A Comparative Analysis of the Bleeding Profile and Quality of Life Among Women With Hemophilia Genotype Compared to Other Bleeding Disorders.

Introduction Women with bleeding disorders continue to be underdiagnosed as well as undertreated. Women with bleeding disorders include those with genotype for hemophilia (traditionally named hemophilia carriers), von Willebrand disease (VWD), platelet function disorders, and rare bleeding disorders. Among these women, the carriers of hemophilia are usually considered asymptomatic. The present study compares the bleeding profile and quality of life (QOL) of women and girls with hemophilia and compares it to those diagnosed with VWD and rare bleeding disorders. Methods The present study is part of a prospective observational study (August 2023-July 2028) done on women and girls >12 years in two groups. Group 1 was mothers, sisters, or daughters of patients with hemophilia A who were proven carriers. Group 2 was girls and women registered at our center as following bleeding symptoms and diagnosed as either suffering from VWD or rare bleeding disorders. The bleeding profile was assessed by 1:1 interview using the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT). Health-related QOL (HRQOL) was assessed using the EuroQOL five dimension (EQ5D5L) questionnaire. Results The baseline data collected in the first six months of this prospective study is being presented here. At the time of submission, the center caters to 970 patients with hemophilia and inherited bleeding disorders. Eighty girls (post pubertal) and women with either obligate carrier status for hemophilia (n=68) or a previously diagnosed bleeding disorder (10 VWD, one afibrinogenemia, one factor VII deficiency) were enrolled. The median age of Group 1 was 35 years (25-70 years), whereas that of Group 2 was 15.5 years (13-23 years). In Group 1 (women and girls with hemophilia (WGH)), 58 and 10 were carriers of hemophilia A and B, respectively. Additionally, 83% of WGH had more than one family member with bleeding disorder, whereas 75% of Group 2 had a positive family history. The number of family members with the same disorder ranged from 0-4. Among 68 hemophilia carrier women, 20 reported bleeding symptoms (29.4%), of which 18 reported menorrhagia, one antepartum hemorrhage, and one post-partum hemorrhage and two had joint/muscle bleeds and one each had ENT and gastrointestinal bleeding. Three of them were admitted for treatment of excessive bleeding and treated with plasma/red cells. Three women reported gynecological procedures for excessive bleeding, one was on treatment for ovarian cysts, and four received packed red cells after delivery. The BAT score above 6 was reported only in 10% of WGH. Eighteen patients had undergone a surgical procedure in their life, and three of these women required a transfusion during surgery. Only one woman reported similar complaints in her daughter. The comparative analysis of HRQOL showed a significantly worse score for Group 1 in EQ5D5L domains for pain and anxiety/depression compared to that of Group 2. Conclusions A significant proportion of previously asymptomatic women with hemophilia carrier status were recognized to have significant bleeding tendencies. The QOL of these carriers is comparable to girls with VWD and rare bleeding disorders and requires special attention.

Low von Willebrand factor-unraveling an enigma wrapped in a conundrum.

The 2021 ASH ISTH NHF WFH guidelines recommendation that patients with von Willebrand factor (VWF) levels of 30 to 50 IU/dL and an increased bleeding phenotype be categorized as type 1 von Willebrand disease (VWD) rather than Low VWF has proved controversial. However, in support of that decision, recent data have demonstrated that individuals with partial quantitative VWF deficiency exhibit an age-dependent evolving phenotype and confirmed that Low VWF represents a subgroup within heterogeneous type 1 VWD. Nonetheless, type 1 VWD heterogeneity continues to pose significant diagnostic challenges. In this Forum article, we address outstanding issues critical to preventing the inappropriate overdiagnosis of type 1 VWD while maximizing access to healthcare and minimizing diagnostic delays. In addition, we propose an algorithm for type 1 VWD diagnosis. This algorithm pays special attention to individuals with plasma VWF levels in the 30 to 50 IU/dL range who have no or minimal bleeding history and have not yet been exposed to significant hemostatic challenges.

Efficacy of a 1:1 ratio VWF/FVIII concentrate in patients with von Willebrand disease.

