Diagnosis Of Von Willebrand Disease Research Articles

Recurrent Auricular Keloid After Childbirth in a Patient With von Willebrand Disease.

The authors present a case of a 34-year-old female patient with von Willebrand disease who developed a recurrent right auricular keloid after childbirth. The patient had previously undergone surgical excision of the keloid in 2017, which led to the diagnosis of von Willebrand disease due to uncontrolled bleeding. After a successful pregnancy in 2023, the patient experienced keloid recurrence. Surgical excision and radiotherapy were performed in April 2023, followed by DDAVP administration to control postoperative bleeding. At 1-year follow-up, no recurrence was observed. This case highlights the potential impact of pregnancy on keloid recurrence and the challenges of managing keloids in patients with bleeding disorders.

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.

To Repeat or Not Repeat, That Is the Question: Von Willebrand Testing in Adolescent Girls with Heavy Menstrual Bleeding

Heavy menstrual bleeding (HMB) is often the initial manifestation of a bleeding disorder in adolescent females. Von Willebrand disease (VWD) is the most common bleeding disorder, yet diagnosing VWD in HMB is challenging given that menstruation, acute illness, and physiologic stress all elevate von Willebrand factor (VWF) laboratory values. Thus, the interpretation of initial VWF results may be challenging, and the need for repeat VWF testing in this population may be unclear. The aims of this study were to understand VWD diagnostic testing patterns in adolescent females evaluated within the Texas Children's Hospital (TCH) network and to develop a prediction model to determine whether repeat testing was indicated based on initial VWF testing results. Female patients aged 9 to 21 years who had any VWF laboratory test over a 5-year period (January 1, 2017 through December 31, 2021) at a TCH facility (greater Houston metroplex) were identified. Data collection included patient demographics, VWF-related testing (antigen and activity [ristocetin cofactor or glycoprotein Ib]), factor VIII activity, hemoglobin concentration and serum ferritin. Both initial and subsequent laboratory evaluations were collected. The site of clinical testing was also identified, including both acute care settings (emergency department, inpatient, and critical care), and outpatient settings (adolescent medicine, gynecology, hematology, otolaryngology, other outpatient TCH primary care clinics). To ensure that subsequent laboratory testing was not mistaken as the initial testing within the cohort, patients who underwent VWF laboratory testing from 2010 to 2016 were excluded. VWF levels obtained after the administration of VWF replacement products were also removed from the data set. Based on the ASH ISTH NHF WFH 2021 guidelines on the diagnosis of VWD, and with the presumption that adolescents with HMB met the criteria for abnormal bleeding, we analyzed the need to repeat VWF testing to identify any patient with a low VWF antigen level consistent with Type 1 VWD, defined as <50%. A Bayesian linear regression model was developed to predict follow-up VWF antigen levels using the initial levels. Prediction intervals were analyzed to identify thresholds for patients who may not require retesting. This study was approved by the Baylor College of Medicine Institutional Review Board. A total of 6,125 adolescent females underwent VWD testing at a TCH facility during the study period; 1,204 (19.7%) had repeat VWF antigen values performed and were included in the analysis (TABLE). Of those, 1,037 subjects (86.1%) had normal VWF values (≥50%) on both initial and repeat testing. Seventy-five subjects (6.2%) had low VWF antigen values on both initial and repeat testing. Ninety-two subjects had discrepant initial and repeat testing. Forty-seven (3.9%) had low initial VWF antigen values that normalized on subsequent testing. Forty-five (3.7%) had normal initial VWF values that subsequently fell below 50%. Based on our prediction model, in subjects with initial VWF antigen values of ≥80% there was ≥97% probability of having normal repeat VWF values. Values of ≥100% carry a 99.4% probability of having normal repeat VWF testing (FIGURE). No association was identified between age and VWF antigen level. Subjects assessed in outpatient adolescent medicine or gynecology clinics were more likely to have low VWF values (on any testing) whereas subjects with normal values were more frequently assessed in the acute care settings (P<0.001). The median serum ferritin and hemoglobin values in the cohort were 13 ng/ml and 12.8 g/dl, respectively, without a significant difference between those with normal versus low VWF antigen values. Repeat testing in adolescent females whose initial VWF antigen testing values are 80% and higher is unlikely to identify more patients with VWF values below 50%. In this cohort, subjects undergoing hemostatic evaluation, presumably for HMB, by adolescent medicine or gynecology providers were more likely to identify abnormal VWD testing compared to the acute care setting. Iron deficiency screening should be considered for all adolescent females with HMB and not just those girls with a confirmed bleeding disorder. Additional studies are needed to determine the effects of iron deficiency and anemia on VWD laboratory testing in adolescent females with HMB and to validate the accuracy of the prediction model. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Type 2M VWD Laboratory Defects More Consistent Than Bleeding Symptoms across Family Members

