Association of Obesity on Laboratory Profiles of Individuals with Type 1 Von Willebrand Disease and Low VWF in the Athn Dataset

Introduction: Obesity is associated with endothelial dysfunction, hemostatic and fibrinolytic disturbances. The relationship between obesity and elevated Von Willebrand Factor (VWF) is complex and not fully elucidated. There is a significant knowledge gap regarding the impact of BMI on VWF levels. Given the proinflammatory effect associated with abdominal obesity, we hypothesized that there would be an increased prevalence of obesity among individuals with Low VWF (LVWF) compared to Type 1 Von Willebrand Disease (T1VWD) in the ATHN (American Thrombosis and Hemostasis Network) dataset. Methods: A retrospective review of de-identified patients included in the ATHN dataset as of March 2018 was performed. The dataset was queried for all patients with a diagnosis of "T1VWD," who were over 18 years of age when labs were drawn and when BMI was recorded, who had VWF Ristocetin cofactor (RCO) levels <50 IU/dL and who had BMI entered within 24 months of the date of lab entry. Subjects were categorized with VWF RCO ≤30% as T1VWD and 30-50% as LVWF. We used the NIH definitions for BMI (BMI<18.5, underweight; 18.5-24.9, normal; 25-29.9, overweight; 30-39.9, obese; BMI >40, extremely obese). Results: Of the 6939 patients with T1VWD in the ATHN dataset, 4754 patients had VWF RCO <50%, 1019 were above the age of 18, resulting in 548 evaluable subjects with BMI and laboratory metrics. There were 186 patients in the T1VWD cohort, and 362 patients in the LVWF cohort, with a Female:Male ratio >3:1 (Table 1). BMI was treated as a continuous measurement and on bivariate analysis there was not a statistically significant difference (p=0.593), with mean BMI 28.2 (17.2-52) in T1VWD and 28.6 (15.3-55.4) in LVWF. Prevalence of obesity (BMI ≥30) was not significantly different between cohorts (T1VWF 32% vs. LVWF 36%, p=0.345, Table 1). The prevalence of obesity by age (18-39, 40-59, >60 years) was similar among both cohorts with the exception of a larger proportion of obese individuals over the age of 60 in the LVWF cohort (63% vs 25%). Mean FVIII level for LVWF cohort was significantly higher compared to that for T1VWD cohort (80% vs. 53%; p<0.001). In addition, extremely obese patients had an elevated mean FVIII level compared to overweight patients (81% vs. 60%; p=0.041, Table 2). Among individuals with BMI≥30, there were increased rates for Black race (p=0.013), and Medicaid and Medicare rates (p=0.028) when compared to non-obese individuals (Table 3). While rates of obesity are known to vary regionally, no conclusions could be drawn as there was disproportionate geographic clustering in states with well-established hemophilia treatment centers. Conclusions: Our analysis identified that 34.8% of adults categorized as VWD in the ATHN data set are obese, with similar prevalence among T1VWD and LVWF. This finding, coupled with associated race, ethnic and socioeconomic risk factors can help prioritize prevention and weight management as a critical component of the comprehensive care model. Increasing degree of obesity may be associated with elevated FVIII, and should be studied prospectively in larger cohorts and the potential impact on cardiovascular risk. Limitations of this analysis include incomplete laboratory data, lack of longitudinal laboratory data, unknown potential confounders including pregnancy or medication effect, and non-uniform geographic distribution of patients. Further research is needed to evaluate the impact of obesity on bleeding phenotype, bleeding related complications, and management practices, as well as the effects of weight change on VWF and FVIII levels. Disclosures Schaefer: Siemens: Research Funding; Stago: Research Funding.

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Wish-Qol Study - Assessment of Health-Related Quality of Life (HRQoL) and Health-Economic Aspects in Patients with Von Willebrand Disease (VWD) in France: Results of the Women Cohort

Blood ◽

10.1182/blood.v128.22.1395.1395 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1395-1395

Author(s):

Annie Borel-Derlon ◽

Jenny Goudemand ◽

Dominique Desprez ◽

Fabienne Volot ◽

Yves Gruel ◽

...

Keyword(s):

