Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

Diagnosis and treatment of von Willebrand disease in 2024 and beyond.

MANUSCRIPT BACKGROUND AND AIM: The diagnosis and clinical care of patients with von Willebrand disease (VWD) has continued to evolve since the characterization of the von Willebrand factor (VWF) gene in 1985. This condition is almost certainly the most common inherited bleeding disorder, and the major symptomatic burden of the disease is experienced by females during their reproductive years. Diagnosis relies on the identification of a personal and family history of excessive mucocutaneous bleeding, and laboratory features consistent with quantitative and/or qualitative abnormalities of VWF. This review focuses on three aspects of VWD management, with current updates and a look into the future. MANUSCRIPT THEMES: First, we will address the role of genetics in the diagnosis and possible therapies for VWD. With current technologies, VWD genetic diagnosis is usually confined to the confirmation of type 2 subtypes of the disease and type 3 VWD analysis for family planning. While type 3 VWD is a potential candidate for the application of gene therapy, no treatments are currently close to entering the clinic. Second, the peri-procedural management of patients with VWD remains an important element of care. The choice of product, its dose and schedule all require careful consideration depending upon the type and disruptive nature of the planned procedure. Lastly, in addition to gene therapy, several other novel therapeutic interventions are also being developed for bleeding and prophylaxis in VWD. These include a VWF aptamer interfering with VWF clearance and bioengineered forms of VWF.

Progress in von Willebrand Disease Treatment: Evolution towards Newer Therapies.

von Willebrand disease (VWD) is a very heterogenous disease, resulting in different phenotypes and different degrees of bleeding severity. Established therapies (i.e., desmopressin, antifibrinolytic agents, hormone therapy for heavy menstrual bleeding, and von Willebrand factor [VWF] concentrates) may work in some subtypes, but not in all patients. In recent years, progress has been made in improving the diagnosis of VWD subtypes, allowing for more specific therapy. The impact of VWD on women's daily lives has also come to the fore in recent years, with hormone therapy, tranexamic acid, or recombinant VWF as treatment options. New treatment approaches, including the replacement of lacking factor VIII (FVIII) function, may work in those subgroups affected by severe FVIII deficiency. Reducing the clearance of VWF is an alternative treatment pathway; for example, rondaptivon pegol is a VWFA1 domain-binding aptamer which not only improves plasma VWF/FVIII levels, but also corrects platelet counts in thrombocytopenic type 2B VWD patients. These approaches are currently in clinical development, which will be the focus of this review. In addition, half-life extension methods are also important for the improvement of patients' quality of life. Targeting specific mutations may further lead to personalized treatments in the future. Finally, a few randomized controlled trials, although relatively small, have been published in recent years, aiming to achieve a higher level of evidence in future guidelines.

von Willebrand disease: A guide for the internist.

von Willebrand disease (VWD), the most common inherited bleeding disorder, results when patients either do not make enough von Willebrand factor (VWF) or make defective VWF. The pathophysiology of this disorder is complex but needs to be understood to interpret the diagnostic tests. Most patients have mild to moderate symptoms and can be adequately counseled and managed by a general internist, but some need to consult a hematologist. We review the pathophysiology of VWD, its subtypes, common presentations of each subtype, diagnostic testing, and management of mild as well as severe clinical manifestations of VWD.

The Role of the von Willebrand Factor Collagen-Binding Assay (VWF:CB) in the Diagnosis and Treatment of von Willebrand Disease (VWD) and Way Beyond: A Comprehensive 36-Year History.

The von Willebrand factor (VWF) collagen binding (VWF:CB) assay was first reported for use in von Willebrand diagnostics in 1986, by Brown and Bosak. Since then, the VWF:CB has continued to be used to help diagnose von Willebrand disease (VWD) (correctly) and also to help assign the correct subtype, as well as to assist in the monitoring of VWD therapy, especially desmopressin (DDAVP). However, it is important to recognize that the specific value of any VWF:CB is predicated on the use of an optimized VWF:CB, and that not all VWF:CB assays are so optimized. There are some good commercial assays available, but there are also some "not-so-good" commercial assays available, and these may continue to give the VWF:CB "a bad reputation." In addition to VWD diagnosis and management, the VWF:CB found purpose in a variety of other applications, from assessing ADAMTS13 activity, to investigation into acquired von Willebrand syndrome (especially as associated with use of mechanical circulatory support or cardiac assist devices), to assessment of VWF activity in disease states in where an excess of high-molecular-weight VWF may accumulate, and lead to increased (micro)thrombosis risk (e.g., coronavirus disease 2019, thrombotic thrombocytopenic purpura). The VWF:CB turns 37 in 2023. This review is a celebration of the utility of the VWF:CB over this nearly 40-year history.

