Diagnosis Of Von Willebrand Disease Research Articles

The predictive value of bleeding score on the diagnosis of Von Willebrand disease in children applied to the hematologic clinic with epistaxis

Aim: Epistaxis may be a symptom of an inherited bleeding disease.. We aimed to analyze an approved pediatric bleeding score (PBS) as a screening test for von Willebrand Disease (VWD) in children with epistaxis 
 Material and Method: We retrospectively reviewed the medical records of pediatric patients, who applied to the Pediatric Hematology Department with the complaint of epistaxis between January 2018 and December 2019.
 Results: One hundred and sixty eight patients enrolled in this study There were 65(38.7%) girls and 103(61.3%) boys, with a mean age of 114±49 months (range 8 months to 18 years).The PBS of 34 patients was greater than/ or equal to 2. Factor 8, von Willebrand factor antigen, and von Willebrand Ristocetin cofactor levels were significantly lower in patients with PBS≥2 compared to those in patients with PBS

Utilization of a surgical database to provide care and assess perioperative treatment and outcomes in patients with bleeding disorders.

To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019. Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period. Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p=.164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p<.001), complications (14.3% vs. 12.3%; p<.001), and plan deviations (34.2% vs. 25.1%; p<.001). The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care.

Establishing reference intervals for von Willebrand factor multimers.

Backgroundvon Willebrand factor (VWF) multimers (VWF:MM) methodologies are technically difficult, laborious, time consuming, non-standardized and results vary between laboratories. A new semi automated VWF:MM assay is available for routine use (Sebia). Due to lack of reference values for VWF:MM fractions, results interpretation can be challenging in some cases. The aim of this study was to determine reference intervals for low molecular weight (LMWM), intermediate molecular weight (IMWM) and high molecular weight (HMWM) multimers.MethodsBy the international cooperation initiated between 4 countries (Estonia, Latvia, France, and USA) 131 samples of relatively healthy individuals were analyzed for VWF:MM (in total 51 males and 80 non-pregnant females aged 17-69 years). Reference intervals were calculated according to CLSI C28-A3 standard.ResultsThe proposed reference intervals for VWF:MM were calculated for LMWM 10.4-22.5%, IMWM 22.6-37.6%, HMWM 45.6-66.6%. Age related differences were seen in IMWM and HMWM (p<0.001 and 0.038). There was no gender related difference observed. Geographically LMWM results of France were different from the other regions (p<0.05).ConclusionsQuantification of VWF:MM fractions, in addition to qualitative assessment of VWF:MM patterns, has the potential to aid in differential diagnosis of von Willebrand disease (VWD) subtypes. The reference values calculated in this study can be used in future research to establish clinical decision limits.

Von Willebrand Factor Multimer Analysis by Low Resolution SDS-Agarose Gel Electrophoresis.

Von Willebrand factor (VWF) is a complex glycoprotein found in plasma, composed of disulfide-bond-linked multimers with apparent molecular weights between 500 kDa and 20,000 kDa. After release of VWF from storage granules, it is cleaved in flowing blood by the specific metalloproteinase ADAMTS13, resulting in a highly characteristic cleavage pattern and structure. As the structure of VWF multimers determines diagnosis of von Willebrand disease, which has different sub-types with different multimer- and cleavage patterns, VWF analysis is performed using low-resolution horizontal SDS-agarose gel electrophoresis. However, almost every laboratory uses a different protocol, and all experimental details are rarely, if at all, described. Therefore, the results from similar methods may be substantially different. Here, we present a detailed description of a validated VWF multimer method that we have developed. It has been successfully used for over more than 20 years in quality control of recombinant and plasma-derived VWF drug products, and in preclinical and clinical studies with VWF drug candidates. As most of the published methods, it enables visualization of VWF multimers separated by electrophoresis by immunostaining with a polyclonal anti-human VWF antibody followed by a secondary antibody coupled to alkaline phosphatase. VWF appears as a series of regularly spaced bands on the low and middle molecular weight range of the gel, with an unresolved zone in the high molecular weight (HMW) range, where ultra-large multimers are found. An example is shown below. This low-resolution agarose gel electrophoresis allows the determination of the number of VWF multimers with high reproducibility. Graphical abstract: Example of electrophoretic analysis of multimer structure of four batches of a recombinant VWF drug substance.

Off-label use of emicizumab in persons with acquired haemophilia A and von Willebrand disease: A scoping review of the literature.

