Semin Thromb Hemost 2014; 40(01): 017-027
DOI: 10.1055/s-0033-1363155
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

von Willebrand Factor: Form for Function

Andrew Yee
1   Life Sciences Institute, University of Michigan, Ann Arbor, Michigan
,
Colin A. Kretz
1   Life Sciences Institute, University of Michigan, Ann Arbor, Michigan
› Author Affiliations
Further Information

Publication History

Publication Date:
13 December 2013 (online)

Abstract

The mechanisms by which von Willebrand factor (VWF) achieves hemostasis lie in its structure. Whereas low-molecular-weight forms have diminished hemostatic potential, ultralarge VWF (ULVWF) in excess is potentially thrombogenic. VWF comprises many subunits, which themselves comprise many repeated domains/assemblies possessing characteristic function(s). Organization of these domains/assemblies into a multimeric structure effectively links and replicates these functions. Each domain/assembly influences the synthesis, assembly, secretion, or hemostatic potential of plasma VWF. The C-terminal CT/CK domain mediates dimerization of VWF subunits in the endoplasmic reticulum, while the N-terminal D1D2 assemblies catalyzes disulfide binding between juxtaposed D3 assemblies in the trans-Golgi, creating multimers. The pH-sensitive domains (A2–CT/CK) allow ULVWF multimers to orderly pack into tubules that unravel upon secretion into the circulation. Hemodynamic forces regulate the conformation of the A2 domain and thus, its accessibility to proteolytic enzyme(s) that regulate VWF's hemostatic potential. Binding to the VWF D'D3 assemblies stabilizes coagulation factor VIII. The VWF A1 and A3 domains facilitate platelet capture onto exposed collagen(s) at sites of vascular injury. Our deeper understanding of VWF provided through the recent growth in VWF structure-function studies may potentially guide novel therapeutics for clotting or bleeding disorders.

 
  • References

  • 1 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117 (11) 1449-1459
  • 2 Sadler JE, Budde U, Eikenboom JC , et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
  • 3 Sanders YV, Eikenboom J, de Wee EM , et al; WiN Study Group. Reduced prevalence of arterial thrombosis in von Willebrand disease. J Thromb Haemost 2013; 11 (5) 845-854
  • 4 Qureshi W, Hassan S, Dabak V, Kuriakose P. Thrombosis in VonWillebrand disease. Thromb Res 2012; 130 (5) e255-e258
  • 5 Westein E, van der Meer AD, Kuijpers MJ, Frimat JP, van den Berg A, Heemskerk JW. Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner. Proc Natl Acad Sci U S A 2013; 110 (4) 1357-1362
  • 6 Nesbitt WS, Westein E, Tovar-Lopez FJ , et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation. Nat Med 2009; 15 (6) 665-673
  • 7 Bark Jr DL, Ku DN. Wall shear over high degree stenoses pertinent to atherothrombosis. J Biomech 2010; 43 (15) 2970-2977
  • 8 Kim J, Zhang CZ, Zhang X, Springer TA. A mechanically stabilized receptor-ligand flex-bond important in the vasculature. Nature 2010; 466 (7309) 992-995
  • 9 Colace TV, Diamond SL. Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow. Arterioscler Thromb Vasc Biol 2013; 33 (1) 105-113
  • 10 International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on von Willebrand Factor . ISTH-SSC VWF Online Database (VWFdb). Available at: http://www.ragtimedesign.com/vwf/mutation/ . Accessed August 13, 2013
  • 11 Larsen DM, Haberichter SL, Gill JC, Shapiro AD, Flood VH. Variability in platelet- and collagen-binding defects in type 2M von Willebrand disease. Haemophilia 2013; 19 (4) 590-594
  • 12 Flood VH, Gill JC, Christopherson PA , et al. Comparison of type I, type III and type VI collagen binding assays in diagnosis of von Willebrand disease. J Thromb Haemost 2012; 10 (7) 1425-1432
  • 13 Denis C, Methia N, Frenette PS , et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci U S A 1998; 95 (16) 9524-9529
  • 14 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 (4706) 1401-1406
