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Thromb Haemost 2007; 98(01): 178-185
DOI: 10.1160/TH06-10-0571
Platelets and Blood Cells
Schattauer GmbH

The A/T1381 polymorphism in the A1-domain of von Willebrand factor influences the affinity of von Willebrand factor for platelet glycoprotein Ibα

Tímea Szántó
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
2   Clinical Research Center, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Ágota Schlammadinger
3   2nd Department of Medicine, University Medical School of Debrecen, Debrecen, Hungary
,
Stephanie Staelens
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Simon F. De Meyer
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Kathleen Freson
4   Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
,
Inge Pareyn
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Stephan Vauterin
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Jolán Hársfalvi
2   Clinical Research Center, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary
,
Hans Deckmyn
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
,
Karen Vanhoorelbeke
1   Laboratory for Thrombosis Research, IRC, KU Leuven Campus Kortrijk, Kortrijk, Belgium
› Author Affiliations
Further Information

Publication History

Received 07 October 2007

Accepted after resubmission 26 April 2007

Publication Date:
29 November 2017 (online)

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Summary

Many polymorphisms in vonWillebrand factor (VWF) have been reported and their association with VWF plasma levels or cardiovascular diseases has been investigated. The aim of this study was to examine whether the amino acid polymorphis mA/T1381 in the VWF A1-domain would affect VWF binding to platelet GPIbα. Sixty-one normal individuals were genotyped at the A/T1381 locus. Twenty-one A/A1381 homozygotes, 30 A/T1381 heterozygotes and 10 T/T1381 homozygotes were identified. Remarkably, when compared to VWF of A/T1381 and A/A1381 individuals, VWF of individuals carrying the T/T1381 variant showed an increased affinity for its platelet receptor GPIbα under static conditions, as reflected by an increased sensitivity to low concentrations of ristocetin or botrocetin. In addition, also the rVWF-T1381 demonstrated a higher affinity for GPIbα than rVWF-A1381. Interestingly, this enhanced affinity of the T/T variant over the A/T and A/A variant was, however, too subtle to affect platelet adhesion under physiological flow conditions, which fully corroborates the normal haemostatic phenotype of all individuals. We demonstrate that the VWF A/T1381 polymorphism plays an important role in inter-individual variability of the affinity of VWF for GPIbα, with T/T variants having a higher affinity than A/A and A/T variants, at least under static conditions in vitro. Further genetic linkage and association studies are necessary to establish whether the A/T1381 polymorphism could correlate with an increased risk of thrombotic events.

Keywords

von Willebrand factor - platelet glycoprotein Ibα - A/T1381 polymorphism - vonWillebrand disease - thrombosis
 

