Vol.:(0123456789) 1 3 International Journal of Hematology https://doi.org/10.1007/s12185-019-02814-8 ORIGINAL ARTICLE Molecular and clinical profle of type 2 von Willebrand disease in Iran: a thirteen‑year experience Maryam Rassoulzadegan 1  · Fereydoun Ala 1  · Mohammad Jazebi 1  · Mohammad Said Enayat 1  · Shadi Tabibian 2  · Mahmood Shams 3  · Mehran Bahraini 2  · Akbar Dorgalaleh 2 Received: 17 June 2019 / Revised: 25 December 2019 / Accepted: 25 December 2019 © Japanese Society of Hematology 2020 Abstract 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 profle 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 identifed mutations were confrmed in family members and by relevant bioin- formatics 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 identifed 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 ten- dency and a heterogeneous molecular basis in patients in Iran. Keywords von Willebrand disease type 2 · Clinical manifestations · Diagnosis · Molecular analysis Introduction von Willebrand disease (VWD) is the most common congen- ital bleeding disorder, with a worldwide estimated incidence of ~ 1%. It is classifed into type 1 (60–80% of all VWD) with a mild decrease in von Willebrand factor (VWF) con- centration, type 2 (20–35%) with VWF qualitative defects, and type 3 with the absence of VWF [1–3]. The bleeding ten- dency varies from asymptomatic, mainly in type 1, to severe, life-threatening bleeding, mainly in type 3. Patients with VWD present a variety of clinical manifestations, including easy bruising and epistaxis, commonly in children, as well as menorrhagia and hematoma in adults [3]. Diagnostically, type 2 is the most difcult and challenging form of the dis- order [3, 4]. Type 2, mostly inherited in autosomal dominant manner, is classifed into four subtypes: 2A, 2B, 2M, and 2N [5]. Patients with type 2 demonstrated various presentations, depending on the subtype. For example, patients with type 2A sufer from postsurgical bleeding, postdental extraction bleeding, menorrhagia, and gastrointestinal bleeding, while easy bruising, epistaxis, and prolonged bleeding from minor wounds are the most common manifestations of type 2B. As with type 2B, prolonged bleeding from minor wounds is considered the most common presentation in patients with types 2M and 2N [3]. An exhaustive laboratory approach is mandatory for correct diagnosis and classifcation. A cutof of less than 0.7 of VWF: activity/VWF: antigen ratio is the hallmark for diagnosis of this type of VWD [3]. Type 2 is mostly due to mutations that afect VWF multimer assem- bly, proteolysis, or the particular functions of VWF. A wide range of mutations has been identifed, including missense, frameshift, duplication, and insertion (Fig. 1) [3]. In this study, we reported the clinical and molecular characteristics of a large number of Iranian patients with type 2 VWD. * Akbar Dorgalaleh dorgalaleha@gmail.com 1 Iranian Comprehensive Hemophilia Care Centre, Tehran, Iran 2 Department of Hematology and Blood Transfusion, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran 3 Department of Medical Laboratory, Faculty of Paramedical Science, Babol University of Medical Science, Babol, Iran