Interim Analysis ◽

Research Funding ◽

Von Willebrand Disease ◽

Female Group ◽

Bleeding Score ◽

Type 3 ◽

Von Willebrand

Abstract Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of 1% in the general population. VWD results from a deficiency in or a dysfunction of von Willebrand factor which is a protein that is necessary for normal platelet adhesion and protection of factor VIII from proteolysis in the circulation. Nevertheless, prevalence of the most symptomatic forms such as bleeds requiring replacement treatment and /or hospitalization is about 0.01%. Although VWD affects both genders, there is a higher proportion in females than in males.VWD seems to be more symptomatic in women because of their reproductive life. Women with VWD have an increased bleeding risk in numerous situations including anemia, menorrhagia, bleeding during pregnancy, postpartum hemorrhage and impairments in their quality of life (QoL).The prevalence of menorrhagia in women with VWD is 74-92%. According to the Francecoag Network, the referral-based prevalence of moderate-to-severe VWD patients is about 1,750 cases in France. Aim: Since the disease and its treatment can affect every-day life of patients and their families, a French HRQoL Study (WiSH-QoL) exploring this impact started 22 months ago. Methods: This non-interventional 5-year study evaluates patients HRQoL and costs of care in France. At least 350 patients will be followed for 24 months in minimum 30 centers. HRQoL is assessed with the generic SF-36 and the disease-specific VWD-QoL questionnaires. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Results: Since October 2014, 245 patients have been included. We present here the first interim analysis with a focus on the female group. At the first interim analysis, data from 140 patients were documented: 91 adults with a median age of 40.0 years [18.3-78.0] and 49 children with a median age of 10.1 years [2.9-17.5]. VWD Types were already identified for 122 (87%) of these patients: 33 with VWD type 1 (27%) including 5 type 1 Vicenza; 76 type 2 (62%) and 13 type 3 (11%). The median Tosetto bleeding score reported for 124 patients (males and females) was +7 ranging from -1 to +28. From the 95 female patients, 70 were aged ≥18 years, 21 were adolescents between 8-17 years and 4 were girls below 4 years of age. Median age was 29.4 (range 4.3-78.0) years. A total of 25 women had type 1 VWD (31%), 49 had type 2 VWD (60%), and 7 had type 3 VWD (9%), for 14 patients VWD type is undetermined. The median Tosetto bleeding score of the female group was +8 ranging from -1 to +28. Out of 95 patients, 45 patients (47.4%) have received a concomitant treatment due to menorrhagia, such as iron therapy, oral contraceptive, levonorgestrel intrauterin system: 5/21 patients in the group between 8 and 17 years and 40/70 in the group ≥18 years. Out of the 60 women of childbearing potential defined as age between 15-50 years, 6 women were pregnant at time of inclusion. A total of 46 patients, aged 18 years or more have had obstetrical history prior to study inclusion. The mean number of childbirth was more than 2 i.e 2.39 range (1-8) per woman, 75% of these deliveries were natural delivery and 25% were caesarean section. Out of 108 deliveries, 28 (26%) were experienced with post-partum hemorrhages. Conclusions: With the results of the WiSH-QoL study, the first prospective study of von Willebrand disease conducted in France, especially the VWD-specific evaluation of HRQoL and treatment satisfaction a deeper insight will be gathered into the patients' daily life, their perception of well-being and their specific health care needs. With the additional domain 'pregnancy' included in the French version of the VWD-QoL questionnaire for female adult patients, it will possible to better understand how women may be affected by VWD during childbearing years. Disclosures Borel-Derlon: LFB: Other: Reference expert and national coordinator for VWD; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee; Shire - Baxalta: Research Funding. Chatelanaz:LFB Biomedicaments: Employment. Doriat-Robin:LFB Biomedicaments: Employment. von Mackensen:SOBI: Research Funding; Shire: Research Funding.

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Clinical Study to Investigate the Efficacy and Safety of Wilate during Prophylaxis in Previously Treated Patients with Von Willebrand Disease (VWD)

Blood ◽

10.1182/blood-2019-128339 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4931-4931

Author(s):

Robert F. Sidonio ◽

Bruce A. Schwartz

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prophylactic Treatment ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Previously Treated Patients ◽

Previously Treated ◽

Type 3 ◽

Von Willebrand

Background: Inherited von Willebrand disease (VWD) is the most common inherited hemorrhagic disorder, with an estimated prevalence of 1 in every 100 individuals. Type 1 and type 3 (the most severe form) are characterized by a quantitative deficiency of von Willebrand factor (VWF) and type 2 arises from a qualitative deficiency of VWF. Treatment of VWD depends on the type and severity of the disease. Severe bleeding is reported in patients with all subtypes, leading to progressive joint disease as well as diminished quality of life (QoL). VWF/factor VIII (FVIII) concentrates have become the mainstay of VWD treatment for these patients with severe disease or for those patients in whom other treatments (e.g., desmopressin) are ineffective or contraindicated but this is broadly applicable only for on demand treatment. Aims: The primary objective of this study is to determine the efficacy of VWF/FVIIII concentrate in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD. Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time and, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication. The study will also examine, the efficacy of VWF/FVIIII concentratein the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the QoL during prophylaxis with VWF/FVIIII concentrate. Methods: The study is planned to enroll 28 patients aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run-in observational study to collect the bleeding profile prior to the start of prophylaxis. From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated. Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none) In patients that undergo surgeries, efficacy of VWF/FVIIII concentratewill be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator. Results: Data will be monitored on an ongoing basis and the study is expected to end Q2 2021. Conclusions: Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve QoL in patients but to date, this form of treatment in VWD is not well characterized. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the QoL in VWD patients. Disclosures Sidonio: Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees. Schwartz:Octapharma: Employment.

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Semiautomatic VWF Multimer Densitometric Analysis: Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease

Blood ◽

10.1182/blood-2020-142287 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Ferdows Atiq ◽

Johan Boender ◽

Marjon H. Cnossen ◽

Johanna G van der Bom ◽

Karin Fijnvandraat ◽

...

Keyword(s):

