Seventh Åland Island Meeting on von Willebrand Disease.

This article was funded by Octapharma AG.

The seventh Åland Island meeting provided a fitting venue to discuss the latest developments in diagnosis and management of VWD, a century after the first case of VWD was documented on the islands (video summary available in Supporting Information ). Although the complexities of VWD diagnosis are being unravelled, navigating the diagnostic landscape in VWD remains still challenging. Our understanding of the complex genetics of VWD has increased in recent years, along with improved laboratory testing. Current research will further increase this understanding and improve the diagnosis and treatment of VWD. Timely and easily accessible guidance on the diagnosis of VWD is needed to ensure that the best practice is widely available and can be adopted. Despite progress in defining VWD severity, an accepted and practical definition of severe disease is needed to better guide treatment decisions. Addressing the under‐recognition of the seriousness of VWD bleeding symptoms on health‐related QoL and the relatively limited use of prophylaxis in people with severe VWD are key priorities. Recent data from clinical trials have shown that long‐term prophylaxis with VWF‐containing concentrates is effective and well tolerated in people with severe VWD. The use of personalised therapy for VWD merits further investigation. The efficacy of VWF‐containing concentrates as short‐term prophylaxis to provide haemostatic cover for medical procedures is well documented. More recently, a welcome increase in focus on the challenges and management of VWD in women having HMB and bleeding risk during pregnancy and childbirth. In addition to obstetrics and gynaecology, gastroenterology is another multidisciplinary field, which needs vivid education and interactions with the clinical and research experts of VWD. Much has been achieved in the diagnosis and treatment of VWD, and the outlook is positive for people with VWD, who can expect continued improvements in their care in the coming years. To ensure optimal translation of increased understanding to improved management and care of people with VWD, a multidisciplinary approach with biochemists, geneticists, and cell biologists partnering with clinicians and industry is needed.

Key points: VWF has roles beyond haemostasis, including immune modulation, angiogenesis and wound healing; VWF has been implicated in a variety of pathologies, including tumour metastasis, sepsis, malaria, sickle cell disease and liver disease. VWF plays a well‐known role in haemostasis, and there is increasing evidence linking VWF to other biological processes, such as inflammation, angiogenesis, wound healing and bone metabolism. It remains unclear how exactly VWF exerts these diverse effects, although depending on the context, VWF can function as an adhesion protein, a carrier protein or a ligand for cell signalling [ 148 ] (Figure  13 ). Novel roles for VWF. Adapted from [ 148 ]. COVID, coronavirus disease; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; TTP, thrombotic thrombocytopenic purpura; VWD, von Willebrand disease; VWF, von Willebrand factor. VWF is synthesised and secreted by endothelial cells into the lumen of blood vessels as ultra‐large VWF and into the subendothelial matrix as low molecular weight VWF [ 149 ]. There is a good understanding of the concentration of VWF and its function within the bloodstream. Very little is known, however, about its concentration and functions in the vascular bed where VWF will be in contact with cell types other than endothelial cells and blood cells [ 149 ]. VWF is unique when compared with other coagulation factors in that it has numerous binding sites, enabling interaction with a wide variety of structurally diverse binding partners (including FVIII, GPIb, p‐selectin, collagens, integrins, glycosaminoglycans, proteoglycans and cell surface receptors) [ 148 ]. Additionally, VWF is functionally regulated by some of these interactions and by fluid shear forces, which can trigger a conformational change of VWF and expose hidden cryptic interaction sites on VWF, thereby altering its subsequent interactome [ 148 , 150 ]. One emerging area of VWF function is in the promotion of inflammation [ 148 ]. In mouse models, inhibition of VWF expression or activity decreased inflammation and vascular permeability [ 151 , 152 ]. Studies have also observed interaction of VWF with various innate immune cells, including neutrophils, macrophages and dendritic cells. VWF induced a pro‐inflammatory phenotype in macrophages, much like the classically inflammatory lipopolysaccharide (LPS), acting via LRP1 and MAP kinase‐dependent signalling [ 153 ]. These immune cell interactions specifically link primary haemostasis with innate immunity, which play important and overlapping roles during vascular injury. VWF has also been implicated in angiogenesis, with different studies suggesting both anti‐angiogenic and pro‐angiogenic roles [ 148 ]. VWF can act as a carrier for both anti‐angiogenic (angiopoietin‐2) and pro‐angiogenic (VEGF‐A and angiopoetin‐1) factors. These opposing angiogenic functions of VWF are likely due to time‐ and context‐specific differences [ 148 ]. VWF has also been shown to regulate vascular smooth muscle cell proliferation and migration via LRP4 and MAP kinase‐dependent signalling [ 154 ]. VWF also has a heparin‐binding site that enables binding to several growth factors, and there is evidence that VWF plays a role in wound healing. For example, mice deficient in VWF show reduced wound healing and reduced levels of growth factors at the site of injury [ 155 ]. VWF may act as a reservoir for growth factors and support the role of fibronectin in wound healing [ 155 ]. VWF has also been shown to regulate vascular smooth muscle proliferation and migration via LRP4‐ and MAPK‐dependent signalling [ 154 ]. VWF has been implicated in a variety of pathologies, including tumour metastasis, sepsis, malaria, sickle cell disease and liver disease [ 148 ]. Our understanding of VWF's many roles beyond haemostasis is expanding rapidly and might uncover new potential therapeutic targets to improve treatment of these conditions. Key points: Bleeding disorders of unknown cause remain a diagnostic challenge; diagnosis and their management can vary considerably between centres and between countries; bleeding complications still occur in people with bleeding disorders of unknown cause treated prophylactically, suggesting that they are undertreated. When an individual presents with a bleeding tendency and is referred to a haematologist, 60%–70% of cases will be diagnosed with a ‘bleeding disorder of unknown cause’ (BDUC) [ 156 ]. The clinical definition of a BDUC is normal results from a haemostatic investigation despite clinically significant bleeding [ 157 ]. This diagnosis is typically given after exclusion of known bleeding disorders such as VWD, haemophilia A/B, platelet function disorders and connective tissue disorders (such as Ehlers–Danlos or Mb Osler–Weber collagenose). BDUC diagnosis is also based on the severity of bleeding as determined by BAT scores and clinical gestalt [ 156 ]. People diagnosed with BDUC are typically female (60%–80%) and 30–40 years old [ 158 , 159 , 160 ]. Despite this majority and despite often presenting with common symptoms of BDUC (HMB and postpartum bleeding), females typically face longer diagnostic delays than males [ 160 ]. Excess bleeding during surgery and dental procedures is also present, and between 30% and 40% of individuals diagnosed with BDUC have a family history of bleeding [ 160 , 161 ]. Compared with the general population, individuals living with BDUC have worse physical and mental health QoL scores comparable to individuals with VWD or platelet function defects [ 162 ]. Diagnosis and management of BDUC can vary considerably between centres and between countries [ 163 , 164 ]. To address this need, the ISTH developed a diagnostic algorithm for BDUC, which identified a panel of essential laboratory investigations that should be carried out during the initial consultation (including complete blood count and peripheral blood smear, prothrombin time, activated partial thromboplastin time, Clauss Fibrinogen, VWF:Ag and VWF activity, FVIII, FIX, FXI and light transmission platelet aggregation) [ 156 ]. Once the BDUC diagnosis is confirmed, a stepwise and personalised treatment plan is typically suggested. This plan is based on bleeding history, and how bleeding complications have been managed in the past. Treatment options are the same as those used for known bleeding disorders. Tranexamic acid is almost always used, sometimes together with desmopressin, and occasionally, platelet transfusions are given. Recombinant activated FVII is prescribed rarely and is often only used in cases of major bleeding complications [ 156 , 164 ]. It is worth noting that treating BDUC with desmopressin or factor replacement therapies can increase the risk for thrombosis, as the underlying cause of bleeding tendency is unknown [ 160 ]. However, bleeding complications still occur in people with BDUC treated prophylactically, suggesting that BDUC is undertreated [ 161 , 165 ]. The degree of care provided to people with BDUC can be improved by optimising diagnosis strategies, reducing the diagnostic delay faced by women, identifying what constitutes clinically relevant abnormal bleeding and understanding underlying causes and potential genetic inheritance patterns [ 156 , 160 , 161 ]. BDUC is likely a heterogeneous group of aetiologies, and the cause(s) remain elusive. This is despite a number of approaches being used to study BDUC, including functional testing of fibrinolysis and anticoagulant factors, viscoelastic testing, thrombin generation assays, genomics, proteomics and microfluidics using flow chambers or endothelial vessel‐on‐a‐chip models [ 160 ]. In the meantime, identifying the optimal care pathway for BDUC is vital in order to improve outcomes, quality of care and compliance with guidelines, while supporting communication with people with BDUC and reducing costs [ 164 , 166 , 167 , 168 , 169 ] (Figure  14 ). Identifying the BDUC care pathway. Adapted from [ 160 ]. BDUC, bleeding disorder of unknown cause. Key points: Novel therapeutic approaches for VWD are limited compared to haemophilia; gene therapy is complicated by the large size of the gene; new treatment avenues include protein‐based agents, and modulation of VWF clearance and secretion; antibodies and aptamers targeting VWF cleavage and clearance are under investigation, as are agents promoting VWF release. In comparison with haemophilia A, for which there are over 100 active interventional studies, there are fewer than 10 for VWD (ClinicalTrials.gov Dec 2025). This lower level of attention given to VWD translates to fewer treatment options. The past decade saw the development of extended half‐life products, non‐factor therapies and gene therapies for haemophilia, whilst VWD advancements have been limited, centring mainly on the development of rVWF [ 170 ]. There are multiple reasons for this discrepancy, both clinical and biological (which have been discussed in previous sections). Nevertheless, new treatment avenues for VWD are actively being investigated. One potential treatment avenue is gene therapy. In theory, as VWD is entirely monogenic, it is a promising candidate for gene therapy. However, the large size of the VWF gene (vWF cDNA approximately 8.3 kb) limits feasible development options, due to packaging limitations of currently used Adeno‐associated virus (AAV) vectors (∼4.7 kb) [ 171 ]. The VWF protein is also complex, with many functional domains and large multimeric structures; it also requires protein secretion machinery, mostly expressed in the endothelium [ 172 ]. Gene therapy has been attempted in pre‐clinical models, using AAV vectors with larger carrying capacity, but expression titres were very low [ 171 ]. An alternative gene‐related approach is that of targeted RNA interference to reduce the impact of dominant negative mutants. Early attempts resulted in a partial restoration of VWF function, but efficiency was low [ 173 ]. Protein‐based approaches are also being investigated. Off‐label use of the bispecific antibody emicizumab has been reported in several cases of type 3 VWD [ 174 ]. The haemostatic agent anti‐protein S antibody (VGA039) is in clinical trials for various bleeding disorders, including VWD [ 174 , 175 ]. HMB‐002, a monovalent antibody designed to modulate VWF activity by targeting the C‐terminal cystine knot (CK) domain of VWF, is currently undergoing clinical trials [ 176 , 177 ]. KB‐V13A12 is a novel preclinical bispecific nanobody designed to reduce endogenous VWF clearance by bridging it to albumin, thereby promoting higher VWF levels [ 178 ]. Other approaches to modulate VWF clearance and release are also being investigated. For example, antibodies and nanobodies are being developed that target and block ADAMTS13‐mediated cleavage of VWF (Mab508, SZ‐179) [ 174 , 179 , 180 ]. Rondoraptivon pegol (BT200), a pegylated A1 domain binding aptamer, reduces clearance of VWF via the scavenger receptor LRP‐1 [ 181 ]. Overall, an improved understanding of VWF biology, from synthesis, trafficking and secretion to clearance, will help to identify additional therapeutic opportunities for testing and translation into novel VWD therapies.