Since the approval of emicizumab,a bispecific, factor VIII-mimetic antibody, for use in persons with congenital haemophilia A in 2018, there have been increasing case reports and case series of off-label use of emicizumab in other bleeding disorders, including acquired haemophilia A (AHA) and von Willebrand disease (VWD). We conducted a scoping review on the use of emicizumab in AHA and VWD, focusing on the clinical presentation and outcomes. We conducted a comprehensive search in PubMed, EMBASE and Scopus up to July 15, 2021. The following criteria were applied to the studies identified in the initial search: patients had a diagnosis of AHA or VWD; and the study reported on the clinical outcome of emicizumab use. Seventeen studies were included in the final review for a total of 41 patients (33 AHA, eight type 3 VWD). The majority of AHA patients and all type 3 VWD patients were started on emicizumab for active/recurrent bleeds. The dosing regimen of emicizumab used varied significantly in AHA patients. All patients had a clinical response to emicizumab use. One AHA patient developed a stroke on emicizumab use in association with concomitant recombinant FVIIa use for surgery. Data on adverse events from emicizumab use were not specifically reported in 24.4% of patients (four AHA, six type 3 VWD). Based on published case reports and case series, emicizumab appears to be an effective haemostatic therapy for AHA and VWD. Larger confirmatory clinical trials are needed to confirm these findings.

IX international curse of continuing formation in haemophilia and other congenital coagulopathies. The role of the Laboratory in coagulation disorders. Diagnosis of von Willebrand disease.

Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder caused by quantitative or qualitative defects of von Willebrand factor (VWF). This protein far from simplicity constitutes a very complex molecular model, remaining unravelled yet many aspects of it, even though the VWF gene (VWF) was cloned already in 1985 and the structure of VWF well defined. VWD diagnosis is difficult to achieve in a significant proportion of patients due to both disease heterogeneity and limitations in existing test processes. The cornerstone of diagnosis relies on interpretation of VWF test results, the presence of clinical manifestations of bleeding, especially mucocutaneous, and (in most cases) a positive family history. However, even with a significant bleeding history, a family history may not be positive due to factors of incomplete penetrance and variable expressivity that affect genetic changes. The laboratory diagnosis of VWD can be difficult, as the disease is heterogeneous and an array of assays is required to describe the phenotype. Basic classification of quantitative (type 1 and 3) and qualitative (type 2 variants) VWD requires determination of VWF antigenic (VWF:Ag) levels and assaying of VWF ristocetin cofactor (VWF:RCo) activity. The latter is required for identifying and subtyping VWD, but the assay is poorly standardized. For that reason, novel VWF activity assays have been developed awaiting more extensive comparison data between different methodologies and requiring validation on larger patient series. The qualitative type 2 VWF deficiency can be further divided into four different subtypes (A, B, M and N) using specific assays that measure other activities or the size distribution of VWF multimers. However, frequently, it may be difficult to correctly classify the VWD phenotype, and genetic analysis is through mutation identification may provide a tool to clarify the disorder.

Bleeding patterns in patients before and after diagnosis of von Willebrand disease: Analysis of a US medical claims database.

IntroductionVon Willebrand disease (VWD) is the most common inherited bleeding disorder. The bleeding phenotype is variable, and some individuals have persistent symptoms post‐diagnosis.AimTo characterize bleeding patterns in patients with VWD before and after diagnosis.MethodsDe‐identified claims data for commercially insured patients in the IQVIA PharMetrics® Plus US database (Jan‐2006 to Jun‐2015) were extracted. Eligible patients had ≥2 claims for VWD (ICD‐9 code 286.4), and continuous health‐plan enrolment for ≥2 years before and after diagnosis. Bleeding event, treatment and treating‐physician type were analysed for 18 months before and 7‐24 months after diagnosis, according to pre‐diagnosis bleeding phenotype (claims from one vs multiple bleed sites) and post‐diagnosis bleeding status (resolved [no post‐diagnosis bleed claims] vs continued [≥1 claim]).ResultsData for 3756 eligible patients (72.6% female; 71.0% aged ≥18 years at diagnosis) were analysed. Overall, 642 (17.1%) and 805 (21.4%) patients had single‐ and multiple‐site bleed claims pre‐diagnosis, respectively, and 1263 (33.6%) patients (38.5% of women, 20.8% of men) continued to bleed post‐diagnosis. Multiple‐site bleeding was associated with pre‐diagnosis heavy menstrual bleeding (HMB), oral contraceptive (OC) use and nasal cauterization. Continued bleeding post‐diagnosis was associated with pre‐diagnosis gastrointestinal bleeding, HMB and epistaxis; pre‐diagnosis use of OCs, aminocaproic acid and nasal cauterization; and younger age at diagnosis. Few patients consulted a haematologist for bleed management.ConclusionMany patients with VWD have persistent bleeding from multiple sites and continue to bleed post‐diagnosis. Our findings suggest a need to optimize management to reduce the symptomatic burden of VWD following diagnosis.

