BACKGROUND:Inheritable bleeding disorders (BDs) research has not historically reflected the diversity or needs of the entire community. The National Bleeding Disorders Foundation charged seven multidisciplinary working groups (WGs) with developing a U.S. National Research Blueprint (NRB) for a Bleeding Disorders Research Collaborative (BDRC) inspired by Lived Experience Experts (LEE) and grounded in health equity, diversity, and inclusion (HEDI). RESEARCH DESIGN AND METHODS:The Research and Development and Workforce WGs, in collaboration with the HEDI and LEE WGs, met virtually and in-person to develop recommendations for BDRC operationalization. RESULTS:An agenda of 327 feasible research priorities spanning nine main topics, each with four to six scientific areas of interest is proposed. It captures the hope that new diagnostic and therapeutic technologies and innovative research approaches enriched by LEE and HEDI expertise may advance health equity for all. Key constraints of time, expertise, funding, resources, and diversity were identified as important barriers to the capacitation of the interdisciplinary research workforce required to successfully achieve this research. Mentorship, partnership, training and education, collaboration, and advocacy solutions to these barriers are proposed. CONCLUSIONS:The BDRC seeks to capacitate a diverse, inclusive, collaborative workforce, and effectively accelerate research that advances health equity for all.

INTRODUCTION:The seventh Åland Island Meeting on von Willebrand Disease (VWD) was held on the Åland archipelago in Finland, from 26 to 28 September 2024. AIM:The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. RESULTS AND DISCUSSION:The topics covered both clinical aspects of management and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology of VWD, the diagnostic landscape and treatment strategies. Special attention was paid to the challenges of VWD in women and to the definition of disease severity, both key areas of ongoing clinical debate. Emerging research in bleeding disorders was also highlighted. 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 care of people with VWD, a multidisciplinary approach with biochemists, geneticists and cell biologists partnering with clinicians and industry is needed.

Von Willebrand factor (VWF) is a key coagulation protein, tethering platelets to sites of injury through binding sites for platelet GPIbα and for exposed subendothelial collagen. VWF synthesis occurs in endothelial cells and megakaryocytes, a complex process involving the VWF propeptide, dimerization and multimerization, and glycosylation. Von Willebrand disease (VWD) results from defects or dysfunction in VWF and includes both quantitative and qualitative issues with the VWF protein. VWF is cleaved by ADAMTS13 and ultimately cleared from circulation. While it is clear that VWF plays an important role in clot formation, it may also be important in a number of other areas including angiogenesis. Our knowledge of VWF has come a long way in the 100 years since the first publication by Erik von Willebrand in 1926 thanks to a large number of researchers in the VWF biology field.

ABSTRACT:An essential component of low von Willebrand factor (VWF)/type 1 von Willebrand disease (VWD) diagnosis is to identify patients with an increased bleeding phenotype, as most individuals with VWF levels in the 30 to 50 IU/dL range do not bleed. The International Society on Thrombosis and Haemostasis-bleeding assessment tool (ISTH-BAT), widely used for assessing bleeding severity, has recently been shown to be age dependent. Although age may also influence ISTH-BAT scores in individuals with VWF levels between 30 and 50 IU/dL, and subsequently affect low VWF diagnosis, this relationship has not been investigated. Therefore, we analyzed 325 participants from the Zimmerman Program, of whom 220 (67.7%) had abnormal ISTH-BAT scores, whereas 105 (32.3%) had normal scores. Our analysis demonstrates that age critically influences the likelihood of attaining an abnormal ISTH-BAT score and, consequently, being registered with a formal diagnosis of low VWF/type 1 VWD. For example, children first assessed at ≥10 years, are twice as likely to have an abnormal ISTH-BAT compared with those first investigated at <10 years (P < .001). In addition, the prevalence of abnormal ISTH-BAT scores was significantly higher in women aged ≥44 years (91.8%) compared with women aged 18 to 28 years (66.7%; P = .004). Finally, we demonstrate that the change in abnormal ISTH-BAT threshold at the age of 18 years critically affects low VWF diagnosis, owing to lower rates of abnormal scores in young adults (P = .006). In conclusion, we demonstrate that the likelihood of a low VWF/type 1 VWD diagnosis is influenced by the age at which ISTH-BAT is first assessed in individuals with mild-to-moderately reduced VWF levels.