Key points: Diagnosis of VWD can be challenging and often delayed; BATs should form a key part of diagnostic procedures; newer diagnostic assays (VWF:GPIbM and VWF:GPIbR) are favoured over the more traditional VWF:RCo assay; VWD types differ in diagnostic criteria. Accurate and timely diagnosis of VWD is essential for directing treatment and remains a challenge for clinicians and people with VWD. A major obstacle in VWD diagnosis is a lack of clinician awareness, particularly among non‐haematologists, leading to delays in diagnosis and uncertainty regarding clinical management. Mostly, the patients with VWD first encounter specialists, such as gastroenterologists, gynaecologists or surgeons, without yet having the diagnosis. VWD diagnosis often requires specialised assays, which can vary between laboratories, sometimes leading to misdiagnoses [ 28 ]. Genotyping can be costly and is currently only recommended in certain types of VWD [ 10 ]. A survey conducted on the diagnosis and management of VWD, prior to the development of the 2021 international guidelines on diagnosis, recruited 601 participants (people with VWD, caregivers and healthcare providers) across 71 countries [ 29 ]. Among the highest priority topics identified were diagnostic criteria and classification, BATs and treatment options for women. People with VWD and clinicians agreed that the quality of testing and standardised laboratory processes are crucial. Interestingly, there was a discrepancy in the perception of the importance of the diagnostic journey, highlighting the impact of delayed diagnosis on quality of life and treatment outcomes. The use of BATs in diagnosis was a key recommendation in the guidelines [ 10 ]. Validated BATs are a central initial step in the diagnostic journey, although their performance can vary depending on the setting in which they are used [ 30 ]. If there is a low probability that an individual has VWD, in settings such as primary care, BATs are effective in excluding VWD as an initial screening test. However, if VWD is a medium‐to‐high probability, such as in haematology clinics, BATs are less effective. Here, they should not be used to exclude the need for further laboratory testing, especially in individuals with a family history of VWD. Despite these limitations, BATs can be useful in the referral setting to assess the severity of bleeding and in conjunction with specific tests as part of the initial diagnostic approach. For women with VWD, use of BATs should take into account changing circumstances throughout their lifetimes (e.g. HMB, pregnancy and menopause). An evaluation of the ISTH‐BAT in a cohort of healthy female individuals showed increasing variability in normal ranges for the ISTH‐BAT with increasing age (18–30 years vs. 52–88 years), linked to older women having higher menorrhagia scores and experienced more haemostatic challenges across their lifetimes [ 31 ]. Screening tools specifically for women with HMB have been evaluated and shown to be useful [ 32 ]. Informing the publication of the 2021 guidelines, a systematic review and meta‐analysis assessed the utility of laboratory assays for VWF activity and use of desmopressin trials in the diagnosis of VWD [ 33 ]. Newer diagnostic assays that measure the platelet‐binding activity of VWF to glycoprotein Ib (GPIb), such as VWF:GPIbM (using mutant GPIb) and VWF:GPIbR (using wild‐type GPIb and ristocetin), were favoured over VWF:RCo due to their lower coefficient of variation and higher reproducibility compared with VWF:RCo [ 10 , 33 ]. The 2021 guidelines recommend that a VWF level of <30 IU/dL be used for VWD diagnosis, regardless of bleeding symptoms. In individuals with abnormal bleeding suspected of type 1 VWD, a higher VWF level of <50 IU/dL should be used [ 10 ]. These recommendations are based on studies showing that many adults with 30–50 IU/dL often have abnormal bleeding, such as HMB, and that there can be an age‐dependent increase in VWF levels; adults with 30–50 IU/dL likely had levels <30 IU/dL when they were younger [ 34 ]. Additional testing should also be considered when VWF levels do not explain bleeding symptoms, to exclude the possibilities of other concomitant conditions (e.g., platelet function disorders) [ 10 ]. For those with suspected type 1C VWD, a desmopressin trial with 1‐ and 4‐h post‐administration blood work should be used in preference to the VWFpp/VWF:Ag (ratio of pro‐peptide to antigen) to confirm increased clearance of VWF [ 10 ]. This approach is favoured because setting a threshold for VWFpp/VWF:Ag is challenging, and the desmopressin trial also informs treatment strategy [ 10 ]. When diagnosing type 2 VWD, it is more accurate to use a higher platelet‐dependent VWF activity/VWF:Ag ratio threshold of <0.7 instead of <0.5 to avoid missing those that could benefit from treatment [ 10 , 33 , 35 ]. For diagnosing subtypes of type 2 VWD, recommended assays include multimer analysis or collagen binding assays (VWF:CB). Multimer analysis has a high sensitivity and specificity [ 33 ] and is preferred over collagen assays, but this is a difficult, labour‐intensive and costly technique [ 36 , 37 ]. If a collagen assay is performed as an alternative to multimer analysis, it is important that the correct type of collagen is used. Types I and/or III collagen are generally preferred because type IV is not very sensitive to high molecular weight multimers [ 33 ]. If possible, both assays should be performed, especially in cases where VWF levels are close to threshold levels. When available, genetic testing is preferred over low‐dose ristocetin‐induced platelet aggregation (RIPA) for diagnosing type 2B, due to the ease of sequencing the relevant area and its value in informing prognosis and treatment [ 10 ]. The diagnostic algorithm outlined in the 2021 guidelines was based on the presumption that access to and costs of testing were unlimited factors. The algorithm was developed to provide guidance on the ideal diagnostic procedure, recognising that, even in high resources countries, not all diagnostic tools are available [ 10 ]. Adaptation of the guidelines for differently resourced settings, such as low‐ and middle‐income countries, is needed to improve the diagnosis of VWD globally and increase access to care. The guidelines identified several knowledge gaps and research priorities for VWD diagnosis (Figure  3 ). Emphasis should be placed on understanding the performance of diagnostic tools and assays in specific populations, such as children, women and in different racial/ethnic groups. Since the guidelines were published, VWD has been included in the World Bleeding Disorders Registry ( https://wfh.org/research‐and‐data‐collection/world‐bleeding‐disorders‐registry/ ). Such real‐world data will be important for improving the understanding of the use/accuracy of diagnostic tools and management strategies in different subgroups on an international level. Summary of knowledge gaps and research priorities outlined in the 2021 international guidelines on the diagnosis of von Willebrand disease. Adapted from [ 10 ]. Key points: VWF:RCo assay uses a non‐physiological method of inducing VWF‐platelet binding; newer platelet binding activity assays (VWF:GPIbM and VWF:GPIbR) are recommended; challenges remain with complex multimer analysis. The VWF:RCo assay for assessing VWF function may be problematic. The assay uses a non‐physiological method of inducing VWF‐platelet binding (binding to ristocetin in vitro versus shear stress in vivo) and exhibits a high coefficient of variation between different testing sites, in some cases up to 50% [ 38 , 39 ]. As discussed above, there are many non‐pathogenic variants of VWF that do not cause disease but can impact test results, and this can lead to overdiagnosis. For example, the p.D1472H variant (which is present at a higher frequency in African Americans) causes a lower VWF:RCo/VWF:Ag ratio [ 40 ]. Individuals with this variant will demonstrate a ristocetin dose‐dependent decrease in the VWF:RCo/VWF:Ag ratio, despite normal direct platelet GPIb binding assays and minimal bleeding symptoms [ 41 ]. The 2021 guidelines conditionally recommended against the use of ristocetin cofactor assays and recommended the newer platelet binding activity assays (e.g., VWF:GPIbM and VWF:GPIbR) [ 10 ]. Since publication of the guidelines, there is increasing evidence to support this recommendation, with studies suggesting that GPIb assays are superior to ristocetin‐based assays [ 42 , 43 ]. GPIb assays are automated and easy to run, exhibiting a much lower coefficient of variation and higher sensitivity than ristocetin‐based ones. The GPIb assays are becoming standard in the field, despite being more costly. More evidence is needed to strengthen this recommendation and convince payers of its validity. One limitation of the GPIb assays is that they do not provide information on the collagen‐binding activity of VWF. As discussed above, multimer assays for VWD diagnosis are complex and challenging to perform, and there is increasing evidence that collagen‐binding assays can substitute for