Anticoagulation Use and Outcomes Among Patients with Atrial Fibrillation and Von Willebrand Disease

Intro: Von Willebrand disease (VWD) is a coagulopathy caused by deficiency or dysfunction of von Willebrand factor (VWF), resulting in prolonged and excessive bleeding. Patients are advised to avoid aspirin (ASA), P2Y12 inhibitors, or anticoagulation (AC) so as not to exacerbate this condition. However, typical treatment for atrial fibrillation (AF) includes anticoagulation, particularly if the risk of stroke by CHA 2DS 2-VASC score is 2+. Current recommendations suggest giving necessary antiplatelet (AP) or AC therapy over no treatment with assessment of bleeding risk throughout the course. However, this is a conditional recommendation based on low certainty in evidence, and there are no specific guidelines on treating AF in patients with VWD. This study aims to assess anticoagulation use, bleeding risk, and stroke risk in patients with VWF and AF.Methods: We conducted an IRB-approved analysis of coded data from institutional electronic medical records to select patients with diagnosis of VWD, low ristocetin cofactor level, or any abnormal VWF panel as well as patients with diagnosis of AF or atrial flutter. Three hundred and forty patients met criteria. Patients were manually screened for inclusion criteria and excluded for inaccurate diagnosis or insufficient data. Eighty-nine patients were included in the analysis. Primary endpoint was rate of major bleeding defined by ISTH criteria while on AC or AP. Categorical data were tested using the Fisher exact test at the nominal 0.05 two-sided significance level, and all person-time comparisons are made against the rate of bleeding on AC alone.Results: Most patients were female (64.0%; 57/89), and 28.1% (25/89) were deceased at the time of data collection. Date of diagnosis of AF ranged from 1980-2020. 42.7% (38/89) of patients were ever prescribed ASA, 43.8% (39/89) a P2Y12 inhibitor, 56.2% (50/89) AC, and 23.6% (21/89) had never been prescribed AP or AC. Of patients with a CHA 2DS 2-VASC of 2+, 57.5% (46/80) were ever prescribed AC. 32.0% (16/50) of patients ever prescribed AC and 25.6% (10/39) patients never prescribed AC had at least one major bleeding event (p=0.428). The rate of major bleeding on AC alone was 8.9 events per 100 person-years (32 events/359.2 years), 10.2 events per 100 person-years on AP alone (41 events/402.3 years) (p=0.572), and 1.06 events per 100 person-years (8 events/757.47 years) in patients never prescribed AC or AP (p=<0.0001). Notably, the rate of major bleeding on AC and AP together was 28.07 events per 100 person-years (23 events/81.94 years) (p=<0.0001) occurring in 7 patients, 6 of whom also had a diagnosis of acute coronary syndrome (ACS). Length of time to first major bleed is shown in Figure 1. 16.9% (15/89) of patients had thromboembolic strokes after diagnosis of AF, and 53.3% (8/15) of those strokes occurred when patients were not prescribed AC.Discussion: This retrospective observational study over 40 years characterizes AC and AP use in patients with VWD and AF. Only 57.5% of patients with CHA 2DS 2-VASC of 2+ received standard of care AC despite conditional recommendations to give necessary anticoagulation to patients with VWD. In parallel with the general population, AC use significantly increases the rate of major bleeding in patients with VWD, but there was no difference in bleeding rate between standard AC and AP monotherapy. However, major bleeding rates were notably elevated in patients prescribed concomitant AC and AP which most commonly occurred in the setting of ACS. This analysis is limited by its retrospective nature, the lack of granular details in the coded database, and incomplete data in older charts. Overall, these data do not support the use of AP monotherapy over standard AC to reduce bleeding rates for patients with VWD and AF. Additionally, AC and AP co-administration should be avoided due to high rates of major bleeding, but more studies are required to understand AP and AC strategies in patients with VWD, AF, and ACS. Although the rate of major bleeding is elevated with AC use in patients with VWD, there is no difference in lifetime prevalence of major bleeding events by AC vs no AC use. Finally, over half of thromboembolic strokes occurred when not prescribed AC. Shared decision-making around stroke and bleeding risk is advised in considering AC use for AF in patients with VWD. Prospective studies should further evaluate the risk of major bleeding and stroke in patients with VWD and AF on standard AC vs no AC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Depression and Anxiety in Persons with Von Willebrand Disease

Depression and Anxiety in Persons with Von Willebrand Disease

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe Von Willebrand Disease (VWD)

