Download PDF
Hamostaseologie 2021; 41(01): 063-068
DOI: 10.1055/a-1334-8002
Review Article

Functional Roles of the von Willebrand Factor Propeptide

Orla Rawley
1   Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, Ontario, Canada
,
David Lillicrap
1   Department of Pathology and Molecular Medicine, Richardson Laboratory, Queen's University, Kingston, Ontario, Canada
› Author Affiliations Funding D.L. is the recipient of a Canada Research Chair in Molecular Hemostasis. The authors' research concerning the VWFpp is funded in part by the Canadian Institutes of Health Research Foundation Grant (FDN154285).
› Further Information
Also available at
   Permissions and Reprints

Abstract

The primary polypeptide sequence of von Willebrand factor (VWF) includes an N-terminal 741-amino acid VWF propeptide (VWFpp). In cells expressing VWF, the VWFpp performs two critical functions. In the Golgi, VWFpp mediates the intermolecular disulfide linkages that generate high-molecular-weight VWF multimers. Subsequently, the VWFpp, which is proteolytically cleaved from mature VWF by furin, functions to generate the endothelial storage organelles (Weibel-Palade bodies) in which VWF and a distinct collection of proteins are stored, and from where they undergo regulated secretion from the endothelium. The VWFpp is secreted from endothelial cells as dimers and circulates in plasma with at least some of the dimers associating with a noncovalent manner with the D′D3 domain of mature VWF. The VWFpp has a half-life of 2 to 3 hours in plasma, but to date no extracellular function has been determined for the molecule. Nevertheless, its large size and several biologically interesting structural features (two sets of vicinal cysteines and an RGD sequence) suggest that there may be roles that the VWFpp plays in hemostasis or associated physiological processes such as angiogenesis or wound repair.