multimer distribution [ 36 , 37 , 44 ]. As genetic variants of VWF also affect collagen binding, the VWF:CB can be useful in differentiating VWD type 2 variants. Other emerging options for testing include microchip‐based systems, such as the total thrombus‐formation analysis system (T‐TAS). This has been shown to be useful in detecting severe VWD in several studies, but is unable to discriminate milder forms of the disease [ 45 ]. In the future, testing for VWD should be simplified by employing methods that are less susceptible to errors in pre‐analytical variables and result interpretation. As GPIb assays are still non‐physiological, the need remains for a shear‐based assay that more closely reflects the biology of VWF. Finally, evidence‐based guidelines must continue to be updated to reflect accumulating evidence. Key points: The diagnosis of VWD in infants and young children is complex due to limited dedicated paediatric data, infrequent haemostatic challenges and high variability of BATs. The diagnosis of VWD in infants and toddlers poses unique problems when compared with older children and adults. At this age, VWD‐related symptoms, such as epistaxis, bruising and oropharyngeal bleeding, are common irrespective of VWD status [ 46 ]. Bruising and head trauma are also frequent as children learn to crawl and walk [ 47 ]. Conversely, many children may remain asymptomatic in the absence of significant haemostatic challenges [ 48 ]. Diagnosis is particularly difficult in children referred solely because of a family history of VWD, but with a minimal bleeding phenotype [ 49 ]. Additionally, bleeding manifestations in children do not always correlate with VWF residual levels or activity [ 48 , 50 ]. When there is a strong clinical suspicion of VWD in an infant or toddler, based on family history or a positive BAT, it is recommended that the child undergoes a complete panel of VWD‐specific laboratory testing. Laboratory evaluation in young children presents specific challenges, including developmental differences in the haemostatic system, as well as practical issues related to blood volume requirements [ 51 , 52 ]. Repeat testing is often needed to establish an accurate diagnosis, as intravenous blood draws can be stressful, resulting in increased levels of VWF [ 53 , 54 ]. A diagnostic algorithm for children presenting with mucocutaneous bleeding has been recently proposed [ 55 ] (Figure  4 ). Proposed algorithm for the diagnosis of VWD in children who present with mucocutaneous bleeding. Adapted from [ 55 ]. Although most individuals with VWD start to experience bleeding symptoms during the first decade of their life, diagnosis is frequently delayed until adulthood, with a median age at diagnosis of 33 years [ 1 ]. Data on clinical presentation and laboratory findings in children under 2 years of age remain scarce [ 47 ]. A study using data from the US Hemophilia Treatment Center Network (USHTCN) evaluated infants and children with VWD diagnosed before the age of 2 [ 47 ]. Most were referred for diagnostic evaluation because of a family history of VWD, and 63% were diagnosed with Type 1 VWD, lower than the 75% reported in broader age cohorts. Forty‐one percent of first bleeding events occurred within the first year of life. The most common bleeding manifestations included oral mucosal bleeding, circumcision‐related bleeding and intracranial or extracranial bleeding, differing from spontaneous epistaxis, oral cavity bleeding or prolonged bleeding after skin laceration, which are more commonly reported in older children and adults. Notably, intracranial haemorrhage occurred in up to 5% of cases and was not limited to individuals with type 3 VWD. Boys tended to be diagnosed earlier than girls across all VWD types, suggesting possible sex‐based differences or bias in the recognition of abnormal bleeding [ 48 ]. As screening tools, BATs, including the Paediatric Bleeding Questionnaire (PBQ), which was specifically developed for paediatric use, perform sub‐optimally in young paediatric populations [ 56 , 57 ]. Similar to adults, bleeding scores in young children demonstrate high variability regardless of VWD type [ 57 ]. In children, the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH BAT) performs and correlates well with the PBQ [ 58 ]. However, due to the lack of significant haemostatic challenges in early childhood, initial bleeding scores are often low, even among affected individuals. Longitudinal data suggest that bleeding scores in children eventually resemble those observed in adults, supporting the potential role of BATs in tracking bleeding phenotypes over time [ 49 ]. VWD imposes a significant burden to children and is associated with reduced quality of life (QoL) [ 1 ]. This burden naturally extends to caregivers, particularly in those with moderate disease, which is often undertreated compared with more severe forms [ 59 ]. Despite early symptom onset, delayed diagnosis remains common [ 1 ]. Improved awareness of VWD among non‐haematologists, including paediatricians, parents and the general population, is urgently needed [ 19 ]. VWDtest.com is a global initiative led by Erik Berntorp and Fernando Corrales‐Medina, with the aim of improving awareness and early identification of VWD. The platform provides multilingual, region‐specific educational content and tools for self‐assessment of bleeding symptoms. Dedicated sections are available for individuals with VWD and non‐haematologists who frequently encounter undiagnosed children, and parents of children experiencing abnormal bleeding. Since its launch in 2019, more than 680,000 users have visited the site, and over 15,000 individuals with a potential bleeding disorder have been identified.

Key points: HMB and pregnancy related bleeding have profound health implications for women with VWD; women with VWD and female VWD carriers report multiple unmet needs, including the need for improved treatment; HMB can complicate management of VWD; improvements are needed in collaborations between gynaecology and haematology care teams. Numerous stages of a woman's life can be impacted by bleeding disorders, from childhood nose or trauma‐related bleeds, through to menstrual‐associated difficulties or complications during pregnancy [ 60 ]. Increased bleeding during menstruation (HMB) or postpartum haemorrhage (PPH) can have profound health implications, including the development of anaemia [ 61 ]. Importantly, as red blood cells are critical in vascular interactions for haemostasis, the development of anaemia can further worsen the individual's haemostasis and cause additional risks [ 62 ]. A systematic review and meta‐analysis showed that severe prenatal anaemia might increase the risk of PPH [ 63 ], highlighting the importance of preventing anaemia, particularly in people with VWD and other bleeding disorders as well. Women with VWD and female VWD carriers reported multiple unmet needs, including the need for improved treatment, during a Nordic survey of women with bleeding disorders [ 64 ] (Figure  5 ). These needs were related to delayed diagnosis, recurrent bleeds, bleeding complications associated with pregnancy and childbirth, lack of medical follow‐up, lack of awareness and negative social perceptions. Overall, 56% of respondents (including those who had a bleeding disorder other than VWD) reported weekly or monthly bleeding problems, and 48% only learned of their carrier/diagnostic status during their first pregnancy. Over 60% of respondents had also experienced misconception, prejudice or stigma related to their bleeding disorder or carrier status [ 64 ]. Women living with bleeding disorders or carriership: insights from a Nordic survey [ 64 ] (WFH congress abstract 2024, oral presentation). Management of VWD can be particularly burdensome in the context of menstrual bleeding, although tailored treatment plans and therapies are becoming more common. One retrospective cohort study in women with moderate and severe VWD reviewed interventions for HMB, with the majority of participants (70%) receiving a combined hormonal and haemostatic intervention (hormonal and tranexamic acid treatment, with iron supplementation) [ 65 ]. After the first year of treatment, in participants with moderate and severe VWD, respectively, 32% and 37% reductions in mean pictorial bleeding assessment chart (PBAC) scores were reported, mean SF‐36 scores improved by 34% and 36% and mean haemoglobin concentrations improved by 19% and 21%. Longer‐term follow‐up showed that overall cumulative response to treatment peaked in the third year, with an 88% improvement in PBAC scores from baseline. Improved haemoglobin levels were sustained at the 5‐year follow‐up, and overall improvement in PBAC scores was 52%. Some women, particularly adolescents, reported relapse of bleeding symptoms during long‐term therapy (>3 years), although this was often associated with treatment non‐compliance, highlighting the importance of regular personal engagement and follow‐up by healthcare professionals. The study demonstrated that HMB can be effectively managed, with concurrent