Diagnosis Of Von Willebrand Disease Research Articles

Predictors of diagnostic delays and loss to follow-up in women with von Willebrand disease: a single-center retrospective cohort study

BackgroundWomen with von Willebrand disease (VWD) often face diagnostic delays, leading to increased bleeds, stress, and healthcare use. The factors influencing these delays and their effects on gynecologic outcomes are not well understood. ObjectivesThis study aimed to 1) identify the prevalence and predictors of diagnostic delays and loss to follow-up in women with VWD and 2) determine how these delays affect severe gynecologic bleeding, emergency visits, transfusions, and hysterectomies. MethodsWe conducted a single-center retrospective cohort study and included women aged ≥18 years diagnosed with VWD. Delayed diagnosis was defined as ≥3 bleeding events prior to VWD diagnosis, excluding easy bruising due to its subjectivity. Loss to follow-up was defined as ≥5 years since the last hematology visit. We used logistic regression for analysis. ResultsAmong 178 diagnosed women (median age, 27 years), 71 (40%) experienced ≥3 bleeding events before diagnosis. The median time from the first bleeding event to VWD diagnosis was 14.2 years. Severe bleeding events significantly predicted diagnostic delays (adjusted odds ratio, 3.1; 95% CI, 1.5-6.2). Fifty-four (30%) women were lost to follow-up, with remote era of initial bleed and VWD type identified as significant predictors. Delays were associated with increased risks of hysterectomies (odds ratio, 2.7; 95% CI, 1.2-6.3) and other gynecologic procedures. ConclusionDelayed diagnosis and loss to follow-up in VWD are common even in a specialized Hemophilia Treatment Centre. Such delays lead to more severe bleeding and increased gynecologic interventions. Prompt diagnosis is paramount for better patient outcomes and reduced healthcare utilization.

Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy

BackgroundSnake venom botrocetin facilitates von Willebrand factor (VWF) binding to platelet GPIbα and has been widely used for the diagnosis of von Willebrand disease and GPIb-related disorders. Botrocetin is also commonly employed for the development/characterization of antithrombotics targeting the GPIb-VWF axis. ObjectivesTo explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation. MethodsThe effects of botrocetin on platelet aggregation were examined using platelets from wild-type, VWF- and fibrinogen-deficient, GPIbα-deficient, IL4Rα/GPIbα-transgenic and αIIbβ3-deficient mice and Bernard–Soulier syndrome and healthy human samples. Platelet-fibrinogen and platelet-VWF interaction were measured using flow cytometry. GPIbα-VWF binding was evaluated utilizing enzyme-linked immunosorbent assay. Botrocetin-αIIbβ3 and botrocetin-GPIbα interactions were measured using enzyme-linked immunosorbent assay and fluorescence anisotropy assays. Heparinized whole blood from healthy donors was examined for thrombus formation and growth in a perfusion chamber. ResultsBotrocetin could induce aggregation of platelets from a Bernard–Soulier syndrome patient and GPIbα-deficient mice as well as platelets lacking the N-terminal extracellular domain of GPIbα. Botrocetin could interact with αIIbβ3 and facilitated αIIbβ3-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting αIIbβ3. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to αIIbβ3 and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited αIIbβ3- and GPIb-mediated platelet aggregation, spreading, and thrombus formation. ConclusionOur study provides insights into avoiding the misdiagnosis of GPIb-related disorders and developing botrocetin mutants as potential new antithrombotics that may simultaneously target both αIIbβ3 and GPIbα.