Background:Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, occurring in ~0.1% of the population. VWD results from either a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multimeric plasma protein involved in platelet adhesion and aggregation at the vascular injury site. Accurate diagnosis of VWD is complex due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding persons with VWD and a clinically severe bleeding phenotype.Aims:To characterize the bleeding phenotype and safety of treatment regimens in participants with clinically severe VWD in the United States (US).Study Design and Methods:ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at 25 ATHN-affiliated sites across the US. Participants are identified by the site investigators with a projected goal to enroll 130 individuals. Patients with severe VWD defined as type 3 VWD, or a VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30%, or persons with “clinically severe VWD” defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% and requiring recurrent use of factor concentrates and prior enrollment in the ATHNdataset national surveillance data collection project are included. Participants with platelet-type or acquired VWD are excluded. Laboratory assessments including a standardized diagnostic battery, VWF genetic analysis (Next-gen sequencing), and inhibitor testing, performed by a central laboratory. Bleeding tendency is assessed by International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children) and the Pictorial Bleeding Assessment Chart (PBAC; heavy menstrual blood loss ≥100) if applicable.Results:Initial data on 81 participants was analyzed. Given that the enrollment occurred during the pandemic, the completion of data varied as follows: Baseline Demographics Forms 81 completed, Baseline History Forms 73 completed, and VWD Diagnostic Testing Results Forms 38 completed. Most were adult (53%), female (58%), Caucasian (82%) and non-Hispanic (82%). Approximately half (38/81, 47%) have undergone central lab diagnostic testing (Table 1) while the remaining had previous diagnostic studies. About half of the patients had Type 1, a quarter have Type 3, and the remaining had Type 2 VWD or unknown. The majority of patients (91%) had VWF:GPIbM activity <30IU/dL and (61%) had a VWF:Ag <30IU/dL. One participant had an inhibitor (1/22, 4%) to VWF. Of the participants with a baseline history form submission (73 in total), more than half (42/73, 57%) had undergone surgery, the most common being nasal cautery (11/42, 26.2%) and dental extraction (11/42, 26.2%); complicated by bleeding most commonly during or following dental extraction (2/11, 18.2%) and endoscopy/colonoscopy (2/4, 50%). Few participants (6/73, 8%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was variable with a mean ISTH BAT score of 10 (range 0-39) with the first bleeding event commonly occurring prior to age 10 years (51%), with 20% occurring prior to age 12 months (20%). The PBAC was performed on 6 of the 47 female participants in reference to their last period and was abnormal(mean 247; range 0-754). The majority (70 participants, 96%) utilized factor concentrates for prophylaxis or on-demand treatment; 27 participants (39%) were on continuous prophylaxis, while 8 (11%) were on event-based while less (10%) were on heavy menstrual bleeding (HMB) prophylaxis, and the remainder (40%) received episodic treatment. Participants used plasma derived VWF concentrate most commonly (64.3%) with the remainder using recombinant VWF or DDAVP/antifibrinolytics.Discussion: Initial evaluation of 81 participants with clinically severe VWD were diagnostically determined to be type 1 VWD with a majority having a bleeding phenotype (mean (ISTH BAT 10) and HMB (mean PBAC 247). In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on response to factor replacement therapy, genotype-phenotype correlation and quality of life. DisclosuresWeyand: Novo Nordisk: Research Funding; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Friedman: Siemens: Consultancy; Bayer: Consultancy; Alexion: Speakers Bureau; Genentech: Consultancy; Instrumentation Laboratories: Consultancy; Sanofi: Consultancy. Haley: American Thrombosis and Hemostasis Network: Research Funding. He: ATHN: Ended employment in the past 24 months. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Wynn: Sanofi: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. OffLabel Disclosure:Vonvendi (recombinant VWF) does not have a product indication for prophylaxis

Prevalence of Acute and Chronic Migraine Among Patients with Von Willebrand Disease

