Development of Awareness Materials to Promote Early Diagnosis of Undiagnosed von Willebrand Disease: Integration of Multidisciplinary Perspectives Based on a Literature Review

To the Editor: Bleeding symptoms in von Willebrand disease (VWD) significantly impair quality of life (QOL) [1], and estimates suggest that up to one in 500 individuals may have undiagnosed symptomatic VWD [2]. Reports indicate that socioeconomic factors influence VWD diagnosis rates [3]. While high-income countries report an average of 60.3 diagnosed individuals per million population, Japan lags significantly behind, with only 13.34 individuals per million diagnosed as of 2023 [4, 5]. Several factors may explain this disparity. In mild to moderate cases, bleeding symptoms are often subtle, leading individuals to remain unaware of their condition. Additionally, the variations in von Willebrand factor (VWF) levels upon repeat testing further complicates diagnosis [6]. Insufficient awareness of VWD among hematologists evaluating referred cases has also been identified as a significant barrier to accurate diagnosis [7]. As noted in the report by Colonne CK, challenges in diagnosing VWD include lack of knowledge and difficulties in interpreting test results. However, enhanced education, standardized bleeding assessment tools (BAT), and comprehensive testing algorithms can significantly improve diagnostic accuracy [8]. A recent comprehensive expert review further outlines the multifaceted nature of VWD, including its epidemiology, clinical manifestations, diagnosis, management, and persistent global underrecognition [9]. Improving the diagnosis rate of VWD is critical to preventing major bleeding during invasive procedures or perinatal periods and to mitigating QOL impairment due to bleeding symptoms. To address these challenges, we developed educational materials aimed at raising awareness of VWD among the public, gynecologists, pediatricians, otolaryngologists, dentists, general practitioners (GP), and hematologist-oncologists. In November 2024, we conducted a literature search using the PubMed database to identify articles published over the past decade related to “von Willebrand disease.” A total of 4036 articles with accessible abstracts were retrieved. After narrowing the results using the term “diagnosis,” 1968 articles remained. Among these, case reports, studies on acquired VWD, severe VWD, the development of diagnostic kits, and treatment efficacy were excluded, leaving 176 articles for analysis. Following a full-text review and further exclusion of review articles and those fitting the exclusion criteria, 76 articles were summarized (Table S1). In the United States, patients suspected of having VWD were most seen in gynecology, GP, and emergency departments, followed by gastroenterology, pediatrics, and otolaryngology, notably, dentistry was not included in the referenced study [2]. Therefore, in this study, the educational materials were designed to target the public, including individuals potentially affected by VWD, as well as healthcare providers who may encounter undiagnosed patients, such as gynecologists, pediatricians, otolaryngologists, dentists, and GPs. Additionally, hematologist-oncologists involved in the diagnostic process were included as a key audience. To develop the educational materials, we convened a multidisciplinary team including internists, pediatricians, a nurse, a gynecologist, a patient representative, and a hematologist-oncologist. The summarized literature was reviewed, and feedback was collected via email to consolidate opinions and finalize the materials. The illustrations included in the educational materials were generated using an AI assistant (ChatGPT). Prior to their use, we reviewed OpenAI's terms of service and confirmed that the generated content is assigned to the user, with permission for commercial use. This study was limited to gathering opinions from healthcare professionals and did not involve the collection of patient-derived data. Therefore, ethical review board approval was deemed unnecessary. The educational materials developed in this study are shown in Figure 1. For the public, we used catchy phrases to raise awareness of VWD and help individuals recognize their bleeding symptoms, prompting them to consider the possibility of having VWD. Special attention was given to heavy menstrual bleeding (HMB), as it is rarely discussed openly and remains a taboo topic in many contexts, particularly in Japan. To make it easier for individuals to identify potential HMB, we provided simple criteria such as