  • 15 Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci U S A 1985; 82 (19) 6394-6398
  • 16 Shelton-Inloes BB, Titani K, Sadler JE. cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms. Biochemistry 1986; 25 (11) 3164-3171
  • 17 Shelton-Inloes BB, Broze Jr GJ, Miletich JP, Sadler JE. Evolution of human von Willebrand factor: cDNA sequence polymorphisms, repeated domains, and relationship to von Willebrand antigen II. Biochem Biophys Res Commun 1987; 144 (2) 657-665
  • 18 Meitinger T, Meindl A, Bork P , et al. Molecular modelling of the Norrie disease protein predicts a cystine knot growth factor tertiary structure. Nat Genet 1993; 5 (4) 376-380
  • 19 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424
  • 20 Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA. Sequence and structure relationships within von Willebrand factor. Blood 2012; 120 (2) 449-458
  • 21 Marti T, Rösselet SJ, Titani K, Walsh KA. Identification of disulfide-bridged substructures within human von Willebrand factor. Biochemistry 1987; 26 (25) 8099-8109
  • 22 Zhou YF, Eng ET, Nishida N, Lu C, Walz T, Springer TA. A pH-regulated dimeric bouquet in the structure of von Willebrand factor. EMBO J 2011; 30 (19) 4098-4111
  • 23 Zhu L, Lee P, Yu D, Tao S, Chen Y. Cloning and characterization of human MUC19 gene. Am J Respir Cell Mol Biol 2011; 45 (2) 348-358
  • 24 Katsumi A, Tuley EA, Bodó I, Sadler JE. Localization of disulfide bonds in the cystine knot domain of human von Willebrand factor. J Biol Chem 2000; 275 (33) 25585-25594
  • 25 Sun PD, Davies DR. The cystine-knot growth-factor superfamily. Annu Rev Biophys Biomol Struct 1995; 24: 269-291
  • 26 Vitt UA, Hsu SY, Hsueh AJ. Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol 2001; 15 (5) 681-694
  • 27 Voorberg J, Fontijn R, Calafat J, Janssen H, van Mourik JA, Pannekoek H. Assembly and routing of von Willebrand factor variants: the requirements for disulfide-linked dimerization reside within the carboxy-terminal 151 amino acids. J Cell Biol 1991; 113 (1) 195-205
  • 28 Purvis AR, Sadler JE. A covalent oxidoreductase intermediate in propeptide-dependent von Willebrand factor multimerization. J Biol Chem 2004; 279 (48) 49982-49988
  • 29 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 (2) 482-487
  • 30 Berriman JA, Li S, Hewlett LJ , et al. Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells. Proc Natl Acad Sci U S A 2009; 106 (41) 17407-17412
  • 31 Purvis AR, Gross J, Dang LT , et al. Two Cys residues essential for von Willebrand factor multimer assembly in the Golgi. Proc Natl Acad Sci U S A 2007; 104 (40) 15647-15652
  • 32 Dang LT, Purvis AR, Huang RH, Westfield LA, Sadler JE. Phylogenetic and functional analysis of histidine residues essential for pH-dependent multimerization of von Willebrand factor. J Biol Chem 2011; 286 (29) 25763-25769
  • 33 Wise RJ, Barr PJ, Wong PA, Kiefer MC, Brake AJ, Kaufman RJ. Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. Proc Natl Acad Sci U S A 1990; 87 (23) 9378-9382
  • 34 Vischer UM, Wagner DD. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel-Palade bodies. Blood 1994; 83 (12) 3536-3544
  • 35 Hilbert L, Nurden P, Caron C , et al; INSERM Network on Molecular Abnormalities in von Willebrand Disease. Type 2N von Willebrand disease due to compound heterozygosity for R854Q and a novel R763G mutation at the cleavage site of von Willebrand factor propeptide. Thromb Haemost 2006; 96 (3) 290-294
  • 36 Wise RJ, Dorner AJ, Krane M, Pittman DD, Kaufman RJ. The role of von Willebrand factor multimers and propeptide cleavage in binding and stabilization of factor VIII. J Biol Chem 1991; 266 (32) 21948-21955
  • 37 Casonato A, Sartorello F, Cattini MG , et al. An Arg760Cys mutation in the consensus sequence of the von Willebrand factor propeptide cleavage site is responsible for a new von Willebrand disease variant. Blood 2003; 101 (1) 151-156
  • 38 Valentijn KM, Eikenboom J. Weibel-Palade bodies: a window to von Willebrand disease. J Thromb Haemost 2013; 11 (4) 581-592