Background: The prevalence of migraine in the general population is approximately 18% in females and 6% in males (Lipton, et. al. Headache 2001;41:646). Among migraineurs, 7-8% experience chronic migraines (CM) (Adams AM, et. al. Cephalalgia 2015;35:563). Von Willebrand factor (VWF), secreted from endothelial cells, is reported to be elevated in migraineurs and in particular during the course of migraine, although its role is unclear (Cesar, et. al. Acta Neurol Scand 1995;91:412; Tietjen, et. al. Neurology 2001;57:334; Tietjen, et. al. Cephalalgia 2018;38:511). Patients with Von Willebrand Disease (VWD) have low levels of or a defective form of VWF, which has led some to hypothesize a lower prevalence of migraine in the VWD population. Conversely, a retrospective case control study found that migraine in VWD patients (n=197) was 6 times more prevalent when compared with age- and sex-match healthy controls (n=197) (18% vs. 3%, respectively)(Hassan, et. al. Intl Journal of Hem, Blood Diseases and Disorders 2014;2:23-5). The current investigation was performed to further explore the relationship between migraine and VWD. Methods: A cross-sectional study was conducted in March 2021 using the InCrowd digital survey tool in which patients with self-reported diagnosis of VWD were invited to participate. The study included 75 VWD patients ≥18 years of age. Survey questions detailed VWD sub-type, gender, clinical diagnosis of migraine, medical specialty diagnosing migraine, migraine treatments, and age of diagnosis. The Lipton Identify Chronic Migraine (ID-CM) tool was used within the survey to identify patients who had experienced chronic migraine(Lipton, et al. Cephalalgia. 2016;36:203). Criteria for designation of chronic migraine from the ID-CM was either the combination of Frequency of Migraine and Symptoms or the combination of Use of Medication and Activity Avoidance. Results: The gender distribution of the 75 participants was 83% female and 17% male. The sub-type of VWD diagnosed was: Type 1 (57%), Type 2 (28%), Type 3 (15%). Fifty-seven percent (57%) of all VWD patients reported being diagnosed with migraine. Rates did not vary significantly by VWD sub-type. Diagnosed migraine was only slightly more common in females (60%, n=62) compared with males (46%, n=7). Average age of diagnosis was 22 years with a median of 17 years (n=43). Two clear clusters defined the age of diagnosis with migraine. The first was between ages 10 and 20 (n=24, 56% of total sample reporting age) and the second was approximately age 30 [28-32] (n=8, 19% of total sample reporting age). Migraine diagnosis was established by primary care physicians (44%), neurologists (44%) hematologists (9%), and headache specialists (2%). Only 4% of surveyed patients met the ID-CM criteria for chronic migraine, yet 71% of patients met the criteria for migraine symptoms. Chronic migraine diagnosis using the ID-CM tool requires a combination of headache frequency (at least half of the past 30 or 90 days), multiple migraine symptoms (present >rarely in the past 30 days), medication use for headache as well as interference with activities (≥10 of the past 30 days) and a headache that either interfered with plans or caused worry for making plans (>rarely in the past 30 days). Frequency of migraine was mentioned by 11% of patients and symptoms by 71%, medication use by 31%, activity limitation by 15%, and changing plans by 25%. Conclusions: This survey illustrates that migraine is significantly more common in people with VWD than in the general population, regardless of VWD sub-type. However, the age-associated incidence pattern follows a similar bimodal distribution as observed in the general population(Victor, et al. Cephalalgia. 2010;30:1065). Notably, the prevalence of diagnosed migraine in VWD males approaches the prevalence in VWD females and exceeds that of females in the general population (Lipton RB, et. al. Headache 2001;41:646). These results suggest a distinct etiology of VWD that makes affected patients more susceptible to migraine. Notably, migraine treatment options may be more limited for these patients, given that traditional NSAIDs are commonly used for fast-acting migraine relief, but their antiplatelet effects and potential for gastrointestinal bleeding make them undesirable in VWD. Further investigation of both the etiology and treatment for VWD migraine is warranted. DisclosuresMacgregor: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Helm: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Cerasoli: RX Medical Dynamics LLC: Consultancy, Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boice: Tremeau Pharmaceuticals Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Sidonio: Novo Nordisk: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Biomarin: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Evaluating errors in the laboratory identification of von Willebrand disease using contemporary von Willebrand factor assays

von Willebrand disease (VWD) arises from deficiency and/or defects of von Willebrand factor (VWF). Assessment requires test panels, including VWF activity and antigen. Appropriate diagnosis including differential identification of qualitative versus quantitative defects remains problematic but has important management implications. Data using a large set (n=27) of varied plasma samples comprising both quantitative VWF deficiency ('Type 1 and 3') vs qualitative defects ('Type 2') tested in a cross-laboratory setting have been evaluated to assess contemporary VWF assays for utility to differentially identify sample types. Different VWF assays and activity/antigen ratios showed different utility in VWD and type identification. Identification errors were linked to assay limitations, including variability, and laboratory issues (e.g., test result misinterpretation). Quantitative deficient (type 1) samples were misinterpreted as qualitative defects (type 2) on 35/467 occasions (7.5% error rate); 11.4% of these errors were due to laboratories misinterpreting their own data, which was instead consistent with quantitative deficiencies. Conversely, qualitative defects were misinterpreted as quantitative deficiencies at a higher error rate (14.3%), but this was more often due to laboratories misinterpreting their data (40% of errors). For test-associated errors, VWF:RCo and VWF:GPIbM were associated with the highest variability and error rate, which was many-fold higher than that using VWF:CB. Chemiluminescence ('CLIA') procedures were associated with lowest inter-laboratory variability and errors overall. These findings in part explain the high rate of errors associated with VWD diagnosis. VWF:GPIbM showed a surprisingly high rate of test associated errors, whilst CLIA procedures performed best overall.