the need for oversized sanitary products and menstruation lasting longer than 7 days. The literature review also revealed that limited access to VWD specialists and delays in diagnosis are common challenges. To address this, we included a Quick Response (QR) code, a type of two-dimensional barcode, in the materials directing users to a list of nearby specialists and consultation resources (Figure 1). For gynecologists, the materials emphasize the recommendation in the Japanese gynecological guidelines to consider VWD in cases of HMB, highlighting the attention this issue has received at the professional society level. The literature review identified HMB, postpartum hemorrhage, and ovarian bleeding as characteristic manifestations of VWD in the gynecological field. By prominently presenting these symptoms, which gynecologists may have encountered in their practice, the materials aim to facilitate the recognition of VWD. Despite this, VWD screening rates among gynecologists remain low, and women with VWD are often overlooked, leading to delayed care (Table S1 [1]–[38]).These findings underscore the critical role of gynecologists in the early diagnosis of VWD. The educational materials developed in this study have the potential to increase awareness among gynecologists, ultimately improving diagnosis rates. Severe HMB in adolescent females is associated with feelings of isolation and stress, but receiving a diagnosis can foster improved self-identity and confidence (Table S1 [10]). For pediatricians, otolaryngologists, dentists, and GPs, the materials emphasized VWD-related bleeding symptoms that they may encounter in their clinical practice. These include epistaxis, oral mucosal bleeding, subcutaneous hematomas, prolonged bleeding following tooth extractions, and recurrent unexplained iron deficiency anemia. Multiple studies have identified subcutaneous hematomas, oral mucosal bleeding, and epistaxis as particularly characteristic in children with VWD. Furthermore, adolescent females with HMB require attention to the possibility of iron deficiency anemia, which may sometimes manifest as nonspecific complaints such as fatigue or irritability, prompting pediatric consultations (Table S1 [27]–[38]). To support diagnosis, the materials outlined essential screening tests, including VWF activity, antigen levels, and factor VIII activity. Recognizing that access to specialists may be limited in some areas, the materials also incorporated QR codes linking to directories of VWD specialists, thereby lowering barriers to referrals and encouraging further evaluation for suspected cases. The materials designed for hematologist-oncologists focused on essential clinical evaluation of patient history for diagnosing VWD and emphasized access to guidelines for the management of VWD. In Japan, referral pathways from frontline clinicians to VWD specialists remain unclear. To address this, QR codes were included to direct users to a list of facilities with VWD specialists or, where access to specialists is limited, to provide hematologist-oncologists with resources from the guidelines to facilitate diagnosis. The literature review revealed a substantial body of research on low VWF levels (Table S1 [18, 21, 29, 33, 42, 55, 57, 59, 64, 73]). International guidelines recommend diagnosing VWD type 1 in individuals with VWF levels of 30–50 IU/mL if abnormal bleeding is present. However, the 2021 Japanese clinical guidelines categorize this range as “low VWF levels associated with bleeding risk” rather than VWD type 1 [10, 11]. This discrepancy may cause confusion in clinical practice, especially when patients with suspected VWD are referred to hematologist-oncologists, potentially delaying diagnosis and treatment. Nevertheless, since the publication of the international guidelines, several studies have reported on bleeding symptoms in patients with VWF levels of 30–50 IU/mL. These findings suggest that accumulating further data may eventually lead to changes in the Japanese clinical approach. The materials also include information on the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) to aid in recognizing VWD in patients presenting with subtle bleeding symptoms. The ISTH-BAT is a critical tool for the initial diagnosis of VWD, providing a standardized approach to assess bleeding symptoms and identify patients requiring further evaluation (Table S1 [50, 51]). The materials developed in this study are planned to be distributed and displayed through local government offices, medical societies, and hospitals. Additionally, campaigns leveraging social