improvement in QoL and anaemia [ 65 ]. To provide women with VWD with the care that they require, improvements are needed in regular and case‐based collaboration between gynaecology teams and haemophilia treatment centres at national and international levels. Regular QoL assessment should be integrated into clinical practice, and educational efforts should be made to improve societal and individual understanding of bleeding disorders, including the benefits of proactive and hormonal and haemostatic combination treatments. Key points: HMB can complicate VWD diagnosis; multiple therapeutic options are available to manage HMB; treatment options should be tailored to an individual's needs and preferences. HMB is the one of the most common symptoms for women with VWD who menstruate, with 60%–100% of individuals affected [ 1 ]. Diagnosing VWD when HMB is the presenting symptom can be difficult because HMB may be caused by other conditions, such as anovulation [ 66 ], and VWF/FVIII levels can be elevated during acute bleeding and while iron‐deficient [ 67 ]. This makes it difficult to measure factor levels at specific times in the cycle, as is done in adults. Once a VWD diagnosis is made, multiple therapeutic and surgical options are available to manage monthly bleeds, although not all options are suitable for all individuals. For example, adolescents are often not yet sexually active, and therefore they and/or their parents might be hesitant to begin hormonal treatment, or may decline such treatments due to concerns of side effects [ 65 ]. Preservation of fertility and growth in younger individuals is important when considering hormonal therapies; for example, exogenous oestrogen (found in oral contraceptives) may promote premature closure of growth plates [ 68 ]. Younger individuals also typically have not had pelvic examinations before and may be hesitant about more invasive treatment options, for example, insertion of an intrauterine device (IUD). Mental health concerns and iron deficiency are highly prevalent in adolescents with HMB and should be addressed as part of the overall treatment plan [ 69 , 70 ]. Real‐world data suggest that initial therapy may be ineffective for most people with HMB and bleeding disorders [ 71 , 72 ]. For adolescents in particular, non‐compliance with treatment can be a concern [ 65 ]. A survey of healthcare professionals, mainly haematologists and obstetrician–gynaecologists, found IUDs to be the most commonly preferred treatment option for HMB [ 73 ]. Real‐world data indicate a high level of satisfaction and efficacy with IUDs [ 72 ], with some individuals achieving amenorrhea [ 74 ]. Despite this efficacy, IUDs are not suitable for all individuals, and there is a gap in the treatment landscape for alternative treatment options. Prophylaxis with a VWF concentrate is an underutilised non‐hormonal therapy that should be increasingly considered for treatment of HMB in people with VWD. The WIL‐31 study assessed the efficacy and safety of prophylaxis with plasma‐derived VWF/FVIII in a 1:1 activity ratio (wilate) and included five females with VWD and HMB (four of whom were ≤18 years) [ 75 ]. In all five individuals, HMB annualised bleeding rate (HMABR) was lower during 12 months of prophylaxis compared with the previous 6 months with on‐demand therapy [ 76 ] (Figure  6 ). Improvements in PBAC scores were also observed in the three individuals for whom data were available. During prophylaxis, no HMB episode required additional treatment. The two individuals who still had HMB during prophylaxis had concomitant comorbidities that may have affected their menstrual health (polycystic ovaries in one individual and hypothyroidism, obesity, anaemia, type 2 diabetes and hypertension in the other) [ 76 ]. Wilate prophylaxis reduced heavy menstrual bleeding in all women of childbearing age in the WIL‐31 study. Adapted from [ 76 ]. *Ongoing polycystic ovaries. † Ongoing hypothyroidism, obesity, anaemia, type 2 diabetes and hypertension. ABR, annualised bleeding rate; HMABR, heavy menstrual ABR. Key points: Management of pregnant women with VWD is complex; FVIII and VWF levels should be monitored during pregnancy; clinical practice can vary during pregnancy; prospective clinical trials are needed to improve guidance and optimize care for pregnant women with VWD. Levels of VWF start to increase early in the first trimester and continue to rise progressively with advancing gestational age [ 77 , 78 ]. FVIII/VWF ratios are preserved in some women but reduced in others, due to a relatively greater rise in VWF levels, especially during the third trimester [ 77 ]. The management of pregnant women with VWD is complex, as physiological pregnancy‐induced increases in VWF may be blunted or absent [ 78 ]. FVIII and VWF levels should be checked at the first prenatal visit and during the third trimester, as well as prior to any invasive procedures [ 78 ]. Women with type 1 VWD, who achieve normal VWF:RCo activities (>50 IU/dL) by the third trimester can be managed in standard obstetric units. Individuals with type 2 and 3 VWD (and those with type 1 in whom VWF levels are unlikely to normalise) should be managed in specialist obstetric units, with close collaboration between bleeding disorder management unit, obstetric, anaesthetic and neonatal teams [ 78 ]. Type 2B VWD poses specific challenges during pregnancy [ 79 ], as while individuals may appear to have normalised VWF activity levels, the occupation of GPIb‐alpha receptors by soluble VWF renders platelets functionally inactive [ 80 ]. There is a lack of robust evidence to guide clinical decision‐making and significant variation in clinical management practice, in particular in relation to neuraxial anaesthesia [ 78 , 81 , 82 ]. The 2021 international guidelines recommend that if neuraxial anaesthesia is deemed suitable, a VWF activity level of 50–150 IU/dL should be targeted [ 2 ]. However, the recommendation is based on a low certainty of evidence and does not address the suitability of neuraxial anaesthesia itself or refer to the effects of VWF levels on PPH. There is also some variation in practice surrounding thresholds for haemostatic management during delivery. In general, haemostatic therapy to achieve VWF activity and FVIII levels >100 IU/dL is recommended prior to vaginal delivery or C‐section, with levels maintained >50 IU/dL [ 78 , 83 ]. Blood loss in women with type 1 VWD and normal VWF levels at term who do not receive any haemostatic treatment at delivery has been shown to be comparable to healthy controls [ 84 ]. In contrast, women of all VWD types whose VWF levels have not normalised at term have been shown to remain at increased risk of bleeding following delivery, despite haemostatic treatment [ 84 , 85 ]. This suggests that current treatment strategies fall short of achieving sufficient intra‐ and postpartum haemostasis. A small, retrospective, observational study did not show a significant reduction in bleeding with the use of higher dose recombinant or plasma‐derived VWF concentrates [ 86 ]. There are ongoing efforts to better define and inform the optimal dose and duration of treatment required to prevent PPH in people with VWD, including the US‐based VIP study [ 87 ] and the PRIDES study in the Netherlands [ 88 ]. Thrombotic risk should be considered, and there is a lack of data in relation to the use of VWF concentrates. Tranexamic acid is recommended and can be given together with desmopressin or VWF concentrates, either being administered orally at the onset of labour or intravenously prior to C‐section [ 7 , 78 ]. It has also been shown to significantly reduce excessive bleeding rates in the postpartum period [ 89 ]. Postpartum use of tranexamic acid is recommended for those with type 1 VWD or low VWF levels, although this conditional recommendation is based on low certainty of evidence [ 2 ]. The risk of increased postpartum bleeding may persist for several weeks. VWF levels begin to decline approximately 3 days after delivery, taking a period of between a few days to several weeks postpartum to return to near‐baseline values [ 78 ]. This risk should be emphasised to women with VWD, who should be encouraged to report excessive or worsening bleeding (Figure  7 ). Additionally, increased iron demands during pregnancy can lead to the development of iron deficiency anaemia [ 61 ] and an increased bleeding risk [ 63 ]. This can complicate the management of VWD during pregnancy. Postpartum management in VWD. Adapted from [ 78 ]. Alternate assays (VWF:GPIbM, VWF:GPIbR) can replace VWF:RCo if available. Similarly, tranexamic acid can be replaced with aminocaproic acid (EACA) if tranexamic acid is unavailable. FVIII:C, factor VIII coagulant activity; VWF, von Willebrand factor; VWF:GPIbM, VWF‐glycoprotein Ib (mutant) binding assay; VWF:GPIbR, VWF‐glycoprotein Ib binding assay (with ristocetin); VWF:RCo, ristocetin cofactor activity. Overall, there is a lack of robust evidence to inform clinical practice, and prospective clinical trials are needed to improve guidance and optimize care for pregnant women with VWD.