Clinical Practice ◽

Research Funding ◽

Von Willebrand Disease ◽

Densitometric Analysis ◽

Travel Grant ◽

Bleeding Score ◽

Type 3 ◽

Von Willebrand

Introduction Von Willebrand factor (VWF) multimer analysis is an essential tool in the diagnosis and classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is observer dependent, time consuming and is inaccurate in detecting subtle changes in multimer patterns. Therefore, recent studies have investigated VWF multimer quantification using semiautomatic densitometric analysis. The accuracy of VWF multimer densitometric analysis in clinical practice needs further investigation before it can be widely used. The aim of the study was to validate the accuracy of VWF multimer densitometric analysis in clinical practice. Additionally, we aimed to identify patient characteristics associated with VWF multimer densitometry outcomes in type 1 and type 2 VWD patients, and we investigated whether subtle differences in VWF multimer pattern are associated with the bleeding phenotype of VWD patients. Methods We included patients from the nationwide Willebrand in the Netherlands (WiN) study. The inclusion criteria of the WiN study were a personal hemorrhagic diathesis or family history of VWD, and historically lowest VWF antigen (VWF:Ag), VWF activity (measured with the monoclonal antibody assay: VWF:Ab) or VWF collagen binding (VWF:CB) ≤0.30 IU/mL or FVIII activity (FVIII:C) ≤0.40 IU/mL in case of type 2N VWD. At inclusion in the WiN study, blood was drawn and patients filled in an extensive questionnaire containing a self-administered Tosetto bleeding score (BS). For multimer analysis, citrated blood samples were separated on 0.9% agarose gel and visualized by Western blotting. We used IMAGEJ for densitometric analysis. The five smallest bands on densitometric images were defined as small multimers, next five bands were defined as medium multimers and the remaining bands were defined as large multimers. Medium-large VWF multimer index was calculated by dividing the patient's multimer ratio (intensity of the medium and large multimers divided by the total intensity of all multimers) by the multimer ratio of a normal control in the same western blot. If no multimers could be detected, the multimer index was set as 0. Results We included 561 VWD patients: 328 type 1, 211 type 2 and 21 type 3 patients. The median age was 44 [IQR 29-58] and 351 patients (62.7%) were female (Table 1). Figure 1 illustrates typical densitometric outcomes of a type 1 VWD patient with normal VWF multimers (A) and a type 2A patient with reduced high-molecular-weight (HMW) VWF multimers (B). Medium-large VWF multimer index was 1.06 [0.99-1.12] in type 1 and 0.53 [0.29-0.89] in type 2 and 0.00 [0.00-0.00] in type 3 VWD. Medium-large VWF multimer index was in patients visually classified as normal, reduced and absent HMW VWF multimers, respectively 1.07 [1.02-1.12], 0.84 [0.71-0.91] and 0.31 [0.20-0.44] (p<0.001, Figure 2A). With visual examination as gold standard, medium-large VWF multimer index had a very good accuracy in distinguishing normal VWF multimers from reduced HMW VWF multimers (AUC: 0.96 (0.94-0.98) p<0.001, Figure 2B). It could also accurately distinguish reduced HMW VWF multimers from absence of HMW multimers, with an AUC of 0.95 (0.92-0.97, p<0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 (0.94-0.99), p<0.001, Figure 2C and 2D). From VWF activity measurements, medium-large VWF multimer index was strongest correlated with VWF:CB (ρ=0.79, p<0.001). From the ratio of the various functional VWF measurements (divided by VWF:Ag), the strongest correlation was again found for VWF:CB/VWF:Ag ratio (ρ=0.80, p<0.001). In type 1 VWD, an increased clearance of VWF (defined as VWFpropeptide/VWF:Ag ratio ≥2.2) was independently associated with lower medium-large VWF multimer index (β=-0.10 (-0.14; -0.07), p<0.001). Also, type 1 VWD patients with a VWF gene variant had relatively lower medium-large VWF multimer index compared to type 1 patients without a VWF variant, respectively 1.03 [0.95-1.10] vs 1.08 [1.04-1.12] (p<0.001). In the total population, higher medium-large VWF multimer index was associated with a lower bleeding score: β=-4.6 (-7.2; -2.0), p=0.001, adjusted for age, sex, blood group and type of VWD. Conclusion Semiautomatic densitometric analysis of VWF multimers has an excellent accuracy in clinical practice, and may have an additional value in providing a better understanding of the clinical features such as the bleeding phenotype of VWD patients. Disclosures Atiq: CSL Behring: Research Funding; SOBI: Other: travel grant. Boender:SOBI: Current Employment; CSL Behring: Research Funding. Cnossen:Bayer: Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; Sobi: Research Funding; Takeda: Research Funding; CSL behring: Research Funding; Pfizer: Research Funding; Shire: Research Funding; Baxter: Research Funding. van der Bom:Bayer: Speakers Bureau. Fijnvandraat:SOBI: Research Funding; NovoNordisk: Consultancy; Grifols: Consultancy; Takeda: Consultancy; Roche: Consultancy; CSL Behring: Research Funding; NovoNordisk: Research Funding. Van Galen:Bayer: Research Funding; Takeda: Speakers Bureau; CSL Behring: Research Funding. Laros-Van Gorkom:Baxter: Other: Educational grant; CSL Behring: Other: Educational grant. Meijer:Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Eikenboom:CSL Behring: Research Funding; Roche: Other: Teacher on educational activities. Leebeek:Roche: Other: DSMB member for a study; SOBI: Other: Travel grant; Novo Nordisk: Consultancy; Shire/Takeda: Consultancy; Uniqure: Consultancy; Shire/Takeda: Research Funding; CSL Behring: Research Funding.

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Increased Von Willebrand Factor Antigen Clearance in Type 1 Von Willebrand Disease: Investigation of Relationship with ABO Blood Group and Tyr1584Cys Polymorphism.

Blood ◽

10.1182/blood.v104.11.256.256 ◽

2004 ◽

Vol 104 (11) ◽

pp. 256-256 ◽

Cited By ~ 1

Author(s):

Carolyn M. Millar ◽

Anne F. Riddell ◽

Peter V. Jenkins ◽

Christine A. Lee ◽

Simon A. Brown

Keyword(s):

