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Gene Review

VWF  -  von Willebrand factor

Homo sapiens

Synonyms: F8VWF, VWD, vWF
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Disease relevance of VWF

  • Alterations in the intrinsic properties of the GPIbalpha-VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val [1].
  • Furthermore, it could provide a tool to investigate the role of VWF in the development of thrombocytopenia in various diseases [2].
  • The level of VWF-cleaving protease activity in the patient was remarkably low (<5%) throughout her disease, even after she entered complete remission [3].
  • The patient was deficient in plasma high molecular weight (HMW)-VWF multimers during acute disease but had increased amounts of the HMW-VWF multimers during periods of remission [3].
  • In fact, VWF level also correlates with thrombosis risk and inversely with bleeding risk within the apparently healthy population [4].
  • Anti-beta(2) GPI antibodies isolated from a subset of antiphospholipid syndrome patients neutralized the beta(2) GPI-VWF interactions and thus the inhibitory activity of beta(2) GPI [5].
  • There were no thrombotic complications and none of the 18 patients with type 3 VWD developed anti-VWF or anti-FVIII antibodies [6].

Psychiatry related information on VWF


High impact information on VWF


Chemical compound and disease context of VWF


Biological context of VWF


Anatomical context of VWF


Associations of VWF with chemical compounds

  • Integrin activation (inside-out signaling) in platelets can be initiated by agonists such as von Willebrand factor (VWF) and thrombin [25].
  • This mutation, which was present in the proband and his father, predicts the substitution of Cys for Arg at position 760 of pre-pro-VWF, 4 residues before the propeptide cleavage site belonging to a consensus sequence for substrate recognition by the processing enzyme paired dibasic amino acid-cleaving enzyme (PACE)/furin [26].
  • Raised levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, as well as membrane-permeable calcium chelators, inhibited these [Ca(++)](i) oscillations and prevented stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GPIbalpha [27].
  • We conclude that reduction in the number of terminal sugars on N-linked glycan increases susceptibility of globular VWF to ADAMTS13 proteolysis and is associated with reduced plasma VWF:Ag and VWF:CB levels [20].
  • The specific inhibitory effect of anions was due to their binding to VWF, which caused a conformational change responsible for quenching the intrinsic fluorescence of the protein and reducing tyrosine exposition to bulk solvent [28].
  • VWF collagen binding activity (VWF:CB) and ristocetin cofactor activity (VWF:RCo) were significantly lower for Y/C1584 heterozygotes than for Y/Y1584 homozygotes, and a qualitative difference in Y/C1584 plasma VWF multimer profile was observed compared with that for Y/Y1584 VWF [29].
  • We demonstrate that some of the plasma VWF multimers contain surface-exposed free thiols [30].
  • We detected a marked decrease in PNA binding in post-DDAVP (1-deamino-8-D-arginine vasopressin) samples from various patients, indicating that the O-linked glycosylation profile of VWF stored in endothelial storage organelles may differ from circulating VWF [31].
  • Mutation of N1574 increased the susceptibility of VWF to ADAMTS13 proteolysis and allowed cleavage in the absence of urea [32].
  • The data indicate that in vivo C1584 and blood group O are associated with increased VWF clearance, and that clearance contributes to differing VWF level within a given blood group [33].

Physical interactions of VWF


Enzymatic interactions of VWF

  • ADAMTS-13 specifically cleaves a peptidyl bond between Y1605 and M1606 in the A2 domain of VWF [40].
  • VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP [41].
  • The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wild-type enzyme but its secretion from transfected COS-7 cells was about 14% of the wild type [42].
  • In previous reports, plasmin was shown in vitro to inactivate FVIII and cleave the vWF subunit extensively, but to cause only a modest decrease in vWF platelet-agglutinating activity [43].
  • The inability of PC2 and PC3 to cleave vWF was apparently not due to the absence of a transmembrane domain, since deletion of the transmembrane domain from PACE resulted in a secreted form which retained its propeptide processing activity within the secretory apparatus [44].

