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Thromb Haemost 2008; 99(05): 916-924
DOI: 10.1160/TH07-09-0565
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Survival of von Willebrand factor released following DDAVP in a type 1 von Willebrand disease cohort: Influence of glycosylation, proteolysis and gene mutations

Carolyn M. Millar
1   Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK
,
Anne F. Riddell
1   Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK
,
Simon A. Brown
1   Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK
,
Richard Starke
2   Haemostasis Research Unit, University College London, London, UK
,
Ian Mackie
2   Haemostasis Research Unit, University College London, London, UK
,
Derrick J. Bowen
3   Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK
,
P. Vincent Jenkins
1   Katharine Dormandy Haemophilia Centre and Thrombosis Unit, University College and Royal Free Medical School, London, UK
,
Jan A. van Mourik
4   Department of Plasma Proteins, Sanquin Research, Amsterdam and Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 17 September 2007

Accepted after major revision 23 March 2008

Publication Date:
30 November 2017 (online)

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Summary

Reduced plasma survival of von Willebrand factor (VWF) may contribute towards the pathogenesis of type 1 von Willebrand disease (VWD). However, little is known about mechanism(s) of VWF clearance and factors that may affect it. The half-life of VWF-related parameters following the administration of DDAVP was measured in 26 patients with type 1 VWD and 10 haemophilia A controls. Binding of lectins Ricinus communis (RCA-I) and Erythina crystagalli (ECA) agglutinins to VWF and VWF susceptibility to ADAMTS-13-mediated proteolysis were investigated. Sequence analysis of targeted regions of the VWF gene was performed to inspect for mutations that have been associated with increased clearance. Post-DDAVP clearance of VWF was increased approximately three-fold in the type 1 VWD cohort overall. However this was not shown to consistently associate with steady-state VWF antigen (VWF:Ag) levels. Furthermore, increased VWF clearance was not consistently associated with increased ratios of VWF propeptide (VWFpp) to VWF:Ag indicating that a normal ratio does not necessarily reflect normal post-DDAVP survival in type 1 VWD patients. RCA-I and ECA binding to VWF were increased in type 1 VWD patients and, although inversely correlated with VWF levels, this was independent of VWF clearance. There was no association between VWF clearance and ADAMTS-13-mediated proteolysis. Three novel candidate mutations with an increased clearance phenotype were identified. The data are consistent with heterogeneity in pathogenic mechanisms in type 1 VWD and are consistent with type 1 VWD representing a complex genetic trait.

Keywords

Clearance - glycosylation - proteolysis - von Willebrand factor - von Willebrand disease
 