Blood Group ◽

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Abo Blood Group ◽

Haemophilia A ◽

Significant Difference ◽

Von Willebrand ◽

Willebrand Factor ◽

Increased Susceptibility

Abstract Type 1 von Willebrand disease (VWD) is a heterogeneous bleeding disorder in which genetic modifying factors, including ABO blood group, contribute towards the variability in von Willebrand factor (VWF) levels. Recent findings have reported an increased incidence of the Tyr1584Cys polymorphism in the VWF-A2 domain of patients with type 1 VWD. Presence of Cys1584 has been shown to cause increased intracellular retention of VWF, as well as lead to increased susceptibility of VWF to proteolysis by the metalloprotease ADAMTS13. An increased susceptibility to proteolysis by ADAMTS13 has also been demonstrated in the VWF of blood group O individuals. We have investigated the relationship between increased VWF antigen (VWF:Ag) clearance, ABO blood group and the presence of the Tyr1584Cys polymorphism in a group of patients with type 1 VWD. The VWF:Ag half-life (VWF:Ag t1/2) was prospectively evaluated in 45 patients with type 1 VWD, which included three families of two or more first-degree relatives. Median VWF:Ag level was 36.0iu/dl (range 4–50iu/dl); median VWF ristocetin cofactor activity (VWF:RCo) level was 35.0iu/dl (range 3–52iu/dl) and VWF:RCo/VWF:Ag ratio 0.97 (range 0.70–1.37). A normal multimeric pattern was demonstrated in all patients. 25 (55.5%) and 20 (44.5%) of the patients were of blood groups O and A respectively. The control group comprised eight patients with haemophilia A. VWF:Ag levels were measured over a 6 hour period following the administration of intravenous DDAVP. VWF:Ag t1/2 was calculated using the formula: C(t)=C0e−k.t, where C(t)=plasma [VWF:Ag] as a function of time; C0=[VWF:Ag] at time zero; e=base for natural logarithms; k=first order rate constant for the elimination phase (ß phase); t=time. The median value of the VWF:Ag t1/2 in the VWD group was 4.1 hours (95% C.I. 3.2–4.9h) and in the haemophilia A group 9.5 hours (95% C.I. 5.3–19h). This represents a significant difference in VWF:Ag t1/2 between the two groups (p<0.05). However, within the VWD patient group, there was no significant difference between the median VWF:Ag t1/2 values of patients of blood group O and those of blood group A (p>0.05). Within the three families, two affected family members of the same ABO blood group were studied and a concordant reduction in the VWF:Ag t1/2s was found in these subjects. To date, 24 of the VWD patients have been genotyped for the A/G polymorphism at nucleotide 24/1282 in the VWF gene, encoding a Tyr1584Cys polymorphism. The heterozygous presence of the G allele encoding Cys 1282 was demonstrated in one patient. The frequency of this polymorphism in normal and type 1 VWD individuals has been reported to be ~1% and 14% respectively. The median VWF:Ag t1/2 value of the 23 homozygous Tyr1584 patients was 3.4 hours (95% C.I. 3.2–4.8h), representative of the whole VWD group. The VWF:Ag t1/2 in the heterozygous patient was 4.8 hours. The finding of increased plasma VWF:Ag clearance as reflected by a reduction in VWF:Ag half-life in a significant number of patients with type 1 VWD, suggests that increased VWF:Ag clearance may be a contributory factor in the aetiology of type 1 VWD. However, this study suggests there is no relationship between increased VWF:Ag clearance and ABO blood group. Furthermore, the Tyr1584Cys polymorphism is not a major determinant of VWF:Ag clearance within this group of type 1 VWD patients.

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Unique ELISA-Based Assays for VWF-GPIb Interactions and the Impact of Racial Differences on VWF Testing

Blood ◽

10.1182/blood.v112.11.423.423 ◽

2008 ◽

Vol 112 (11) ◽

pp. 423-423

Author(s):

Veronica H. Flood ◽

Patricia A. Morateck ◽

Pamela A. Christopherson ◽

Kenneth D. Friedman ◽

Joan Cox Gill ◽

...

Keyword(s):

Racial Differences ◽

Von Willebrand Disease ◽

Mutant Form ◽

Plasma Samples ◽

Healthy Donors ◽

Significant Difference ◽

The Mean ◽

Clinical Biology ◽

Von Willebrand ◽

The Impact

Abstract Diagnosis of von Willebrand disease (VWD) relies primarily on assays of von Willebrand factor (VWF) function (VWF:RCo) and concentration of VWF protein (VWF:Ag). VWF:RCo is a surrogate measure of VWF activity for VWF interaction with the GPIb receptor on platelets. For VWD screening purposes, some have advocated that VWF:RCo is the most appropriate single test, but variability and reproducibility of VWF:RCo assays between laboratories has been problematic. Alternative assays have therefore been sought. Type 2 VWD variants, 2A, 2B, and 2M, are characterized by a discrepancy between the VWF:Ag and VWF:RCo, yet numerous factors can affect this ratio. Previously, our laboratory has reported a cell based assay to measure VWF interaction with the GPIb complex by flow cytometry, but such assay instrumentation is not available in hemostasis testing laboratories. Plasma samples were collected from 75 healthy donors enrolled in the TS Zimmerman Program for the Molecular and Clinical Biology of VWD, including 44 African American (AA) and 31 Caucasian subjects. VWF:Ag and VWF:RCo levels were performed in a central laboratory, as were collagen binding (VWF:CB) and propeptide (VWFpp) testing. Two ELISA-based assays were developed to measure VWF interaction with GPIb using recombinant GPIbα – one using normal GPIb with ristocetin (VWF:RCo ELISA) and the other a mutant form of GPIbα containing the platelet-type mutations D235Y and M239V that does not require ristocetin (VWF:IbCo ELISA). A monoclonal antibody is used to capture the rGPIb and to orient the GPIb for subsequent interaction with VWF. Serially diluted plasma samples were incubated for 1 hour with or without added ristocetin and monoclonal antibodies to VWF were used to detect the presence of VWF. Both assays utilized a 10 minute agitation at the end of the plasma incubation step. For all subjects, the mean VWF:Ag was 142, the mean VWF:RCo was 124, and the mean VWF:RCo/VWF:Ag ratio was 0.90. The two new assays yielded similar activity results when all the control subjects were analyzed, with a mean of 104 for the VWF:RCo ELISA and a mean of 108 for the VWF:IbCo ELISA. Both assays correlated well with each other and with the VWF:RCo. R squared values as determined by linear regression were 0.79 for the comparison of the VWF:RCo ELISA with the VWF:IbCo ELISA and 0.80 for comparison of either with the regular VWF:RCo. When the results were analyzed by race, however, a significant difference was seen for the two ristocetin-containing assays. The mean VWF:RCo/VWF:Ag ratio for the AA controls was 0.85, compared to 0.95 for the Caucasian controls (p<0.025). For the ristocetin ELISA, the mean was 0.54 for the AA controls and 0.79 for the Caucasian controls (p<0.001). However, no significant racial difference was seen for the VWF:IbCo ELISA with mean of 0.72 for the AA controls and 0.81 for the Caucasian controls (p=NS). Other VWF ratios have been proposed to be used to classify VWD – VWF:CB/VWF:Ag, FVIII/VWF:Ag, and VWFpp/VWF:Ag, but none were significantly different by race. The use of ELISA-based assays to determine VWF function is therefore feasible and may alleviate some of the problems inherent in the traditional VWF:RCo assay, including reproducibility and the technical demands of the assay. The VWF:IbCo assay may also eliminate racial differences in the VWF activity to antigen ratio, thus preventing the potential for erroneous diagnosis of VWD. Furthermore, the ELISA-based assays can be performed using standard hemostasis laboratory instrumentation.

