Von Willebrand Disease Patients Research Articles

Identification of Diagnostic SNPs in Exon 28 of the Von Willebrand Factor Gene for Diagnosis of VWD Type 2B in Patients Referred to IBTO Coagulation Lab: In-silico Approach

Background and Aims: von Willebrand disease (VWD) is brought on by hereditary impairments in the von Willebrand factor (VWF). It has been determined that most of the molecular abnormalities are present in exon 28 of the VWF gene qualitative variations. In this regard, investigating mutations in exon 28 of the VWF coding gene can help identify the VWD type and can be used to manage patients by using appropriate strategies.
 Materials and Methods: 10 suspected VWD type 2B patients were investigated for the genotype of exon 28. Routine coagulation tests were performed for the patients. Molecular sequencing was also used for the evaluation of mutations in exon 28. Determining the tertiary structure of VWF can aid in understanding its functional residues and interactions. The nsSNVs’ pathogenicity was examined utilizing potent bioinformatics methods. Step-by-step testing of the high-risk mutations was done using SIFT, PolyPhen-2, I-Mutant 2.0, PHD-SNPg, and SNPs&GO. Then, the secondary structure, amino acid conservation, and feature of amino acids were investigated via Protparam, Cofactor, Interprosurf, ConSurf, NetSurfP-2.0, and HOPE.
 Results: N1231T, V1229G, V1316M, and P1266Q missense mutations in VWF were detected. 3D structure of VWF predicted and evaluated. Putative conserved domains were identified. P1266Q and V1316M amino acid substitutions are predicted as “Not tolerated substitution” damaging and Disease, while V1229G and N1231T amino acid substitutions are predicted as “tolerated substitution” benign and Neutral.
 Conclusion: V1316M and P1266Q amino acid substitutions were determined as high-risk mutations using powerful bioinformatics tools in VWD patients.

Desmopressin (DDAVP) use in patients with von Willebrand disease: A single-centre retrospective review of test response and clinical outcomes.

Peri-procedural management of von Willebrand disease (VWD) utilizes von Willebrand factor (VWF) concentrates or desmopressin (DDAVP) to increase VWF levels. DDAVP is safe, easily administered, and inexpensive. Currently, a consensus definition for adequate DDAVP response is lacking, and outcomes of peri-procedural DDAVP use in VWD patients are seldom reported. This single-centre retrospective review aims to characterize DDAVP-responsiveness and assess clinical outcomes of peri-procedural DDAVP use in VWD. We reviewed records for all our adult VWD patients (age ≥18 years) who underwent DDAVP challenge testing between January 2007 and January 2022. DDAVP-responsiveness was assessed using six definitions. Bleeding outcomes following procedures covered by DDAVP were classified as excessive or expected bleeding. Eighty-four of 94 (89.4%) patients were DDAVP-responsive by our definition (1-h VWF Activity/Factor VIII ≥0.50 IU/mL). However, the proportion of DDAVP-responders varied from 53.2% to 91.5%, depending on the literature definition used. Ninety-nine procedures pre-treated with DDAVP were performed during the study period. Eighty-six (86.7%) procedures (31 major; 55 minor) were covered with only DDAVP±tranexamic acid (TXA). Excessive bleeding occurred following 4/31 major procedures and 2/55 minor procedures (both performed in a single patient with a bleeding score of 16). When covered with DDAVP+Factor±TXA, one each of 10 major and 3 minor procedures (performed in 2 patients with bleeding scores 15-16) resulted in post-procedural bleeding. Peri-procedural DDAVP prophylaxis appears to be effective among individuals with VWD. Beyond DDAVP-responsiveness, patient bleeding history and procedure invasiveness should be considered in determining suitability for DDAVP prophylaxis.

Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial.