Von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The disorder is characterized by excessive mucocutaneous bleeding. The most common bleeding manifestations of this condition include nosebleeds, bruising, bleeding from minor wounds, menorrhagia or postpartum bleeding in women as well as bleeding after surgery. Other less frequent symptoms include gastrointestinal bleeding, haematomas or haemarthroses. VWD pathophysiology is complex and results from defects in von Willebrand factor (VWF) glycoprotein. Quantitative deficiencies are responsible for type 1 VWD with a partial decrease of VWF and type 3 with the complete absence of VWF. Qualitative abnormalities cause type 2 VWD, being further divided into types 2A, 2B, 2M and 2N. Although common, VWD is at risk of misdiagnosis, overdiagnosis and underdiagnosis owing to several factors, including complex diagnosis, variability of bleeding symptoms, presence of external variables (blood groups and other physiological modifiers such as exercise, thyroid hormones, oestrogens, and ageing), and lack of disease awareness among non-specialist health-care providers. Establishing the correct VWD diagnosis requires an array of specialized phenotypic assays and/or molecular genetic testing of the VWF gene. The management of bleeding includes increasing endogenous VWF levels with desmopressin or infusion of exogenous VWF concentrates (plasma-derived or recombinant). Fibrinolytic inhibitors, topical haemostatic agents and hormonal therapies are used as effective adjunctive measures.

Current Diagnosis of von Willebrand Disease in Italy: 3 Years Following the Release of the International Guidelines.

The American Society of Hematology-International Society on Thrombosis and Haemostasis-National Hemophilia Foundation-World Federation of Hemophilia 2021 International Guidelines (IGL) on von Willebrand disease (VWD) have pointed out many challenges, mainly in the diagnostic approach of VWD patients. To determine the impact of these IGL on the current clinical and laboratory diagnosis of Italian VWD patients, we have recently conducted a survey among 43 centers affiliated with the Italian Association of Hemophilia Centers (AICE). Directors and colleagues responsible for the management of VWD patients were invited to report in a detailed questionnaire how IGL recommendations about the assessment of the specific activities of von Willebrand Factor (VWF) could be applied at their local sites. Results from such a survey showed that bleeding assessment tools, VWF antigen, and factor VIII procoagulant are currently in use in all centers. The automated assays for platelet-dependent VWF activity with or without ristocetin described in IGL have been used since 2021 in 37/43 (86%) centers. Among other laboratory tests, VWF collagen binding, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF:FVIII binding assay were available in 49, 63, 26, 7, and 28% of AICE, respectively. Analyses of VWF gene defects are available only at 3/43 (7%) centers. Desmopressin (DDAVP) infusion trials at diagnosis, with measurements of VWF activities at 1 and 4 hours post-DDAVP, is currently performed at 38/43 (88%) centers. Based on this information, a simplified clinical diagnosis using a few automated tests before and after DDAVP has been proposed. Such a diagnostic approach will be validated prospectively in a large cohort of Italian VWD patients.

Hemoglobin concentration and body mass index are determinants of plasma von Willebrand factor and factor VIII levels

BackgroundVon Willebrand Disease (VWD) is the most common inherited bleeding disorder. VWD is characterized by an abnormal quantity or quality of von Willebrand Factor (VWF). Anemia is often found at presentation for a bleeding disorder evaluation due to chronic blood loss. Objectives/HypothesisWe hypothesized that anemia is associated with elevations in both VWF and factor VIII (FVIII) over baseline. We also hypothesized that obesity would be associated with increased levels of VWF. MethodsWe conducted a single-center review of the electronic health record for patients that had proximal von Willebrand profiles and Hb data. ResultsWe identified 4552 unique subjects with VWF studies and a CBC within 24 h. We found that decreasing hemoglobin inversely correlated with VWF antigen, VWF ristocetin cofactor activity, and FVIII activity. We also found that obesity and Black race were independently associated with increased VWF antigen, activity, and FVIII activity. Hb, race, and body mass index (BMI) continued to be determinants of VWF and FVIII levels in multivariable analysis. ConclusionOur study demonstrates that anemia, race, and BMI were found to be associated with elevation of VWF antigen, VWF activity, and FVIII levels. As many individuals with anemia present for evaluation for a bleeding disorder, these variables need to be considered. Key points- Anemia was found to be associated with elevation of VWF antigen, VWF activity and FVIII levels.- Testing von Willebrand factor at times of anemia may mask a diagnosis of von Willebrand Disease.