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Depression and Anxiety in Persons with Von Willebrand Disease

Blood ◽

10.1182/blood-2021-151625 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4052-4052

Author(s):

Jonathan C. Roberts ◽

Roshni Kulkarni ◽

Peter A. Kouides ◽

Robert F. Sidonio ◽

Shannon L Carpenter ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Important Variable ◽

Von Willebrand Disease ◽

Depression And Anxiety ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand

Abstract Background: Depression and anxiety are associated with poor health-related quality of life (HRQoL), lower functioning and decreased treatment adherence. In 2019, 7% adults in the US had moderate/severe symptoms of depression, while <5% had anxiety. Impacts of depression and anxiety in persons with von Willebrand disease (VWD) are unclear and less studied. Objective: We assessed sociodemographic and clinical characteristics associated with depression and anxiety in a geographically diverse cohort of individuals with VWD obtaining care at seven US Hemophilia Treatment Centers (HTCs). Methods: The study enrolled and collected data on individuals age ≥12 with VWD Type 1 (VWF:Ag/RCo: ≤30%), low VWF(VWF:Ag/RCo: 30-50%), Type 2, and type 3 between September 2018-June 2021. Participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported pain, joint problems and HRQoL measured by the EQ-5D-3L. A quarterly survey administered one year post-enrollment collected similar data. The patient health questionnaire (PHQ-8) and the generalized anxiety disorder (GAD-7) were administered with the last follow-up survey after August 2019. Chart reviews abstracted VWD type information. The association of sociodemographic and clinical characteristics with depression or anxiety was assessed using Chi-square tests for categorical variables, as well as logistic regression models with stepwise selection. Results: We analyzed data from 77 participants who completed both baseline and last follow-up surveys. Mean age was 34.2 (standard deviation (SD)=18.8) years, 74.0% were adults ≥18 years, 79.2% were female, 60.8% had Type 1/low VWF, and 3.9% had Type 3 VWD. Mean age at VWD diagnosis was 13.9 (SD=13.2) years. Overall reported depression rate was 63.4%, and 58.3% for anxiety (values ≥10 on either PHQ-8 or GAD-7). Proportion of those with depression (75% vs. 62%) or anxiety (58% vs. 58%) prior to and during the COVID-19 pandemic were not significantly different. Persons with low VWF had higher rates of depression (86.7%) or anxiety (69.2%) as compared to those with type 1 VWD (55.3% for depression, 52.8% for anxiety) or types 2 and 3 (62.5%, 60.9%, p=0.10, not significant (NS) for depression and p=0.56, NS for anxiety, respectively). Females reported a higher rate of anxiety (61.4%) than males (46.7%, p=0.30, NS). When compared to individuals who rated their general health as the same or better than 3-months ago, those who rated their health as worse had significantly higher rates of depression (92.3% vs. 57.8%, p=0.02) and anxiety (83.3% vs. 53.3%, p=0.05). Participants with chronic pain reported a significantly higher depression rate (81.6% vs. 36.8%, p=0.0003). Those who reported having joint problems also reported depression at a significantly higher rate (82.4% vs. 48.8%, p=0.002) or anxiety (74.1% vs. 46.3%, p=0.02) than those without joint problems. Logistic regression analyses demonstrated that among adults or parents of pediatric patients, being single or not with a partner was the most important variable associated with depression (odds ratio (OR)=7.0, confidence interval (CI): 1.7-29.0), followed by having joint problems (OR=6.3, CI=2.0-20.1). The most important variable associated with anxiety was being a youth aged 12-18 years old (OR=6.7, CI=1.6-26.9), followed by being single or not with a partner (OR=10.8, CI=2.5-47.5), or having worse health compared to 3-months prior (OR=12.3, CI=1.3-116.2). Mean covariates adjusted EQ index scores were lower among persons with depression (0.75±standard error (SE) 0.03 vs. 0.83±0.04, p=0.06 NS) or anxiety (0.75±0.03 vs. 0.82±0.04, p=0.7 NS) than among those without depression or anxiety. As compared to individuals without depression or anxiety, mean covariates adjusted EQ VAS was significantly lower in persons with depression (68.7±3.1 vs. 77.6±4.2, p=0.03), but not among those with anxiety (69.3±3.7 vs. 71.3±4.3, p=0.66 NS). Conclusions: Our study revealed higher rates of major depression and anxiety in this VWD sample than the general US population. Depression had a significant negative impact on HRQoL. Mental health screening is imperative for persons with VWD, especially those with low VWF, chronic pain or joint problems. Special attention should be paid to women and youth. This study underscores the need for a multidisciplinary approach in the comprehensive care of patients seen at HTCs. Disclosures Roberts: Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding. Kulkarni: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sidonio: Bayer: Consultancy; Catalyst: Consultancy; Genentech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Guardian Therapeutics: Consultancy; Octapharma: Consultancy, Research Funding; Biomarin: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding. Carpenter: Genentech: Honoraria; Novo Nordisk: Honoraria; Kedrion Pharmaceuticals: Honoraria; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy; University of Southern California: Consultancy. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