To describe efficacy/safety of recombinant von Willebrand factor (rVWF) prophylaxis in patients with type 3 von Willebrand disease (VWD). This post hoc analysis of a phase 3 open-label trial provides a more detailed analysis of adults with type 3 VWD, categorized based on prior treatment at screening: "Prior On-Demand (OD)" (OD VWF; ≥3 documented spontaneous bleeding events [BEs] requiring VWF in previous 12 months) or "Switch" (plasma-derived [pd] VWF prophylaxis for ≥12 months). Annualized bleeding rates (ABRs) were evaluated during 12 months of rVWF prophylaxis versus historical data from medical records. In the Prior OD group (n = 10), mean spontaneous ABR (sABR) for treated BEs was reduced by 91.6% (ratio, 0.08; 95% CI, 0.02-0.45) versus mean historical sABR. In the Switch group (n = 8), mean sABR for treated BEs was reduced by 47% (ratio, 0.53; 95% CI, 0.08-3.62). One non-serious adverse event (AE) was considered possibly related to rVWF. No treatment-related, fatal, or life-threatening serious AEs were reported, and no patient developed VWF inhibitors. rVWF prophylaxis reduced sABR in type 3 VWD patients previously treated with OD VWF therapy, and maintained a similar level of hemostatic control in those switching from pdVWF prophylaxis to rVWF prophylaxis.

An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland

Von Willebrand Disease (VWD) is the most common inherited bleeding disorder. However, recognition of the disease by both the public and healthcare professionals lags behind that of other bleeding disorders, leading to delays in diagnosis and treatment for patients. Updated national guidelines are needed to highlight an appropriate pathway for managing VWD patients in a timelier manner. To identify ways in which care for VWD can be achieved on a more equitable basis. Using a modified Delphi approach, a panel of VWD experts developed 29 statements across five key themes. These were used to form an online survey that was distributed to healthcare professionals involved in VWD care across the UK and Republic of Ireland (ROI). Stopping criteria comprised 50 responses received, a 3-month window for response (February-April 2022) and 90% of statements passing consensus threshold. Threshold for consensus for each statement was agreed at 75%. A total of 66 responses were analysed with 29/29 statements achieving consensus of which 27 attained ≥90% agreement. From the high degree of consensus, eight recommendations were derived regarding how detection and management of VWD can be improved to provide equity of care between men and women. Implementation of these eight recommendations across the VWD pathway has the potential to raise the standard of care for patients in the UK and ROI by reducing delays to diagnosis and treatment initiation.

Phenotypic and genotypic (exon 28) characterization of patients diagnosed with von Willebrand disease type 1 in Eastern Saudi Arabia.

Von Willebrand factor (VWF) is a plasma glycoprotein that plays a key role in hemostasis. Mutations in this protein can result in von Willebrand disease (VWD), the most common form of bleeding disorder in humans. Patients with type 1 VWD have a quantitative plasmatic deficiency of normal structural and functional VWF. Our study aimed to investigate the phenotypic and genotypic characteristics of VWD type 1 patients in eastern Saudi Arabia, focusing on exon 28. We included patients previously diagnosed with WWD type 1 at the King Fahad teaching hospital in Al Khobar and their family members. The correlations between various phenotypic data and genotypic (exon 28) were analyzed using statistical software (SPSS) version 21. While these variants were generally considered benign with minor clinical effects, our analysis did identify two pathogenic variants that could lead to severe VWD symptoms. Specifically, we found these two pathogenic variants in three VWD patients from Saudi Arabia, providing essential insights into pathogenic VWD mutations in this population. Our study, therefore, sheds light on the prevalence of VWF variants in the eastern province of the Kingdom and highlights the need for continued research into the genetic causes of VWD in this region.

Assessing the bleeding severity in patients with type I von Willebrand using the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) questionnaire

Abstract Background In the recent decade, bleeding evaluation methods have evolved to standardize the severity of bleeding symptoms in a uniform manner. In 2010, the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) was developed and validated. Aim and objectives The aim of the study was to evaluate bleeding score (BS) in Egyptian patients with von Willebrand disease (VWD) type I and correlate it with laboratory parameters. Patients and methods This cross-sectional cohort study was conducted at Assiut University Hospital. It included 100 participants that were divided into 49 patients with type I VWD and 51 healthy participants with no known problem with bleeding or bruising. The duration of the study was ~12 months. Results Study revealed that there was significant relation between BS severity and laboratory parameters such as level of von Willebrand factor: Ag (P=0.02) while there was no significant relation between BS and sex (P=0.390). By using receiver operating characteristic curve analysis, ISTH-BAT BS can detect type I VWD patients in total with excellent accuracy (98%), area under the curve was 0.989 with sensitivity and specificity of 96 and 100%, respectively (P<0.001). Conclusion The ISTH-BAT BS is designed to reflect the severity of bleeding. Our results demonstrate the inherent variability of this bleeding pattern. We also found that the ISTH-BAT BS has high sensitivity and specificity to detect type I VWD patients in total with excellent accuracy.