Key points: The bleeding phenotype of VWD is highly heterogeneous; there are challenges in defining severe VWD; a consensus opinion on the definition of severe VWD has been proposed. VWD is a heterogeneous disease with symptoms ranging from mild to severe and life‐threatening (Figure  1 ) [ 1 ]. In contrast to haemophilia A, where prophylaxis is the standard of care for severe disease, prophylaxis remains underutilised in people with VWD. International guidelines recommend the use of prophylaxis for individuals with VWD who have a severe bleeding phenotype [ 2 ]. In practice, however, characterising severe disease is not straightforward, as individuals with the same type of VWD and similar levels of von Willebrand factor (VWF) activity can exhibit variable bleeding phenotypes [ 3 , 4 ]. Failure to recognise and diagnose clinically severe VWD can lead to reduced acceptance of timely treatment and prophylaxis, as well as problems with insurance and reimbursement, if insurance companies/ payers do not have objective proof of severity. The resulting uncertainty can, in turn, hamper tailoring of effective treatment, leading to suboptimal prophylactic regimens and schedules. The clinical picture of VWD: mucosal bleeding as a hallmark. The prevalence of different bleeding symptoms and associated complications varies between individuals. Adapted from [ 1 ]. CNS, central nervous system; GI, gastrointestinal. Over the years, there have been numerous attempts to define severe VWD. Federici et al. [ 5 , 6 ] classified severe disease as VWF ristocetin cofactor activity (VWF:RCo) levels <10 international units (IU)/dL and factor VIII (FVIII) coagulant activity (FVIII:C) <20 IU/dL, which mainly includes individuals with type 1, 2A or 3 VWD [ 5 , 6 ]. In contrast, Leebeek and Atiq [ 7 ] define severe VWD as VWF activity <10 IU/dL and/or FVIII <20 IU/dL. Applying the same numeric thresholds more flexibly, that is, considering VWF and FVIII either together or separately, broadens the definition of severe VWD to include more individuals, notably most with type 2B VWD. A recent consensus opinion study attempted to define severe disease using Delphi methodology [ 8 ]. The expert panel consisted of 17 participants and comprised of clinicians as well as individuals with VWD/carers, mostly based in the United States. The questions used to determine the definition criteria for severe VWD focused on several key topics as follows: genetic factors associated with severe disease, disease‐related factors (e.g., frequency, type and consequences of bleeding), diagnostic classifications and criteria for laboratory results (e.g., thresholds for VWF activity, recommended assays). The panel proposed the following definition of severe VWD: any VWF antigen (Ag) or activity level of <20%, regardless of bleeding phenotype or <30% with excessive bleeding symptoms. Severity of VWD needs to be better and more universally defined to facilitate access to and reimbursement of treatment and to improve the design and execution of clinical trials. Additionally, it is important to recognise that the severity of VWD can change with age and sex; people with low VWF levels might not experience bleeding symptoms until later in life, while with the onset of haemostatic challenges such as heavy menstrual bleeding (HMB) or childbirth, the picture is the reverse. Key points: Determining the genotype of people with VWD can be clinically useful as it can inform diagnosis, treatment and management; genotyping of VWD is particularly challenging due to the complexity of the VWF gene. Similar to variation in bleeding phenotypes, there is considerable variability in VWF levels in people with VWD, as well as in the general population [ 9 ]. Approximately two‐thirds of this variation has a genetic basis, and one‐third is acquired or environmental. This variation makes determining the threshold VWF level for diagnosis of VWD challenging. Determining the genotype of people with VWD can be clinically useful as it can inform diagnosis, treatment, the need for laboratory monitoring, family planning, familial testing and the risk of developing inhibitors in type 3 VWD. Reflecting these implications, the 2021 international guidelines on the diagnosis of VWD have, for the first time, outlined situations in which genotyping is beneficial [ 10 ]. Genotyping of VWD is particularly challenging due to the complexity of the VWF gene, which has 52 exons and spans 178 kb on chromosome 12 [ 11 ]. Additionally, the VWF pseudogene ( VWFP1 ) on chromosome 22 shares 97% homology with VWF , further complicating genotyping. Variants are identified by comparing sequences to reference sequences and include single‐nucleotide variants, insertions, deletions and large structural variants. Current methods for genotyping VWD variants include Sanger sequencing and next‐generation sequencing through targeted or whole‐genome sequencing [ 11 ]. When interpreting the significance of VWF variants, it is important to consider the guidance provided by the American College of Medical Genetics and Genomics [ 12 ]. Variants should be classified systematically as either pathogenic or benign based on the certainty of evidence. If there is less than 90% certainty that a variant is pathogenic or benign, it should be termed a variant of unknown significance (VUS) [ 11 ]. This means that if a variant is found that has not previously been identified, it will almost always be termed a VUS due to lack of evidence, even if there is clinical suspicion that it is a pathogenic variant of VWD [ 12 ]. Most people with VWD (with VWF levels <30%) have identifiable VWF variants [ 11 ]. While type 1 and type 3 variants are located throughout the VWF gene, type 2 VWD variants are predominantly located in domains that influence the VWF's functional properties (Figure  2 ). There are also benign VWF variants, some of which can modulate VWF levels but do not cause VWD alone. Some benign variants can artificially impact diagnostic test results, such as the VWF ristocetin cofactor assay, without affecting VWF biology [ 11 ]. Reporting these benign variants is therefore crucial to fully understand the diagnostic test results and avoid over‐diagnosis of VWD. Location of VWF type 2 disease‐causing variants. Type 1 and type 3 VWD variants are located throughout the VWF gene. Adapted from [ 11 ]. The complexity of the large VWF gene and its pseudogene necessitates a high level of expertise in both the technical aspects of genotyping and the interpretation of results. To accurately interpret genetic variation, it is important to understand the VWD phenotype and to compare it to the phenotypes of known variants. Whenever possible, comprehensive sequencing of the entire gene is recommended, as large structural variants may not be recognisable by common methods [ 11 ]. The Clinical Genome Resource (ClinGen) has established a von Willebrand Disease Variant Curation Expert Panel, which aims to curate VWF clinically relevant variants using specific classification rules [ 13 ]. Additionally, a large investigator‐initiated genotyping study in VWD in the US is planned [Genetics of VWD in the US (VUS) study], which will investigate the relationship between VWF genotype and VWD phenotype. This study will examine the impact of VWF genotyping on the diagnosis and treatment of VWD and establish a research repository to improve VWF genotyping and support research. Key points: Although VWD is the most common inherited bleeding disorder, many cases remain unidentified, due to non‐specific symptoms and heterogeneity in disease phenotype; there is a pressing need to better understand the population of individuals with mild VWD and improve their diagnosis. VWD is the most common inherited bleeding disorder, with studies demonstrating reduced VWF activity levels (<50 IU/dL) in approximately 1% of the population [ 14 ]. However, most individuals with lowered VWF levels exhibit mild bleeding symptoms and do not require specific therapy. Estimates from specialised centres, where individuals with bleeding symptoms are referred, suggest a VWD prevalence of ∼0.01% [ 6 ]. Registry estimates suggest a type distribution of approximately 75%, 22% and 4% for type 1, type 2 and type 3 VWD, respectively [ 15 ]. There are now registries for VWD in many countries, including the United Kingdom, Italy, Sweden, the Netherlands and the United States [ 16 , 17 ]. Despite VWD being the most common bleeding disorder, specialised centres treat proportionally more people with haemophilia than people with VWD. This discrepancy arises because many people with VWD remain unidentified, and there are relatively fewer individuals with severe VWD compared with severe haemophilia A [ 18 ]. Identifying and diagnosing those with VWD is challenging because the bleeding symptoms characteristic of VWD, such as nosebleeds and HMB, are not specific to VWD [ 19 ]. The heterogeneity of the disease phenotype further complicates diagnosis, particularly for milder cases where VWF levels are between 30 and 50 IU/dL. The considerable variability in VWF and FVIII levels within VWD types also leads to differing severities. For example, type 1 VWD can be mild, moderate or severe [ 5 ]. This heterogeneity in VWD phenotypes stems from the biology of VWF and how defects in VWF can differently affect its various functions, such as binding to and aggregating platelets, binding to collagen in the subendothelial matrix and serving as a carrier for FVIII [ 20 ]. There is a pressing need to better understand the population of individuals with mild VWD and improve their diagnosis. Individuals with mildly reduced VWF levels (30–50 IU/dL) typically experience bleeding only after significant trauma or surgery and often remain undiagnosed until faced with a major haemostatic challenge [ 5 , 11 , 21 ]. A retrospective study investigating management of surgical procedures in children with mild VWD, demonstrated a low incidence of bleeding complications during surgery and that these complications could generally be managed without requiring VWF concentrate infusions [ 21 ]. Large‐scale prospective studies in this population will require a more simplified diagnostic approach. For example, a simplified algorithm has been developed that utilises bleeding assessment tools (BATs) and standard laboratory tests, eliminating the need for multimer analyses or genotyping, as recently proposed by Members of the Italian Association of Haemophilia Centres [ 22 ]. The prospective observational study designed by Italian investigators not only will evaluate the use of desmopressin in managing mild and moderate VWD using this simplified diagnostic algorithm, but will also identify at diagnosis those patients who may require only VWF concentrates because of unresponsiveness and/or contraindication to desmopressin [ 22 ]. Key points : Impaired synthesis and secretion of VWF can contribute to the low levels of plasma VWF in people with VWD; ex vivo models can be used to explore the mechanisms of VWD; VWD can be caused by genetic variations beyond VWF variants. VWF is produced in endothelial cells, megakaryocytes and platelets; in endothelial cells, it is the main component of the large intracellular secretory organelles known as Weibel–Palade bodies (WPBs) [ 20 ]. A continuous low‐level turnover of WPBs results in basal VWF in the plasma. Impaired synthesis and secretion of VWF can contribute to the low levels of plasma VWF in people with VWD [ 23 ]. Endothelial colony‐forming cells (ECFCs) can be a powerful ex vivo model to dissect the pathogenic mechanisms of bleeding disorders such as VWD [ 24 ]. Using samples from individuals in the WiN‐Pro study (Willebrand in the Netherlands study, a large cohort study of VWD; NCT03521583 ), this ex vivo model was used to show that p.M771V VWF variants cause defects in cellular transport and processing of VWF and impaired secretion [ 25 ]. Ex vivo blood vessels on a chip, created using microfluidics and ECFCs from people with VWD, more closely reflect the physiological environment of endothelial cells. Using this model and cells from an individual with VWD 2A with a heterozygous C1190R variant, it was found that the large majority of VWF is retained in the endoplasmic reticulum (Van Moort, unpublished data). This defect in anterograde trafficking altered the morphology of WPBs and impaired their secretion from endothelial cells upon stimulation, in comparison with healthy controls. Genetic modifiers of VWF exist beyond variants of the VWF gene, with 60% of individuals with low VWF levels having no identified pathogenic variants of VWF [ 11 ]. Alternative variants responsible for VWD can be found in proteins involved in the exocytosis of WPBs. MAP kinase activating death domain (MADD) is responsible for recruitment of exocytotic regulators to WPBs and is crucial for VWF secretion [ 26 ]. A recent study investigated three paediatric patients with a severe multi‐system disorder caused by biallelic mutations in MADD [ 27 ]. All three individuals studied had low VWF levels, despite normal levels observed in their heterozygous parents. In vitro studies using endothelial cells derived from these individuals demonstrated loss of MADD protein expression, defective recruitment of WPB exocytotic mediators and impaired exocytosis of WPBs. This study identified MADD as the first causal gene for type 1 VWD in people with no pathogenic VWF variants and highlights defective WPB release as a novel pathogenic mechanism for quantitative VWD [ 27 ].