Von Willebrand disease combined with coagulation defects in Iran.

Although Von Willebrand disease (VWD) is the most common inherited bleeding disorder, few cases of VWD combined with coagulation defects have been reported. This study sought to determine the clinical and laboratory features of VWD combined with other coagulation defects and to evaluate the prevalence of this combination in Iran. A total of 3,120 cases were evaluated to confirm a suspected diagnosis of VWD. Clinical and laboratory phenotypes, including bleeding scores (BS), were also obtained. A diagnosis of VWD was established for 130 patients. Following their further characterisation, a subgroup of 25 patients with a dual or triple combination of VWD with coagulation defects (FXII, FXI, FIX, FVII, FV, and lupus anticoagulant) was identified. Their laboratory and clinical data were compared with those of healthy controls (n=25) and VWD-only patients (n=25). No differences were observed for VWF-related laboratory measurements between the combined deficient cases and those with VWD only, results being expectedly lower than in healthy controls. The median BS of combined patients was 4, higher than for VWD-only and control groups (median BS 3 and 1; p=0.55 and p<0.001, respectively). The prevalence of combined coagulation defects was 19.2% among all the VWD cases. The co-occurrence of VWD with clotting factor deficiencies may lead to more severe clinical presentations. To ensure adequate treatment, combined defects should be considered in VWD patients presenting with a more severe bleeding phenotype than expected or with a poor response to treatment.

Symptoms in Infants and Toddlers With von Willebrand Disease

Source: Dupervil B, Abe K, O’Brien SH, et al. Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD. Blood Adv. 2021;5(8):2079-2086; doi:10.1182/bloodadvances.2020004141Investigators from multiple institutions conducted a retrospective study to describe the diagnosis and bleeding history among infants and toddlers with von Willebrand disease (VWD). For the study, data from the CDC Universal Data Collection (UDC) surveillance system established in the US Hemophilia Treatment Center (HTC) Network were reviewed. Children <24 months old, diagnosed with VWD and treated at one of 135 HTCs from 2003 to 2011 were enrolled. For the UDC, data on demographics, VWD diagnosis, family history of bleeding disorders, and history and treatment of bleeding episodes were collected at enrollment and regularly scheduled visits in a systematic manner. VWD type (1, 2, or 3) was classified based on the diagnosis made by the treating physician at the HTC. Descriptive statistics were used to characterize demographics, age at diagnosis, reason for diagnosis (family history or unusual bleeding), and number and anatomic location of bleeding episodes. Chi-square, Fisher exact, or Wilcoxon rank sum tests were used to assess differences when groups were compared.Data on 105 infant and toddlers were analyzed. The mean age of enrollment was 14 months, and 61 (58%) of the patients were male. Among these infants and toddlers, 63% had VWD type 1, 28% type 2, and 9% type 3. There was a family history of bleeding disorders in 79.1%. A family history of VWD prompted diagnostic testing in 68% of study patients; 93% of children diagnosed with type 2 disease had a family history of VWD, compared to 77% of those with type 1 and 44% of those with type 3 (P = 0.02). The mean age at diagnosis of all study patients was 7 months. Children with type 2 VWD were diagnosed at a significantly younger age than those with types 1 and 3 (mean age, 4.7, 8.0, and 6.8 months, respectively; P = 0.04).Among study participants, 22% experienced a bleeding episode before the diagnosis of VWD, 22% were diagnosed at the time of an episode, and approximately 50% were diagnosed before their first notable bleeding event (with testing done because of a family history). Overall, 274 bleeding events were documented in 73 patients. The most common types of bleeding episodes were oral/nasal bleeds (166 episodes, 60.6%) and soft-tissue hematomas (57 episodes, 20.8%); 9 boys (14.8%) experienced unusual bleeding with circumcision. There were 7 episodes of subdural hemorrhages among the study children, occurring both after trauma and spontaneously.The authors conclude that the majority of infants and toddlers with VWD have a family history of the disease, and bleeding episodes are common.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Von Willebrand disease affects up to 1% of the U.S. population.1 Von Willedbrand Factor (VWF) is an acute-phase reactive glycoprotein that aggregates and adheres platelets to damaged blood vessel walls.2 Many with Type 1 VWD, a partial VWF deficiency associated with autosomal dominant inheritance, are unaware of their bleeding disorder due to mild gum bleeding, epistaxis, petechiae, bruising, gastrointestinal bleeding, and heavy menses often attributable to co-morbidities, medications, or trauma (See AAP Grand Rounds. 2020;44[5]:54.)3 Those with subtypes of type 2 VWD, due to different qualitative VWF defects, have variable inheritance and bleeding symptoms.4 Those with the rarest, type 3 VWD, due to an autosomal recessive inheritance manifesting with an absence of VWF, have severe bleeding symptoms.4In older children, teens, and adults, screening for bleeding disorders includes family history and symptom scores using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.5 Falsely abnormal or normal blood test results for CBC, PT, PTT, VWF antigen, VWF activity, Factor VIII, and multimeric analysis arise due to issues with phlebotomy, specimen handling, and assay variability.6 Interpretation of diagnostic test results are affected by blood type, hormones, and concurrent stressors such as fear, exercise, or infection.2 Currently, complex genetic testing plays a limited role in diagnosis and clinical severity in some type 2 VWD cases.7The current investigators review a large cohort of newborns, infants, and toddlers with VWD and describe bleeding episodes, which occur most often before 1 year of age. Limitations of this study include overrepresentation of non-Hispanic whites and missing data for bleeding characteristics or scores, VWF antigen/activity levels, and vitamin K administration at birth. No control cohort with or without bleeding symptoms was available for comparison.A family history of VWD or personal history of oropharyngeal, circumcision-related, hematomas, or intracranial bleeds in children <2 years of age indicate the need for evaluation for VWD.