How I treat von Willebrand disorders in older adults.

ABSTRACT: von Willebrand disease (VWD) is the most common bleeding disorder and especially milder type 1 VWD might not be cared for in specialty clinics. VW factor levels rise with age, but the rise of these levels does not necessarily correlate with bleeding risk. A recent bleeding history combined with recent labs are important for hemostatic management decision during surgical interventions. Antifibrinolytics appear safe in the population of older adults, whereas desmopressin (DDAVP) should be used cautiously. Where needed, factor concentrates present a great treatment option. Acquired von Willebrand syndrome is vastly underrecognized, but likely to surface in the aging, especially in the setting of comorbidities, such as plasma-cell dyscrasias. Intravenous immunoglobulin can be an effective treatment in this scenario, but potentially increases thrombotic risk.

Surprise diagnosis of acquired von Willebrand syndrome in a patient previously thought to have type III von Willebrand disease: evaluation and periprocedural management.

Acquired von Willebrand syndrome (AVWS) is a rare disorder that is characterised by an acquired deficiency of von Willebrand factor. AVWS was suspected in a patient with type III von Willebrand disease (VWD) who did not respond to factor replacement therapy. Given the crucial implications for management, we describe this patient's clinical presentation, diagnosis and periprocedural management. To facilitate pericardiocentesis, periprocedural management included steroids, intravenous immunoglobulin and factor replacement therapy. In other patients with suspected immune-mediated AVWS, a similar approach may be effective. This case also highlights the importance of distinguishing AVWS from inherited VWD.

Management of pregnant women who have bleeding disorders.

Bleeding disorders, including von Willebrand disease (VWD), hemophilia, other coagulation factor deficiencies, platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Successful management of bleeding disorders in pregnant women requires not only an understanding of bleeding disorders but also an understanding of when and how bleeding occurs in pregnancy. Bleeding does not occur during a normal pregnancy with a healthy placenta. Bleeding occurs during pregnancy when there is an interruption of the normal utero-placental interface, during miscarriage, during an ectopic pregnancy, or at the time of placental separation at the conclusion of pregnancy. Although mild platelet defects may be more prevalent, the most commonly diagnosed bleeding disorder among women is VWD. Other bleeding disorders are less common, but hemophilia carriers are unique in that they are at risk of bleeding themselves and of giving birth to an affected male infant. General guidance for maternal management of a woman who is moderately or severely affected includes obtaining coagulation factor levels at a minimum in the third trimester; planning for delivery at a center with hemostasis expertise; and anticipating the need for hemostatic agents. General guidance for fetal management includes pre-pregnancy counseling; the option of preimplantation genetic testing for hemophilia; delivery at a tertiary care center with pediatric hematology and newborn intensive care; consideration of cesarean delivery of a potentially severely affected infant; and avoidance of invasive procedures such as scalp electrodes and operative vaginal delivery in any potentially affected infant.

Prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding: A systematic review.

BACKGROUND: Optimal peri-operative management for women with Von Willebrand disease (VWD) and heavy menstrual bleeding (HMB) remains undetermined. AIM AND METHODS: To evaluate (pre)operative management in relation to (post)operative bleeding after endometrial ablation (EA) and hysterectomy in VWD women with HMB by performing a database search between 1994 and 2023. RESULTS: Eleven cohort studies and 1 case-report were included, of overall 'low' quality, describing 691 operative procedures. Prophylaxis (Desmopressin, clotting factor concentrates or tranexamic acid) to prevent bleeding was described in 100% (30/30) of EA procedures and in 4% (24/661) of hysterectomies. Bleeding complications despite prophylaxis were described in 13% (3/24) of hysterectomies vs 0% (0/30) in EA. CONCLUSION: VWD women often seem to experience bleeding complications during hysterectomy and all women with VWD received preprocedural hemostatic agents during EA, indicating potential under- and overdosing of current prophylactic strategies. Prospective studies are needed to determine the optimal (pre)operative strategy for gynecological surgical procedures in women with VWD.