Co-localisations of VWF


Regulatory relationships of VWF

  • The results of the present study demonstrate that independent modulation of vWF and fibrinogen binding to stimulated platelets can be attained with monoclonal antibodies directed against distinct epitopes of GPIIb/IIIa [34].
  • Vasopressin-induced vWF secretion is mimicked by DDAVP and inhibited by the selective V2R antagonist SR121463B [45].
  • The finding that an amino acid polymorphism in VWF may influence susceptibility to ADAMTS13 has potentially significant implications in diverse areas [21].
  • These results establish that genetic differences in the adhesion receptor subunits alpha(2), alpha(IIb,) and GPVI can influence the phenotype of VWD type 1 [46].
  • The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve [47].

Other interactions of VWF

  • We report that DDAVP stimulates vWF secretion in a cAMP-dependent manner in HUVECs after transfection of the V2R [45].
  • Thus, binding of vWF to its major physiological ligands may promote the feedback inhibition of platelet adhesion by stimulating the cleavage of domain A2 by ADAMTS13 independent of fluid shear stress [48].
  • For tPA but not for PAI-1 and vWF, this association is independent of established risk factors [49].
  • The results suggest that vWF domain A1 inhibits the cleavage of domain A2, and that inhibition can be relieved by interaction of domain A1 with platelet GPIbalpha or certain glycosaminoglycans [48].
  • CD9 and PECAM-1 were found lining the membrane of the same granules that contained fibrinogen and vWF in their matrix [50].

Analytical, diagnostic and therapeutic context of VWF

  • Blood was drawn on admission (baseline) and 48 hours later for plasma VWF, IL-6 (both enzyme-linked immunosorbent assay [ELISA]), and CECs (CD146 immunomagnetic separation) [51].
  • Sequence analysis of VWF exon 28 indicated that increased susceptibility to proteolysis tracked with the "G" allele of the A/G polymorphism at position 24/1282, encoding the amino acid polymorphism Tyr/Cys1584 ("G" = Cys1584) [21].
  • Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the presence of both processed and unprocessed VWF in the patient's plasma, with unprocessed VWF relatively less represented [26].
  • Treatment of multimer but not protomer VWF with random homobifunctional linker BS(3) prior to reduction of intermonomer disulfide linkages and Western blotting reveals a pattern of dimer and trimer units that indicate the presence of stable intermonomer non-covalent interactions within the multimer [52].
  • However, despite no improvement in the level of VWF-cleaving protease activity, this patient had complete resolution of disease following splenectomy and commencing hemodialysis, without need for ongoing plasma therapy [3].