Recognition and management of vascular lesions in von Willebrand disease

Recognition and management of vascular lesions in von Willebrand disease

A Comparative Evaluation of an Automated Functional Assay for Von Willebrand Factor Activity in Type 1 Von Willebrand Disease.

Backgroundvon Willebrand factor ristocetin cofactor activity (VWF:RCo) is the standard functional assay used for von Willebrand disease (VWD) diagnosis. However, it has some drawbacks including being time consuming and labor intensive and having high inter-laboratory variability. The HemosIL VWF activity assay has the advantages of both high speed and automation. The purpose of this study was to prospectively compare these two functional assays for type 1 VWD detection.MethodsPlasma samples from 108 subjects were assessed in this study. HemosIL VWF activity was measured with the HemosIL latex immunoturbidimetric commercial kits by the ACL TOP coagulation analyzer. VWF:RCo was measured by platelet aggregation method. Pearson correlation analyses were performed to estimate the correlation of HemosIL VWF activity with VWF:RCo. Receiver-operator characteristic (ROC) curve analysis was used to evaluate the performance of the two diagnostic tests.ResultsThe correlation coefficient between VWF:RCo and HemosIL VWF activity was 0.874 overall and was 0.761 and 0.811 in the cohorts of type 1 VWD and non-VWD, respectively. The sensitivity and specificity of HemosIL VWF activity assay for type 1 VWD identification were 94.7% and 80.0%, respectively, and the ROC curve of HemosIL VWF activity was larger than that of VWF:RCo (0.928 vs 0.863, p=0.0138). Finally, the positive and negative predictive values of the HemosIL VWF activity assay for type 1 VWD detection were 72.0% and 96.6%, respectively.ConclusionOur results demonstrate that the HemosIL VWF activity assay was an effective method for type 1 VWD screening and diagnosis. It carried good sensitivity and specificity and had a higher ROC curve than VWF:RCo besides showing good correlation with VWF:RCo. With its advantages of greater speed and automated performance, these results suggest that the HemosIL VWF activity assay was reliable and precise in the clinical setting.

Diagnosis of von Willebrand disease: An assessment of the quality of testing in North American laboratories

Laboratory diagnosis of von Willebrand Disease (VWD) is complex. Reliance on laboratory testing can be problematic as different VWD screening panels, assays and methodologies can produce analytic variability in test results. To compare the degree of imprecision among the VWD assays and within the platelet binding activity (PBA) assays, to determine the consensus among the VWD assays for correct classification of sample results, and to determine consensus among laboratories' von Willebrand factor (VWF) multimer interpretations and final interpretations of the VWD panels. Proficiency testing results from the North American Specialized Coagulation Laboratory Association (NASCOLA) submitted by laboratories from 2010 to 2019 for all normal, type (T) 1 VWD and T2 VWD samples were analysed. Imprecision was lowest for VWF antigen and highest for collagen binding activity (CBA) with median coefficient of variation (CV) of 12% (interquartile range (IQR) 7%) and 23% (IQR 21%) respectively. Within the VWF PBA assays, the gain-of-function mutant GP1b binding (VWF: GP1bM) methods had the least imprecision (CV 9%, IQR 10%). All assays, including the various PBA methods had excellent consensus. The majority of laboratories agreed that normal (median consensus-82%, IQR 16%) and T1 VWD (median consensus-100%, IQR 9%) samples had normal multimer distribution. Consensus among laboratories for final interpretations was excellent for normal samples (median 81%, IQR 8%), good for T1 VWD samples (median 59%, IQR 9%), and fair for T2 VWD samples (median 44%, IQR 21%). Consensus on final interpretation decreased as sample complexity increased.