Early diagnosis of persons with von Willebrand disease using a machine learning algorithm and real-world data

ABSTRACT Background Von Willebrand disease (VWD) is underdiagnosed, often delaying treatment. VWD claims coding is limited, including no severity qualifiers; improved identification methods for VWD are needed. This study’s aim: identify and characterize undiagnosed symptomatic persons with VWD in the US using medical insurance claims to develop predictive machine learning (ML) models. Research design andmethods Diagnosed andpotentially undiagnosed VWD cohorts were defined using Komodo longitudinal USclaims data (January 2015-March 2020). ML models were built using keycharacteristics predictive of VWD diagnosis from the diagnosed cohort. Two MLmodels predicted VWD diagnosis with the highest accuracy in females (randomforest; 84%) and males (gradient boosting machine; 85%). Undiagnosed personssuspected to have VWD were identified using an 80% cutoff probability; profilesof key characteristics were constructed. Results The trained MLmodels were applied to the undiagnosed cohort (28,463 females; 20439 males)with suspected VWD. 52% of undiagnosed females had heavy menstrual bleeding, akey pre-diagnosis symptom. Undiagnosed males tended to have more frequentmedical procedures, hospitalizations, and emergency room visits compared withundiagnosed females. Conclusions ML algorithmssuccessfully identified potentially undiagnosed symptomatic people with VWD,although many may remain undiagnosed and undertreated. External validation ofthe algorithms is recommended.

The Impacts of Genetic Polymorphisms on the Von Willebrand Factor Level in Type 1 Von Willebrand Disease

Background: von Willebrand disease (VWD) is the most common inherited bleeding disease, which results from deficiency or defect of von Willebrand factor (VWF). In type 1 VWD, there are only 53-81% patient whose mutations of VWF gene can be identified. Some studies reported that variants outside the VWF gene may also contribute to the VWF level. There are 7 genetic variants of single nucleotide polymorphism ( SNP ) reported to be associated with the variation of VWF levels, including CLEC4M, STXBP5, SCARA5, ABO, VWF, STAB2 and UFM1. The aims of this study were to explore the frequency of SNPs of the 7 genes among type 1 VWD patients and the effects of the 7 genetic variants on the VWF levels in type 1 VWD patients. Patients and methods: There were 62 patients ( the ratio of M/F: 1 ) with type 1 VWD enrolled in this study, including 35 (56.5%) patients with found mutations of VWF gene. Each patient's bleeding symptoms were assessed by the MCMDM-1 VWD bleeding score. The results of VWF levels: VWF:Ag and VWF activity ( VWF:ACL or VWF:RCo ) and FVIII: C at the VWD diagnosis were retrospectively collected, as shown in Table 1. Each enrolled patient's genomic DNA was extracted and the SNPs of the 7 gene were targeted by PCR amplification followed by direct sequencing. Results: There was high correlations between VWF:Ag and VWF activity ( r = 0.73, p < 0.0001 ) and between VWF:Ag and FVIII:C ( r = 0.60, p < 0.0001 ), respectively. The patients without variant ( A/A) of UFM1 has significantly lower median VWF:Ag of 33% than 44.7% of patients with heterozygous variant ( A/C ) type ( p = 0.033 ). Patients without variant (A/A ) of STXBP gene had both significantly lower median value of VWF:Ag ( 31.9% vs 46.1%, p = 0.017 ) and VWF activity (26.55% vs 30.4%, p = 0.0467 ) than those patients with heterozygous variant ( A/G ). Four alleles substitution of SNP of UFM1( C>A ) and STXBP genes ( G>A ) variant has remarkably lowest median VWF antigen level of 27.4%, which was significantly lower than 43.05% of the three alleles substitution ( p = 0.0014 ) and the 48.6% of the two alleles substitution ( p = 0.0279 ), as shown in Figure 1. Conclusions: Our study demonstrates that both C to A variant of UFM1 gene and G to A variant of STXBP5 gene were associated with lower VWF: Ag level than those without variant, respectively. The combination of four allelic variant of UFM1 and STXBP5 genes had the most reducing effect on VWF: Ag level.