INTRODUCTION: Patients with von Willebrand disease (VWD) require administration of von Willebrand factor (VWF) concentrates peri-operatively. Concerns about FVIII accumulation after repetitive injections of a 1:1 ratio VWF/FVIII clotting factor concentrate (CFC) led this study to explore the recovery and FVIII accumulation over time. METHODS: This monocentre study examined patients with VWD receiving perioperative 1:1 ratio CFC infusions. CFC dosing was based on body weight and endogenous VWF/FVIII activity. FVIII and VWF activity was monitored at T0 (baseline), T1 (15 min postinfusion), and trough levels at T2-T6 (24-120 h). RESULTS: We included 125 patients, undergoing 125 procedures (63 major surgeries, 62 minor), with a median of two CFC infusions (IQR 1-3). With a mean administered dose of 35.7 IU/kg CFC, recovery rates of FVIII and VWF were 2.6 IU/dL per IU/kg and 2.4 IU/dL per IU/kg, respectively. Mean FVIII levels at T0 were 62 (SD 51.9), T1: 164 (SD 80.4), T2: 155 (SD 62.8), T3: 162 (SD 59.8), T4: 124 (SD 78.4), and T5: 120 (SD 65.3) IU/dL. Mean VWF activity levels at T0 were 29 (SD 25.0), T1: 133 (SD 43.7), T2: 92 (SD 37.2), and T3: 86 (SD 37.5) IU/dL. Subgroup analysis in 47 patients with more than three infusions, showed no accumulation of mean FVIII levels. CONCLUSION: This perioperative study demonstrated excellent FVIII and VWF recovery of a 1:1 ratio VWF product in patients with VWD. Stable FVIII and VWF activity levels were observed after repeated infusions, without accumulation. Most major surgeries required only three CFC infusions.

R1205H (Vicenza) causes conformational changes in the von Willebrand factor D'D3 domains and enhances von Willebrand factor binding to clearance receptors LRP1 and SR-AI.

BACKGROUND: von Willebrand factor (VWF)-R1205H variant (Vicenza) results in markedly enhanced VWF clearance in humans that has been shown to be largely macrophage-mediated. However, the biological mechanisms underlying this enhanced clearance remain poorly understood. OBJECTIVES: This study aimed to investigate the roles of (i) specific VWF domains and (ii) different macrophage receptors in regulating enhanced VWF-R1205H clearance. METHODS: In vivo clearance of full-length and truncated wild-type (WT)-VWF and VWF with R1205 substitutions was investigated in VWF-/- mice. Plate-binding assays were employed to characterize VWF binding to purified scavenger receptor class A member 1 (SR-AI), low-density lipoprotein receptor-related protein-1 (LRP1) cluster II or cluster IV receptors, and macrophage galactose-type lectin. RESULTS: In full-length VWF missing the A1 domain, introduction of R1205H led to significantly enhanced clearance in VWF-/- mice compared with WT-VWF missing the A1 domain. Importantly, R1205H in a truncated VWF-D'D3 fragment also triggered increased clearance compared with WT-VWF-D'D3. Additional in vivo studies demonstrated that VWF-R1205K (which preserves the positive charge at 1205) exhibited normal clearance, whereas VWF-R1205E (which results in loss of the positive charge) caused significantly enhanced clearance, pinpointing the importance of the positive charge at VWF-R1205. In vitro plate-binding studies confirmed increased VWF-R1205H interaction with SR-AI compared with WT-VWF. Furthermore, significantly enhanced VWF-R1205H binding to LRP1 cluster IV (P < .001) and less marked enhanced binding to LRP1 cluster II (P = .034) was observed. In contrast, VWF-R1205H and WT-VWF demonstrated no difference in binding affinity to macrophage galactose-type lectin. CONCLUSION: Disruption of the positive charge at amino acid R1205 causes conformational changes in the VWF-D'D3 domains and triggers enhanced LRP1-mediated and SR-AI-mediated clearance.

Review of interventions and effectiveness for heavy menstrual bleeding in women with moderate and severe von Willebrand disease.