Burden of Illness and Treatment Patterns Among Patients With von Willebrand Disease in US Clinical Practice.

In this retrospective cohort study, data from an integrated US healthcare system containing both electronic medical record data and linked claims data (from 01/2004 to 12/2020) were used to evaluate the clinical burden, treatment patterns, and healthcare resource use (HRU) in patients with von Willebrand disease (VWD). Two patient cohorts were analyzed: the overall VWD population (n = 396) and a subset of these patients (n = 75) who were considered potentially eligible for prophylaxis treatment with von Willebrand factor (VWF) based on a history of severe and frequent bleeding. HRU (hospitalizations, outpatient visits, and emergency department visits) were measured in patients with linked claims data (n = 110, overall VWD patients; n = 23 potentially VWF-prophylaxis-eligible VWD patients). In general, patients with VWD experienced a substantial burden of bleeding events, comorbidities, and HRU. Patients with VWD who were considered potentially eligible for prophylaxis owing to severe and frequent bleeds suffered from a higher clinical burden and HRU than the overall VWD population, and thus may benefit from VWF prophylactic treatment. The findings from this study could help improve clinical outcomes and manage HRU for patients with VWD.

Laboratory Testing for von Willebrand Factor: Factor VIII Binding for the Diagnosis or Exclusion of Type 2N von Willebrand Disease: An Update.

von Willebrand factor (VWF) is a large adhesive plasma protein that expresses several functional activities. One of these activities is to bind coagulation factor VIII (FVIII) and to protect it from degradation. Deficiency of, and/or defects in, VWF can give rise to a bleeding disorder called von Willebrand disease (VWD). The defect in VWF that affects its ability to bind to and protect FVIII is captured within type 2N VWD. In these patients, FVIII is produced normally; however, plasma FVIII quickly degrades as it is not bound to andprotected by VWF. These patients phenotypically resemble those with hemophilia A, where instead, FVIII is produced in lower amount. Both hemophilia A and 2N VWD patients therefore present with reduced levels of plasma FVIII relative to VWF level. However, therapy differs, since patients with hemophilia A are given FVIII replacement products, or FVIII mimicking products; instead, patients with 2N VWD require VWF replacement therapy, since FVIII replacement will only be effective for a short term, given this replacement product will quickly degrade in the absence of functional VWF. Thus, 2N VWD needs to be differentiated from hemophilia A. This can be achieved by genetic testing or by use of a VWF:FVIII binding assay. The current chapter provides a protocol for the performance of a commercial VWF:FVIII binding assay.

A nanobody against the VWF A3 domain detects ADAMTS13-induced proteolysis in congenital and acquired VWD

Abstractvon Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A–group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high–molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.

Safety and Feasibility of Catheter Ablation Procedures in Patients with Bleeding Disorders.