A Retrospective Analysis and Characterization of Female Patients with Bleeding Disorders Hemophilia B, Hemophilia B and Von Willebrand's Disease and Their Treatment Type at Banner MD Anderson Cancer Center

Introduction: Women with bleeding disorders experience bleeding in mucocutaneous tissues, uterine bleeding, and in muscles and joints. In men, bleeding of more than 1 or 2 bleeds per year is justification for starting prophylaxis with factor and non-factor replacement therapy. At Banner MD Anderson Cancer Center (BMDACC), women are offered prophylaxis according to the same standard. Uterine bleeding classified as excessive or disruptive to daily activity is considered bleeding requiring prophylaxis. Aim: Describe the number of women in the bleeding disorder database from June 2018 to December 2022 with Hemophilia A (HemA), Hemophilia B (HemB) and Von Willebrand Disease (VWD) with respect to number on prophylaxis to prevent bleeds. Specific factor levels and subtype of VWD were not gathered as part of this project. Rather, patients were offered prophylaxis based on symptoms of bleeding. Prophylaxis is defined as treatment to prevent bleeding associated with day-to-day activity, but not prior to planned procedures. The type of treatment was recorded, type of access if needed (peripheral intravenous access v. central venous access) and why treatment was started. Results: Among 101 female patients in the BMDACC bleeding disorder database, 64 had a diagnosis of HemA, HemB or VWD. Among HemA, 13 of 17 (76%) were on prophylaxis with factor replacement or emicizumab. Joint bleeding and pain were the most common reasons for starting prophylaxis in 6 of 13 patients and menorrhagia was the second most common in 3 patients. Among HemB, 2 of 4 (50%) were on factor replacement. Rectal bleeding and menorrhagia were reasons to start prophylaxis. Among VWD, 24 of 43 (56%) were on prophylaxis with one or more of the following treatments: factor replacement, desmopressin or antifibrinolytic replacement. Menorrhagia was the most common reason for starting prophylaxis in 13 of 24 patients and joint bleeding was the next most common in 4 patients. Additional reasons were trauma, mucocutaneous, urinary tract bleeding, and bleeding during pregnancy. Patients with VWD were much more likely to require central IV access in the form of a chest port-a-cath 14 of 43 (33%) than patients with HemA or HemB, of which no patients required central access. Patients with HemA or HemB were more likely to use factor replacement than VWD to prevent bleeding symptoms. Patients with VWD were more likely than patients with HemA or Hem B to have a diagnosis prior to age 18; VWD had 16 of 43 (37%), HemA had 3 of 17 (18%) and HemB had 0 of 4 (0%). Conclusions: Female patients with inherited bleeding disorders have bleeding symptoms that may require the initiation of routine treatment to prevent bleeding and should be offered treatment with hemostatic agents to prevent bleeding when bleeding frequency exceeds more than 1 or 2 bleeds per year. Heavy menstrual bleeding, joint bleeding, joint pain, gastrointestinal and genitourinary bleeding are reported in this patient population as reasons to start prophylaxis with hemostatic agents. Further study is underway to assess the efficacy of starting prophylaxis in these patients. In the Author's experience, once factor replacement is started, patients are pleased with the change in their health status after initiation of treatment and continue to be compliant with treatment recommendations although they may have difficulty in administering those treatments. Patients with VWD were much more likely than those with HemA or HemB to require placement of a central venous access device. Further study into this observation is needed to understand why this is so.

A Feasibility Study Evaluating Von Willebrand Factor in Patients with Gastrointestinal Angiodysplasia