Background Von Willebrand disease (VWD) is an inherited bleeding disorder characterized by a defect or decrease of von Willebrand factor (VWF). Type 2 VWD results from qualitative defects in VWF. Type 2M VWD is defined by defective platelet binding to GPIb and/or collagen. While the inheritance of type 2M VWD is autosomal dominant, the extent of symptoms across family members has not been well characterized. Methods Subjects included index cases with type 2M VWD and all enrolled family members from a large US study of VWD (Zimmerman Program). Index cases were enrolled due to a prior diagnosis of VWD. All available family members were enrolled if willing. VWF testing performed included VWF antigen (VWF:Ag), VWF platelet binding by either VWF ristocetin cofactor activity (VWF:RCo) or VWF:GPIbM, collagen binding with types I, III or IV collagen (VWF:CB1, VWF:CB3, VWF:CB4) and VWF multimer distribution. Bleeding scores were calculated using the ISTH bleeding assessment tool (BAT). DNA sequencing was performed for the full length VWF gene. Statistics were calculated using GraphPad Prism with a p value of <0.05 considered significant. Family members were defined as affected if they had VWF activity levels consistent with type 2M VWD and presence of genetic variant if identified. Results 24 index cases, 51 affected family members and 40 unaffected family members were available for analysis. The mean VWF:RCo/VWF:Ag ratio for index cases was 0.5 and the mean VWF:CB/VWF:Ag ratio was 1.05. The VWF:RCo/VWF:Ag ratio was similar in affected family members (0.44, p=NS) but higher as expected in unaffected members (0.89, p<0.001 for index case vs. unaffected, p<0.001 for affected vs. unaffected). In contrast, there was no difference in VWF:CB/VWF:Ag ratios between index cases and affected family members (0.94, p=NS). Data for VWF:GPIbM, collagens I and IV were available only on index cases, and showed low VWF:GPIbM/VWF:Ag (mean 0.79), higher VWF:CBI/VWF:Ag (mean 1.31) and lower VWF:CBIV/VWF:Ag (mean 0.85). There was a negative correlation between VWF:GPIbM and VWF:CBIV, with subjects having either low VWF:GPIbM and normal VWF:CBIV or low VWF:CBIV and normal VWF:GPIbM. Similar results were seen for VWF:CB1 although only 1 subject was diagnosed with type 2M VWD and low VWF:CB1. Median bleeding scores were highest in index cases (7.5), intermediate in affected family members (3) and normal in unaffected family members (1). There was a significant difference between index cases and affected family members (<0.015), and between index cases and unaffected family members (p<0.001). One subject had a genetic variant in the VWF A3 domain, one in the VWF D3 domain and the remainder of index cases had a defect in the VWF A1 domain. Conclusions These findings suggest that decreases in platelet and collagen binding activity increase bleeding risk in families with type 2M VWD. Index cases had higher bleeding scores as compared to affected family members, suggesting that diagnosis of family members may require more attention. Precise understanding of these defects may assist in better diagnosis and treatment of von Willebrand disease.

Repeated Testing Unfolds the Challenge of Diagnosing Von Willebrand Disease: Longitudinal Data from the Vienna Bleeding Biobank