Aims/Objectives: Patients with bleeding disorders are a rare and complex population in catheter ablation (CA) procedures. The most common types of bleeding disorders are von Willebrand disease (VWD) and hemophilia A (HA). Patients with VWD or HA tend to have a higher risk of bleeding complications compared to other patients. There is a lack of data concerning peri- and postinterventional coagulation treatment. We sought to assess the optimal management of patients with VWD and HA referred for catheter ablation procedures. Methods and Results: In this study, we analyzed patients with VWD or HA undergoing CA procedures at two centers in Germany and Switzerland between 2016 and 2021. Clotting factors were administered in conjunction with hemostaseological recommendations. CA was performed as per the institutional standard. During the procedure, unfractionated heparin (UFH) was given intravenously with respect to the activated clotting time (ACT). Primary endpoints included the feasibility of the procedure, bleeding complications, and thromboembolic events during the procedure. Secondary endpoints included bleeding complications and thromboembolic events up to one year after catheter ablation. A total of seven patients (three VWD Type I, one VWD Type IIa, three HA) underwent 10 catheter ablation procedures (pulmonary vein isolation (PVI): two × radiofrequency (RF), one × laser balloon (LB), one × cryoballoon (CB); PVI + cavotricuspid isthmus (CTI): one × RF; PVI + left atrial appendage isolation (LAAI): one × RF; Premature ventricular contraction (PVC): three × RF; Atrioventricular nodal reentrant tachycardia (AVNRT): one × RF). VWD patients received 2000−3000 IE Wilate i.v. 30 to 45 min prior to ablation. Patients with HA received 2000−3000 IE factor VIII before the procedure. All patients undergoing PVI received UFH (cumulative dose 9000−18,000 IE) with a target ACT of >300 s. All patients after PVI were started on oral anticoagulation (OAC) 12 h after ablation. Two patients received aspirin (acetylsalicylic acid; ASA) for 4 weeks after the ablation of left-sided PVCs. No anticoagulation was prescribed after slow pathway modulation in a case with AVNRT. No bleeding complications or thromboembolic events were reported. During a follow-up of one year, one case of gastrointestinal bleeding occurred following OAC withdrawal after LAA occlusion. Conclusions: After the substitution of clotting factors, catheter ablation in patients with VWD and HA seems to be safe and feasible.

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

Colorectal Cancer Screening in Patients with Inherited Bleeding Disorders: High Cancer Detection Rate in Hemophilia Patients

Introduction: Non-invasive stool tests are the most commonly used colorectal cancer (CRC) screening modalities worldwide. The population-based CRC screening program in the Netherlands uses fecal immunochemical testing (FIT), to detect human hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. The target population consists of women and men aged 55-75 years. No studies have been conducted on the performance of this screening program in patients with inherited bleeding disorders, such as Von Willebrand disease (VWD) and hemophilia, whereas the FIT performance in these patients may substantially differ from the general population. We hypothesized that the false-positive rate of FIT is higher in patients with inherited bleeding disorders than in the general population. Therefore, our study aims to assess the false-positive rate and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with VWD or hemophilia. Methods: We performed a multicenter, nationwide cross-sectional study embedded in two nationwide studies on VWD and hemophilia in the Netherlands, the Willebrand in the Netherlands-Prospective study and the Haemophilia in the Netherlands 6 study, respectively. Results: In total, 551 patients with inherited bleeding disorders (hemophilia, n=387; VWD, n=164) were included of whom 351 patients participated in the CRC screening program (63.7%). The FIT positivity rate and false-positive rate in hemophilia and VWD patients were significantly higher than in the general population (14.8% vs 4.3%, p<0.001 and 10.3% vs 2.3%, p<0.001, respectively). In hemophilia patients, the detection rate of CRC and/or AA (i.e., the proportion of participants in whom CRC and/or AA was detected) was significantly higher than in the general male population (4.5% vs 1.8% respectively, p=0.012). The positive predictive value of FIT for CRC and/or AA in hemophilia patients was comparable to the general male population (32.3% vs 39.6% respectively, p=0.28). In VWD patients, the positive predictive value of FIT for CRC and/or AA was significantly lower than in the general population (6.3% vs 36.8% respectively, p=0.01). However, the detection rate in VWD patients was similar to the general population (0.8% vs 1.4% respectively, p=0.83). Conclusion: This study indicates that the false-positive rate of FIT is higher in patients with inherited bleeding disorders than in the general population. Nevertheless, the detection rate of CRC and/or AA in hemophilia patients is high and the positive predictive value of FIT for CRC and/or AA is not affected. In VWD patients, the positive predictive value is lower than in the general population. Therefore, the benefit of the CRC screening program seems different in patients with hemophilia and VWD compared to the general population. Additional studies are needed to evaluate possible adjustment of the CRC screening program for these patients.