INTRODUCTION: Women with VWD have an increased risk of gynaecological complications due to haemostatic challenges of menstruation. AIM: Review gynecological bleeding symptoms and their management in women with moderate-severe VWD. MATERIALS AND METHODS: Retrospective cohort analysis of prospectively collected data for women with moderate and severe VWD attending a joint multidisciplinary clinic between January 2010 and December 2020. Data was collected from electronic patient records on response to treatment options using PBAC, quality of life (QoL) assessment using SF-36 scores, haemoglobin and ferritin in comparison to pre-treatment values. RESULTS: Of the 67 women managed in the clinic; all reported heavy menstrual bleeding (HMB). Combination therapy with concurrent hormonal agents and tranexamic acid was required in 80% of women. There was an overall 64% improvement in PBAC scores in the first year, reflecting on QoL with 35% improvement in SF-36 score and correction of anaemia in 21% of cases. The cumulative effect of continued treatment culminated in greater reduction of blood loss, with an overall 71% improvement in PBAC scores by 5 years. One in 10 women required surgical treatment for a gynaecological pathology. Non-compliance was the cause of excessive unscheduled bleeding in 50% of adolescents. After 3 years, one in five women experienced a relapse of symptom, of whom 46% became perimenopausal and 54% discontinued hormonal treatments due to concerns about fertility, hair loss and weight gain. CONCLUSION: Management of HMB requires careful monitoring and follow-up by MDT with close collaboration between the gynaecology team and HTC. Control of HMB often requires a combination therapy.

Application of genetic testing for the diagnosis of von Willebrand disease.

von Willebrand disease (VWD) is the most frequent inherited bleeding disorder, with an estimated symptomatic prevalence of 1 per 1000 in the general population. VWD is characterized by defects in the quantity, quality, or multimeric structure of von Willebrand factor (VWF), a glycoprotein being hemostatically essential in circulation. VWD is classified into 3 principal types: low VWF/type 1 with partial quantitative deficiency of VWF, type 3 with virtual absence of VWF, and type 2 with functional abnormalities of VWF, being classified as 2A, 2B, 2M, and 2N. A new VWD type has been officially recognized by the ISTH SSC on von Willebrand factor which has also been discussed by the joint ASH/ISTH/NHF/WFH 2021 guidelines (ie, type 1C), indicating patients with quantitative deficiency due to an enhanced VWF clearance. With the advent of next-generation sequencing technologies, the process of genetic diagnosis has substantially changed and improved accuracy. Therefore, nowadays, patients with type 3 and severe type 1 VWD can benefit from genetic testing as much as type 2 VWD. Specifically, genetic testing can be used to confirm or differentiate a VWD diagnosis, as well as to provide genetic counseling. The focus of this manuscript is to discuss the current knowledge on VWD molecular pathophysiology and the application of genetic testing for VWD diagnosis.

Laboratory diagnosis of von Willebrand disease in the age of the new guidelines: considerations based on geography and resources.

von Willebrand disease (VWD) is considered the most common bleeding disorder and arises from deficiency and/or defect in the adhesive plasma protein von Willebrand factor (VWF). Diagnosis of VWD requires clinical assessment and is facilitated by laboratory testing. Several guidelines for VWD diagnosis exist, with the latest American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia 2021 guidelines presenting 11 recommendations, some of which have drawn controversy. In the current narrative review, we provide additional context around difficulties in laboratory diagnosis/exclusion/typing of VWD, with a focus on developing countries/resource-poor settings. In particular, there are many variations in assay methodology, and some methods express high assay variability and poor low-level VWF sensitivity that compromises their utility. Although we favor an initial 4-test assay panel, comprising factor (F) VIII coagulant activity, VWF antigen, VWF glycoprotein Ib binding (VWF:GPIbR or VWF:GPIbM favored over VWF Ristocetin cofactor) and VWF collagen binding, we also provide strategies for laboratories only able to incorporate an initial 3-test assay panel, as favored by the latest guidelines, to improve diagnostic accuracy.

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

INTRODUCTION: 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. AIM: To analyze the reported prevalence of VWD worldwide in relation to income classification. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Real-world healthcare costs and resource utilization in patients with von Willebrand disease and angiodysplasia.