Background: Diagnosis of von Willebrand disease (VWD) in patients with a mild to moderate bleeding tendency (mild bleeding disorders, MBD) bears special challenges, as von Willebrand factor (VWF) levels are influenced by several factors, such as age, acute phase reaction and blood group, and might be unstable. Unstable VWF levels might lead to under- or over-diagnosis of VWD in MBD patients, and repeated measurements to identify VWD patients might be required. Aims: We aimed to identify clinical and epidemiological factors associated with unstable VWF levels, leading to change of the diagnosis based on the recommended diagnostic cut-off levels. Furthermore, we wanted to investigate cut-off of baseline VWF levels with a low probability to decrease below the diagnostic cut-off and, thus, not require subsequent VWF measurements. Methods: All patients enrolled into the Vienna bleeding biobank (VIBB, EC no. 603/2009) before October 2021 with at least two separate assessments of VWF levels, in particular VWF antigen (VWF:Ag) and activity (VWF:GPIbM and/or ristocetin-cofactor activity [VWF:RCo]), were included in this analysis. Detailed inclusion and exclusion criteria of the VIBB, a single-center cohort study on patients with MBD, have been published previously (Gebhart et al. Haemophilia.2018). For this analysis, pathological VWF levels were defined as any measurement of VWF:Ag, VWF:GPIbM or VWF:RCo ≤50 IU/dL, according to current guidelines (James et al. Blood Adv. 2021). We defined 3 subgroups of patients according to lowest VWF (VWF:Ag or VWF:GPIbM or VWF:RCo) at baseline and at each measurement: patients with steadily pathological measurements ≤50 IU/dL ("steady pathological"), patients with repeatedly normal measurements >50 IU/dL ("steady normal") and patients crossing the 50 IU/dL threshold between study visits ("changing"). Measurements were excluded from the analysis if an evident VWF influence such as pregnancy, infection, surgery or acute phase reaction was identified. Results: In total, 281 of 691 patients (40.7 %) from the VIBB study who had records of at least two VWF measurements of VWF antigen and activity levels were included in this analysis. Patients had a median number of 2 VWF measurements (Q1-Q3, 2-2) over a median follow-up time of 781 days (Q1-Q3, 105-1679) for a total of 660 measurements. 212 patients had 2 measurement of VWF antigen and activity, followed by 3 (n=47), 4 (n=11), 5 (n=5) and 6 (n=1) measurements. Of all analyzed patients, 217 patients (77.2 %) had VWF levels consistently above the cut-off of 50 IU/dL ( "steady normal"), 28 patients (10.0%) had repeatedly values ≤50 IU/dL ("steady pathological"), while 36 patients (12.8%) had changing results with values both below and above the cut-off of 50 IU/dL ( "changing"; Figure 1). The clinical and laboratory characteristics of each subgroup are summarized in Table 1. Patients in the "steady pathological” and "changing” groups compared to the "steady normal” group were younger and more commonly had blood group O. The values of VWF activity (VWF:RCo or VWF:GPIbM) at inclusion appeared to be more unstable than the VWF:Ag values (Figure 1). Seventeen (47.2%) patients in the changing group had pathological VWF activity values but VWF:Ag values above the cut-off of 50 IU/dL at study inclusion. VWF antigen and activity values at baseline within the changing group ranged from 36 IU/dL to 101 IU/dL and 28 IU/dL to 86 IU/dL, respectively. In a logistic regression model, modeling changing status as a binary outcome and lowest VWF at baseline using linear splines with a knot set at 50 IU/dL, the probability of changing was 37.2% (95%CI, 25.7-50.3), 18.6% (95%CI, 12.2-27.4) and 1.1% (95%CI, 0.2-4.8) at 40, 60 and 80 IU/dL, respectively (Figure 2). The added value of the clinical predictors age, sex, the Vicenza score and blood type O beyond lowest VWF at baseline, however, was only weak (χ2 5.0, p = 0.290). Conclusion: Based on our data, the reproducibility of VWF measurements is poor in patients with MBD. Re-evaluation of suspected patients for VWD who do not clearly fulfill the diagnostic criteria should be considered, especially if VWF levels are close to the cut-off level, as targeted treatment before surgical interventions might be warranted. Further studies are needed to better understand the reproducibility of VWF measurements and improve the diagnosis of VWD in patients with MBD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Documentation of Menstrual Concerns in Patients with Inherited Bleeding Disorders

Introduction: Inherited bleeding disorders (IBD) such as von Willebrand disease (VWD) and clotting factor deficiencies may be associated with heavy menstrual bleeding (HMB) in patients with a uterus. Identification of HMB and development of an adequate management plan is fundamental to the care of these patients. However, the frequency with which hematologists discuss, document, and recommend treatment or gynecologic (GYN) consultation in women with IBD has not been well described. In this retrospective review, our aim was to assess the frequency and breadth of documented discussions about menstrual concerns in women with IBD during initial consultative visits with a hematologist. Methods: We performed a retrospective chart review of women ages 18 to 50 with a confirmed diagnosis of VWD, hemophilia A or hemophilia B seen for an initial consultative visit at the Penn Comprehensive Hemophilia and Thrombosis Program (PCHP) between January 2017 and July 2022. We collected information regarding patient demographics and laboratory values related to the bleeding disorder diagnosis and the frequency of documentation of menstrual periods in general, as well as specific rates of discussion of concerns related to HMB (passage of clots, amount of flow), documentation of management recommendations (oral contraceptive, IUD, adjunctive antifibrinolytic agents) and/or referral to GYN. Results: Forty-two patients were included in the analysis including 39 (92.8%) with VWD, 2 (4.8%) with hemophilia A, and 1 (2.4%) with hemophilia B). Thirty-eight of 42 patients (90.5%) had a documented discussion regarding menstrual periods at the time of the initial consultative visit. Thirty-four of the 38 (89.5%) who had a documented discussion about menstruation subjectively reported having "heavy menstrual bleeding" (sHMB), although the quantity was not documented in any case with a verified tool such as the PBAC. Nineteen of 38 (50%) patients had a documented discussion regarding the amount of menstrual blood flow. Ten (52.6%) had documentation of the number of pads/tampons/products used per day. Three (15.8%) had documented menses duration (number of period days). Six (31.6%) had documentation both of period duration and the number of pads/tampons used per day. Male hematologists documented amount of flow in 41.7% of patient visits, while female hematologists did so for 53.3% of visits. Twelve of 38 (31.6%) patients had a documented discussion regarding passage of clots during their periods. Five (41.7%) had a description only of clot presence, 4 (33.3%) of clot frequency and presence and 2 (16.7%) of clot size and presence; 1 (8.3%) reported no clot passage. Male hematologists documented the presence of clots for 33.3% of visits, while female hematologists did so 26.7% of visits. There was a documented discussion of treatment options in 29 of 34 patients reporting sHMB (85.3%). Treatment options included either those in use at the time of the initial consult visit or those recommended during the initial visit in patients who reported inadequate control of sHMB with prior treatments. Treatments discussed included: 15 oral contraceptives (51.7%), 8 IUD (27.6%), 2 subdermal implant (Nexplanon) (6.9%), 1 Depo Provera (3.4%), 1 contraceptive patch (3.4%), and 2 who reported not having any response to hormonal contraception and were treated with antifibrinolytic therapy alone (6.9%). There was a documented discussion of referral to GYN in 14 of 34 (41.2%) of patients who reported sHMB. Conclusions: In this retrospective study, we found that hematologists often document menstrual bleeding concerns in female patients with IBD, but do not consistently document specific components of sHMB such as amount of menstrual blood flow and/or passage of clots. Documentation rates were similar for hematologists of both sexes. Standardized templates for evaluation of HMB (both subjectively reported and formally assessed) may improve documentation rates in the future. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utility of Von Willebrand Testing during Acute Bleeding Episodes