  • 39 Wise RJ, Pittman DD, Handin RI, Kaufman RJ, Orkin SH. The propeptide of von Willebrand factor independently mediates the assembly of von Willebrand multimers. Cell 1988; 52 (2) 229-236
  • 40 Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes. Blood 2000; 96 (5) 1808-1815
  • 41 Nightingale T, Cutler D. The secretion of von Willebrand factor from endothelial cells; an increasingly complicated story. J Thromb Haemost 2013; 11 (Suppl. 01) 192-201
  • 42 Rosenberg JB, Haberichter SL, Jozwiak MA , et al. The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF. Blood 2002; 100 (5) 1699-1706
  • 43 Nilsson IM, Blomback M, Blomback B. v. Willebrand's disease in Sweden; its pathogenesis and treatment. Acta Med Scand 1959; 164: 263-278
  • 44 Vlot AJ, Koppelman SJ, van den Berg MH, Bouma BN, Sixma JJ. The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor. Blood 1995; 85 (11) 3150-3157
  • 45 Saenko EL, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von willebrand factor. J Biol Chem 1997; 272 (29) 18007-18014
  • 46 Saenko EL, Scandella D. A mechanism for inhibition of factor VIII binding to phospholipid by von Willebrand factor. J Biol Chem 1995; 270 (23) 13826-13833
  • 47 Bendetowicz AV, Morris JA, Wise RJ, Gilbert GE, Kaufman RJ. Binding of factor VIII to von willebrand factor is enabled by cleavage of the von Willebrand factor propeptide and enhanced by formation of disulfide-linked multimers. Blood 1998; 92 (2) 529-538
  • 48 Vlot AJ, Koppelman SJ, Meijers JC , et al. Kinetics of factor VIII-von Willebrand factor association. Blood 1996; 87 (5) 1809-1816
  • 49 O'Brien LA, Sutherland JJ, Hegadorn C , et al. A novel type 2A (Group II) von Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers. J Thromb Haemost 2004; 2 (7) 1135-1142
  • 50 Turecek PL, Schrenk G, Rottensteiner H , et al. Structure and function of a recombinant von Willebrand factor drug candidate. Semin Thromb Hemost 2010; 36 (5) 510-521
  • 51 Hollestelle MJ, Lai KW, van Deuren M , et al. Cleavage of von Willebrand factor by granzyme M destroys its factor VIII binding capacity. PLoS ONE 2011; 6 (9) e24216
  • 52 Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262 (18) 8443-8446
  • 53 Necina R, Amatschek K, Schallaun E, Schwinn H, Josic D, Jungbauer A. Peptide affinity chromatography of human clotting factor VIII. Screening of the vWF-binding domain. J Chromatogr B Biomed Sci Appl 1998; 715 (1) 191-201
  • 54 Jorieux S, Fressinaud E, Goudemand J, Gaucher C, Meyer D, Mazurier C. Conformational changes in the D' domain of von Willebrand factor induced by CYS 25 and CYS 95 mutations lead to factor VIII binding defect and multimeric impairment. Blood 2000; 95 (10) 3139-3145
  • 55 Castro-Núñez L, Bloem E, Boon-Spijker MG , et al. Distinct roles of Ser-764 and Lys-773 at the N terminus of von Willebrand factor in complex assembly with coagulation factor VIII. J Biol Chem 2013; 288 (1) 393-400
  • 56 Smith DE, Babcock HP, Chu S. Single-polymer dynamics in steady shear flow. Science 1999; 283 (5408) 1724-1727
  • 57 Sing CE, Alexander-Katz A. Elongational flow induces the unfolding of von Willebrand factor at physiological flow rates. Biophys J 2010; 98 (9) L35-L37
  • 58 Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 324 (5932) 1330-1334
  • 59 Themistou E, Singh I, Shang C, Balu-Iyer SV, Alexandridis P, Neelamegham S. Application of fluorescence spectroscopy to quantify shear-induced protein conformation change. Biophys J 2009; 97 (9) 2567-2576
  • 60 Schneider SW, Nuschele S, Wixforth A , et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A 2007; 104 (19) 7899-7903
  • 61 Wagner DD, Urban-Pickering M, Marder VJ. Von Willebrand protein binds to extracellular matrices independently of collagen. Proc Natl Acad Sci U S A 1984; 81 (2) 471-475
  • 62 Pareti FI, Niiya K, McPherson JM, Ruggeri ZM. Isolation and characterization of two domains of human von Willebrand factor that interact with fibrillar collagen types I and III. J Biol Chem 1987; 262 (28) 13835-13841