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Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Blood ◽

10.1182/blood-2018-99-113996 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2465-2465

Author(s):

Alberto Tosetto ◽

Zahra Badiee ◽

Mohammad-Reza Baghaipour ◽

Luciano Baronciani ◽

Javier Battle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Von Willebrand Disease ◽

Severe Bleeding ◽

Advisory Committees ◽

Bleeding Score ◽

Type 3 ◽

Von Willebrand

Abstract Patients with type 3 von Willebrand Disease (VWD) usually have markedly reduced FVIII/VWF levels and very severe bleeding manifestations but, because of their rarity, their bleeding phenotype is poorly described. We aimed at evaluating the distribution of bleeding symptoms in patients with type 3 VWD, comparing them with previously available data from a cohort of type 1 patients, and describing site-specific clustering of bleeding symptoms in these patients. We analyzed clinical data from the type 3 Von Willebrand International RegistrieS Inhibitor Prospective Study (3WINTERS-IPS),a no-profit, investigators initiated, multicenter, European-Iranian observational, retrospective and prospective study on patients with diagnosis of type 3 VWD. Aims of the 3WINTERS-IPS is 3-fold: a) to identify the main phenotypic and molecular characteristics of a large cohort of VWD patients; b) to evaluate the risk factors responsible for the severe bleeding phenotype; c) to assess the efficacy and safety of the treatment with VWF concentrates with or without FVIII including the risk of anti-VWF antibodies. Retrospective information on bleeding symptoms at presentation was collected using the MCMDM-1 VWD bleeding questionnaire, and bleeding severity summarized as bleeding score. Individual bleeding symptoms were considered as relevant when having a score >1 (hence requiring medical attention). Data was compared with that retrieved from the MCMDM-1 VWD study database on patients affected by type 1 VWD (index cases and affected family members). The study enrolled a total of 260 patients, of which we analysed 243 patients with available bleeding score at recruitment. The median age at study inclusion was 29 years (interquantile range, 26.5 years); 140 were females (53.8%). There were 108 patients of Iranian descent, while the remaining of patients were from Europe. The median number of bleeding symptoms was 5, and the median bleeding score was 15 (interquantile range, 13). Only 7/243 patients (2.8%) had a single bleeding symptom. Epistaxis was the most frequent relevant symptom, being present in 195 patients (80.2%), followed by menorrhagia in 99 females (70.7%). Males had a higher frequency of hemarthroses and hematomas than females (53.4% vs 42.1% and 40.8% vs 27.1%, respectively). When comparing the clinical presentation of type 3 vs. type 1 VWD, clearly increased bleeding scores were evident for all age-classes and even in paediatric cases. The association between symptoms having a relative frequency >20% is presented in the circle diagram, showing that some symptoms appeared to cluster with others in a variable degree (e.g., menorrhagia with epistaxis, hemarthrosis or oral cavity bleeding; post-extraction bleeding again with epistaxis, hemarthrosis or oral cavity bleeding; surgical bleeding or gastrointestinal bleeding with epistaxis alone). These findings confirm the severity of type 3 VWD and extend the knowledge of symptoms distribution in the widest available cohort of type 3 VWD patients. Disclosures Tosetto: Stago, Novo-Nordisk, BMS: Speakers Bureau; Werfen: Other: Member of Advisory Board, Speakers Bureau. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Eikenboom:CSL: Research Funding. Mazzucconi:Baxalta-Shire: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novartis,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau. Oldenburg:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peyvandi:Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Shire: Speakers Bureau; Roche: Speakers Bureau; Shire: Speakers Bureau; Kedrion: Consultancy; Kedrion: Consultancy; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Roche: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Kedrion: Consultancy; Shire: Speakers Bureau; Roche: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Shire: Speakers Bureau; Ablynx: Other: Member of Advisory Board, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Speakers Bureau; Octapharma US: Honoraria; Octapharma US: Honoraria; Sobi: Speakers Bureau; Grifols: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Consultancy; Sobi: Speakers Bureau; Roche: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Novo Nordisk: Speakers Bureau; Sobi: Speakers Bureau; Octapharma US: Honoraria; Sobi: Speakers Bureau. Schneppenheim:SHIRE: Consultancy; CSL Behring: Consultancy. Tiede:Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Consultancy; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Honoraria; Alnylam, Bayer, Biogen Idec, Biotest, Bristol-Myers-Squibb, Boehringer Ingelheim, CSL Behring, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and SOBI: Research Funding.

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Von Willebrand Disease Minimize Menorrhagia (VWDMin) Trial

Blood ◽

10.1182/blood-2019-124234 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1130-1130

Author(s):

Margaret V. Ragni ◽

Craig D. Seaman ◽

Diana Gilligan ◽

Claire S. Philipp ◽

Anne T. Neff ◽

...