media platforms are scheduled to enhance public and professional awareness. A limitation of this study is that the effectiveness of the materials in enhancing VWD diagnosis rates has not yet been evaluated in clinical or public health settings. Future research should focus on assessing their impact on clinical decision-making and patient outcomes. To address this, we are currently planning an observational study to evaluate the materials' impact on VWD diagnosis rates, patient care pathways, and behavioral changes among both patients and healthcare professionals. These materials aim to enhance VWD diagnosis through increased awareness and early referral. Ongoing evaluation is required for effective implementation. This project was conducted as part of the activities of the VWD/TMA Subcommittee of the Japanese Society on Thrombosis and Hemostasis (JSTH). We would like to thank the subcommittee members for their assistance in the final review of the educational materials.: Dr. Hideo Yagi, Dr. Koichi Kokame, Dr. Masanori Matsumoto, Dr. Kazuya Sakai, Dr. Toshihiro Tamura, Dr. Kenji Nishio, Dr. Hisanori Horiuchi, Dr. Tadashi Matsushita, Dr. Yoshitaka Miyakawa, Dr. Noritaka Yada, Dr. Kazuma Yamakawa and Dr. Hideo Wada. This study received no funding. Azusa Nagao conducted the literature search and summarized the findings. All authors reviewed and interpreted the summarized data, contributed to the development of the educational materials, approved the final version, and reviewed the final draft of this manuscript. Azusa Nagao has received investigator-initiated research/education grant funding from Bayer Yakuhin Ltd., Pfizer Japan Inc., and Chugai Pharmaceutical Co., Ltd, is a medical advisor of Chugai Pharmaceutical Co., Ltd. and KM Biologics, and has received honoraria from Sanofi K.K., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Bayer Yakuhin Ltd., Fujimoto Pharmaceutical Corporation, KM Biologics, Pfizer Japan Inc., Novo Nordisk Pharma Ltd., and CSL Behring. Masahiro Takeyama has received payment or honoraria from Chugai Pharmaceutical Co., Ltd., CSL Behring, Sanofi K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Fujimoto Pharmaceutical Corporation, Bayer Yakuhin Ltd., K.M. Biologics Co., Ltd., and Pfizer Japan Inc.; has received investigator-initiated research grant funding from Chugai Pharmaceutical Co., Ltd. and Japan Blood Products Organization; and has participated on advisory boards for Chugai Pharmaceutical Co., Ltd. and Sanofi K.K. Kenichi Ogiwara has received honoraria Takeda Pharmaceutical Co., Ltd. Ryosuke Matsuno has received lecture fees and chairing fees from Novo Nordisk Pharma Ltd, Chugai Pharmaceutical Co., Ltd, Sanofi S.A., CSL Behring, Takeda Pharmaceutical Co., Ltd., and AbbVie GK. Additionally, Azusa Nagao has received research funding from the Gold Ribbon Research Grant in Japan. Emika Kobayashi has received honoraria Takeda Pharmaceutical Co., Ltd. Nana Ishida has received honoraria Chugai Pharmaceutical Co., Ltd, Ltd. Sanofi S.A., Bayer AG and CSL Behring. Satoshi Higasa has received honoraria Takeda Pharmaceutical Co., Ltd. Kagehiro Amano has received consultancy fees from Chugai Pharmaceutical Co., Ltd; research funding from KM Biologics Co., Ltd; speaker's bureau from Chugai Pharmaceutical Co., Ltd, Sanofi S.A., Bayer AG, Takeda Pharmaceuticals Co. Ltd, Novo Nordisk A/S, CSL Behring, KM Biologics Co., Ltd, Pfizer Inc., Japan Blood Products Organization, Fujimoto Pharmaceutical Co., Ltd and is listed as an entity's board of directors or advisory committee member for Chugai Pharmaceutical Co., Ltd and CSL Behring. Keiji Nogami has received research funding from Chugai Pharmaceutical Co., Ltd, Sanofi, Takeda, Bayer, Novo Nordisk, KM Biologics, CSL Behring, Fujimoto Seiyaku, Sekisui Medical, Sysmex, Asahi Kasei; honoraria from Chugai Pharmaceutical Co., Ltd, Sanofi, Takeda, Bayer, Novo Nordisk, CSL Behring, KM Biologics, Fujimoto Seiyaku, Sekisu Medical, Sysmex; speaker's bureau and patents from Chugai Pharmaceutical Co., Ltd; and participation on a Data Safety Monitoring Board or Advisory Board for Chugai Pharmaceutical Co., Ltd. Yasuharu Nishida has received a speaker honorarium from Takeda, JB, Bauer, Chugai, Fujimoto, Novo nordisk, Sanofi and CSL. Akihiro Sawada and Yojiro Maruyama have nothing to declare. This study did not involve the collection of patient-derived data or intervention in human subjects. Therefore, approval from an ethics review board was not required. No datasets were generated or analyzed during the current study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.