Key points: Prophylaxis in VWD remains underutilised, despite guideline recommendations; efficacy and safety of long‐term prophylaxis in VWD have been demonstrated by recent prospective trials with wilate (pdVWF/FVIII concentrate) and Vonvendi/ Veyvondi (rVWF). Prophylaxis in VWD is underutilised [ 90 , 91 ], despite guideline recommendations for long‐term prophylaxis in people with VWD who have a history of severe and frequent bleeds [ 2 ]. The feasibility, efficacy and safety of long‐term prophylaxis in VWD have been documented by many studies over the past 20 years [ 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ], with prophylaxis shown to decrease rates of all types of bleeding in VWD, including HMB [ 97 , 102 ]. While most of these studies have been retrospective or observational, two key prospective phase 3 clinical trials investigated the efficacy and safety of prophylaxis, one with a recombinant VWF concentrate (rVWF, vonicog alfa [Vonvendi in the US/Veyvondi in Europe]) [ 99 ], and one with a pdVWF/FVIII concentrate (wilate) in the WIL‐31 study [ 75 ]. The trials shared some similarities in study design: both were prospective, open‐label, single‐arm studies conducted at a similar time, with similar evaluation periods (12 months). There were, however, some notable differences. The Vonvendi study included two cohorts, one switching from prophylaxis with a different product ( N = 13) and one on prior on‐demand treatment ( N = 10), whereas all participants ( N = 33) in WIL‐31 had completed a 6‐month, run‐in on‐demand study. The Vonvendi study enrolled adults only, whereas WIL‐31 enrolled children (≥6–16 years) and adults (≥17 years). The median age of participants was therefore higher in the Vonvendi study versus WIL‐31: 30 years for the prior on‐demand group and 34 years for the switch group versus 18 years in WIL‐31. The primary outcome of both studies was the annualised bleeding rate (ABR) during prophylaxis compared with the ABR during prior treatment. This was based on historical bleed data for Vonvendi, whereas bleed diary data from a 6‐month prospective run‐in study were used for WIL‐31. The primary endpoint was the spontaneous ABR for treated bleeds in the Vonvendi study and the total ABR for treated and untreated bleeds in WIL‐31. In the Vonvendi study, most participants received twice per week dosing, with a median weekly dose of 96 IU/kg in the prior on‐demand group and 107 IU/kg in the switch group [ 99 ]. In the prior on‐demand group, total and spontaneous ABR were reduced following 12 months of prophylaxis compared with prior on‐demand treatment: Mean total ABR was reduced by 46% from 5.1 to 2.7 and mean spontaneous ABR was reduced by 57% from 4.9 to 2.1 [ 103 ]. In the switch group, there was no significant difference in total ABR following 12 months of prophylaxis with Vonvendi compared with prior prophylaxis with a different product. With Vonvendi, there was a single reported case of thromboembolism (purpura) in an individual receiving prophylaxis [ 99 ]. The US FDA approved Vonvendi for VWD prophylaxis in adults (≥18 years). A phase 3 study ( NCT05582993 ) evaluating the efficacy and safety of Vonvendi in children under 18 years of age is ongoing [ 104 ]. WIL‐31 [ 75 ] is the largest prospective prophylaxis study in VWD to date. Most participants received twice‐weekly dosing, with a median weekly dose of 58 IU/kg, which was lower than that used in the Vonvendi study and other studies of prophylaxis in VWD. The mean total annualised bleeding rate (TABR) decreased by 84% from 33.4 during on‐demand treatment to 5.2 during prophylaxis. Similarly, the mean spontaneous annualised bleeding rate (SABR) decreased by 87% from 24.4 during on‐demand treatment to 3.2 during prophylaxis. Efficacy of wilate was consistent in subgroup analyses according to VWD type, gender and age (children 6–11 years, adolescents 12–16 years and adults ≥17 years). Bleeding at different bleeding sites was reduced, including nose and oral bleeds, joint bleeds and HMB during prophylaxis compared with on‐demand treatment [ 76 , 105 , 106 ] (Figure  8 ). Wilate prophylaxis was well tolerated, with no accumulation of VWF or FVIII, thrombotic events or serious treatment‐related adverse events observed [ 75 ]. In December 2023, the US FDA approved wilate for prophylaxis in individuals ≥6 years with all types of VWD. The efficacy and safety of wilate prophylaxis in children <6 years with severe VWD is being investigated in the phase 3 WIL‐33 study ( NCT04953884 ) [ 107 ]. Wilate prophylaxis reduced bleeding across all sites in the WIL‐31 study. Adapted from [ 75 , 105 ]. *‘Other’ bleeds in WIL‐29 include arm, back, buttock, cutaneous, cyst, ecchymosis, haematuria, haemorrhoid, hand, hip, leg, nasal contraction, post‐surgery, shoulder, subcutaneous, thigh, toe, tonsil, uterus and wrist. ‘Other’ bleeds in WIL‐31 include cutaneous, haemorrhoid, head, hip, ocular, rectal, toe and tonsil. † One patient with relapsing and remitting small bowel ulcers experienced many bleeds, including 12 gastrointestinal bleeds during WIL‐31 resulting in a higher ABR in WIL‐31 compared with WIL‐29. This patient is considered an ‘outlier’, without this patient, the reduction is 100%. ABR, annualised bleeding rate. Key points: PK‐based prophylaxis regimens have been used successfully to personalise therapy in haemophilia; data on PopPK guidance for VWF concentrate prophylaxis in VWD are limited; a PopPK study is being planned to evaluate the utility of PopPK‐guided prophylaxis with wilate in people with clinically severe VWD. Unlike haemophilia [ 108 ], there is no guidance on target VWF or FVIII trough levels or individualised dosing for long‐term prophylaxis in VWD. In haemophilia, prophylaxis should be personalised [ 108 ] and PK‐based prophylaxis regimens have been used successfully to personalise therapy [ 108 , 109 , 110 ]. The PK approach aims to maintain a predetermined trough FVIII level using individual or population‐based PK curves [ 108 , 109 ]. Population PK (PopPK)‐guided dosing compares an individual response to a large population and models the response based on that, with the advantage of requiring fewer blood samples [ 111 ]. Although a PopPK model has been developed to improve dosing of a VWF/FVIII concentrate during surgery for people with VWD [ 112 ], data on PopPK guidance for VWF concentrate prophylaxis in VWD are limited. Differences in PK profiles between different VWF concentrates can add further complications [ 113 ]. A PopPK study is being planned to evaluate the utility of PopPK‐guided prophylaxis with wilate in people with clinically severe VWD [ 114 ] (Figure  9 ). The primary objective of the study is to assess the impact of PopPK‐guided prophylaxis on bleeding outcomes. Secondary objectives include the assessment of the impact of PopPK‐guided prophylaxis on QoL, the consumption of wilate and concomitant medications/blood products and safety. Children and adults with clinically severe VWD intending to start PK‐guided prophylaxis with wilate will be enrolled in the study. Participants will first receive standard wilate prophylaxis for 6 months in accordance with standard clinical practice at their local centre at the discretion of the treating physician. During this 6‐month period, participants will undergo a PK assessment. PK data will be analysed using a PopPK model developed by the Amsterdam University Medical Center in the Netherlands. The model will be used to propose a tailored dosing regimen for subsequent PopPK‐guided prophylaxis over 12 months. Summary of population‐PK study design. PopPK model based on data from WIL‐31 [ 75 ] and WIL‐12 [ 182 ]. ABR, annualised bleeding rate; PK, pharmacokinetic. It is hoped that the results of the PopPK study will lead to the development of a personalised approach to dosing for prophylaxis in VWD, which has the potential to emulate the success of personalised treatment in haemophilia A. Key points: For perioperative management, it may be more appropriate to target activity levels specific to people with VWD rather than ‘normal’ ranges; prophylaxis with VWF concentrates has been shown to be safe and effective for managing surgery. For the management of bleeding during surgery in people with VWD, the 2021 guidelines recommend targeting VWF and FVIII activity levels of ≥50 IU/dL for at least 3 days after surgery; such levels are within the ‘normal’ range of 50–200 IU/dL [ 2 ]. However, this recommendation is based on limited evidence, raising concerns that some individuals may be overtreated by targeting these levels, potentially increasing the risk of thrombosis unnecessarily. Instead, it may be more appropriate to determine the factor levels needed to achieve haemostasis in VWD, rather than mirroring the ‘normal’ levels for people without VWD. Monitoring of VWF and FVIII levels is necessary both during and after surgery to ensure haemostasis and avoid adverse events such as thrombosis [ 115 ]. For elective surgeries, real‐time monitoring of both VWF and FVIII levels is recommended; however, not all facilities have this testing capacity [ 2 ]. In clinical practice, monitoring FVIII levels alone may be sufficient, especially for type 1 and type 3 VWD, as FVIII is thought to be the best predictor of surgical bleeding and correlates with VWF levels [ 116 ]. There is good evidence for the efficacy and safety of prophylaxis with VWF concentrates for managing surgery in people with VWD, and