The interaction between VWF and platelet αIIbβ3 is thought to be essential for clot formation at injury sites, but its biological properties remain poorly understood due to the complexity and overlap with other αIIbβ3 ligands. Here, we developed a novel binding assay using a recombinant αIIbβ3 headpiece to evaluate VWF-αIIbβ3 binding in plasma from 441 Zimmerman Program participants. The VWF:αIIbβ3 to VWF:Ag ratio was significantly lower in patients with type-1, 2A, and 2B VWD than healthy controls. We identified five index cases with the p.R2464C variant in the VWF-C-domain, where affected family members displayed significantly reduced VWF:αIIbβ3/VWF:Ag ratios. To investigate the function of the VWF-αIIbβ3 interaction, we created a mouse model (VWFRGES/RGES) by altering the VWF-RGDS motif to RGES, which abolished VWF-αIIbβ3 binding. VWFRGES/RGES mice exhibited increased blood loss following lateral TVT and reduced thrombus stability in a laser injury model, showing a 59-fold larger AUA for emboli compared to wild-type. However, initial bleeding times and outcomes of carotid artery injury were comparable. Overall, our VWF:αIIbβ3 binding assay is valuable for characterizing VWD, and the VWFRGES mouse model underscores the physiological significance of the VWF-αIIbβ3 interaction, highlighting that VWF-αIIbβ3 interaction is crucial for stabilizing platelet plug formation at injury sites.

ABSTRACT:The American Society of Hematology (ASH), International Society on Thrombosis and Haemostasis (ISTH), National Hemophilia Foundation (NHF; now National Bleeding Disorders Foundation), and World Federation of Hemophilia (WFH) 2021 guidelines on the diagnosis and management of von Willebrand disease (VWD) included 11 recommendations on the diagnosis of VWD and 12 recommendations on the management of VWD, the most common inherited bleeding disorder. We describe the results of a review of the 2021 guidelines by the clinical co-chairs of the guideline panels requested by ASH to inform decision-making about the need for and timing of a guideline revision. An updated MEDLINE and Embase search applied the same terms as the ASH ISTH NHF WFH 2021 guidelines limited to studies from 2020 to 30 July 2024 (diagnosis) or 24 July 2024 (management). For the diagnosis of VWD, 432 studies were identified and underwent title and abstract review, with 17 undergoing full text review, and for the management of VWD, 288 studies were identified and underwent title and abstract review, with 37 undergoing full text review, to determine whether the data would change the strength or directionality of the existing recommendation or merit development of a new recommendation. Based on this review, the clinical co-chairs noted that none of the reviewed studies would change the direction or strength of the existing guideline recommendations. There will be continued monitoring of the ASH ISTH NHF WFH 2021 guidelines on the diagnosis and management of VWD to evaluate whether there is sufficient new evidence to warrant additional revisions.

Diagnosis of von Willebrand disease (VWD) is a challenge due to variability in laboratory assays, variability in patient von Willebrand factor (VWF) levels, and variability in the different types of VWD. Because of these challenges, it can be difficult to make the diagnosis, especially in young children. On the other hand, older individuals may carry a diagnosis of VWD and not truly have VWD, creating the necessity for thoughtful evaluation of patients for whom “undiagnosing” VWD is appropriate. The most important factor is clinical bleeding history, although repeated laboratory testing and individual considerations are also critical. More research is needed on aging and VWF to best understand this challenge.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative defects in the von Willebrand factor protein (VWF). Type 3 VWD has a severe bleeding phenotype caused by the absence of VWF where treatment usually involves replacement therapy with VWF-containing products. The immune system can react to the VWF product and form anti-VWF antibodies to neutralize or clear the VWF which can compromise efficacy of treatment or lead to anaphylaxis. Current diagnostic testing is limited to the detection of anti-VWF antibodies that neutralize VWF binding to platelets by using a ristocetin cofactor assay. We set out to develop assays to identify both neutralizing and non-neutralizing antibodies to screen, quantify, and characterize anti-VWF antibodies in samples from the Zimmerman Program, a large multicenter study of VWD subjects. We detected anti-VWF IgG or IgM antibodies in 18% of 49 unrelated type 3 VWD individuals. The antibodies ranged in concentration and consisted of 33% non-neutralizing and 67% neutralizing to factor VIII, collagen III, platelet GPIbα, and/or collagen IV binding. Of the positive type 3 VWD samples, 8/9 were IgG which were further subclassified into mostly IgG1 and IgG4 antibodies. Through a series of testing methods, we identified VWF specific antibodies in 9 unrelated type 3 VWD individuals with varying demographics, bleeding phenotypes, and genetic variants. This anti-VWF antibody testing strategy provides a useful tool to assess risk and better navigate treatment options for type 3 VWD patients.