OBJECTIVE: To describe the economic burden among VWD patients with angiodysplasia compared to VWD patients without angiodysplasia and the general population. METHODS: This was a retrospective analysis using the Merative MarketScan Commercial and Medicare Databases® (January 2011-September 2020). Selected patients had ≥1 medical claim for VWD or low VWF, ≥1 medical claim for AGD, and ≥3 GI-related bleeding episodes within a year. HCRU and all-cause costs were compared with the VWD (only) and the general cohorts. RESULTS: The mean total all-cause costs were $150,101 among patients with VWD and angiodysplasia (n = 34), higher compared to $48,249 among matched VWD patients without angiodysplasia (n = 136) and $31,029 among matched individuals of the general population [n = 136; p-value < 0.0001]. The differences in costs between groups were primarily due to inpatient care. During the 12-month follow-up, VWD patients with symptomatic (n = 35), asymptomatic (n = 81), and suspected (n = 378) angiodysplasia had an average of 4.1, 0.6, and 3.8 gastrointestinal (GI) bleeds, respectively. Desmopressin, VWF concentrates, and aminocaproic acid were the most frequent treatments used. The most frequent procedures to treat GI-related bleeding and underlying lesions were blood transfusion and laser therapy. CONCLUSIONS: Despite recent therapeutic advances, there is room for considerable reduction of the disease burden in patients with VWD and angiodysplasia.

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.

Laboratory Testing for von Willebrand Disease Using a Composite Rapid 3-Test Chemiluminescence-Based von Willebrand Factor Assay Panel.

von Willebrand disease (VWD) is the most commonly reported inherited bleeding disorder and may alternatively occur as an acquired von Willebrand syndrome (AVWS). VWD/AVWS develops from defects and/or deficiency in the adhesive plasma protein von Willebrand factor (VWF). VWD/AVWS diagnosis/exclusion remains challenging because of the heterogeneity of VWF defects and the technical limitations of many VWF tests, as well as the VWF test panels (number and type of tests) chosen by many laboratories. Laboratory testing for these disorders utilizes evaluation of VWF level and activity, with activity assessment needing several tests due to the many functions performed by VWF in order to help counteract bleeding. This report explains procedures for evaluating VWF level (antigen; VWF:Ag) and activity by means of a chemiluminescence-based panel. Activity assays comprise collagen binding (VWF:CB) and a ristocetin-based recombinant glycoprotein Ib-binding (VWF:GPIbR) assay that reflects a contemporary alternative to classical ristocetin cofactor (VWF:RCo). This 3-test VWF panel (Ag, CB, GPIbR [RCo]) reflects the only such composite panel available on a single platform and is performed on an AcuStar instrument (Werfen/Instrumentation Laboratory). Certain regional approvals may also allow this 3-test VWF panel to be performed on the BioFlash instrument (Werfen/Instrumentation Laboratory).

Laboratory Testing for von Willebrand Factor Activity by a Glycoprotein Ib-Binding Assay (VWF:GPIbR): HemosIL von Willebrand Factor Ristocetin Cofactor Activity on ACL TOP®.

von Willebrand disease (VWD) is a lifelong and common inherited bleeding disorder caused by a quantitative deficiency and/or qualitative defect of von Willebrand factor (VWF). In order to establish the correct diagnosis of VWD, various tests must be conducted, including evaluation of factor VIII activity (FVIII:C), VWF antigen (VWF:Ag), and VWF functional activity. The platelet-dependent VWF activity is measured in different ways, with the historical ristocetin cofactor assay (VWF:RCo) using platelet aggregometry now replaced with newer assays that offer better precision, lower limits of detection, low coefficient of variation, and are fully automated. The VWF activity by glycoprotein Ib-binding assays (VWF:GPIbR) measured on the ACL TOP® platform represents an automated assay that instead of using platelets employs latex beads coated with recombinant wild-type GPIb. VWF in the test sample agglutinates the polystyrene beads coated with GPIb in the presence of ristocetin. The reduction of turbidity as beads agglutinate represents a linear relationship with VWF:GPIbR activity. Using a ratio of VWF:GPIbR/VWF:Ag, the VWF:GPIbR assay also provides good sensitivity and specificity for distinguishing type 1 VWD from type 2. The following chapter describes a detailed protocol for the VWF:GPIbR assay.