guidelines for loading and maintenance doses have been published (Figure  10 ) [ 117 ]. In the prospective phase III WONDERS trial, surgical prophylaxis with wilate was successful in 97% of surgeries, with efficacy assessed intra‐ and postoperatively using an objective 4‐point scale [ 118 ]. For major surgeries, peak perioperative levels of VWF were 100%, with trough levels of VWF to be maintained for at >50% for at least 6 days post‐operatively. For minor surgeries, peak perioperative levels were 50%, and trough levels were maintained at >30% for at least 2 days post‐operatively [ 118 ]. Real‐world observations support these data, with the effectiveness of wilate rated as ‘excellent’ or ‘good’ in 99% of surgeries in a prospective, observational phase 4 study [ 93 ]. Different VWF concentrates can have differing PK properties and, importantly, vary in their ratios of VWF and FVIII [ 119 ]. Recommended dosing of VWF concentrate for management of surgical procedures. Adapted from [ 117 ]. Alternate assays (VWF:GPIbM, VWF:GPIbR) can replace VWF:RCo if available. FVIII, factor VIII; IU, international units; NHLBI, National Heart, Lung and Blood Institute; VWF, von Willebrand factor; VWF:GPIbM, VWF‐glycoprotein Ib (mutant) binding assay; VWF:GPIbR, VWF‐glycoprotein Ib binding assay (with ristocetin); VWF:RCo, ristocetin cofactor activity. When treatment with factor concentrates is not available, for example, in developing countries, evidence supports the use of cryoprecipitates in low doses for surgery [ 120 ]. Depending on the surgery, this could be combined with antifibrinolytic therapy such as tranexamic acid, which is inexpensive and effective in reducing perioperative bleeding [ 121 ]. For individuals with VWD at elevated thrombotic risk, venous thromboembolism prophylaxis should be considered alongside haemostatic therapy, as long as VWF and FVIII activity levels are within or above the haemostatic range [ 119 ]. Systematic, prospective studies are needed to guide evidence‐based strategies for optimal peri‐operative dosing strategies in people with VWD. Key points: Different plasma‐derived VWF concentrates provide varying VWF:FVIII activity ratios, which influence how quickly FVIII levels rise and how long they remain elevated; regular FVIII monitoring remains an important safety measure; monitoring FVIII levels alone could be a practical surrogate for VWF levels. Implementing current guideline recommendations for surgical prophylaxis in VWD, especially maintaining VWF levels ≥50 IU/dL, can be a challenging clinical practice. Many centres have limited access to real‐time VWF monitoring or experience long turnaround time for assays [ 2 ]. In addition, the use of VWF concentrates carries the risk of FVIII accumulation, since VWF acts as the carrier protein for FVIII, which can increase the risk of venous thromboembolism [ 122 ]. Furthermore, the target threshold of 50 IU/dL does not account for the physiological rise in VWF and FVIII that naturally occurs during acute stress. At the Van Creveldkliniek in the Netherlands, the perioperative management of people with VWD undergoing major surgery includes three bolus injections of VWF concentrate: one preoperatively, followed by doses at 12 and 24 h post‐surgery [ 116 ]. Target levels are >80 IU/dL for both VWF and FVIII pre‐operatively and during the first 24 h, then >50 IU/dL for FVIII between Days 2 and 6, and >30 IU/dL between Days 7 and 14 post‐surgery. Different plasma‐derived VWF concentrates provide varying VWF:FVIII activity ratios, which influence how quickly FVIII levels rise and how long they remain elevated. Wilate, with its physiological 1:1 VWF:FVIII activity ratio, achieves synchronous increases and clearance of VWF and FVIII, maintaining the haemostatic balance and predictable kinetics [ 113 , 123 ]. In contrast, products with higher VWF:FVIII ratios (e.g., >2:1) may result in delayed FVIII recovery, while those with lower ratios (e.g., 150 IU/dL) can increase thrombotic risk, particularly in older people or perioperative settings, regular FVIII monitoring remains an important safety measure [ 126 , 127 ]. The potential for FVIII accumulation with repeated administration of wilate was investigated in a perioperative setting [ 116 ]. A total of 125 people of VWD (types 1, 2A, 2B, 2 M, 2N and 3) received wilate. Over half (58%) of the cohort were female, and 23 were children. Among 63 major surgeries, the most common procedures were gynaecological ( n = 15) and gastroenterological ( n = 12). Of the 62 minor surgeries, most were oral and maxillofacial procedures ( n = 19). Recovery rates for both VWF and FVIII were higher than expected (2.4 IU/dL per IU/kg for VWF, and 2.6 IU/dL per IU/kg for FVIII), with a strong correlation ( r = 0.638, p  < 0.0001) (Figure  11 ). Importantly, no accumulation of FVIII was observed after repeated wilate dosing, and no bleeding or thrombotic events were reported. These results demonstrate that surgical prophylaxis with wilate can be effectively managed without the need for complex PK/pharmacodynamic modelling. Furthermore, monitoring FVIII levels alone was shown to be a practical surrogate for VWF levels, potentially reducing the need for real‐time VWF monitoring. Further studies are needed to determine how to best personalise perioperative management in people with VWD. Surgical experience in the Van Creveldkliniek [ 116 ]. VWF activity measured by VWF ristocetin cofactor activity (VWF:RCo) and VWF:GPIbR assay. FVIII, factor VIII; IU, international units; VWF, von Willebrand factor; VWF:GPIbR, VWF‐glycoprotein Ib binding assay (with ristocetin); VWF:RCo, VWF ristocetin cofactor activity. Key points: Individualised VWD management requires assessment of many variables; VWF‐containing products vary in both quality and content, careful selection and dosing of a concentrate is essential; when using VWF concentrates, FVIII levels need careful monitoring. Many variables need to be considered when determining individualised treatment strategies for people with VWD, including type, bleeding phenotype, age, gender, ethnicity and blood group [ 128 , 129 ]. Those who have anaemia need its management, or those with comorbidities such as cardiovascular disease may require anticoagulant or antiplatelet therapy and/or prophylaxis with VWF to ensure optimal outcomes. Special considerations may be required for individuals who are pregnant, undergoing delivery, or in the postpartum period, as well as those experiencing heavy menstruation, menopause or undergoing surgery. An individual's response to previous treatments is also critical knowledge for tailoring the treatment strategy. Multidisciplinary collaboration is important: Individuals having VWD should have ready access to a local coagulation laboratory, as well as input from gastroenterologists, gynaecologists and obstetricians, as needed [ 129 ] (Figure  12 ). Regular follow‐up is essential to re‐assess treatment needs, adjust dosing while minimizing risk of adverse events. Individualising VWD treatment. Overview of factors important for individualizing VWD treatment. Adapted from [ 129 ]. VWD, von Willebrand disease. Prophylaxis for VWD is context‐dependent [ 92 ]. Short‐term or episodic prophylaxis is primarily used to provide haemostatic coverage during invasive procedures and surgery. Intermittent replacement therapy is provided when needed, for example, in women with HMB requiring administration at least once per menstrual cycle. Secondary, long‐term prophylaxis is defined as the prevention of severe recurrent bleeds over a period of at least 3–6 months, with dosing occurring at least once weekly [ 92 , 128 ]. Guidelines recommend the use of long‐term prophylaxis in individuals experiencing severe and frequent bleeds [ 2 ]. As VWF‐containing products vary in both quality and content, careful selection and dosing of a concentrate are essential. Factors such as the PK profile, half‐life and in vivo recovery should be evaluated when individualising treatment. Recombinant VWF (rVWF) has a longer half‐life and contains a higher proportion of HMW multimers than plasma‐derived VWF concentrates [ 130 ]. However, there is considerable inter‐individual variability in half‐lives for VWF products, highlighting the importance of using PK assessment to guide dosing. For instance, individuals with type 1C VWD show increased clearance of VWF and may therefore require more frequent dosing [ 128 ]. The clinical impact of differences in HMW multimer composition remains unclear, although it has been hypothesised that products with a higher percentage of HMWs may contribute to improved haemostatic efficacy [ 131 ]. Unlike plasma‐derived VWF concentrates, rVWF lacks endogenous FVIII, so FVIII must be co‐administered when immediate haemostatic correction is required, such as during surgery or acute bleeding episodes [ 126 , 128 ]. rVWF binds to and stabilises endogenous FVIII, resulting in a gradual and delayed increase in FVIII activity. Peak FVIII levels are typically reached 6–12 h post‐infusion, meaning that FVIII accumulation is less likely early on, although FVIII may remain elevated for longer once the peak levels are achieved due to the extended half‐life of rVWF [ 130 ]. FVIII levels also need to be considered when choosing and dosing VWF concentrates. The VWF:FVIII activity ratio varies between the plasma‐derived VWF concentrates [ 128 ]. When using VWF concentrates, FVIII levels need careful monitoring to