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Thromb Haemost 2001; 86(06): 1459-1465
DOI: 10.1055/s-0037-1616749
Review Article
Schattauer GmbH

Defect of Heparin Binding in Plasma and Recombinant von Willebrand Factor with Type 2 von Willebrand Disease Mutations

Ghassem Rastegar-Lari
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Nadine Ajzenberg
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Anne-Sophie Ribba
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Valérie Vereycken-Holler
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Paulette Legendre
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Bruno O. Villoutreix
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Dominique Meyer
1   INSERM U143, Bicetre and INSERM U428, Paris, France
,
Dominique Baruch
1   INSERM U143, Bicetre and INSERM U428, Paris, France
› Author Affiliations
Further Information

Publication History

Received 24 March 2001

Accepted after resubmission 28 August 2001

Publication Date:
12 December 2017 (online)

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Summary

The aim of our study was to characterise heparin-binding properties of mutated von Willebrand factor (VWF) in 24 patients plasmas with type 2 von Willebrand disease (VWD), and in 15 recombinant VWF (rVWF) with the corresponding mutations. Binding of mutated rVWF or plasma VWF was compared to that of WT-rVWF or normal pool plasma VWF. Four mutations, at positions C509, V551, R552 and R611 lead to significantly decreased binding to heparin in both plasma and rVWF. Interestingly, whereas these four residues are distant in the primary structure of VWF-A1 domain, they are close to each other in its three-dimensional structure. Structural analysis suggested how folding problems and destabilisation due to these mutations could induce reorganisation of surface regions involved in heparin binding. In contrast, no heparin-binding defect was found associated with different type 2 VWF mutants, at positions G561, E596, I662, R543, R545, V553, R578 or L697.