Von Willebrand Factor Multimeric Assay in Acquired von Willebrand Disease Diagnosis: A Report of Experience from North Estonia Medical Centre.

Objectives Acquired von Willebrand syndrome (AVWS) is a rare and frequently underdiagnosed bleeding disorder with an unknown prevalence. The diagnosis of AVWS is made based on laboratory investigations and the presence of clinical symptoms. Evaluation and management of affected patients are complex due to the need for multiple laboratory assays. Materials and Methods Here, we describe the clinical and laboratory data of seven patients with a diagnosis of AVWS. All patients met the criteria for AVWS based on laboratory findings, bleeding symptoms, and the absence of any previous history of a bleeding disorder. Results In all cases, the laboratory findings, lack of bleeding anamnesis, and family history suggested the presence of AVWS. Von Willebrand factor multimeric analysis showed decreased high-molecular weight (HMW) multimers in six cases. Patients with lower HMW multimers experienced more severe bleeding complications. Conclusions The diagnosis of AVWS is complex and requires extensive laboratory evaluation. Interdisciplinary collaboration and complex laboratory evaluations are of paramount importance for the early recognition of AVWS and optimal AVWS diagnosis as well as successful clinical management.

Quantitative Analysis of Von Willebrand Factor (VWF) Multimers in Von Willebrand Disease (VWD) Patients Recruited through the Zimmerman Program for the Molecular and Clinical Biology of VWD

Quantitative Analysis of Von Willebrand Factor (VWF) Multimers in Von Willebrand Disease (VWD) Patients Recruited through the Zimmerman Program for the Molecular and Clinical Biology of VWD

Self-Reported Reproductive Health Experiences in Women with Von Willebrand Disease: A Qualitative Interview-Based Study

Background: Women with von Willebrand disease (VWD) may experience multiple reproductive health challenges, particularly related to menstruation and pregnancy. Patient-reported experiences in this setting have not been well characterized.Aim: To elicit patient-reported menstrual health experiences in women with VWD.Methods: We conducted a physician-administered telephone survey of women seen at Mayo Clinic for workup and/or management of VWD. Patients were asked to discuss their diagnosis of VWD and questioned about menstrual health, contraception, and pregnancy and asked to describe how their VWD had impacted their reproductive health experiences. Quantitative data were analyzed using R (version 3.2.0). Qualitative comments were analyzed by frequency of response (specific adjectives) and general thematic elements.Results: Of 130 women diagnosed with VWD, 82 (63%) agreed to participate, including 58 (71%) with type 1, 9 (11%) with type 2A, 4 (5%) with type 2B, 8 (10%) with type 2M, 1 (1%) with type 2N, and 3 (2%) with type 3. 89% of women self-reported a history of heavy menstrual bleeding; for 23 (28%) this was their first bleeding event. 28 women (34%) ultimately underwent hysterectomy for heavy menstrual bleeding. Women used several forms of contraception, most commonly estrogen-containing oral contraceptives (61, 74%) and intrauterine device (9, 11%). 65 women (79%) reported at least one pregnancy. There were 200 total pregnancies (median 3 per woman, range 1-10). 142 pregnancies (71%) resulted in live term birth, 47 (24%) in spontaneous abortion (at a median of 12 weeks), 9 (4%) in a live preterm birth, and 2 (1%) in therapeutic abortion. Patients' self-reported comments are described in the Table, with responses in bold indicating the same themes were used by more than one patient. Women used primarily negative adjectives to describe heavy menstrual bleeding and reported a significant negative impact on their academic, home, and sexual lives. Despite this, women often reported that they “just dealt with it” and “thought it was normal.” Regarding pregnancy and VWD, women again used primarily negative adjectives to describe their experiences. Many described pregnancy-associated bleeding events (generally postpartum hemorrhage). Overall, women reported that it was often “uncomfortable” to discuss their reproductive concerns with their medical providers (including hematologists). One woman reported that she “wished [she] had been more confident speaking with [her] doctor” and another that “it is important to be your own advocate.”Conclusions: VWD is a relatively common bleeding condition which appears to significantly impact women's reproductive health. In this qualitative interview study, women often used negative adjectives to describe their reproductive experiences as related to VWD. Additionally, many were uncomfortable discussing their reproductive health with their providers. Physicians (particularly hematologists and obstetrician-gynecologists) should be trained to recognize the impact of VWD on reproductive health and include reproductive health as part of their essential health maintenance conversations with their patients. More compassionate and informational patient-physician conversations may help to optimize reproductive health experiences and outcomes in women with VWD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.