Iron Deficiency Anemia and Von Willebrand Disease in Women with Menorrhagia

Introduction Von Willebrand disease (VWD) is the most common bleeding disorder in adolescents and adult women that causes heavy menstrual bleeding (HMB) (Blood Adv 2020;13:3209-3216). HMB is defined as bleeding lasting >7 days or > 80 mL of blood per menstrual cycle; a broader definition includes an excessive blood loss that interferes with a woman´s physical, emotional, social and material quality of life; an underlying bleeding disorder should be considered if IDA is present (Am J Obstet Gynecol 2009;201:12.e1-12.e8 and Blood 2018;132:2134-2142). Objective Identify VWD causing HBM in patients with IDA. Materials and Methods Retrospective databased study from 2017 to 2021 of 292 women with IDA due HMB referred to our Institution. HMB was not related to systemic disease, hormonal disorders, renal or hepatic disease. The IDA studies included CBC, iron panel with ferritin levels; diagnosis was based in Clinical Guidelines: Hb< 12 gr/L, transferrin saturation (TS) <20% and ferritin <15 mcg/L (Adv Ther 2021;38:201-225); in all cases sonography was performed to rule out ovarian cyst and fibroma. For VWD, personal and familiar history of bleeding were assessed, studies included bleeding time, fibrinogen, factor VIII, factor XIII, vW antigen and vW activity on first to fourth day of menstruation, all studies were performed twice in different menstrual cycle; diagnosis was based in review articles: vW below 50 IU and bleeding history, including IDA (Hematol Oncol Clin N Am 2021;35:1085-1101). Results From 292 women with IDA, 23 (7.9%) was diagnosed with VWD. Age ranges from 14 to 54 years, median 21. vW antigen levels from 3 to 47 IU, median 28 IU. vW activity 4 to 45 IU, median 27 IU. Eleven patients had vW activity levels below 30 IU and had more significant history of mucocutaneous bleeding: epistaxis 52%, cutaneous bleeding 45%, oral cavity bleeding 42%; compared with 12 patients with vW activity between 31 and 50 IU: epistaxis 35%, cutaneous bleeding 19%, oral cavity bleeding 15%. Both groups had similar frequency of bleeding after surgical and dental procedure, 46% and 44% respectively. Treatment for IDA included oral and IV iron; treatment for HMB included hormonal therapy, desmopressin and tranexamic acid. Discussion VWD has been objectively reported in México in the first systematic analysis (Haemophila 2013;19:231-235); this observation was made mainly in mestizos of Spanish heritage and the true frequency could not be determinate, as is in the case in the majority of studies in countries worldwide; from 133 patients with bleeding disorders, 53 (39.8%) had VWD. In 124 Mexican women with history of postpartum hemorrhage, VWD was diagnosed in 61 (49.2%) (Haemophilia 2020;26:97-105). In a more recently study, VWD rate was estimated in 7.2 per million inhabitants in western Mexico (Haemophilia 2022;21:e78-e87). Our study demonstrates that VWD is present in Mexican population and has almost a rate of 8% in women with HMB, similar to reported in other studies, but this rate may be underrepresented and underdiagnosed as is in general population because lack of hematologists and diagnostic test in smaller cities, and misconception of the disease, as Mexico has heritage from Spain, England and France among other European countries with higher rates of VWD. Our study also compares the levels of VW factors, and found that patients with low levels of VW (31-50 IU) has the same bleeding phenotype as patients with VWD (< 30 IU), supporting that VWD should be diagnosed in patients with bleeding manifestations and VW factor below 50 IU (Hematol Oncol Clin N Am 2021;35:1085-1101). Finally, based in our results we recommend to investigate for VWD in patients with IDA from HMB.

Efficacy and Safety of Prophylaxis with a Plasma-Derived Von Willebrand Factor/ Factor VIII Concentrate in Previously Treated Patients with Von Willebrand Disease