  • 63 Morales LD, Martin C, Cruz MA. The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen. J Thromb Haemost 2006; 4 (2) 417-425
  • 64 Bonnefoy A, Romijn RA, Vandervoort PA, VAN Rompaey I, Vermylen J, Hoylaerts MF. von Willebrand factor A1 domain can adequately substitute for A3 domain in recruitment of flowing platelets to collagen. J Thromb Haemost 2006; 4 (10) 2151-2161
  • 65 Rand JH, Patel ND, Schwartz E, Zhou SL, Potter BJ. 150-kD von Willebrand factor binding protein extracted from human vascular subendothelium is type VI collagen. J Clin Invest 1991; 88 (1) 253-259
  • 66 Mazzucato M, Spessotto P, Masotti A , et al. Identification of domains responsible for von Willebrand factor type VI collagen interaction mediating platelet adhesion under high flow. J Biol Chem 1999; 274 (5) 3033-3041
  • 67 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 (12) 4033-4039
  • 68 Brondijk TH, Bihan D, Farndale RW, Huizinga EG. Implications for collagen I chain registry from the structure of the collagen von Willebrand factor A3 domain complex. Proc Natl Acad Sci U S A 2012; 109 (14) 5253-5258
  • 69 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 (11) 2135-2143
  • 70 Yago T, Lou J, Wu T , et al. Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J Clin Invest 2008; 118 (9) 3195-3207
  • 71 Versteeg HH, Heemskerk JW, Levi M, Reitsma PH. New fundamentals in hemostasis. Physiol Rev 2013; 93 (1) 327-358
  • 72 Arya M, Anvari B, Romo GM , et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99 (11) 3971-3977
  • 73 Samady H, Eshtehardi P, McDaniel MC , et al. Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease. Circulation 2011; 124 (7) 779-788
  • 74 Huizinga EG, Tsuji S, Romijn RA , et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 2002; 297 (5584) 1176-1179
  • 75 Emsley J, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand Factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273 (17) 10396-10401
  • 76 Yee A, Tan F-L, Ginsburg D. Functional display of platelet-binding VWF fragments on filamentous bacteriophage. PLoS ONE 2013; 8 (9) e73518
  • 77 Ulrichts H, Udvardy M, Lenting PJ , et al. Shielding of the A1 domain by the D'D3 domains of von Willebrand factor modulates its interaction with platelet glycoprotein Ib-IX-V. J Biol Chem 2006; 281 (8) 4699-4707
  • 78 Nowak AA, Canis K, Riddell A, Laffan MA, McKinnon TA. O-linked glycosylation of von Willebrand factor modulates the interaction with platelet receptor glycoprotein Ib under static and shear stress conditions. Blood 2012; 120 (1) 214-222
  • 79 Auton M, Sowa KE, Behymer M, Cruz MA. N-terminal flanking region of A1 domain in von Willebrand factor stabilizes structure of A1A2A3 complex and modulates platelet activation under shear stress. J Biol Chem 2012; 287 (18) 14579-14585
  • 80 Nakayama T, Matsushita T, Dong Z , et al. Identification of the regulatory elements of the human von Willebrand factor for binding to platelet GPIb. Importance of structural integrity of the regions flanked by the CYS1272-CYS1458 disulfide bond. J Biol Chem 2002; 277 (24) 22063-22072
  • 81 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451 (7181) 914-918
  • 82 Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol 2008; 28 (3) 403-412
  • 83 Fukuda K, Doggett T, Laurenzi IJ, Liddington RC, Diacovo TG. The snake venom protein botrocetin acts as a biological brace to promote dysfunctional platelet aggregation. Nat Struct Mol Biol 2005; 12 (2) 152-159
  • 84 Flood VH, Friedman KD, Gill JC , et al. Limitations of the ristocetin cofactor assay in measurement of von Willebrand factor function. J Thromb Haemost 2009; 7 (11) 1832-1839
  • 85 Dong JF, Berndt MC, Schade A, McIntire LV, Andrews RK, López JA. Ristocetin-dependent, but not botrocetin-dependent, binding of von Willebrand factor to the platelet glycoprotein Ib-IX-V complex correlates with shear-dependent interactions. Blood 2001; 97 (1) 162-168