Background: Abnormalities of von Willebrand Factor (VWF), such as those found in von Willebrand Disease (VWD) are associated with the development of abnormal blood vessels known as angiodysplasia. Angiodysplasia occurs primarily in the gastrointestinal (GI) tract, particularly the small bowel. Among patients with VWD, angiodysplasia is significantly overrepresented as a cause of GI bleeding and occurs in all VWD subtypes although it is reported more frequently in those with loss of the high molecular weight multimer of VWF. Recent studies have demonstrated more than a third of patients with VWD and GI bleeding have angiodysplasia when systematically assessed with Video Capsule Endoscopy (VCE) to examine the small bowel. Given the relationship between angiodysplasia and VWD our objective was to assess the feasibility of evaluating patients with GI angiodysplasia for abnormalities of VWF. Methods: We undertook a prospective single center pilot study to assess patients over the age of 18 with GI angiodysplasia for underlying abnormalities of VWF. Patients were identified based on angiodysplasia being present on a VCE study. Patients who consented to enrollment completed a self-administered bleeding assessment tool (BAT) as well as baseline demographic data. VWF testing included VWF antigen (VWF:Ag), VWF functional assay (VWF:GPIbM), Factor VIII coagulant activity (FVIII:C), and VWF pro-peptide (VWFpp) levels. Results: After reviewing 190 consecutive VCE studies performed at our institution between April 2021 and April 2023, we identified 50 patients who had capsule endoscopies demonstrating angiodysplasia of the GI tract. Thirteen of these patients consented to enrollment in the study. The bleeding histories of included patients are detailed in Table 1 along with their baseline clinical, laboratory, and demographic data. Two patients endorsed lifelong bleeding symptoms and three reported a significant family history of bleeding - all in a female relative. ISTH-BAT scores ranged from 0 to 18 with a median score of 2. Since our population is older than other studies that report on bleeding scores, we considered an abnormal bleeding score to be >6 as recent evidence indicates normal BAT scores increase over time. Five patients (38.6%) in our study had an ISTH-BAT abnormal bleeding score. VWF levels were assessed (Table 1) and one patient aged 88 years old with a significant family and lifelong history of bleeding received a new diagnosis of Type 2A VWD. Severe iron deficiency anemia requiring ongoing IV iron was diagnosed in two patients. Conclusion: In our feasibility study, we demonstrated a feasible protocol for recruitment of patients with GI angiodysplasia for clinical and laboratory testing of VWF. A significant proportion of our patients (38.6%) had abnormal bleeding scores and one patient had an underlying Type 2A VWD diagnosis.

PB0854 Could Gynecologists Contribute to an Increased Diagnosis of von Willebrand Disease among Women with Heavy Menstrual Bleeding?

PB0854 Could Gynecologists Contribute to an Increased Diagnosis of von Willebrand Disease among Women with Heavy Menstrual Bleeding?

PB0837 Analysis of the Change in Diagnosis of von Willebrand Disease by Region and Economic Status

PB0837 Analysis of the Change in Diagnosis of von Willebrand Disease by Region and Economic Status

OC 60.1 Delineating VonWillebrand Factor Genetic Variants in Patients with a Von Willebrand Disease Diagnosis

OC 60.1 Delineating VonWillebrand Factor Genetic Variants in Patients with a Von Willebrand Disease Diagnosis

The necessity of repeat testing for von Willebrand disease in adult patients with mild to moderate bleeding disorders

BackgroundIn patients with mild-to-moderate bleeding disorders (MBD), von Willebrand disease (VWD) is diagnosed at von Willebrand factor (VWF) levels ≤50 IU/dL. Although VWF levels are unstable, repeated testing for VWD diagnosis is not necessarily advised in recent guidelines. ObjectivesTo analyze the relevance of repeated VWF testing to diagnose VWD in patients with MBD. MethodsData of 277 patients with MBD from the Vienna Bleeding Biobank with at least 2 separate assessments of VWF antigen (VWF:Ag) and activity (VWF:Act) were analyzed. ResultsIn repeated VWF measurements, 36 patients (13.0%) had “changing” VWF levels (≤/>50 IU/dL), 27 (9.7%) had persistent levels ≤50 IU/dL (“pathologic”), and 214 (77.3%) had levels >50 IU/dL (“normal”). Of the 36 changing patients, 22 (61%) were diagnosed with VWD at baseline, whereas the others only met VWD diagnostic criteria at repeated measurements. Using logistic regression, we estimated a probability of change of 26.4% (95% CI, 12.5-47.4) at baseline VWF levels of 30 IU/dL, 50.8% (95% CI, 35.6-65.8) at 50 IU/dL, 18.8% (95% CI, 12.3-27.6) at 60 IU/dL, and 1.2% (95% CI, 0.3-4.9) at 80 IU/dL. Baseline VWF was a strong predictor for changing status (Χ2 = 49.9; P < .001), while age, sex, Vicenza score, and blood type O had limited added value (Χ2 = 5.1; P = .278). Baseline VWF:Ag or VWF:Act cutoffs of 80 IU/dL had negative predictive values of 98.1% and 99.1% for changing status, respectively. ConclusionOur data emphasize an overlap between patients with VWD and MBD with bleeding disorder of unknown cause and underline the need for repeated VWF testing, especially in patients with VWF levels <80 IU/dL.