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 and protected 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.

Clinical and laboratory presentation of von Willebrand disease: Experience from a single center in Saudi Arabia.

Objectives: This study was aimed at assessing the clinical presentations and laboratory findings among patients diagnosed with vWD at a Saudi tertiary care unit. Methods: This retrospective study included 189 patients with vWD who were followed up in our unit over 4 years. Clinical and laboratory data were collected and analyzed in SPSS. Results: The median age of the study cohort was 30 years (range 11 months-56 years). The cohort had a female preponderance, with 32.30% males and 66.70% females. Bleeding from different sites was observed, mostly from the joints and muscles (23.90%), followed by the mucus membranes (14.60%), genitourinary areas (7.70%), ecchymoses (2.80%), and gastrointestinal areas (2.80%). A total of 48% of participants presented with more than one type of bleeding. A total of 105 (58.01%) participants had type 1; 29 (16.02%) had type 2; and 47 (25.96%) had type 3 vWD. Blood tests indicated the following mean value: hemoglobin, 116 ± 25.60 gm/L; ferritin, 75.80 ± 166.80 µg/L (median 28.5); vWAg, 0.40 ± 0.27IU/ml; and vWD:RCo, 0.32 ± 0.20IU/dL. The partial thromboplastin time was prolonged in 49.20% and normal in 50.80% of participants. Platelet function analysis values were prolonged in 92.90% and normal in 7.10% of participants. Comparative analysis of the O-type and non-O blood type showed that blood type O was significantly correlated with factor VIII (p-value = 0.013), vWF:RCo (p-value = 0.004), and vWF:Ag (p-value = 0.019). Conclusion: Joint and muscle bleeds were the most common clinical presentations in our cohort. Although type 1 vWD was most prevalent in our cohort, we observed a comparatively higher prevalence of type 3, possibly because of ethnic differences or referral bias. We found a significant difference between O and non-O blood type regarding FVIII and vWF:Ag, and observed a more pronounced difference for vWD activity measuresd by vWF:RCo with blood type O being the systematic factor.

ß-Cyclodextrin functionalized magnetic polyamine-amine dendrimers for high enrichment and effective analysis of trace bisphenolic pollutants in beverages.

Bisphenols (BPs) are typical endocrine disruptors, which can cause great effects on environmental, organisms and human health. In this study, ß-Cyclodextrin (ß-CD) functionalized polyamidoamine dendrimers-modified Fe3O4 nanomaterials (MNPs@PAMAM (G3.0)@ß-CD) were facilely synthesized. It exhibited good adsorption capacities for BPs, which was utilized to construct a sensitive tool in combination with high performance liquid chromatography for monitoring BPs such as bisphenol A (BPA), tetrabromobisphenol A (TBBPA), bisphenol S (BPS), bisphenol AF (BPAF) and bisphenol AP (BPAP) in beverage samples. The factors affecting the enrichment were examined such as generation of adsorbent, dosage of adsorbent, type and volume of eluting solvent, elution time and pH value of sample solution. The optimal parameters for enrichment was as follows: dosage of adsorbent, 60 mg; adsorption time, 50min; sample pH, pH7; elutent, 9 mL mixture of methanol and acetone(1:1); elution time, 6min; sample volume, 60 mL. The experimental results demonstrated that the adsorption conformed to pseudo-second-order kinetic model and Langmuir adsorption isotherm model. The results showed the maximum adsorption capacities of BPS, TBBPA, BPA, BPAF and BPAP were 131.80 µgg-1, 139.84 µgg-1, 157.08 µgg-1, 142.11 µgg-1 and 134.23 µgg-1, respectively. Under optimal conditions, BPS had good linear relationship over range from of 0.5-300 µgL-1, and the linear ranges of BPA, TBBPA, BPAF and BPAP ranged from 0.1 to 300 µgL-1. The limits of detection (S/N = 3) for BPs were good in range of 0.016-0.039 µgL-1. The spiked recoveries of target bisphenols (BPs) in beverages were approving over range from 92.3% to 99.2%. The established method possessed merits of easy to operate, good sensitivity, rapidness as well as environmental friendliness, and which earned great application potential for the enrichment and detection of trace BPs in practical samples.