Patient-centered care in von Willebrand disease: are we there yet?

INTRODUCTION: Von Willebrand Disease is the most common inherited bleeding disorder. Paradoxically, affected individuals are often misdiagnosed and experience substantial diagnostic delay. There are sex-specific health disparities in VWD rooted in the stigmatization of vaginal bleeding, which leads to symptom dismissal, lack of timely access to care and lower health-related quality of life. AREAS COVERED: Following the core elements of patient-centered care - respect for patient preferences, values, and needs, we describe the current state of VWD care. Challenges of diagnostic delay, serial misrecognition of abnormal bleeding, and symptom dismissal are barriers that disproportionately affect women with VWD. These negative effects are further amplified in individuals living in low- and middle-income countries. We describe the importance of coordinated multidisciplinary care, as well as the need for patient education and empowered self-advocacy. EXPERT OPINION: While tremendous work has been done to improve the diagnosis and management of VWD, timely and high-quality research is urgently needed to address care gaps. Systemic changes such as resource investment, dedicated research funding for novel treatment modalities, and effective knowledge translation strategies to address structural barriers are needed to facilitate effective patient-centered care for VWD.

Gastrointestinal bleeding in von Willebrand patients: special diagnostic and management considerations.

INTRODUCTION: Severe and recurrent gastrointestinal (GI) bleeding caused by angiodysplasia is a significant problem in patients with von Willebrand disease (VWD) and in those with acquired von Willebrand syndrome (AVWS). At present, angiodysplasia-related GI bleeding is often refractory to standard treatment including replacement therapy with von Willebrand factor (VWF) concentrates and continues to remain a major challenge and cause of significant morbidity in patients despite advances in diagnostics and therapeutics. AREAS COVERED: This paper reviews the available literature on GI bleeding in VWD patients, examines the molecular mechanisms implicated in angiodysplasia-related GI bleeding, and summarizes existing strategies in the management of bleeding GI angiodysplasia in patients with VWF abnormalities. Suggestions are made for further research directions. EXPERT OPINION: Bleeding from angiodysplasia poses a significant challenge for individuals with abnormal VWF. Diagnosis remains a challenge and may require multiple radiologic and endoscopic investigations. Additionally, there is a need for enhanced understanding at a molecular level to identify effective therapies. Future studies of VWF replacement therapies using newer formulations as well as other adjunctive treatments to prevent and treat bleeding will hopefully improve care.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder. It is caused by problems with von Willebrand factor (VWF), a protein in blood that helps stop bleeding. People with VWD either have low levels of VWF or VWF that does not work properly. The disease causes bleeding symptoms in 1 in 1000 individuals. Three main types of VWD exist. Depending on the type, people can have minimal symptoms or serious bleeding that needs hospital care.Patients with severe VWD may often experience repeated bleeding from the gastrointestinal tract. This is usually due to the formation of abnormal fragile vessels (malformations) called angiodysplasia, which have been linked to the absence or abnormal function of VWF. These fragile vessels are very difficult to find and diagnose. At present, available treatments for angiodysplasia, including long-term VWF replacement therapy, are not very effective. As a result, VWD patients with angiodysplasia have a poor quality of life.More research is needed to better evaluate current treatments and explore the contribution of abnormal VWF in the development of angiogenesis and angiodysplasia in VWD which may reveal new targets for treatment.

Patient with von Willebrand Disease Presenting for Selective Scaling and Root Planning.

Von Willebrand disease is a platelet phase bleeding disorder, affecting platelet aggregation and adhesion. It can be inherited or acquired in origin. Patients with von Willebrand disease can be successfully treated in a dental setting. This article discusses the dental management of a 74-year-old white woman presenting with pain and gingival erythema in the maxillary anterior area. The article emphasizes the importance of consultation with the hematologist in treating patients with von Willebrand disease, and understanding that disease severity varies in patients. A patient-specific protocol recommended by the hematologist should be followed for each patient.

An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland.