  • References

  • 1 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 8: 1227-1234.
    CrossrefPubMedGoogle Scholar
  • 2 Mayadas TN, Wagner DD. Von Willebrand factor biosynthesis and processing. Ann NY Acad Sci 1991; 614: 153-166.
    CrossrefPubMedGoogle Scholar
  • 3 Savage B. et al. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor. Cell 1996; 84: 289-297.
    CrossrefPubMedGoogle Scholar
  • 4 Ruggeri ZM. Von Willebrand factor. Curr Opin Hematol 2003; 10: 142-149.
    CrossrefPubMedGoogle Scholar
  • 5 Siedlecki CA. et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88: 2939-2950.
    PubMedGoogle Scholar
  • 6 Howard MA, Firkin BG. Ristocetin-a new tool in the investigation of platelet aggregation. Thromb Diath Haemorrh 1971; 26: 362-369.
    PubMedGoogle Scholar
  • 7 Read MS. et al. Role of botrocetin in platelet agglutination: formation of an activated complex of botrocetin and von Willebrand factor. Blood 1989; 74: 1031-1035.
    PubMedGoogle Scholar
  • 8 De Lange M. et al. Genetic influences on fibrinogen, tissue plasminogen activator-antigen and von Willebrand factor in males and females. Thromb Haemost 2006; 95: 414-419.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Soutu JC. et al. Genome-wide linkage analysis of von Willebrand factor plasma levels: results from the GAIT project. Thromb Haemost 2003; 89: 468-474.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Morelli VM. et al. ABO blood group genotypes, plasma von Willebrand factor levels and loading of von Willebrand factor with A and B antigens. Thromb Haemost 2007; 97: 534-541.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Keightley AM. et al. Variation at the von Willebrand factor (VWF) gene locus is associated with plasma VWF:Ag levels: identification of three novel single nucleotide polymorphisms in the VWF gene promoter. Blood 1999; 93: 4277-4283.
    PubMedGoogle Scholar
  • 12 Harvey PJ. et al. A single nucleotide polymorphism at nucleotide -1793 in the von Willebrand factor (VWF) regulatory region is associated with plasma VWF:Ag levels. Br J Haematol 2000; 109: 349-353.
    CrossrefPubMedGoogle Scholar
  • 13 van der Meer IM. et al. Genetic variability of von Willebrand factor and risk of coronary heart disease: the Rotterdam Study. Br J Haematol 2004; 124: 343-347.
    CrossrefPubMedGoogle Scholar
  • 14 Lacquemant C. et al. Association between high von Willebrand factor levels and the Thr789Ala vWF gene polymorphism but not with nephropathy in type I diabetes. The GENEDIAB Study Group and the DESIR Study Group. Kidney Int 2000; 57: 1437-1443.
    CrossrefPubMedGoogle Scholar
  • 15 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.
    PubMedGoogle Scholar
  • 16 Donner M. et al. An HphI-polymorphism in exon 28 of the von Willebrand factor gene, and its frequency among patients with various forms of von Willebrand’s disease. Br J Haematol 1991; 78: 403-407.
    CrossrefPubMedGoogle Scholar
  • 17 Vanhoorelbeke K. et al. A reliable and reproducible ELISA method to measure ristocetin cofactor activity of von Willebrand factor. Thromb Haemost 2000; 83: 107-113.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Vanhoorelbeke K. et al. A reliable von Willebrand factor: ristocetin cofactor enzyme-linked immunosorbent assay to differentiate between type 1 and type 2 von Willebrand disease. Semin Thromb Hemost 2002; 28: 161-166.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Vanhoorelbeke K. et al. Plasma glycocalicin as a source of GPlb alpha in the von Willebrand factor ristocetin cofactor ELISA. Thromb Haemost 2005; 93: 165-171.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Randi AM. et al. Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposedplatelet glycoprotein Ib binding sequences. J Clin Invest 1991; 87: 1220-1226.
    CrossrefPubMedGoogle Scholar
  • 21 Ribba AS. et al. Ser968Thr mutation within the A3 domain of von Willebrand factor (VWF) in two related patients leads to a defective binding of VWF to collagen. Thromb Haemost 2001; 86: 848-854.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Mancuso DJ. et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264: 19514-19527.
    PubMedGoogle Scholar
  • 23 Vanhoorelbeke K. et al. A consensus tetrapeptide selected by phage display adopts the conformation of a dominant discontinuous epitope of a monoclonal Anti-VWF antibody that inhibits the von Willebrand factor-collagen interaction. J Biol Chem 2003; 278: 37815-37821.
    CrossrefPubMedGoogle Scholar
  • 24 Sixma JJ. et al. 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: 369-375.
    CrossrefPubMedGoogle Scholar
  • 25 Vanhoorelbeke K. et al. Sequence alignment between VWF and peptides inhibiting the VWF-collagen interaction does not result in the identification of a collagen-binding site in VWF. Thromb Haemost 2000; 84: 621-625.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Ruggeri ZM, Zimmerman TS. The complex multimeric composition of factor VIII/von Willebrand factor. Blood 1981; 57: 1140-1143.
    PubMedGoogle Scholar
  • 27 Miller JL. et al. Von Willebrand factor binds to platelets and induces aggregation in platelet-type but not type IIb von Willebrand disease. J Clin Invest 1983; 72: 1532-1542.
    CrossrefPubMedGoogle Scholar
  • 28 Ulrichts H. et al. A monoclonal antibody directed against human von Willebrand factor induces type 2B-like alterations. J Thromb Haemost 2004; 2: 1622-1628.
    CrossrefPubMedGoogle Scholar
  • 29 Ulrichts H. 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: 4699-4707.
    CrossrefPubMedGoogle Scholar
  • 30 Murata M. et al. Low shear stress can initiate von Willebrand factor-dependent platelet aggregation in patients with type IIb and platelet-type von Willebrand disease. J Clin Invest 1993; 92: 1555-1558.
    CrossrefPubMedGoogle Scholar
  • 31 Ajzenberg N. et al. Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation. Blood 2000; 95: 3796-3803.
    PubMedGoogle Scholar
  • 32 Favaloro EJ. Laboratory identification of von Willebrand disease: technical and scientific perspectives. Semin Thromb Hemost 2006; 32: 456-471.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Casana P. et al. New mutations in exon 28 of the von Willebrand factor gene detected in patients with different types of von Willebrand’s disease. Haematologica 2001; 86: 414-419.
    PubMedGoogle Scholar
  • 34 Hilbert L. et al. Identification of two mutations (Arg611Cys and Arg611His) in the A1 loop of von Willebrand factor (VWF) responsible fortype 2 von Willebrand disease with decreased platelet-dependent function of VWF. Blood 1995; 86: 1010-1018.
    PubMedGoogle Scholar
  • 35 Matsushita T. et al. Localization of von Willebrand factor-binding sites for platelet glycoprotein Ib and botrocetin by charged-to-alanine scanning mutagenesis. J Biol Chem 2000; 275: 11044-11049.
    CrossrefPubMedGoogle Scholar
  • 36 Bonnefoy A. et al. Shielding the front-strand beta 3 of the von Willebrand factor A1 domainin hibits its binding to platelet glycoprotein Ib alpha. Blood 2003; 101: 1375-1383.
    CrossrefPubMedGoogle Scholar