Keywords

von Willebrand disease - von Willebrand factor - propeptide - VWFpp


Publication History

Received: 02 November 2020

Accepted: 10 December 2020

Article published online:
15 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ruggeri ZM. The role of von Willebrand factor in thrombus formation. Thromb Res 2007; 120 (01) (Suppl. 01) S5-S9
    CrossrefPubMedSearch in Google Scholar
  • 2 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 (4753): 995-998
    CrossrefPubMedSearch in Google Scholar
  • 3 Kawai Y, Montgomery RR. Endothelial cell processing of von Willebrand proteins. Ann N Y Acad Sci 1987; 509: 60-70
    CrossrefPubMedSearch in Google Scholar
  • 4 Haberichter SL. von Willebrand factor propeptide: biology and clinical utility. Blood 2015; 126 (15) 1753-1761
    CrossrefPubMedSearch in Google Scholar
  • 5 Sadler JE. von Willebrand factor assembly and secretion. J Thromb Haemost 2009; 7 (Suppl. 01) 24-27
    CrossrefPubMedSearch in Google Scholar
  • 6 Lenting PJ, Christophe OD, Denis CV. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends. Blood 2015; 125 (13) 2019-2028
    CrossrefPubMedSearch in Google Scholar
  • 7 Madabhushi SR, Shang C, Dayananda KM. et al. von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. Blood 2012; 119 (20) 4769-4778
    CrossrefPubMedSearch in Google Scholar
  • 8 Canis K, McKinnon TAJ, Nowak A. et al. Mapping the N-glycome of human von Willebrand factor. Biochem J 2012; 447 (02) 217-228
    CrossrefPubMedSearch in Google Scholar
  • 9 McKinnon TAJ, Goode EC, Birdsey GM. et al. Specific N-linked glycosylation sites modulate synthesis and secretion of von Willebrand factor. Blood 2010; 116 (04) 640-648
    CrossrefPubMedSearch in Google Scholar
  • 10 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 (10) 2885-2890
    CrossrefPubMedSearch in Google Scholar
  • 11 Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci U S A 1992; 89 (08) 3531-3535
    CrossrefPubMedSearch in Google Scholar
  • 12 Purvis AR, Sadler JE. A covalent oxidoreductase intermediate in propeptide-dependent von Willebrand factor multimerization. J Biol Chem 2004; 279 (48) 49982-49988
    CrossrefPubMedSearch in Google Scholar
  • 13 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 (02) 229-236
    CrossrefPubMedSearch in Google Scholar
  • 14 Hampshire DJ, Goodeve AC. The international society on thrombosis and haematosis von Willebrand disease database: an update. Semin Thromb Hemost 2011; 37 (05) 470-479
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 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 (05) 1699-1706
    CrossrefPubMedSearch in Google Scholar
  • 16 Lanke E, Kristoffersson AC, Philips M, Holmberg L, Lethagen S. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease. Thromb Haemost 2008; 100 (02) 211-216
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Haberichter SL, Budde U, Obser T, Schneppenheim S, Wermes C, Schneppenheim R. The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF. Blood 2010; 115 (22) 4580-4587
    CrossrefPubMedSearch in Google Scholar
  • 18 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
    CrossrefPubMedSearch in Google Scholar
  • 19 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007; 109 (01) 112-121
    CrossrefPubMedSearch in Google Scholar
  • 20 Baronciani L, Federici AB, Cozzi G. et al. Expression studies of missense mutations p.D141Y, p.C275S located in the propeptide of von Willebrand factor in patients with type 3 von Willebrand disease. Haemophilia 2008; 14 (03) 549-555
    CrossrefPubMedSearch in Google Scholar
  • 21 Bowman M, Tuttle A, Notley C. et al; Association of Hemophilia Clinic Directors of Canada. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost 2013; 11 (03) 512-520
    CrossrefPubMedSearch in Google Scholar
  • 22 Wagner DD, Saffaripour S, Bonfanti R. et al. Induction of specific storage organelles by von Willebrand factor propolypeptide. Cell 1991; 64 (02) 403-413
    CrossrefPubMedSearch in Google Scholar
  • 23 Mourik M, Eikenboom J. Lifecycle of Weibel-Palade bodies. Hamostaseologie 2017; 37 (01) 13-24
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Haberichter SL, Jozwiak MA, Rosenberg JB, Christopherson PA, Montgomery RR. The von Willebrand factor propeptide (VWFpp) traffics an unrelated protein to storage. Arterioscler Thromb Vasc Biol 2002; 22 (06) 921-926
    CrossrefPubMedSearch in Google Scholar
  • 25 Haberichter SL, Jacobi P, Montgomery RR. Critical independent regions in the VWF propeptide and mature VWF that enable normal VWF storage. Blood 2003; 101 (04) 1384-1391
    CrossrefPubMedSearch in Google Scholar
  • 26 Chen CH, Lo RW, Urban D, Pluthero FG, Kahr WHA. α-Granule biogenesis: from disease to discovery. Platelets 2017; 28 (02) 147-154
    CrossrefPubMedSearch in Google Scholar
  • 27 Takagi J, Fujisawa T, Sekiya F, Saito Y. Collagen-binding domain within bovine propolypeptide of von Willebrand factor. J Biol Chem 1991; 266 (09) 5575-5579
    CrossrefPubMedSearch in Google Scholar
  • 28 Rawley O, Brown C, Dwyer C, Nesbitt K, Lillicrap D. Clearance of mouse VWF propeptide is mediated by stabilin-2 and is regulated by N-linked glycan expression. Res Pract Thromb Haemost 2018; 2 (S1): 1-368
    PubMedSearch in Google Scholar
  • 29 Rawley O, Nesbitt K, Dwyer C, Swystun L, Lillicrap D. The scavenger receptor SCARA5 mediates clearance of the von Willebrand factor propeptide. Res Pract Thromb Haemost 2020; 4 (S2): 1-1311
    PubMedSearch in Google Scholar
  • 30 Desch KC, Ozel AB, Halvorsen M. et al. Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease. Blood 2020; 136 (05) 533-541
    CrossrefPubMedSearch in Google Scholar
  • 31 van Mourik JA, Romani de Wit T. Von Willebrand factor propeptide in vascular disorders. Thromb Haemost 2001; 86 (01) 164-171
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Haberichter SL, Castaman G, Budde U. 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). Blood 2008; 111 (10) 4979-4985
    CrossrefPubMedSearch in Google Scholar
  • 33 Haberichter SL, Balistreri M, Christopherson P. et al. Assay of the von Willebrand factor (VWF) propeptide to identify patients with type 1 von Willebrand disease with decreased VWF survival. Blood 2006; 108 (10) 3344-3351
    CrossrefPubMedSearch in Google Scholar
  • 34 Sanders YV, Groeneveld D, Meijer K. et al; WiN Study Group. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015; 125 (19) 3006-3013
    CrossrefPubMedSearch in Google Scholar
  • 35 Haberichter SL. VWF propeptide in defining VWD subtypes. Blood 2015; 125 (19) 2882-2883
    CrossrefPubMedSearch in Google Scholar
  • 36 Hubbard AR, Hamill M, Eikenboom HCJ, Montgomery RR, Mertens K, Haberichter S. SSC Sub-Committee on von Willebrand Factor of ISTH. Standardization of von Willebrand factor propeptide: value assignment to the WHO 6th IS Factor VIII/von Willebrand factor, plasma (07/316). J Thromb Haemost 2012; 10 (05) 959-960
    CrossrefPubMedSearch in Google Scholar
  • 37 Sharma R, Flood VH. Advances in the diagnosis and treatment of Von Willebrand disease. Blood 2017; 130 (22) 2386-2391
    CrossrefPubMedSearch in Google Scholar
  • 38 Mannucci PM. New therapies for von Willebrand disease. Blood Adv 2019; 3 (21) 3481-3487
    CrossrefPubMedSearch in Google Scholar
  • 39 Gill JC, Castaman G, Windyga J. et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood 2015; 126 (17) 2038-2046
    CrossrefPubMedSearch in Google Scholar
  • 40 Peyvandi F, Mamaev A, Wang JD. et al. Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. J Thromb Haemost 2019; 17 (01) 52-62
    CrossrefPubMedSearch in Google Scholar