Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience

  • 22 Accesses


Type 2 von Willebrand disease (VWD) is the most common congenital bleeding disorder, with variable bleeding tendency and a complex laboratory phenotype. In the current study, we report the clinical and molecular profile of a large number of Iranian patients with type 2 VWD. All exons, intron–exon boundaries, and untranslated regions were sequenced by Sanger sequencing for direct mutation detection. All identified mutations were confirmed in family members and by relevant bioinformatics studies. A total of 136 patients with type 2 VWD were diagnosed, including 42 (30.9%), 32 (23.6%), 38 (27.9%), and 24 (17.6%) patients with type 2A, type 2B, type 2M, and type 2N, respectively. Epistaxis (49%), gum bleeding (30.2%), ecchymosis (23.2%), and menorrhagia (16.3%) were the most common clinical presentations, while miscarriage (2.3%) and umbilical cord bleeding (0.8%) were the rarest. Thirty mutations were identified within the VWF gene, nine (30%) being novel, with p.Arg1379Cys (n = 20), p.Val1316Met (n = 13), p.Arg1597Trp (n = 13), p.Arg1374Cys (n = 10), p.Ser1506Leu (n = 10), and p.Arg1308Cys (n = 9) the most common. Type 2 VWD is a hemorrhagic disorder with variable bleeding tendency and a heterogeneous molecular basis in patients in Iran.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Dorgalaleh A, Tabibian S, Shams M, Ala F, Bahoush G, Jazebi M, et al. Von Willebrand disease in Iran: diagnosis and management. Ann Blood. 2018;3(1):4.

  2. 2.

    Bowman M, Hopman WM, Rapson D, Lillicrap D, James P. The prevalence of symptomatic von Willebrand disease in primary care practice. J Thromb Haemost. 2010;8(1):213–6.

  3. 3.

    Dorgalaleh A, Tabibian S, Shiravand Y, Favaloro EJ. von Willebrand disease. Congenital bleeding disorders. Berlin: Springer; 2018. p. 57–102.

  4. 4.

    Castaman G, Linari S. Diagnosis and treatment of von Willebrand disease and rare bleeding disorders. J Clin Med. 2017;6(4):45.

  5. 5.

    Lillicrap D. Translational medicine advances in von Willebrand disease. J Thromb Haemost. 2013;11:75–83.

  6. 6.

    Sadler J, Mannucci P, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D, et al. Impact, diagnosis and treatment of von Willebrand disease. Thromb Haemost. 2000;84(08):160–74.

  7. 7.

    Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J, 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(1):112–21.

  8. 8.

    Casari C, Lenting P, Wohner N, Christophe O, Denis C. Clearance of von Willebrand factor. J Thromb Haemost. 2013;11:202–11.

  9. 9.

    Ahmad F, Jan R, Kannan M, Obser T, Hassan MI, Oyen F, et al. Characterisation of mutations and molecular studies of type 2 von Willebrand disease. Thromb Haemost. 2013;109(01):39–46.

  10. 10.

    Pagliari M, Baronciani L, Stufano F, Garcia-Oya I, Cozzi G, Franchi F, et al. von Willebrand disease type 1 mutation p.Arg1379Cys and the variant p.Ala1377Val synergistically determine a 2M phenotype in four Italian patients. Haemophilia. 2016;22(6):e502–11.

  11. 11.

    Lillicrap D, Murray EW, Benford K, Blanchette VS, Rivard GE, Wensley R, et al. Recurring mutations at CpG dinucleotides in the region of the von Willebrand factor gene encoding the glycoprotein Ib binding domain, in patients with type IIB von Willebrand’s disease. Br J Haematol. 1991;79(4):612–7.

  12. 12.

    Skeith L, Rydz N, O’Beirne M, Goodyear D, Li H, Poon M-C. Pregnancy loss in women with von Willebrand disease: a single-center pilot study. Blood Coagul Fibrinolysis. 2017;28(5):393–7.

  13. 13.

    Kadir RA, Lee CA, Sabin CA, Pollard D, Economides DL. Pregnancy in women with von Willebrand’s disease or factor XI deficiency. BJOG. 1998;105(3):314–21.

  14. 14.

    Kujovich JL. von Willebrand disease and pregnancy. J Thromb Haemost. 2005;3(2):246–53.

  15. 15.

    Reynen E, James P. Von Willebrand disease and pregnancy: a review of evidence and expert opinion. Semin Thromb Hemost. 2016;42(7):717–23.

  16. 16.

    Lillicrap D. The molecular genetics of von Willebrand disease. Haematol Rep. 2005;1:3–8.

  17. 17.

    Zimmerman TS, Dent JA, Ruggeri ZM, Nannini LH. Subunit composition of plasma von Willebrand factor. Cleavage is present in normal individuals, increased in IIA and IIB von Willebrand disease, but minimal in variants with aberrant structure of individual oligomers (types IIC, IID, and IIE). J Clin Invest. 1986;77(3):947–51.

  18. 18.

    Shen M-C, Chen M, Ma G-C, Chang S-P, Lin C-Y, Lin B-D, et al. De novo mutation and somatic mosaicism of gene mutation in type 2A, 2B and 2M VWD. Thromb J. 2016;14(1):36.

  19. 19.

    Rendal E, Penas N, Larrabeiti B, Pérez A, Vale A, López-Fernández M, et al. Type 2B von Willebrand’s disease due to Val1316Met mutation. Heterogeneity in the same sibship. Ann Hematol. 2001;80(6):354–60.

  20. 20.

    Jackson SC, Sinclair GD, Cloutier S, Duan Z, Rand ML, Poon MC. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316M mutation. Blood. 2009;113(14):3348–51.

  21. 21.

    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(4):1220–6.

  22. 22.

    Kroner PA, Kluessendorf M, Scott J, Montgomery RR. Expressed full-length von Willebrand factor containing missense mutations linked to type IIB von Willebrand disease shows enhanced binding to platelets. Blood. 1992;79(8):2048–55.

  23. 23.

    Casaña P, Martínez F, Haya S, Tavares A, Aznar JA. 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(4):414–9.

  24. 24.

    Corrales I, Ramírez L, Altisent C, Parra R, Vidal F. Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene. Thromb Haemost. 2009;101(03):570–6.

  25. 25.

    Shahverdi E, Moghaddam M, Talebian A, Abolghasemi H. Distribution of blood groups in the Iranian general population. J Blood Group Serol Mol Genet. 2016;32(4):135.

Download references


This study was supported by the Iranian Hemophilia Care Center. We appreciate all staff of the Iranian Hemophilia Care Center that collaborated in this study, and patients for their kind participation on the project.

Author information

Correspondence to Akbar Dorgalaleh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rassoulzadegan, M., Ala, F., Jazebi, M. et al. Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience. Int J Hematol (2020).

Download citation


  • von Willebrand disease type 2
  • Clinical manifestations
  • Diagnosis
  • Molecular analysis