Keywords

Heparin - von Willebrand factor - von Willebrand disease
 

  • References

  • 1 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424.
    CrossrefPubMedSearch in Google Scholar
  • 2 Ginsburg D, Sadler JE. von Willebrand disease: a database of point mutations, insertions, and deletions. Thromb Haemost 1993; 69: 177-84.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Meyer D, Fressinaud E, Hilbert L, Ribba AS, Lavergne JM, Mazurier C. Type 2 von Willebrand disease causing defective von Willebrand factor-dependent platelet function In: Best Practice & Research Clinical Haematology. R. Michiels, ed. London: Harcourt Publishers; 2001. Vol 14, No. 2 (In press).
    Search in Google Scholar
  • 4 Ribba AS, Hilbert L, Lavergne JM, Fressinaud E, Boyer-Neumann C, Ternisien C, Juhan-Vague I, Goudemand J, Girma JP, Mazurier C, Meyer D. The Arg552Cys mutation within the A1 loop of von Willebrand Factor (VWF) induces an abnormal folding with a loss-of-function resulting in a 2A-like phenotype. Study of ten patients and of mutated recombinant VWF. Blood 2000; 97: 952-9.
    PubMedSearch in Google Scholar
  • 5 Veyradier A, Fressinaud E, Meyer D. Laboratory diagnosis of von Willebrand disease. Inter J Clin Lab Res 1998; 28: 201-10.
    PubMedSearch in Google Scholar
  • 6 Rastegar-Lari G, Legendre P, Ajzenberg N, Warszawski J, Meyer D, Baruch D. von Willebrand factor binding to heparin in various types of von Willebrand disease. Hematology J 2000; 1: 190-8.
    PubMedSearch in Google Scholar
  • 7 Fujimura Y, Titani K, Holland LZ, Roberts JR, Kostel P, Ruggeri ZM, Zimmerman TS. A heparin-binding domain of human von Willebrand factor. J Biol Chem 1987; 262: 1734-9.
    PubMedSearch in Google Scholar
  • 8 Mohri H, Yoshioka A, Zimmerman TS, Ruggeri ZM. Isolation of the von Willebrand factor domain interacting with platelet glycoprotein Ib, heparin, and collagen and characterization of its three distinct functional sites. J Biol Chem 1989; 264: 17361-7.
    PubMedSearch in Google Scholar
  • 9 Sobel M, Soler D, Kermode J, Harris R. Localization and characterization of a heparin binding domain peptide of human von Willebrand factor. J Biol Chem 1992; 267: 8857-62.
    PubMedSearch in Google Scholar
  • 10 Fretto LJ, Fowler WE, McCaslin DR, Erickson HP, McKee PA. Substructure of human von Willebrand factor: proteolysis by V-8 and characterization of two functional domains. J Biol Chem 1986; 261: 15679-89.
    PubMedSearch in Google Scholar
  • 11 Sixma JJ, Schiphorst ME, Verweij CL, Pannekoek H. Effect of deletion of the A1 domain of von Willebrand factor on its binding to heparin, collagen and platelets in the presence of ristocetin. Eur J Biochem 1991; 196: 369-75.
    CrossrefPubMedSearch in Google Scholar
  • 12 Kroner PA, Frey AB. Analysis of the structure and function of the von Willebrand factor A1 domain using targeted deletions and alanine-scanning mutagenesis. Biochemistry 1996; 35: 13460-8.
    CrossrefPubMedSearch in Google Scholar
  • 13 Lavergne JM, de Paillette L, Bahnak BR, Ribba AS, Fressinaud E, Meyer D, Pietu G. Defects in type IIA von Willebrand disease: a cysteine 509 to arginine substitution in the mature von Willebrand factor disrupts a disulphide loop involved in the interaction with platelet glycoprotein Ib-IX. Br J Haemat 1992; 82: 66-72.
    CrossrefPubMedSearch in Google Scholar
  • 14 Ribba AS, Christophe O, Derlon A, Cherel G, Siguret V, Lavergne JM, Girma JP, Meyer D, Pietu G. Discrepancy between IIA phenotype and IIB genotype in a patient with a variant of von Willebrand disease. Blood 1994; 83: 833-41.
    PubMedSearch in Google Scholar
  • 15 Randi AM, Rabinowitz I, Mancuso DJ, Mannucci PM, Sadler JE. Molecular basis of von Willebrand disease type-IIB – candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein-Ib binding sequences. J Clin Invest 1991; 87: 1220-6.
    CrossrefPubMedSearch in Google Scholar
  • 16 Cooney KA, Nichols WC, Bruck ME, Bahou WF, Shapiro AD, Bowie EJW, Gralnick HR, Ginsburg D. The molecular defect in type-IIB von Willebrand disease – Identification of four potential missense mutations within the putative GPIb binding domain. J Clin Invest 1991; 87: 1227-33.
    CrossrefPubMedSearch in Google Scholar
  • 17 Randi AM, Jorieux S, Tuley EA, Mazurier C, Sadler JE. Recombinant von Willebrand disease mutation affects binding to glycoprotein Ib but not to collagen or heparin. J Biol Chem 1992; 267: 21187-92.
    PubMedSearch in Google Scholar
  • 18 Hillery CA, Mancuso DJ, Sadler JE, Ponder JW, Jozwiak MA, Christopherson PA, Gill C, Scott P, Montgomery RR. Type 2M von Wille-brand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin- but not botrocetin-mediated binding of von Willebrand factor to platelets. Blood 1998; 91: 1572-81.