Introduction: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in von Willebrand disease (VWD) patients with a history of severe and frequent bleeds, regardless of age or VWD type. Data on the efficacy and safety of prophylaxis with a human plasma-derived VWF/factor VIII concentrate (pdVWF/FVIII; wilate®) that contains the two factors in a physiological 1:1 activity ratio have been collected previously from 19 VWD patients in four prospective, multicenter phase 2 and 3 trials. In these patients, bleeding rates were significantly reduced compared with previous treatment. Aims: To investigate the efficacy and safety of regular prophylaxis with a pdVWF/FVIII concentratein previously treated patients with VWD. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled patients of any gender with VWD type 1 (VWF:RCo <30 IU/dL), type 2 (except 2N) or type 3, who were at least 6 years old. Prior to entering the WIL-31 study, all patients had received on-demand treatment with pdVWF/FVIII during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, with at least 2 of these BEs treated with a VWF-containing product, were eligible to enter WIL-31. Patients in WIL-31 received regular pdVWF/FVIIIprophylaxis, 2-3 times per week at a dose of 20-40 IU/kg, for 12 months. The primary endpoint of the study was to demonstrate that prophylaxis with pdVWF/FVIII lowered the mean total annualized bleeding rate (ABR) compared with that during 6 months of on-demand treatment by more than 50%. Secondary outcomes included spontaneous ABR and treatment-emergent adverse events. Results: Thirty-three patients were included in the modified full analysis set, with a median (range) age of 18 years (7-61). Fourteen (42.4%) patients were female, 9 (27.3%) patients were <12 years old. Six (18.2%) patients had severe Type 1 VWD, 7 (21.2%) had type 2, and 20 (60.6%) patients had type 3 VWD. Mean (median, range) total ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 33.4 (24.5, 11-115) and 5.2 (1.9, 0-35.8), respectively (Figure 1), meeting the primary endpoint of a ≥50% reduction in mean ABR. Mean (median, range) spontaneous ABR in the on-demand run-in period and during pdVWF/FVIII prophylaxis was 24.4 (18.7, 5-93) and 3.2 (1.0, 0-24.6), respectively. Of the 33 patients, 10 (30.3%) and 15 (45.5%) patients had zero total or spontaneous BEs during the study period, respectively. A total of 173 BEs occurred, the majority of which (146 BEs; 84.4%) were classified as minor. Of the 173 BEs, 121 (69.9%) were treated with pdVWF/FVIII. The overall efficacy of treatment was assessed as "excellent” or "good” for 120 (99.2%) BEs and "moderate” for 1 (0.8%) BE. Five serious adverse events were reported, none of which were assessed as related to the study treatment. Two patients had adverse events assessed as probably or possibly related to the study treatment by the investigator, and both patients discontinued from the study. One patient developed mild chest tightness (3 events), the other had hypersensitivity reactions of moderate severity (2 events). No thrombotic events occurred. Conclusions: Prophylaxis with a pdVWF/FVIII containing VWF and FVIII in a 1:1 activity ratio was effective in pediatric and adult patients with VWD of all types. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Analysis of Healthcare Resource Utilization and Costs Among Patients Diagnosed with Von Willebrand Disease and Angiodysplasia