maintain therapeutic targets and to avoid supraphysiological FVIII levels, which can increase thrombotic risk [ 132 ]. There is no ‘one size fits all’ approach for prophylaxis in people with VWD. Personalising prophylaxis based on person‐ and treatment‐related factors may enable treatment to be tailored to individual needs and improve their care. Key points: Bleeding symptoms in VWD impact QoL; QoL is generally lower in women with VWD than in men; treatment should be optimised to improve QoL in people with VWD. The impact of VWD on QoL is generally underappreciated. Individuals with VWD report a QoL similar to that of those with both human immunodeficiency virus and severe haemophilia [ 133 ]. QoL in VWD is typically assessed using generic tools, such as SF‐36 and EQ‐5D [ 134 , 135 ]. These tools offer the advantage of being well validated in the general population, which can be used as a comparator. Tools specifically developed to assess QoL in VWD include VWD‐QoL and VWD‐Sat, although few published studies have used them [ 136 ]. Bleeding symptoms are generally associated with reduced QoL, and QoL can be impacted by different types of bleeding, including HMB, oral bleeding and joint bleeding, as highlighted by a recent systematic review [ 137 ]. People with VWD tend to have lower QoL scores related to anxiety and depression versus the general population [ 138 ]. QoL improved following treatment in four out of the six studies analysed by the systematic review that investigated the treatment effect. However, one study reported a negative impact, emphasising the importance of recognising potential negative impacts of treatment, such as self‐infusion and treatment burden, on QoL. The negative impact of VWD on QoL can vary between VWD types; those with the most severe bleeding phenotypes (type 2 and type 3) often report worse QoL outcomes compared with type 1 [ 133 , 139 , 140 ]. QoL is generally lower in women with VWD than in men, due to symptoms such as HMB or pregnancy‐related bleeding [ 133 , 141 , 142 , 143 ]. HMB is the most commonly reported symptom in women with VWD, with considerable impact on QoL [ 1 , 144 ]. In a retrospective cohort analysis of 67 women with VWD being treated for HMB, approximately 35% reported improved QoL following treatment (as measured by increased SF‐36 scores) [ 65 ]. The ability to take part in normal social activities due to improvement in emotional well‐being had the greatest impact on QoL [ 65 ]. The impact of prophylaxis on QoL was examined in a US cohort of 37 adults with clinically severe VWD [ 145 ]. Those on prophylaxis exhibited poorer physical function and a lower ability to participate in social activities compared with those receiving episodic treatment (measured by Patient‑Reported Outcomes Measurement Information System‑29, i.e., PROMIS‐29 scores). However, these results were not adjusted for the severity or type of disease and may reflect the treatment bias towards more severe cases of VWD. Furthermore, the data suggest that prophylaxis is initiated too late when QoL has already been impacted, for example, due to joint dysfunction from recurrent bleeds. Differences in QoL between people with VWD on prophylaxis versus those eligible for prophylaxis were assessed in a European cross‐sectional study [ 90 ]. Individuals who had been on prophylaxis for the prior 12 months were less likely to be hospitalised due to acute bleeds or have chronically damaged joints compared with those not receiving prophylaxis (but who were eligible based on severity/frequency of bleeds). However, there was no significant difference in mean EQ‐5D‐5L scores between the two groups. The study had several limitations, including missing data for QoL assessments, and the results should be interpreted with caution. Analyses generally suggest that children with VWD have poorer QoL than children in the general population [ 146 ]. There are usually no apparent differences between girls and boys, likely due to the lack of symptoms such as HMB in younger girls [ 146 ]. Surprisingly, one US‐based study reported lower levels of depression, better peer relationships, less fatigue and less pain interference in children with VWD versus their peers in the general population [ 145 ]. All children were treated either prophylactically or with episodic treatment, and this might reflect the positive impact of treatment on QoL rather than the impact of the disease itself. In the future, there should be an increased focus on recognising the impact of VWD on QoL and on optimising treatment to improve QoL in people with VWD. The WFH has launched a ‘Shared Decision‐Making Tool’ for patients with haemophilia. This will facilitate patients and their healthcare team working together to make treatment decisions that will take treatment burden and quality of life into account. Extending such a programme to cover other bleeding disorders would be of great benefit to patients with VWD [ 147 ].

The seventh Åland Island Meeting on von Willebrand Disease (VWD) was held on 26–28 September 2024 on the Åland archipelago. This recurring meeting, first held in 1998, was co‐chaired by Erik Berntorp and Riitta Lassila and brought together leading clinicians, scientists and experts dedicated to advancing the understanding and management of VWD. The objectives of the meeting were to provide an update on the latest developments in the diagnosis and management of VWD, to foster scientific discussion among experts and to reflect on the evolution and future direction of VWD care. Special attention was paid to VWD in women, to the definition of disease severity and to bleeding disorders of unknown cause, key areas of ongoing clinical debate. The Åland Islands provided a symbolic and fitting setting for the meeting, marking the centenary of the first recorded index case of VWD, a 5‐year‐old girl named Hjördis from the islands, described by Erik von Willebrand in 1926.

R.L. has received reimbursement for attending the symposium organized by Octapharma, as well as speaking fees from CSL Behring, Roche and Takeda, and consulting fees from LFB, Pfizer and Sanofi. R.B. declares no conflicts of interest. N.T.C. has received honoraria or consultation fees from Bayer, CSL Behring, Genentech/Roche, Medzown, Pfizer, Octapharma, Sanofi, SeraGene and Takeda and is a stock shareholder in Doximity. F.F.C.‐M. has received research grants from Bayer; is an advisory board member for Bayer, CSL Behring, Genentech, Octapharma and Takedaand has received educational grants from Octapharma. A.B.F. has been involved in advisory boards and received honoraria as a speaker at educational meetings organized by CSL‐Behring, Grifols, Kedrion Biopharma, Octapharma, Takeda and Werfen Instrumentation Laboratory. V.H.F. has received honoraria or consultation fees from Octapharma, Novo Nordisk and Takeda. F.H‐M. has received speaker's fees from Octapharma and Takeda; sponsorship for congress visits from Octapharma, Roche and Sobi and sponsorship for investigator‐initiated studies from Octapharma. J.M.J. has received research support from Octapharma (to the University of Washington) and honoraria from Octapharma (to the University of Washington). G.K. has received speaking fees from Octapharma for speaking at the symposium (paid to the institution). D.M. has received research funding from Bayer, Pfizer, Novo Nordisk, Sanofi, Spark, Octapharma and Roche; and has received honoraria from Bayer, Pfizer, Novo Nordisk, Sanofi, Sobi and Octapharma. C.M. has received research support from CSL Behring, Grifols and Takeda; has received speaker's fees from CSL Behring, Leopharma, LFB, Novo Nordisk, Octapharma and Star Therapeutics and has received honoraria/ consultation fees from CSL Behring, LFB, Octapharma, Star Therapeutics and Takeda. I.S. has received research support and a speaker fee from Octapharma. A.S. declares no conflicts of interest. R.F.S. has received grants/research support from Octapharma, Takeda and Hema Biologics; has received honoraria or consultation fees from Takeda, Octapharma, Hema Biologics, Genentech/Roche, Bayer, Novo Nordisk, Vega, Guardian Therapeutics, Sobi/Sanofi, Pfizer, Alnylam, E‐therapeutics and Biomarin; has participated in a company sponsored speaker's bureau for Sobi/Sanofi; has participated on a Data Safety Monitoring Board or advisory board for Uniqure and has had a role as ATHN board member, ISTH Chair, HFA medical adviser and with MASAC. A.Sr. has received research support from Novo Nordisk, Sanofi, Roche, Takeda, Pfizer, Octapharma, Biomarin, Regeneron and INTAS Pharma; is a director, officer, employee of WFH, IAHAD, AHADAP and APBMT; is on advisory committees for Novo Nordisk, Sanofi, Roche, Takeda and Octapharma and is a consultant/speaker for Novo Nordisk, Sanofi, Roche, Takeda, Octapharma, Regeneron and Samsung Bioepis. T.S. has received fees for lectures sponsored by Roche, Sobi, CSL Behring and participated in Advisory Boards for Novo Nordisk, Takeda and Pfizer. A.C.W. has received payment for consultation/advisory boards from Sanofi, Sobi, Genentech, Roche, Biomarin, Novo Nordisk, Pfizer, Bayer, Spark, Hemab, Hema Biologics, Alnylam, Seragene and Takeda; has received honoraria from Octapharma and has received institutional research support from Sanofi, Pfizer, Takeda, Novo Nordisk, Spark Biomedical, Hemab and Genentech. E.B. has acted as a paid consultant for Bayer, LFB, CSL Behring and Octapharma.

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