INTRODUCTION: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. However, recognition of the disease by both the public and healthcare professionals lags behind that of other bleeding disorders, leading to delays in diagnosis and treatment for patients. Updated national guidelines are needed to highlight an appropriate pathway for managing VWD patients in a timelier manner. AIM: To identify ways in which care for VWD can be achieved on a more equitable basis. METHODS: Using a modified Delphi approach, a panel of VWD experts developed 29 statements across five key themes. These were used to form an online survey that was distributed to healthcare professionals involved in VWD care across the UK and Republic of Ireland (ROI). Stopping criteria comprised 50 responses received, a 3-month window for response (February-April 2022) and 90% of statements passing consensus threshold. Threshold for consensus for each statement was agreed at 75%. RESULTS: A total of 66 responses were analysed with 29/29 statements achieving consensus of which 27 attained ≥90% agreement. From the high degree of consensus, eight recommendations were derived regarding how detection and management of VWD can be improved to provide equity of care between men and women. CONCLUSION: Implementation of these eight recommendations across the VWD pathway has the potential to raise the standard of care for patients in the UK and ROI by reducing delays to diagnosis and treatment initiation.

Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in von Willebrand disease murine models.

The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant von Willebrand factor (VWF) concentrates have started to emerge. Here, we report an original approach using synthetic platelet (SP) nanoparticles for the treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF, and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SPs to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from mice with VWD-2B and deficient VWF (VWF-KO, ie, type 3 VWD). In vivo, using a tail-clip assay, SP treatment reduced blood loss by 35% in mice with VWD-2B and 68% in mice with VWF-KO. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen-binding peptide, although not sufficient by itself, was crucial for SP efficacy in VWD-2B; whereas all 3 peptides appeared necessary for mice with VWF-KO. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of mice with VWF-KO led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability.

Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders.

BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community.

More people experience mucocutaneous bleeding (MCB), affecting tissues like skin and gums, than have hemophilia A or B. MCB is not understood as well as hemophilia. Common types of MCB include nosebleeds, bleeding gums, heavy menstrual bleeding, and digestive tract bleeding. Mucocutaneous inherited bleeding disorders include inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS), von Willebrand Disease (VWD), and others. Diagnosing and treating MCB is complicated and sometimes medical providers dismiss the bleeding that patients report when they cannot find a medical explanation for it. Many people with mucocutaneous bleeding (PWMCB) do not receive the care they need; for example, women with VWD live with symptoms for, on average, 16 years before they are diagnosed in the US. This struggle to obtain care has important negative impacts on patients' physical and psychological health and their quality-of-life. The National Hemophilia Foundation (NHF), a large US bleeding disorders patient advocacy organization, set out to develop a National Research Blueprint for Inherited Bleeding Disorders focused on community priorities. They brought together a group of patients, providers, and researchers with MCB expertise to identify the research that would most improve the lives of PWMCB through targeted and accessible diagnostics and therapies. We report in this paper that research is needed to better understand the biology of MCB and to define the mechanisms of disease in these disorders. We also describe high priority research questions for each of the main disorders, novel therapeutics, and aging.

Low von Willebrand Disease: A Bleeding Disorder of Unknown Cause?

von Willebrand disease (VWD) represents the most common inherited bleeding disorder. The majority of VWD cases are characterized by partial quantitative reductions in plasma von Willebrand factor (VWF) levels. Management of patients with mild to moderate VWF reductions in the range of 30 to 50 IU/dL poses a common clinical challenge. Some of these low VWF patients present with significant bleeding problems. In particular, heavy menstrual bleeding and postpartum hemorrhage can cause significant morbidity. Conversely, however, many individuals with mild plasma VWF:Ag reductions do not have any bleeding sequelae. In contrast to type 1 VWD, most patients with low VWF do not have detectable pathogenic VWF sequence variants, and bleeding phenotype correlates poorly with residual VWF levels. These observations suggest that low VWF is a complex disorder caused by variants in other genes beyond VWF. With respect to low VWF pathobiology, recent studies have shown that reduced VWF biosynthesis within endothelial cells likely plays a key role. However, pathological enhanced VWF clearance from plasma has also been described in approximately 20% of low VWF cases. For low VWF patients who require hemostatic treatment prior to elective procedures, tranexamic acid and desmopressin have both been shown to be efficacious. In this article, we review the current state of the art regarding low VWF. In addition, we consider how low VWF represents an entity that appears to fall between type 1 VWD on the one hand and bleeding disorders of unknown cause on the other.