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  2. A novel nanobody that detects the gain-of-function phenotype of von Willebrand factor in ADAMTS13 deficiency and von Willebrand disease type 2B. Hulstein, J.J., de Groot, P.G., Silence, K., Veyradier, A., Fijnheer, R., Lenting, P.J. Blood (2005) [Pubmed]
  3. Dissociation between the level of von Willebrand factor-cleaving protease activity and disease in a patient with congenital thrombotic thrombocytopenic purpura. Snider, C.E., Moore, J.C., Warkentin, T.E., Finch, C.N., Hayward, C.P., Kelton, J.G. Am. J. Hematol. (2004) [Pubmed]
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  5. beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation. Hulstein, J.J., Lenting, P.J., de Laat, B., Derksen, R.H., Fijnheer, R., de Groot, P.G. Blood (2007) [Pubmed]
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  13. Ion channels and their functional role in vascular endothelium. Nilius, B., Droogmans, G. Physiol. Rev. (2001) [Pubmed]
  14. Expression studies on a novel type 2B variant of the von Willebrand factor gene (R1308L) characterized by defective collagen binding. Baronciani, L., Federici, A.B., Beretta, M., Cozzi, G., Canciani, M.T., Mannucci, P.M. J. Thromb. Haemost. (2005) [Pubmed]
  15. Cloning and expression of canine glycoprotein Ibalpha. Kenny, D., Morateck, P.A., Fahs, S.A., Warltier, D.C., Montgomery, R.R. Thromb. Haemost. (1999) [Pubmed]
  16. Endothelial differentiation potential of human monocyte-derived multipotential cells. Kuwana, M., Okazaki, Y., Kodama, H., Satoh, T., Kawakami, Y., Ikeda, Y. Stem Cells (2006) [Pubmed]
  17. An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees. Kunicki, T.J., Baronciani, L., Canciani, M.T., Gianniello, F., Head, S.R., Mondala, T.S., Salomon, D.R., Federici, A.B. J. Thromb. Haemost. (2006) [Pubmed]
  18. Localization of disulfide bonds in the cystine knot domain of human von Willebrand factor. Katsumi, A., Tuley, E.A., Bodó, I., Sadler, J.E. J. Biol. Chem. (2000) [Pubmed]
  19. Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of alpha IIb beta 3 engagement. Mekrache, M., Bachelot-Loza, C., Ajzenberg, N., Saci, A., Legendre, P., Baruch, D. Blood (2003) [Pubmed]
  20. Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis. O'Donnell, J.S., McKinnon, T.A., Crawley, J.T., Lane, D.A., Laffan, M.A. Blood (2005) [Pubmed]
  21. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Bowen, D.J., Collins, P.W. Blood (2004) [Pubmed]
  22. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Padilla, A., Moake, J.L., Bernardo, A., Ball, C., Wang, Y., Arya, M., Nolasco, L., Turner, N., Berndt, M.C., Anvari, B., López, J.A., Dong, J.F. Blood (2004) [Pubmed]
  23. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia. Nurden, P., Debili, N., Vainchenker, W., Bobe, R., Bredoux, R., Corvazier, E., Combrie, R., Fressinaud, E., Meyer, D., Nurden, A.T., Enouf, J. Blood (2006) [Pubmed]
  24. Von Willebrand factor targets IL-8 to Weibel-Palade bodies in an endothelial cell line. Romani de Wit, T., de Leeuw, H.P., Rondaij, M.G., de Laaf, R.T., Sellink, E., Brinkman, H.J., Voorberg, J., van Mourik, J.A. Exp. Cell Res. (2003) [Pubmed]
  25. Sequential activation of p38 and ERK pathways by cGMP-dependent protein kinase leading to activation of the platelet integrin alphaIIb beta3. Li, Z., Zhang, G., Feil, R., Han, J., Du, X. Blood (2006) [Pubmed]
  26. An Arg760Cys mutation in the consensus sequence of the von Willebrand factor propeptide cleavage site is responsible for a new von Willebrand disease variant. Casonato, A., Sartorello, F., Cattini, M.G., Pontara, E., Soldera, C., Bertomoro, A., Girolami, A. Blood (2003) [Pubmed]
  27. Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibalpha mechanoreceptor. Mazzucato, M., Pradella, P., Cozzi, M.R., De Marco, L., Ruggeri, Z.M. Blood (2002) [Pubmed]
  28. Role of chloride ions in modulation of the interaction between von Willebrand factor and ADAMTS-13. De Cristofaro, R., Peyvandi, F., Palla, R., Lavoretano, S., Lombardi, R., Merati, G., Romitelli, F., Di Stasio, E., Mannucci, P.M. J. Biol. Chem. (2005) [Pubmed]