Background: Von Willebrand disease (VWD), an autosomal inherited bleeding disorder, is characterized by deficiency or dysfunction of von Willebrand factor (VWF). Patients with VWD may suffer from recurrent bleeding in the gastrointestinal (GI) tract associated with angiodysplasia (AGD). Recurrent hospitalizations due to bleeding are common in patients with VWD and AGD, causing significant financial burden and poor quality of life. There are limited data on the economic and clinical burden of patients with VWD and AGD. This study aims to understand the healthcare resource utilization (HCRU) and economic burden among patients with VWD related AGD from patient and payer perspectives. Objectives: To describe the sociodemographic & clinical characteristics, HCRU & all-cause costs (ACC), treatment and procedure patterns for patients with VWD of any type and AGD. Methods: This retrospective, observational cohort study used the IBM MarketScan® database (2011-2020), containing healthcare data from the United States (US). Selected patients had ≥1 medical claim for VWD or low VWF, ≥1 medical claim for AGD, and ≥3 GI-related bleed episodes within a year identified using International Classification of Diseases (ICD-9/10) codes. The index date was defined as the date of the first GI bleed-related medical claim before or within 30 days of the first AGD claim. Otherwise, it was defined as the date of the first AGD-related medical claim. Patients were excluded if they did not have 6 months pre- and 12 months post-index continuous enrollment and if they had ≥2 medical claims of hemophilia A (HA), hemophilia B, acquired HA, ulcerative colitis, Crohn's disease, acquired VWD, or other bleeding disorders atleast 30 days apart. HCRU and ACC were compared with a VWD (only) cohort (i.e., continuously enrolled VWD patients without AGD) and a general cohort (i.e., continuously enrolled patients without VWD or AGD) to improve the strength of the evidence via reducing the risk of bias and generating statistical inferences. For comparison of the cohorts, 1:4 exact matching was performed using age, gender, index year, and Charlson Comorbidity Index (CCI) score (relaxing age and index year by ± 5 years). Statistical comparisons were made using ANOVA tests for continuous and Chi-square tests for categorical variables. The ACC were inflated to 2021 US dollars using the annual medical care component of the consumer price index. In addition to the HCRU and ACC comparisons, clinical characteristics of the VWD and AGD cohort were reported along with 2 other cohorts that met 2 of the 3 inclusion criteria to allow for a more relevant description of diagnostics, procedures, and bleed rates. Results: After exact matching, 34 patients were selected from the VWD & AGD cohort with 136 patients each from VWD (only) and general population. Mean (SD) HCRU were significantly higher for the VWD & AGD cohort than the VWD (only) and general cohorts: {2.2 (2.2), 0.6 (1.3), and 0.3 (0.6)} inpatient visits, {17.6 (36.4), 3.4 (10.9), and 2.0 (7.1)} inpatient hospital days, {2.2 (2.6), 0.8 (2.1), and 0.7 (1.5)} emergency visits, and {28.8 (19.4), 18.8 (16.0), and 17.3 (19.6)} outpatient visits, respectively. Mean (SD) total ACC were significantly higher for the VWD & AGD cohort than the VWD (only) and general cohorts {$150,101 ($305,052), $48,249 ($97,689), and $31,029 ($45,512), respectively} (Table 1). Sociodemographic and clinical characteristics (e.g. diagnosis related procedures, bleed rates) of the VWD cohort along with the 2 cohorts that met 2 of 3 inclusion criteria are reported in Table 2. Conclusions: This study found that patients with VWD and AGD were predominantly female with high HCRU and clinical burden due to recurrent bleeding episodes. The data demonstrated a substantial economic burden, primarily driven by hospitalizations. The diagnostic journey for patients and HCRU is highly variable and may benefit from a more structured and empiric understanding of how VWD and AGD patients are diagnosed and treated. Additionally, costs and burden of VWD & AGD could be mitigated by greater outpatient management to prevent recurrent GI bleeds (i.e. VWF prophylaxis). More research is needed to better understand disease management and healthcare outcomes of patients with VWD and AGD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Experimental Gene Therapy on Type 2A/Iic VWD Mouse Model with AAV Vector Delivering Only VWF Propeptide Expression cassette4

Type 2A/IIC von Willebrand Disease (VWD) is caused by mutations in the propeptide of von Willebrand Factor (VWF), and characterized by the impaired multimer assembly. The structural analysis revealed that VWF propeptide (D1D2 domain) serves as a pH-sensing template for VWF multimerization and tubular storage, which implies that D1D2 expression "in trans" has the potential to restore the multimerization defect of type 2A/IIC mutatns. The gene therapy of VWD is challenging due to the huge size of VWF gene, which cannot be packed to the virus vectors, particularly recombinant adeno-associated virus (rAAV). In the pilot studies, we had co-transfected AtT20 cell with plasmid encoding full length VWF, containing the Y87S mutation on propeptide region and causing type 2A VWD phenotype, and plasmid expressing only wild type propeptide of VWF. The co-transfection rescued the multimer formation in a concentration dependent manner (Figure 1A )and corrected the functional defects caused by the Y87S mutation (Figure 1B). Inspired by the results of in vitro studies, we thus have designed a novel gene therapy strategy for type 2A VWD utilizing the machinery of VWF multimer assembling. Instead of trying to squeeze the VWF gene into the AAV vector, we had prepared the AAV vector containing the expression cassette of propeptide region directed by endothelial cell specific promoter FLT-1. The mouse model representing natural occurring VWF Y87S mutation identified in type 2A VWD patient was established by criper9 gene editing technique. The AAV vectors was administered via tail vein injection at a dose of 5Ⅹ1011 genome copies to 6 weeks old male mice to deliver the propeptide of VWF gene and the plasma of the treated mice was collected retroorbital pretreatment and at 2- ,4- and 6-weeks post vector injection. The antigen level of VWF was determined by ELISA and the function activity of VWF was measured by collagen binding assay. The status of VWF multimerization was examined by agarose gel electrophoresis. Although the Y87S mutation led to significant reduce of high molecule weight multimer in mice, unlike observed in mutation harboring patient, the mice still had medium and low molecular weight multimer, maintaining ~30% of activity. The expression of propeptide by AAV delivered vector improved the VWF activity significantly to ~70% of wild type control (Figure 1C), and restored the formation of high molecular weight multimer (Figure 1D). The experimental gene therapy conducted on VWD mouse model showed that it would be efficient to express the propeptide alone to correct the type 2A/IIC VWD defect and the preliminary results provide a novel strategy to overcome technique limits on gene therapy of VWD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patients with von Willebrand disease in China: Results of an online survey.