    PubMedSearch in Google Scholar
  • 19 Hilbert L, Gaucher C, Mazurier C. Identification of two mutations (Arg 611 Cys and Arg 611 His) in the A1 loop responsible for type 2 von Willebrand disease with decreased platelet dependent function of von Willebrand factor. Blood 1995; 86: 1010-8.
    PubMedSearch in Google Scholar
  • 20 Voorberg J, Fontijn R, van Mourik JA, Pannekoek H. Domains involved in multimer assembly of von Willebrand factor (VWF). Multimerization is independent of dimerization. EMBO J 1990; 9: 797-803.
    PubMedSearch in Google Scholar
  • 21 Matsushita T, Sadler JE. Identification of amino acid residues essential for von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1995; 270: 13406-14.
    CrossrefPubMedSearch in Google Scholar
  • 22 Siguret V, Ribba AS, Christophe O, Cherel G, Obert B, Rouault C, Nishikubo T, Meyer D, Girma JP, Pietu G. Characterization of recombinant von Willebrand factors mutated on cysteine 509 or 695. Thromb Haemost 1996; 76: 453-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Ajzenberg N, Ribba AS, Rastegar-Lari G, Meyer D, Baruch D. Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation. Blood 2000; 95: 3796-802.
    PubMedSearch in Google Scholar
  • 24 Hilbert L, Gaucher C, Fressinaud E, Meyer D, Mazurier C. A new type 2M (“type B”) VWD mutation (G1324A) also at position 561 of the mature VWF subunit. Thromb Haemost. 1997 77 suppl: 654 (abstr).
    PubMedSearch in Google Scholar
  • 25 Hilbert L, Gaucher C, Mazurier C. Effects of different amino-acid substitutions in the leucine 649-proline 708 segment of recombinant von Willebrand factor. Br J Haemat 1995; 91: 983-90.
    CrossrefPubMedSearch in Google Scholar
  • 26 Hilbert L, Gaucher C, de Romeuf C, Horellou MH, Vink T, Mazurier C. Leu 697Val mutation in mature von Willebrand factor is responsible for type IIB von Willebrand disease. Blood 1994; 83: 1542-50.
    PubMedSearch in Google Scholar
  • 27 Lankhof H, Wu YP, Vink T, Schiphorst ME, Zerwes HG, de Groot PG, Sixma JJ. Role of the glycoprotein Ib-binding A1 repeat and the RGD sequence in platelet adhesion to human recombinant von Willebrand factor. Blood 1995; 86: 1035-42.
    PubMedSearch in Google Scholar
  • 28 Pietu G, Ribba AS, Cherel G, Siguret V, Obert B, Rouault C, Ginsburg D, Meyer D. Epitope mapping of inhibitory monoclonal antibodies to human von Willebrand factor by using recombinant cDNA libraries. Thromb Haemost 1994; 71: 788-92.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Christophe O, Rouault C, Obert B, Pietu G, Meyer D, Girma JP. A monoclonal antibody (B724) to von Willebrand factor recognizing an epitope within the A1 disulphide loop (Cys509-Cys695) discriminates beween type 2A and type 2B von Willebrand disease. Br J Haemat 1995; 90: 195-203.
    CrossrefPubMedSearch in Google Scholar
  • 30 Schullek J, Jordan J, Montgomery RR. Interaction of von Willebrand factor with human platelets in the plasma milieu. J Clin Invest 1984; 73: 421-8.
    CrossrefPubMedSearch in Google Scholar
  • 31 Baruch D, Ajzenberg N, Denis C, Legendre P, Lormeau JC, Meyer D. Binding of heparin fractions to von Willebrand factor: effect of molecular weight and affinity for antithrombin III. Thromb Haemost 1994; 71: 141-6.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 de Romeuf C, Mazurier C. Heparin binding assay of von Willebrand factor (VWF) in plasma milieu – evidence of the importance of the multimerization degree of VWF. Thromb Haemost 1993; 69: 436-40.
    Thieme ConnectPubMedSearch in Google Scholar
  • 33 Matsushita T, Meyer D, Sadler JE. Localization of von Willebrand Factor-binding sites for platelet glycoprotein Ib and botrocetin by charged-to-Alanine scanning mutagenesis. J Biol Chem 2000; 275: 11044-9.
    CrossrefPubMedSearch in Google Scholar
  • 34 Nitu-Walley IC, Riddell A, Lee CA, Pasi KJ, Owens D, Enayat MS, Perkins SJ, Jenkins PV. Identification of type 2 von Willebrand disease in previously diagnosed type 1 patients: a reappraisal using phenotypes geno-types and molecular modelling. Thromb Haemost 2000; 84: 998-1004.
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Celikel R, Varughese KI, Madhusudan Yoshioka A, Ware J, Ruggeri ZM. Crystal structure of the von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab. Nature Struct Biol 1998; 5: 189-94.
    CrossrefPubMedSearch in Google Scholar
  • 36 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: 10396-401.
    CrossrefPubMedSearch in Google Scholar