Challenges in the classification of von Willebrand disease with a limited test panel: An experience from an upcoming hemostasis laboratory in southern India

Objectives: The diagnosis and classification of von Willebrand disease (VWD) is an intricate process requiring multiple hemostatic tests. Cutoff values of the tests vary with the subtype. Sometimes, all the tests are not available. This study was done to analyze the clinical and coagulation profile of VWD diagnosed and broadly classified based on a simplified algorithm. Material and Methods: This was a cross-sectional study done over 6 years. After screening tests, a simplified algorithm taking cutoff for various tests based on updated guidelines using the primary panel of von Willebrand factor antigen assay (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and Factor VIII:C was used. Multimer assay was done in a few cases. Data were compiled using summary statistics. Results: Forty patients fitted the diagnosis of VWD: Type 3 in 13 (32.5%), Type 2N (likely) in 8 (20%), Type 2 (not further categorized) in 9 (22.5%), and VWD, not further categorized in 10 (25%). The mean age was in the second or third decade with female predominance. Diagnosis of Type 3 was relatively straightforward due to markedly deranged parameters. Type 2N was provisionally diagnosed based on bleeding pattern and markedly reduced Factor VIII:C; further, subtyping of Type 2 and categorization of some cases was not possible due to non-availability of some tests. Conclusion: VWF:Ag assay, VWF:RCo, and Factor VIII:C form the cornerstone for diagnosing major VWD types. The under-representation of milder phenotypes and a greater proportion of severe VWD subtypes observed is likely due to hospital referral bias and may not represent population prevalence.

Pharmacologically Treated Anxiety and Depression in People Diagnosed with von Willebrand Disease: Matched Cohort Study.

People diagnosed with von Willebrand disease (VWD) have reduced quality of life versus the general population, and there is limited evidence of increased rates of anxiety and/or depression among people diagnosed with VWD. To understand the association between VWD and mental health outcomes. A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) GOLD database (1988-2016). People diagnosed with VWD were matched 1:10 to randomly selected people in the database without VWD based on sex, birth year ±2 years, CPRD record start year ±2 years, and general practice attended. Individuals were followed from VWD diagnosis or match date to censoring (first event date, CPRD end date, or death). Treated anxiety and treated depression were identified by a diagnostic Read Code and a prescription for anxiety/depression medication recorded within 90 days of each other, after VWD diagnosis/match date. Treated anxiety was recorded in 89 of 1119 (8.0%) people diagnosed with VWD and 624 of 10,423 (6.0%) without VWD (age- and sex-adjusted incidence rate ratio [IRR], 1.37; 95% confidence interval [CI], 1.10-1.71). Treated depression was recorded in 119 of 1083 (11.0%) people diagnosed with VWD and 846 of 9845 (8.6%) without VWD (adjusted IRR, 1.35; 95% CI, 1.11-1.63). Females aged 20-39 and 0-19 years were at greatest risk for treated anxiety and treated depression, respectively. Higher rates of treated anxiety and depression were observed among people diagnosed with versus without VWD, predominantly in young females.

Reported prevalence of von Willebrand disease worldwide in relation to income classification.