An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease.

INTRODUCTION: Von Willebrand Factor (VWF) containing concentrates have been used for the treatment of von Willebrand Disease (VWD) for many years. Recently, however, a novel recombinant VWF (rVWF or vonicog alpha, VONVENDI [US], VEYVONDI [Europe]) has arrived to the market for the treatment of VWD. Initially, rVWF was approved by the U.S. Food and Drug Administration (FDA) for the on-demand treatment and control of bleeding episodes and for the perioperative management of bleeding for patients with VWD. More recently, however, the FDA has approved rVWF for routine prophylaxis to prevent bleeding episodes for those patients with severe type 3 VWD receiving on-demand therapy. AREAS COVERED: This review will focus on recent phase III trial results from NCT02973087 regarding the use of long-term routine twice weekly prophylaxis with rVWF for the prevention of bleed events in patients with severe type 3 VWD. EXPERT OPINION: A novel rVWF concentrate may have greater hemostatic potential over prior plasma-derived VWF concentrates and is now FDA approved for use in routine prophylaxis for patients with severe type 3 VWD in the United States. This greater hemostatic potential may be due to the presence of ultra-large VWF multimers and a more favorable high-molecular-weight multimer pattern compared to prior pdVWF concentrates.

Genetic determinants of enhanced von Willebrand factor clearance from plasma.

BACKGROUND: Enhanced von Willebrand factor (VWF) clearance from plasma is associated with von Willebrand disease (VWD). However, the genetic background of this disease mechanism is not well defined. OBJECTIVE: To determine VWF variants that are associated with reduced VWF survival. METHODS: Two hundred fifty-four patients with VWD (type 1 = 50 and type 2 = 204) were investigated, and the results were compared with 120 healthy controls. The patients were comprehensively characterized for phenotypic and genetic features. The ratio of VWF propeptide (VWFpp)/VWF antigen (VWFpp ratio) was used to establish in each patient the VWF clearance state. RESULTS: Out of 92 variants associated with type 1 (7 were novel) and type 2 VWD, 19 had a VWFpp ratio ranging from 1.7 to 2.2, 24 had a VWFpp ratio between 2.3 and 2.9, and 24 variants had a ratio of ≥3. The VWFpp median ratio in healthy controls was 0.98 (0.55-1.6) so that a cut-off value of >1.6 was considered an indicator of accelerated VWF clearance from plasma. An enhanced VWF clearance was observed in 34% of type 1 cases, 100% of type 1 Vicenza cases, 81% of 2A cases, 77% of 2B cases, 88% of 2M cases, and 36% of 2N cases. CONCLUSIONS: An accelerated VWF clearance was found in most patients with type 2A, 2B, and 2M VWD, with a lower proportion of type 1 and 2N. Sixty-seven different variants alone or in combination with other variants were associated with an increased VWFpp ratio. The variants with the highest VWFpp ratio were mostly located in the D3-A1 VWF domains.

A need to increase von Willebrand disease awareness: vwdtest.com - A global initiative to help address this gap.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by quantitative or qualitative deficiencies in von Willebrand factor (VWF). People with VWD may experience excessive, recurrent or prolonged bleeding, particularly during menstruation, childbirth, surgery or following trauma. However, many VWD patients are undiagnosed, and therefore inadequately treated. Reasons for the underdiagnosis of VWD include its relatively mild symptoms, complex diagnosis, lack of awareness among non-specialist healthcare providers and the general population, and a lack of prioritisation of disorders disproportionately affecting females. The vwdtest.com platform was launched as part of a global initiative to raise awareness and improve diagnosis of VWD. Besides providing VWD-specific educational resources, the website includes an online bleeding self-assessment tool and offers diagnostic support for individuals, and their providers, who have a score suggestive of a bleeding disorder. vwdtest.com helps to address these unmet needs, especially in regions with limited access to educational and diagnostic resources.