and fibrinogen to human platelets. Proc Natl Acad Sci U S A 1984; 81:4935.
  125. Marguerie GA, Plow EF, Edgington TS. Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem 1979; 254:5357.
  126. Santoro SA. Adsorption of von Willebrand factor/factor VIII by the genetically distinct interstitial collagens. Thromb Res 1981; 21:689.
  127. Morton LF, Griffin B, Pepper DS, Barnes MJ. The interaction between collagens and factor VIII/von Willebrand factor: investigation of the structural requirements for interaction. Thromb Res 1983; 32:545.
  128. Wu XX, Gordon RE, Glanville RW, et al. Morphological relationships of von Willebrand factor, type VI collagen, and fibrillin in human vascular subendothelium. Am J Pathol 1996; 149:283.
  129. Ross JM, McIntire LV, Moake JL, Rand JH. Platelet adhesion and aggregation on human type VI collagen surfaces under physiological flow conditions. Blood 1995; 85:1826.
  130. Flood VH, Schlauderaff AC, Haberichter SL, et al. Crucial role for the VWF A1 domain in binding to type IV collagen. Blood 2015; 125:2297.
  131. Legendre P, Navarrete AM, Rayes J, et al. Mutations in the A3 domain of von Willebrand factor inducing combined qualitative and quantitative defects in the protein. Blood 2013; 121:2135.
  132. Bendetowicz AV, Wise RJ, Gilbert GE. Collagen-bound von Willebrand factor has reduced affinity for factor VIII. J Biol Chem 1999; 274:12300.
  133. Yee A, Gildersleeve RD, Gu S, et al. A von Willebrand factor fragment containing the D'D3 domains is sufficient to stabilize coagulation factor VIII in mice. Blood 2014; 124:445.
  134. Lollar P, Hill-Eubanks DC, Parker CG. Association of the factor VIII light chain with von Willebrand factor. J Biol Chem 1988; 263:10451.
  135. Casari C, Lenting PJ, Wohner N, et al. Clearance of von Willebrand factor. J Thromb Haemost 2013; 11 Suppl 1:202.
  136. Casari C, Du V, Wu YP, et al. Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia. Blood 2013; 122:2893.
  137. Rawley O, O'Sullivan JM, Chion A, et al. von Willebrand factor arginine 1205 substitution results in accelerated macrophage-dependent clearance in vivo. J Thromb Haemost 2015; 13:821.
  138. Wohner N, Legendre P, Casari C, et al. Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance. J Thromb Haemost 2015; 13:815.
  139. Lenting PJ, Casari C, Christophe OD, Denis CV. von Willebrand factor: the old, the new and the unknown. J Thromb Haemost 2012; 10:2428.
  140. Feng S, Liang X, Kroll MH, et al. von Willebrand factor is a cofactor in complement regulation. Blood 2015; 125:1034.