The diagnosis of von Willebrand disease (VWD) is complex and challenging, especially when diagnostic resources are limited. This results in a lack of consistency in identifying and reporting the number of people with VWD and variations in the VWD prevalence worldwide. To analyze the reported prevalence of VWD worldwide in relation to income classification. Data on the VWD prevalence from the World Federation of Hemophilia Annual Global Survey, national registries of Australia, Canada, and the United Kingdom, and the literature were analysed. The income level of each country was classified according to the World Bank. The mean VWD prevalence worldwide was 25.6 per million people. The VWD prevalence for high-income countries (HIC) of 60.3 per million people was significantly greater (p<.01) than upper middle (12.6), lower middle (2.5) and low (1.1) income countries. The type 3 VWD prevalence for HIC of 3.3 per million people was significantly greater (p<.01) than lower middle (1.3) and low income (0.7) countries. The reported VWD prevalence was greater among females than males. The reported VWD prevalence varied considerably across and within income classifications. The variability of type 3 VWD prevalence was less than the VWD prevalence (all types). The variability in detection and diagnosis of type 1 VWD presents a challenge in forming a consistent prevalence value across countries and income classifications.

Von Willebrand factor testing ratios in the diagnosis and subtyping of von Willebrand disease.

Von Willebrand disease (VWD) is a common bleeding disorder of platelet adhesion with six currently recognized subtypes. Laboratory diagnosis consists of an initial test panel including antigen, activity and factor VIII measurements, sometimes followed by further specialized testing. VWF activity/antigen testing ratios help to differentiate type 1 and type 2 disease, which is important for selection of proper therapy. Recommended ratio cutoffs differ by guideline, ranging from 0.5 to 0.7, with 0.7 commonly recommended. The ratio cutoff used affects the sensitivity and specificity for type 2 diagnosis. Variability in VWD due to underlying mutations and patient factors, as well as variability in VWF tests, impact the accuracy of ratios for VWD subtyping. This review discusses the use of activity/antigen ratios in the diagnosis and subtyping of VWD with a focus on technical aspects of the tests.

Von Willebrand disease in a neonate: A case report

Von Willebrand disease (VWD) is a constitutional bleeding disorder of autosomal inheritance characterized by a quantitative or functional abnormality of the factor Willebrand. We report the observation of a neonate with a confirmed diagnosis of von Willebrand disease in the neonatal period. This disease is a very heterogeneous clinically, phenotypically and genetically, and poses a diagnostic difficulty. The biological diagnosis is based on first-line tests (prothrombin level and activated partial thromboplastin time) completed by the measurement of the coagulant activity of factors VIII, IX and XI, as well as the activity and antigen of Von Willebrand factor (VWF). The treatment strategy for VWD should be considered in collaboration with a hematologist aiming to correcting VWF and factor VIII levels. Therefore, a recombinant VWF concentrate has recently been introduced and has proven to be effective.

Von Willebrand Disease Epidemiology, Burden of Illness and Management: A Systematic Review.

Although hereditary von Willebrand disease (VWD) is the most common bleeding disorder, its epidemiology is not well understood. A systematic review (PROSPERO CRD42020197674/CRD42021244374) on the epidemiology/burden of illness of VWD was conducted to better understand patients' unmet needs. Observational studies (published January 1, 2010 to April 14, 2021) were identified in MEDLINE and Embase databases, using free-text keywords and thesaurus terms for VWD and outcomes of interest. Pragmatic web-based searches of the gray literature, including conference abstracts, were performed, and reference lists of retained publications were manually searched for additional sources. Case reports and clinical trials (phase 1-3) were excluded. Outcomes of interest were incidence, prevalence, mortality, patient characteristics, burden of illness, and therapeutic management/treatments currently used for VWD. Of the 3095 identified sources, 168 were included in this systematic review. Reported VWD prevalence (22 sources) ranged from 108.9 to 2200 per 100,000 in population-based studies and from 0.3 to 16.5 per 100,000 in referral-based studies. Reported times between first symptom onset and diagnosis (two sources; mean 669 days; median 3 years) highlighted gaps in timely VWD diagnosis. Bleeding events reported in 72-94% of the patients with VWD (all types; 27 sources) were mostly mucocutaneous including epistaxis, menorrhagia, and oral/gum bleeding. Poorer health-related quality of life (three sources) and greater health care resource utilization (three sources) were reported for patients with VWD than in general populations. Available data suggest that patients with VWD experience high disease burden in terms of bleeding, poor quality of life, and health care resource utilization.

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

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