  • References

  • 1 Sadler JE, Budde U, Eikenboom JC. et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4: 2103-2114.
    CrossrefPubMedSearch in Google Scholar
  • 2 Millar CM, Brown SA. Oligosaccharide structures of von Willebrand factor and their potential role in von Willebrand disease. Blood Rev 2006; 20: 83-92.
    CrossrefPubMedSearch in Google Scholar
  • 3 Brown SA, Eldridge A, Collins PW. et al. Increased clearance of von Willebrand factor antigen post- DDAVP in Type 1 von Willebrand disease: is it a potential pathogenic process?. J Thromb Haemost 2003; 1: 1714-1717.
    CrossrefPubMedSearch in Google Scholar
  • 4 Schooten CJ, Tjernberg P, Westein E. et al. Cysteine- mutations in von Willebrand factor associated with increased clearance. J Thromb Haemost 2005; 3: 2228-2237.
    CrossrefPubMedSearch in Google Scholar
  • 5 Haberichter SL, Balistreri M, Christopherson P. et al. Assay of the von Willebrand factor (VWF) propeptide to identify type 1 von Willebrand disease patients with decreased VWF survival. Blood 2006; 108: 3344-3351.
    CrossrefPubMedSearch in Google Scholar
  • 6 Levy G, Ginsburg D. Getting at the variable expressivity of von Willebrand disease. Thromb Haemost 2001; 86: 144-148.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Bowen DJ. An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13. J Thromb Haemost 2003; 1: 33-40.
    CrossrefPubMedSearch in Google Scholar
  • 8 O’Brien LA, James PD, Othman M. et al. Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease. Blood 2003; 102: 549-557.
    CrossrefPubMedSearch in Google Scholar
  • 9 Bowen DJ, Collins PW. An amino acid polymorphism in von Willebrand factor correlates with increased susceptibility to proteolysis by ADAMTS13. Blood 2004; 103: 941-947.
    PubMedSearch in Google Scholar
  • 10 Sodetz JM, Paulson JC, Pizzo SV. et al. Carbohydrate on human factor VIII/von Willebrand factor. Impairment of function by removal of specific galactose residues. J Biol Chem 1978; 253: 7202-7206.
    PubMedSearch in Google Scholar
  • 11 Ellies LG, Ditto D, Levy GG. et al. Sialyltransferase ST3Gal-IV operates as a dominant modifier of hemostasis by concealing asialoglycoprotein receptor ligands. Proc Natl Acad Sci USA 2002; 99: 10042-10047.
    CrossrefPubMedSearch in Google Scholar
  • 12 Lenting PJ, Westein E, Terraube V. et al. An experimental model to study the in vivo survival of von Willebrand factor. Basic aspects and application to the R1205H mutation. J Biol Chem 2004; 279: 12102-12109.
    CrossrefPubMedSearch in Google Scholar
  • 13 Borchiellini A, Fijnvandraat K, ten Cate JW. et al. Quantitative analysis of von Willebrand factor propeptide release in vivo: effect of experimental endotoxemia and administration of 1-deamino-8-D-arginine vasopressin in humans. Blood 1996; 88: 2951-2958.
    PubMedSearch in Google Scholar
  • 14 Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1994; 71: 520-525.
    Thieme ConnectPubMedSearch in Google Scholar
  • 15 Riddell AF, Jenkins PV, Nitu-Whalley IC. et al. Use of the collagen-binding assay for von Willebrand factor in the analysis of type 2M von Willebrand disease: a comparison with the ristocetin cofactor assay. Br J Haematol 2002; 116: 187-192.
    CrossrefPubMedSearch in Google Scholar
  • 16 Gerritsen HE, Turecek PL, Schwarz HP. et al. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP). Thromb Haemost 1999; 82: 1386-1389.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Bodo I, Katsumi A, Tuley EA. et al. Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood 2001; 98: 2973-2979.
    CrossrefPubMedSearch in Google Scholar
  • 18 Tjernberg P, Castaman G, Vos HL. et al. Dimerization and multimerization defects of von Willebrand factor due to mutated cysteine residues. J Thromb Haemost 2004; 2: 257-265.
    CrossrefPubMedSearch in Google Scholar
  • 19 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: 990-996.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Ruggeri ZM, Mannucci PM, Lombardi R. et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand’s disease subtypes. Blood 1982; 59: 1272-1278.
    PubMedSearch in Google Scholar
  • 21 Mannucci P, Canciani T, Rota L, Donovan B. Response of factor VIII/von Willebrand factor to DDAVP in healthy subjects and patients with haemophilia A and von Willebrand’s disease. Br J Haematol 1982; 47: 283-293.
    PubMedSearch in Google Scholar
  • 22 Sultan Y, Simeon J, Maisonneuve P. et al. Immunologic studies in von Willebrand’s disease: alteration of factor VIII/von Willebrand protein after transfusion with plasma concentrates in patients with von Willebrand’s disease. Thromb Haemost 1976; 35: 110-119.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Denis CV, Christophe OD, Oortwijn BD. et al. Clearance of von Willebrand factor. Thromb Haemost 2008; 99: 271-278.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Casonato A, Pontara E, Sartorello F. et al. Reduced von Willebrand factor survival in type Vicenza von Willebrand disease. Blood 2002; 99: 180-184.
    CrossrefPubMedSearch in Google Scholar
  • 25 Millar CM, Riddell AF, Griffioen A. et al. Investigation of relationship of von Willebrand factor antigen clearance with ADAMTS-13 activity and Tyr1584Cys polymorphism in type 1 von Willebrand disease. J Thromb Haemost 2005; 3 (Suppl. 01) P2067.
    PubMedSearch in Google Scholar
  • 26 Millar CM, Riddell AF, Griffioen A. et al. The Y/C1584 mutation of von Willebrand factor in type 2M von Willebrand disease: frequency and clearance of von Willebrand factor. Br J Haematol, 2005; 130: 462-463.
    CrossrefPubMedSearch in Google Scholar
  • 27 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: 1691-1695.
    PubMedSearch in Google Scholar
  • 28 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: 111-120.
    CrossrefPubMedSearch in Google Scholar
  • 29 van Schooten CJ, Denis CV, Lisman T. et al. Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels. Blood 2007; 109: 2430-2437.
    CrossrefPubMedSearch in Google Scholar
  • 30 Sadler JE. Von Willebrand disease type 1: a diagnosis in search of a disease. Blood 2003; 101: 2089-2093.
    CrossrefPubMedSearch in Google Scholar
  • 31 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: 145-154.
    CrossrefPubMedSearch in Google Scholar
  • 32 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: 112-121.
    CrossrefPubMedSearch in Google Scholar
  • 33 Schneppenheim R, Federici AB, Budde U. et al. Von Willebrand Disease type 2M „Vicenza” in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families. Thromb Haemost 2000; 83: 136-140.
    Thieme ConnectPubMedSearch in Google Scholar