Keyword(s):

Board Of Directors ◽

Real Time ◽

Half Life ◽

Research Funding ◽

Von Willebrand Disease ◽

Phase Iii ◽

Advisory Committees ◽

Phase Iii Trial ◽

Von Willebrand

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo<0.50 IU/dL and menorrhagia, defined as pictorial blood assessment chart score (PBAC)>100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age <18 years (6.2%), pregnancy (6.2%), breastfeeding (6.2%), and VWF prophylaxis (3.1%). Nursing services have been contracted for weekend rVWF infusions. In-person site visits include hands-on web portal training, including a password-protected, FDA-validated data entry system, eSYSDM, use of real-time data form completion by tablet, infusion tracking and training, real-time cycle reporting, patient-training checklists, and protocol training and monitoring. Local gynecologists have been invited to refer potentially eligible patients. Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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No Association Between Normalization of VWF Levels and Bleeding Phenotype in Patients with Type 1 VWD - from the Win Study

Blood ◽

10.1182/blood.v128.22.2577.2577 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2577-2577 ◽

Cited By ~ 3

Author(s):

Johan Boender ◽

Jeroen Eikenboom ◽

Karin Fijnvandraat ◽

Waander van Heerde ◽

Karina Meijer ◽

...

Keyword(s):

Family History ◽

Blood Group ◽

Research Funding ◽

Von Willebrand Disease ◽

Younger Adults ◽

Bleeding Score ◽

Von Willebrand ◽

Index Cases ◽

Over Time

Abstract Von Willebrand factor (VWF) levels vary over time and increase throughout life in both healthy individuals and patients with von Willebrand disease (VWD). Especially in type 1 VWD patients, this increase may result in normalization of VWF levels. It is not yet known if normalization of VWF levels ameliorates bleeding symptoms in VWD patients. We have recently shown that elderly type 1 VWD patients had similar bleeding tendency as younger adults.1 However, many elderly patients in this study had relatively low VWF levels and many younger adults had relatively high VWF levels.1 The aim of the current study was to investigate the association between normalization of VWF levels and the bleeding phenotype in type 1 VWD patients. We included patients from the nationwide cross-sectional "Willebrand in the Netherlands" Study, with lowest historical VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) ≤30 U/dL. At inclusion, blood was sampled for central measurement of VWF:Ag and VWF:Act and VWF to collagen binding (VWF:CB). Central measurements were available in 367 type 1 VWD patients. Based on these central measurements, patients were divided into three groups: definite VWD (central VWF:Ag and/or VWF:Act and/or VWF:CB ≤30 U/dL, n=152); low VWF (central VWF:Ag and/or VWF:Act and/or VWF:CB 31-50 U/dL , n=120) and historical VWD with presently normalized levels (central VWF:Ag and VWF:Act and VWF:CB ≥51 U/dL, n=95). Age differed between groups: median age was 43 years in definite VWD patients, 45 years in low VWF and 50 years in historical VWD patients (p<0.01). No difference in sex distribution was found, see table 1. Of definite VWD patients, 59% had blood group O compared with 77% of low VWF and 73% historical VWD patients (p<0.01). A variant in the VWF gene was most common in definite VWD patients: 55/76 (72%) patients in whom mutation analysis was performed had a variant compared with 22/41 (54%) low VWF and 13/41 (32%) historical VWD patients (p<0.001). Of definite VWD patients, 72% had a positive family history, compared with 39% of low VWF and 27% of historical VWD patients (p<0.001). In contrast, 69% of historical VWD patients were index cases, compared with 67% of "low VWF" and 39% of definite VWD patients (p<0.001). Median Tosetto Bleeding Score (BS) did not differ between the three groups as it was respectively 9, 8 and 9 in definite VWD patients , low VWF patients and historical VWD patients (p=NS), see table 1. The incidence of bleeding episodes requiring treatment with desmopressin or clotting factor concentrate in the year prior to inclusion also did not differ between groups as it was 18% in definite VWD, 22% in "low VWF" and 27% in historical VWD patients (p=NS). In many countries VWF levels 60 IU/dL are used as the cut-off value for abnormal VWF levels. Using this value as cut-off between low VWF and historical VWD, 151 (42%) patients had low VWF and 64 (17%) patients had historical VWD. Using this cut-off value had no major effect on bleeding phenotype or patient characteristics (data not shown). In conclusion, patients with higher VWF levels at the time of study were older and less often had a variant in the VWF gene. More historical VWD patients were index cases, underlining their negative family history. In contrast, blood group O was more common in patients with normalized VWF levels, suggesting that factors outside the VWF gene have a more important effect on VWF levels in this group. Importantly, the bleeding score was similar in all groups. The bleeding score is a reflection of bleeding symptoms that have occurred throughout one's life and may therefore not detect changes in bleeding phenotype over time. Importantly, the bleeding incidence requiring treatment in the year prior to inclusion was also similar in all groups, regardless of VWF levels. Our study suggests that normalization of VWF levels is not associated with the bleeding phenotype in type 1 VWD patients. However, this study is limited by its retrospective design and prospective studies are required to assess the bleeding phenotype and bleeding rate in more detail and to identify patients at increased or decreased risk of bleeding. 1Sanders YV, Giezenaar MA, Laros-van Gorkom BA, et al. von Willebrand disease and aging: an evolving phenotype. J Thromb Haemost. 2014;12(7):1066-1075. Disclosures Boender: CSL Behring: Research Funding. Eikenboom:CSL Behring: Research Funding. Fijnvandraat:CSL Behring: Research Funding; Bayer: Research Funding. Meijer:Bayer: Honoraria, Research Funding; Baxter: Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Mauser-Bunschoten:Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Novo Nordisk: Research Funding; Griffols: Research Funding; Sanquin: Research Funding. Cnossen:Novo Nordisk: Research Funding; CSL Behring: Other: Travel Funding, Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Baxalta: Research Funding; Bayer: Research Funding. Laros-van Gorkom:CSL Behring: Research Funding. van der Bom:CSL Behring: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta: Research Funding. Leebeek:UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; Baxter: Research Funding; CSL Behring: Research Funding.