Little is known about the clinical characteristics of von Willebrand disease (VWD) patients in China, the impact of Covid-19 on them and their genetic mutation. To describe the clinical characteristics of a group of VWD patients in China, the impact of Covid-19 on them and their genetic mutation. An online survey using a self-designed questionnaire was conducted among patients within a WeChat group of VWD patients in China. Data were analysed using t-test, the Chi-square test, Fisher's exact test and rank sum test. Data from a total of 96 patients were collected. Several important findings are yielded. Above all, type 3 patients accounted for over half of the surveyed patients. Secondly, a surprising rate (>40%) of patients had experience of being misdiagnosed. Thirdly, treatment regimens were dominated by cryoprecipitate, blood-derived FVIII and plasma, and only a small percentage of patients received prophylaxis. Fourthly, we identified 17 new von Willebrand factor (VWF) mutant genes which merit further investigation. Additionally, Covid-19 was found to pose some challenges for the patients. In China, the high rates of type 3 patients and misdiagnosis suggest that most of the VWD patients may never be diagnosed in China. When it comes to diagnosis and treatment, there is a large gap between developing countries like China and developed countries.

Von Willebrand factor and cancer: Another piece of the puzzle

Von Willebrand factor and cancer: Another piece of the puzzle

Analysis of von Willebrand Disease in the "Heart of Europe".

Background von Willebrand disease (VWD) is a genetic bleeding disorder caused by defects of von Willebrand factor (VWF), quantitative (type 1 and 3) or qualitative (type 2). The laboratory phenotyping is heterogenic making diagnosis difficult. Objectives Complete laboratory analysis of VWD as an expansion of the previously reported cross-sectional family-based VWD study in the Czech Republic (BRNO-VWD) and Slovakia (BRA-VWD) under the name “Heart of Europe,” in order to improve the understanding of laboratory phenotype/genotype correlation. Patients and Methods In total, 227 suspected VWD patients were identified from historical records. Complete laboratory analysis was established using all available assays, including VWF multimers and genetic analysis. Results A total of 191 patients (from 119 families) were confirmed as having VWD. The majority was characterized as a type 1 VWD, followed by type 2. Multimeric patterns concordant with laboratory phenotypes were found in approximately 83% of all cases. A phenotype/genotype correlation was present in 84% (77% type 1, 99% type 2, and 61% type 3) of all patients. Another 45 candidate mutations (23 novel variations), not found in the initial study, could be identified (missense 75% and truncating 24%). An exon 1–3 gene deletion was identified in 14 patients where no mutation was found by direct DNA sequencing, increasing the linkage up to 92%, overall. Conclusion This study provides a cross-sectional overview of the VWD population in a part of Central Europe. It is an addition to the previously published BRNO-VWD study, and provides important data to the International Society of Thrombosis and Haemostasis/European Association for Haemophilia and Allied Disorders VWD mutation database with identification of novel causal mutations.

Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n =7 studies]), epistaxis (12%-80% [n =6]) and easy bruising (46%-65% [n =2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n =8 studies) and the EQ-5D (n =2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n =1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n =1). Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.