Background: The diagnosis of mild bleeding disorders such as von Willebrand disease (VWD) poses many diagnostic challenges. Several patient-specific factors including physiologic, inflammation, anemia and medications can affect VWD testing and lead to falsely elevated values. Given that the physiologic stress may cause falsely normal levels of VW factor and associated tests, determining the appropriate timing for testing remains an area of debate. Testing is often performed during inpatient or emergency department (ED) visits when patients present for bleeding complaints, although these results may be skewed by stress or illness. Initial normal results may falsely reassure a patient and their health care provider, preventing them obtaining repeat testing or pursuing outpatient hematological evaluation. Further study is needed to determine the reliability of VWD evaluation when obtained during episodes of acute bleeding. Methods: This single-center retrospective cohort study included subjects who were evaluated for acute bleeding complaints in the UPMC Children's Hospital of Pittsburgh ED or inpatient units who had VWD testing sent during that visit over a five-year period. Bleeding complaints included were epistaxis, heavy menstrual bleeding, spontaneous ecchymosis, post-procedural hemorrhage or intracranial hemorrhage. VWD test results including von Willebrand antigen (VWF:Ag), factor VIII (FVIII) and ristocetin co-factor (VWF:RCo) levels obtained at the time of ED or inpatient care were compared with those obtained in outpatient follow-up visits. T-tests and Wilcoxon rank sum tests were used to compare VWD test levels across the two time points. Results: Over a 5-year period, 144 patients had VWD testing completed during ED or inpatient evaluations for acute bleeding complaints. The population was primarily Caucasian (71%) with a median age of 9 years old. Fifty-two percent of the population was male. Epistaxis and post-tonsillectomy/adenoidectomy bleeding were the most common presenting complaints, making up 47 and 22% of the population, respectively. Other presenting bleeding complaints included spontaneous bruising (18%), menorrhagia (6%), post-procedural hemorrhage of a digestive organ (4%), and nontraumatic intracranial hemorrhage (3%). Six subjects (4%) met laboratory criteria for a diagnosis of VWD during an acute bleeding episode. Twenty-four percent of the total population was evaluated subsequently by outpatient hematology, and 23% of patients had repeat VWD testing performed. Median levels of VWD tests obtained at initial presentation were 116% for VWF:Ag, 112% for FVIII, and 85% for VWF:RCo, and were not statistically different from those obtained on repeat testing in outpatient follow up. An additional two patients that were not initially diagnosed with VWD met laboratory criteria for VWD on repeat outpatient testing. Conclusions: Among children presenting for emergency or inpatient care for acute bleeding episodes, VWD testing was unlikely to be diagnostic. Interestingly, our study did not find that median VWF:Ag and FVIII levels were higher during acute bleeding as has been suggested in other studies. A minority of patients who were evaluated in the hospital for acute bleeding were subsequently evaluated by hematology, which may have limited these findings. It is possible that obtaining VWD testing at the time of an acute bleeding episode may provide false reassurance to a patient, thus decreasing hematology referrals and follow up. Based on these results, we recommend that for patients evaluated in the ED with mild mucocutaneous bleeding who warrant a bleeding disorder evaluation, VWD testing be postponed until the patient is seen in steady-state by hematology.