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A Two Centre Experience Of Use Of a Dual Virally Inactivated FVIII/VWF Product (Wilate®) In Patients With Von Willebrand Disease

Blood ◽

10.1182/blood.v122.21.1112.1112 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1112-1112 ◽

Cited By ~ 1

Author(s):

Paul A Batty ◽

Kate Khair ◽

Renu Riat ◽

Yun-Han Chen ◽

Louise Bowles ◽

...

Keyword(s):

Adverse Events ◽

Research Funding ◽

Pathogen Transmission ◽

Von Willebrand Disease ◽

Primary Study ◽

Type 3 ◽

Von Willebrand ◽

Conference Registration

Abstract Introduction von Willebrand disease (VWD) causes mild to severe bleeding, typically following trauma or surgical intervention. These episodes require treatment with a von Willebrand factor (VWF) containing concentrate; at present the only available concentrates are plasma derived. UK guidelines recommend using concentrates manufactured to the highest standards to reduce the risk of pathogen transmission. Methods Wilate® (Octapharma AG, Switzerland) is a dual virally inactivated FVIII/VWF concentrate available in the UK since 2007. Use of Wilate® between 2007 and 2012, including a period of product switching was evaluated in two large haemophilia centres (adult and paediatric). The primary study end-point was efficacy of concentrate usage for the treatment of bleeding and surgery. Efficacy was graded using 4 point ordinal scales that rated efficacy as; excellent, good, moderate or nil. Secondary end points were the occurrence of adverse events (immune, infective or thrombotic) and evidence of response on laboratory parameters. Results Between 01/03/07 and 01/05/12 a total of 4,565,450IU of Wilate® were used with data evaluable for 4,125,800IU (90.4%). Eighty two patients (44 male, 38 female) including 33 children (< 18yrs) and 49 adults (≥18yrs) with type 1 (n=29), type 2 (n=34), type 3 diseases (n=16) and acquired von Willebrand syndrome (AVWS) (n=3) were treated. The median age at first treatment was 22.7 yrs (range 0.01- 82.3). The mean recoveries ± SD, following first dose in adults (n=35) were FVIII:C 2.25 ± 0.65; VWF:Ag 2.4 ± 0.70 and VWF:RCo 1.91 ± 0.53. Fifty three patients (20 < 18yr, 33 ≥ 18yr) received concentrate for 93 surgical interventions (36 major, 36 minor, 21 dental procedures). This included 22 patients with type 1, 22 type 2, 7 type 3 disease and 2 with AVWS. The median loading dose prior to surgery was 2700IU (range 450-7200) corresponding to 43.1IU/kg (range 11.84-125). Surgical procedures were covered with a median of 1 treatment (range 1-13) over a median of 1 day (range 1 – 12). Thirty surgical episodes required ≥2 doses (27 major, 3 minor) with a median second dose of 1800IU (range 450-4500) corresponding to 36.4IU/kg (range 17.9-78.6). Overall efficacy was rated as excellent in 89.2% (n=83), good in 5.4% (n=5), moderate in 4.3% (n=4) and nil in 1.1% (n=1). Thirty five patients (13 < 18yr, 22 ≥ 18yr) were treated for 80 non-surgical episodes of bleeding or trauma (37 major, 43 minor). This included 10 patients with type 1, 14 type 2, 10 type 3 disease and 1 with AVWS. The median first dose given was 2475 IU (range 250-7200) corresponding to 45.7 IU/kg (range 11.8- 97.8). Bleeding episodes were treated with a median of 2 treatments (range 1-80) over a median of 2 treatment days (range 1-78). Forty-three episodes required ≥2 doses (36 major, 7 minor) with a median follow-up dose of 2700IU (range 250-8100) corresponding to 39.3IU/kg (range 11.8-95.7). Overall efficacy was rated as being excellent in 87.5% (n=70), good in 10.0% (n=8), moderate in 2.5% (n=2) and nil in 0.0% (n=0). Nine patients (1 < 18yr, 8 ≥ 18yr) were on home treatment regimens using 2,644,200 IU of Wilate® (64.1% total usage). These patients were treated using either on-demand (n=3), regular prophylaxis (n=5) or targeted prophylaxis (n=1). Two patients on prophylaxis switched to Wilate® within the study period with similar efficacy to the previous six months of treatment. Twelve patients were treated for other indications not covered by these categories. Wilate® was used to cover 3 un-complicated deliveries (1 operative and 2 vaginal deliveries). There were 8 reported adverse events (8 patients), with 4 requiring medical review although not requiring in-patient treatment. One patient had treatment failure (impaired VWF:Ag recovery) on one treatment episode, and has been successfully re-treated. Five patients were re-challenged with only one having a repeat mild reaction. Five patients switched to an alternative product at the discretion of the patient/physician. No accumulation of FVIII was seen in patients treated for ≥3 days (mean change in FVIII:C trough level (first to last) +31.89iu/dl (-124.4 - +116.6)). No thrombosis, TTI or inhibitory antibodies were reported. Conclusion Wilate® was efficacious (excellent or good efficacy in > 94%), safe and well tolerated in this heterogeneous group of 82 patients with VWD. Bleed resolution or prevention was 100% with no accumulation of FVIII seen. Disclosures: Batty: Octapharma: Research Funding, Travel and conference registration fees Other. Khair:Octapharma: Honoraria, Research Funding, Travel to conferences and regsitration fees Other. Hart:Octapharma: Consultancy, Honoraria, Research Funding, Travel and conference registration fees Other. Liesner:Octapharma: Consultancy, Honoraria, Research Funding, Travel and conference registration fees Other. Pasi:Octapharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, travel and conference fees Other.

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