  29. Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group. Davies, J.A., Collins, P.W., Hathaway, L.S., Bowen, D.J. Blood (2007) [Pubmed]
  30. Shear-induced disulfide bond formation regulates adhesion activity of von Willebrand factor. Choi, H., Aboulfatova, K., Pownall, H.J., Cook, R., Dong, J.F. J. Biol. Chem. (2007) [Pubmed]
  31. Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels. van Schooten, C.J., Denis, C.V., Lisman, T., Eikenboom, J.C., Leebeek, F.W., Goudemand, J., Fressinaud, E., van den Berg, H.M., de Groot, P.G., Lenting, P.J. Blood (2007) [Pubmed]
  32. N-linked glycosylation of VWF modulates its interaction with ADAMTS13. McKinnon, T.A., Chion, A.C., Millington, A.J., Lane, D.A., Laffan, M.A. Blood (2008) [Pubmed]
  33. von Willebrand factor: evidence for variable clearance in vivo according to Y/C1584 phenotype and ABO blood group. Davies, J.A., Collins, P.W., Hathaway, L.S., Bowen, D.J. J. Thromb. Haemost. (2008) [Pubmed]
  34. Independent modulation of von Willebrand factor and fibrinogen binding to the platelet membrane glycoprotein IIb/IIIa complex as demonstrated by monoclonal antibody. Lombardo, V.T., Hodson, E., Roberts, J.R., Kunicki, T.J., Zimmerman, T.S., Ruggeri, Z.M. J. Clin. Invest. (1985) [Pubmed]
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  38. Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor. Zannettino, A.C., Holding, C.A., Diamond, P., Atkins, G.J., Kostakis, P., Farrugia, A., Gamble, J., To, L.B., Findlay, D.M., Haynes, D.R. J. Cell. Physiol. (2005) [Pubmed]
  39. Requirements for cellular co-trafficking of factor VIII and von Willebrand factor to Weibel-Palade bodies. van den Biggelaar, M., Bierings, R., Storm, G., Voorberg, J., Mertens, K. J. Thromb. Haemost. (2007) [Pubmed]
  40. VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Kokame, K., Matsumoto, M., Fujimura, Y., Miyata, T. Blood (2004) [Pubmed]
  41. Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light. Yarranton, H., Lawrie, A.S., Mackie, I.J., Pinkoski, L., Corash, L., Machin, S.J. Transfusion (2005) [Pubmed]
  42. Congenital thrombotic thrombocytopenic purpura in association with a mutation in the second CUB domain of ADAMTS13. Pimanda, J.E., Maekawa, A., Wind, T., Paxton, J., Chesterman, C.N., Hogg, P.J. Blood (2004) [Pubmed]
  43. Effects of plasmin on von Willebrand factor multimers. Degradation in vitro and stimulation of release in vivo. Hamilton, K.K., Fretto, L.J., Grierson, D.S., McKee, P.A. J. Clin. Invest. (1985) [Pubmed]
  44. Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes. Rehemtulla, A., Kaufman, R.J. Blood (1992) [Pubmed]
  45. Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. Kaufmann, J.E., Oksche, A., Wollheim, C.B., Günther, G., Rosenthal, W., Vischer, U.M. J. Clin. Invest. (2000) [Pubmed]
  46. An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees. Kunicki, T.J., Federici, A.B., Salomon, D.R., Koziol, J.A., Head, S.R., Mondala, T.S., Chismar, J.D., Baronciani, L., Canciani, M.T., Peake, I.R. Blood (2004) [Pubmed]
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  48. Binding of platelet glycoprotein Ibalpha to von Willebrand factor domain A1 stimulates the cleavage of the adjacent domain A2 by ADAMTS13. Nishio, K., Anderson, P.J., Zheng, X.L., Sadler, J.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  49. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Thögersen, A.M., Jansson, J.H., Boman, K., Nilsson, T.K., Weinehall, L., Huhtasaari, F., Hallmans, G. Circulation (1998) [Pubmed]
  50. Platelet alpha-granule and plasma membrane share two new components: CD9 and PECAM-1. Cramer, E.M., Berger, G., Berndt, M.C. Blood (1994) [Pubmed]
  51. Circulating endothelial cells, von Willebrand factor, interleukin-6, and prognosis in patients with acute coronary syndromes. Lee, K.W., Lip, G.Y., Tayebjee, M., Foster, W., Blann, A.D. Blood (2005) [Pubmed]
  52. Solution structure of human von Willebrand factor studied using small angle neutron scattering. Singh, I., Shankaran, H., Beauharnois, M.E., Xiao, Z., Alexandridis, P., Neelamegham, S. J. Biol. Chem. (2006) [Pubmed]
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