Challenges in the management of women with type 2B von Willebrand disease during pregnancy and the postpartum period: evidence from literature and data from an international registry and physicians' survey-communication from the Scientific and Standardization Committees of the International Society on Thrombosis and Haemostasis.

BACKGROUND: Management of women with type 2B von Willebrand disease (VWD) during pregnancy is challenging because of dysfunctional von Willebrand factor (VWF) and the complexity resulting from discrepant VWF/factor VIII (VWF/FVIII) levels, impaired platelet-dependent VWF activity, progressive thrombocytopenia, and risks associated with the use of desmopressin. There is a lack of high-quality evidence to support clinical decision making. OBJECTIVES: In this study, we examined the current diagnostic and management approaches and outcomes in women with VWD during pregnancy. METHODS: Data were collected via 3 avenues: literature review, an international registry, and an international survey on physicians' practices for the management of pregnancy in women with VWD. The registry and survey were supported by the International Society on Thrombosis and Haemostasis. RESULTS: Data on clinical and laboratory features, management and bleeding complications, and pregnancy outcomes of a total of 55 pregnancies from 49 women across the globe (literature: 35, registry: 20) and data reported by 112 physicians were analyzed. We describe the largest dataset on pregnancies in women with type 2B VWD available to date. The data highlight the following key issues: a) bleeding complications remain a concern in these patients, b) the target safe VWF level and the ideal monitoring approach are unknown, c) there is a wide range of hemostatic management practices in the type and timing of treatment, and d) physicians have diverse views on the mode of delivery and use of neuraxial anesthesia. CONCLUSION: We conclude that an international consensus and guidance are critically required for better care and improved outcomes in this patient cohort.

The diagnosis, natural history, and management of von Willebrand disease in women in the age of guidelines.

INTRODUCTION: Women and girls with bleeding disorders face multiple bleeding challenges throughout their life. The most significant morbidity and mortality are due to heavy menstrual bleeding and postpartum hemorrhage in their reproductive years. The ASH/ISTH/NHF/WFH 2021 guidelines on diagnosing and managing von Willebrand disease (VWD) provide several new updates. AREAS COVERED: Women with VWD have a higher prevalence of heavy menstrual bleeding. The subpopulation of adolescents is particularly vulnerable, as the diagnosis is often delayed with increased comorbidity of iron deficiency anemia and associated symptoms. A detailed review is done on the prevalence of bleeding-related complications, especially heavy menstrual bleeding (HMB) and post-partum hemorrhage (PPH). The management strategies are also reviewed in detail, with a specific focus on the target factor levels and the use of antifibrinolytics. EXPERT OPINION: The 2021 ASH/ISTH/NHF/WFH diagnostic and management recommendations are reviewed with a specific focus on hormonal methods of HMB management and antifibrinolytics in this situation. The reviewed topics include neuraxial anesthesia, factor cutoff, and tranexamic acid use in the postpartum period.

Beyond the guidelines: how we approach challenging scenarios in the diagnosis and management of von Willebrand disease.

Although von Willebrand disease (VWD) is the most common inherited bleeding disorder, its diagnosis and management are often challenging. Clinical practice guidelines, developed through systematic review of the medical literature and considering the best available evidence, provide guidance for common clinical scenarios. However, in the clinical setting, patients often present with characteristics and nuances that may fall outside the realm of available evidence and guidelines, and hence, shared decision-making will be essential in the evaluation and management of these patients. The challenges in the diagnosis of VWD are mainly attributable to the heterogeneity of the disorder, limitations of laboratory assays, and the significant impact of various physiologic processes on von Willebrand factor. The impact of physiologic normalization of von Willebrand factor, which may occur in various settings such as pregnancy, inflammation, or aging, remains uncertain, as is the optimal management in these scenarios. Multidisciplinary and individualized care, based on evolving evidence supported by clinicians, patients, caregivers, and stakeholders, will be needed to ensure the highest quality care for those who live with VWD.