INTRODUCTION:Treatment options are expanding for von Willebrand disease (VWD). A core outcome set (COS)-a minimum set of agreed-upon outcomes to be used in every clinical trial for a given condition-provides guidance on which outcomes are most important to measure to ensure necessary data is collected for a variety of stakeholders and enable comparison across products and trials. AIM:coreVWD aimed to develop a COS for trials for prophylaxis and perioperative treatments for VWD. METHODS:A modified Delphi consensus process was used to condense/prioritize a long list of potential outcomes. Over three Delphi rounds, a multi-stakeholder panel (patients, clinicians, pharmaceutical company representatives, HTA organizations, payer, and government organization representatives) rated each outcome from 1 (not important to include in a COS) to 9 (essential to include). Outcomes were eliminated or retained based on pre-determined criteria; a special provision to elevate patient priorities was included. An in-person consensus meeting was held after Delphi round 2. RESULTS:Thirty-nine panellists participated. The final COS for prophylaxis treatment included 18 outcomes, seven of which are part of a special subset selected for women, girls and people with the potential to menstruate. There were 11 outcomes in the final perioperative branch COS. Six outcomes overlapped both COS. CONCLUSIONS:The coreVWD COS represents a consensus list of outcomes for clinical trials for both factor and non-factor VWD therapies. These outcomes will be useful across the lifecycle of a product, from clinical development through regulatory and market access phases and into patient-provider decision-making.

Type 1 von Willebrand disease (VWD) is characterized by a quantitative deficiency of functionally normal von Willebrand factor (VWF). A subset of type 1 VWD patients have significantly reduced survival of their VWF in plasma, resulting in markedly reduced VWF half-life (<3 hours). These patients can be identified by a substantially increased ratio of VWF propeptide (VWFpp) to VWF antigen, or by measuring VWF levels after DDAVP administration. Type 1 C patients typically have a robust early DDAVP response with a subsequent rapid decline in VWF levels. Identification of a reduced VWF survival phenotype is clinically important, as these subjects will benefit from VWF replacement therapy rather than DDAVP treatment due to the increased clearance of endogenous variant VWF.

Background: Clinical evidence suggests that anemia exacerbates traumatic bleeding and worsens outcomes. Objectives: To study the influence of iron deficiency anemia on traumatic bleeding, coagulopathy, and mortality. Methods: C57BL/6J mice received an iron-deficient diet (8 weeks; +/- 1 mg intraperitoneal iron dextran 2 weeks before trauma). Control mice received a normal diet. Iron deficiency anemia was confirmed by hematocrit, red cell indices, and liver iron. Mice received saline or tranexamic acid (TXA; 10 mg/kg) just before liver laceration. Blood loss, coagulopathy (activated partial thromboplastin time, factor [FiII, FV, FVIII, FX, and fibrinogen), D-dimer, thrombin-antithrombin complexes, and plasmin-alpha-2antiplasmin complexes were analyzed at 15 and 60 minutes, and a cytokine panel was performed at 60 minutes and 6 hours after trauma. Survival was monitored for 7 days. Results: Compared with nonanemic mice, anemic mice had lower hematocrit and hepatic iron content. Anemic mice experienced higher blood loss compared with non- anemic mice, which was reduced by TXA. Both groups developed traumatic coagulopathy characterized by activated partial thromboplastin time prolongation, thrombin-antithrombin complex formation, and depletion of FV, FVIII, and fibrinogen. TXA corrected the coagulopathy. However, plasmin-alpha-2-antiplasmin complex formation and D-dimers, markers of fibrinolysis, were higher in anemic mice and were not corrected by TXA. Seven-day survival was low in anemic mice, and rescued by TXA, but high in nonanemic mice without additional improvement by TXA. Among cytokines, only interleukin-6 increased, which was prevented by TXA most notably in anemic mice. Conclusion: These observations provide first and critical proof-of-principle evidence that anemia accelerates traumatic bleeding and increases mortality, which could be rescued by anemia correction (parenteral iron) or periprocedural TXA.

Genetic testing is crucial in diagnosing and managing von Willebrand disease (VWD), a bleeding disorder caused by genetic variations in the von Willebrand factor ( VWF ) gene. This review discusses the complex genetics of VWD and techniques used in molecular analysis. While most VWD cases can be diagnosed through laboratory tests, genetic testing can help in challenging cases where lab tests are inconclusive or inconsistent. Assessing the pathogenicity of identified VWF variants is important for understanding their clinical significance. This review provides an overview of guidelines and resources for interpreting and classifying variants. Additionally, the molecular spectrum of VWD is provided, highlighting genetic defects associated with different VWD subtypes. This information can assist in selecting appropriate treatments and improving VWD prognosis. Overall, this chapter offers a comprehensive overview of the role and significance of genetic testing in VWD, covering techniques, variant interpretation, and the disease's molecular basis.

INTRODUCTION:There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available.AIM:We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB.METHODS:We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified.RESULTS:In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described.CONCLUSION:Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

Type 2M von Willebrand disease (VWD) is a qualitative defect in von Willebrand factor (VWF) function with preserved multimer formation. Mucosal bleeding is typical but may be more severe than the bleeding seen in type 1 VWD. Laboratory criteria include a decrease in platelet binding as compared to antigen and/or a decrease in collagen binding as compared to antigen. Some genetic variants can affect the ability of VWF to bind ristocetin, so when the ristocetin cofactor assay is used to characterize VWF-platelet binding, an erroneous diagnosis of type 2M VWD may be made. Newer assays, such as the VWF:GPIbM assay, do not rely on ristocetin and therefore raise less concern for misdiagnosis. Treatment generally consists of VWF concentrate, although desmopressin may be adequate for clinical response in some situations.