  • 86 Brinkhous KM, Read MS, Fricke WA, Wagner RH. Botrocetin (venom coagglutinin): reaction with a broad spectrum of multimeric forms of factor VIII macromolecular complex. Proc Natl Acad Sci U S A 1983; 80 (5) 1463-1466
  • 87 Jacobi PM, Gill JC, Flood VH, Jakab DA, Friedman KD, Haberichter SL. Intersection of mechanisms of type 2A VWD through defects in VWF multimerization, secretion, ADAMTS-13 susceptibility, and regulated storage. Blood 2012; 119 (19) 4543-4553
  • 88 Favaloro EJ, Mohammed S, McDonald J. Validation of improved performance characteristics for the automated von Willebrand factor ristocetin cofactor activity assay. J Thromb Haemost 2010; 8 (12) 2842-2844
  • 89 Flood VH, Gill JC, Morateck PA , et al. Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD. Blood 2011; 117 (6) e67-e74
  • 90 Sugimoto M, Matsui H, Mizuno T , et al. Mural thrombus generation in type 2A and 2B von Willebrand disease under flow conditions. Blood 2003; 101 (3) 915-920
  • 91 Pruss CM, Golder M, Bryant A, Hegadorn C, Haberichter S, Lillicrap D. Use of a mouse model to elucidate the phenotypic effects of the von Willebrand factor cleavage mutants, Y1605A/M1606A and R1597W. J Thromb Haemost 2012; 10 (5) 940-950
  • 92 Golder M, Pruss CM, Hegadorn C , et al. Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions. Blood 2010; 115 (23) 4862-4869
  • 93 Banno F, Kokame K, Okuda T , et al. Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura. Blood 2006; 107 (8) 3161-3166
  • 94 Chen J, Reheman A, Gushiken FC , et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 2011; 121 (2) 593-603
  • 95 Favaloro EJ, Bonar R, Chapman K, Meiring M, Funk Adcock D. Differential sensitivity of von Willebrand factor (VWF) 'activity' assays to large and small VWF molecular weight forms: a cross-laboratory study comparing ristocetin cofactor, collagen-binding and mAb-based assays. J Thromb Haemost 2012; 10 (6) 1043-1054
  • 96 Turner N, Nolasco L, Moake J. Generation and breakdown of soluble ultralarge von Willebrand factor multimers. Semin Thromb Hemost 2012; 38 (1) 38-46
  • 97 Fowler WE, Fretto LJ, Hamilton KK, Erickson HP, McKee PA. Substructure of human von Willebrand factor. J Clin Invest 1985; 76 (4) 1491-1500
  • 98 Wang JW, Bouwens EA, Pintao MC , et al. Analysis of the storage and secretion of von Willebrand factor in blood outgrowth endothelial cells derived from patients with von Willebrand disease. Blood 2013; 121 (14) 2762-2772
  • 99 Moake JL, Rudy CK, Troll JH , et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307 (23) 1432-1435
  • 100 Levy GG, Nichols WC, Lian EC , et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413 (6855) 488-494
  • 101 Zheng X, Chung D, Takayama TK, Majerus EM, Sadler JE, Fujikawa K. Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura. J Biol Chem 2001; 276 (44) 41059-41063
  • 102 Gerritsen HE, Robles R, Lämmle B, Furlan M. Partial amino acid sequence of purified von Willebrand factor-cleaving protease. Blood 2001; 98 (6) 1654-1661
  • 103 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 (6) 1662-1666
  • 104 Soejima K, Mimura N, Hirashima M , et al. A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease?. J Biochem 2001; 130 (4) 475-480
  • 105 Uemura M, Tatsumi K, Matsumoto M , et al. Localization of ADAMTS13 to the stellate cells of human liver. Blood 2005; 106 (3) 922-924
  • 106 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 (10) 4223-4234
  • 107 Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87 (10) 4235-4244
  • 108 Chen J, Ling M, Fu X, López JA, Chung DW. Simultaneous exposure of sites in von Willebrand factor for glycoprotein Ib binding and ADAMTS13 cleavage: studies with ristocetin. Arterioscler Thromb Vasc Biol 2012; 32 (11) 2625-2630
  • 109 Xu AJ, Springer TA. Calcium stabilizes the von Willebrand factor A2 domain by promoting refolding. Proc Natl Acad Sci U S A 2012; 109 (10) 3742-3747
  • 110 Gao W, Anderson PJ, Majerus EM, Tuley EA, Sadler JE. Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc Natl Acad Sci U S A 2006; 103 (50) 19099-19104
  • 111 de Groot R, Lane DA, Crawley JT. The ADAMTS13 metalloprotease domain: roles of subsites in enzyme activity and specificity. Blood 2010; 116 (16) 3064-3072
  • 112 Ying J, Ling Y, Westfield LA, Sadler JE, Shao JY. Unfolding the A2 domain of von Willebrand factor with the optical trap. Biophys J 2010; 98 (8) 1685-1693
  • 113 Wiita AP, Ainavarapu SR, Huang HH, Fernandez JM. Force-dependent chemical kinetics of disulfide bond reduction observed with single-molecule techniques. Proc Natl Acad Sci U S A 2006; 103 (19) 7222-7227
  • 114 Zhang Q, Zhou YF, Zhang CZ, Zhang X, Lu C, Springer TA. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci U S A 2009; 106 (23) 9226-9231
  • 115 Zhou M, Dong X, Baldauf C , et al. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13. Blood 2011; 117 (17) 4623-4631
  • 116 Jakobi AJ, Mashaghi A, Tans SJ, Huizinga EG. Calcium modulates force sensing by the von Willebrand factor A2 domain. Nat Commun 2011; 2: 385
  • 117 Luken BM, Winn LY, Emsley J, Lane DA, Crawley JT. The importance of vicinal cysteines, C1669 and C1670, for von Willebrand factor A2 domain function. Blood 2010; 115 (23) 4910-4913
  • 118 Xu AJ, Springer TA. Mechanisms by which von Willebrand disease mutations destabilize the A2 domain. J Biol Chem 2013; 288 (9) 6317-6324
  • 119 Gandhi C, Motto DG, Jensen M, Lentz SR, Chauhan AK. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood 2012; 120 (26) 5224-5230
  • 120 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 (26) 5217-5223
  • 121 Crawley JT, de Groot R, Xiang Y, Luken BM, Lane DA. Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor. Blood 2011; 118 (12) 3212-3221
  • 122 Zanardelli S, Chion AC, Groot E , et al. A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF. Blood 2009; 114 (13) 2819-2828
  • 123 Liu S, Ashok B, Muthukumar M. Brownian dynamics simulations of bead-rod-chain in simple shear flow and elongational flow. Polymer (Guildf) 2004; 45 (4) 1383-1389
  • 124 Fetsko SW, Cummings PT. Brownian Dynamics Simulation of Bead-Spring Chain Models for Dilute Polymer-Solutions in Elongational Flow. J Rheol (NYNY) 1995; 39 (2) 285-299
  • 125 Shim K, Anderson PJ, Tuley EA, Wiswall E, Sadler JE. Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 2008; 111 (2) 651-657
  • 126 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 (42) 36361-36367
  • 127 Rayes J, Hollestelle MJ, Legendre P , et al. Mutation and ADAMTS13-dependent modulation of disease severity in a mouse model for von Willebrand disease type 2B. Blood 2010; 115 (23) 4870-4877
  • 128 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 (39) 32459-32466
  • 129 Chen J, Chung DW, Le J, Ling M, Konkle BA, López JA. Normal cleavage of von Willebrand factor by ADAMTS-13 in the absence of factor VIII in patients with severe hemophilia A. J Thromb Haemost 2013; 11 (9) 1769-1772
  • 130 Chen J, Fu X, Wang Y , et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood 2010; 115 (3) 706-712
  • 131 Fu X, Chen J, Gallagher R, Zheng Y, Chung DW, López JA. Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region. Blood 2011; 118 (19) 5283-5291
  • 132 Lancellotti S, De Filippis V, Pozzi N , et al. Oxidized von Willebrand factor is efficiently cleaved by serine proteases from primary granules of leukocytes: divergence from ADAMTS-13. J Thromb Haemost 2011; 9 (8) 1620-1627
  • 133 Raife TJ, Cao W, Atkinson BS , et al. Leukocyte proteases cleave von Willebrand factor at or near the ADAMTS13 cleavage site. Blood 2009; 114 (8) 1666-1674
  • 134 Wohner N, Kovács A, Machovich R, Kolev K. Modulation of the von Willebrand factor-dependent platelet adhesion through alternative proteolytic pathways. Thromb Res 2012; 129 (4) e41-e46
  • 135 Huizinga EG, Martijn van der Plas R, Kroon J, Sixma JJ, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 5 (9) 1147-1156