Introduction: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder; however, establishing a laboratory diagnosis can be challenging. While the VWF Ag test is highly reproducible, VWF:RCo activity is prone to both intra- and inter-laboratory variation. A landmark study by Flood et al.demonstrated a common polymorphism in African American controls, D1472H, affecting approximately 50% of healthy controls as well as subjects previously labeled as type 1 VWD. This sequence variation results in decreased VWF:RCo levels and, ultimately, lower RCo:Ag ratio in healthy controls without an increase in their bleeding score. A newer GPIbM assay assesses VWF activity which does not depend on ristocetin binding. This assay is hence unaffected by D1472H polymorphism and provides more accurate assessment of VWF activity. However, GPIbM assay is not widely available, and most labs still rely on VWF:RCo assays to measure activity. In this analysis of an ongoing study examining the population prevalence of VWD in adolescents with heavy menstrual bleeding (HMB), we aim to compare VWF activity measured by RCo and GPIbM assay in African American participants with HMB and low RCo activity. Our hypothesis is that many of these subjects may have lower VWF:RCo activity (presumably due to D1472H polymorphism) but normal GPIbM activity resulting in false diagnosis of type 1 VWD. Methods: In this large, ongoing population study, 9 to 21-year-old menstruating adolescents presenting for routine care were recruited from five primary care clinics across Nationwide Children's Hospital (NCH) (Columbus, OH, USA). Patients with a prior diagnosis of a bleeding disorder were excluded. Participants completed the ISTH Bleeding Assessment Tool (BAT). Those with a score of ≥1 on the menses question of the ISTH BAT were considered to have HMB and underwent testing for VWD. Whole blood samples were collected and VWF Ag and RCo tests were performed locally by the NCH clinical lab. Additionally, samples were sent to Versiti research lab (Milwaukee, WI) for VWF Ag and GPIbM activity testing. VWF Ag and activity results obtained from both sites were then compared. Participants with VWF Ag or GPIbM levels of ≤50% were considered to have VWD per our study protocol. Data were summarized with standard descriptive statistics and nonparametric analyses were used to compare labs and clinical characteristics in patients with low VWF:RCo who did and did not have VWD. Results: To date, 695 adolescents agreed to participate in this study and, among these, 433 self-identified as African American (62%). In the African American group, 204 subjects (47%) met the study definition of HMB and were considered eligible for further VWD testing. While some were lost to follow-up, 160 adolescents agreed to and underwent VWD testing. Of these, 32 adolescents (20%) had VWF:RCo ≤50%. Upon further testing at Versiti, 9 (28%) had low GPIbM activity as well and met the criteria for VWD. The remaining 23 participants (72%) had normal GPIbM activity, and hence, no VWD. On comparing the two groups (9 with VWD and 23 without VWD), age at menarche and years since menarche were similar in both groups with a median of 16 years and 5 years, respectively. Bleeding scores (ISTH BAT scores) were also similar in both groups. Median VWF Ag at our local NCH lab was significantly higher at 83% (IQR: 71-99%) for those who did not have VWD compared to 54% (IQR: 52-57%) for those who truly had VWD (p <0.001). This observation was also seen with the Versiti labs where median VWF Ag was higher at 80% (IQR: 64-103%) for those without VWD compared to 47% (44-49%) for those with VWD (p <0.001). All the participants without VWD (n=23, 100%) had VWF Ag above 60% on original testing at our local NCH lab. Conclusion: In this small primary care population, we found that VWD is not uncommon in African American adolescents with HMB, occurring in 1 out of 20 participants who underwent testing. However, our data again demonstrate that African American individuals may have lower RCo activity, likely due to the D1472H polymorphism which could result in false labeling as VWD. Hematology consultation and further testing with GPIbM assay should be pursued for accurate diagnosis of VWD. VWF Ag may give some clues and in individuals with Ag 60% or higher but low RCo, a falsely low RCo should be considered, and confirmatory testing should be pursued.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, and one of the most complex. It is caused primarily by defects in the von Willebrand factor (VWF) protein, and can be divided into both quantitative and qualitative disorders. The current classification system considers type 1 VWD to represent the mild to moderate quantitative deficiencies of VWF, and type 3 VWD to represent the severe quantitative deficiency of VWF. Type 2 refers to the qualitative variants which are divided by VWF defect. Appropriate classification of VWD is important to determine the most appropriate treatment for affected patients.