Pregnancy In Type 1 Von Willebrand Disease: A Prospective Study of VWF Levels and Risk Factors for Bleeding

Abstract Abstract 1410 Women with Type 1 von Willebrand disease (VWD) experience menorrhagia and postpartum hemorrhage (PPH) more than twice as often as women without VWD. VWF levels in women without VWD increase during pregnancy in an exponential manner, and fall postpartum. In type 1 VWD, limited data exist. The goal of this study is to model changes in VWF levels during and after pregnancy in women with Type 1 VWD, and correlate findings with blood loss. Women with Type 1 VWD, defined as at least 1 value of VWF:Antigen (Ag) or VWF:Ristocetin Cofactor (RCo) < 50%, VWF Ag/RCo > 0.7, and compatible history of mucosal bleeding pre-pregnancy, were recruited prior to 36 weeks gestation. Twin gestation, additional bleeding disorder, and anti-coagulant or -platelet therapy were excluded. Baseline demographic and bleeding scores were recorded. FVIII, VWF:Ag, and VWF:RCo were obtained monthly after enrollment, at labor, and postpartum (PP; 12, 24, 48 hours and 1, 2, and 6 weeks) and assayed centrally. Change in VWF:Ag levels during gestation and postpartum were modeled using longitudinal regression analysis. Twelve women were recruited from 4 HTCs with median (range) age 31.3 years (19-43), BMI 24.3 kg/m2 (18.1-40.5). All were Caucasian and of non-Hispanic ethnicity. One patient dropped out at 21 weeks gestation. 67% were blood type O; 25% A; 8% B; and 5/12 (42%) were primigravidae. Four patients reported prior PPH. Mean (SD) baseline bleeding score was 8 (7). Mean weeks gestation at delivery was 39 (1), with 2 Cesarean sections (18%). Seven women (64%) used epidural anesthesia, and 1 woman each used spinal, general, local, or no anesthesia. Seven women (64%) suffered genital laceration. Estimated blood loss (EBL) was mean 643 cc (309). One woman experienced immediate PPH, likely due to uterine atony, requiring 2 U PRBC. Three women experienced bleeding at 24–48h PP, and 1 at 1–2 weeks PP. One woman received DDAVP; 3 treated with VWF concentrate peri- and postpartum. Mean length of stay was 2 days (1). None required readmission, ICU stay, or procedures to stop bleeding. Mean (SD) VWF:Ag, VWF:RCo, and FVIII levels (%), respectively, at baseline were (n=11, 41.1 (7.1), 34.4 (8.4), 76.4 (70.8)), labor (n=11, 136.4 (50.8), 128.9 (47.8), 134.2 (42.7)), and 6 weeks PP (n=10, 57.8 (22.8), 52.1 (25.4), 80.9 (32.2)). VWF:Ag and VWF:RCo levels correlated well throughout for each woman (r 0.91–1, p <0.01). The rate of change of VWF levels was heterogeneous and varied individually, with differences between VWF:Ag value at baseline vs. labor ranging from 43–164% and from labor vs. 6 weeks PP 21–128%. During the gestational period, an exponential growth model best fit the rise in VWF:Ag level at labor relative to pre-pregnancy, VWF:Ag=exp(0.029 × gestational age in weeks), SD 0.0077. VWF:Ag is predicted to double from 17 weeks upwards. Postpartum, an exponential decay model predicted VWF:Ag levels should return to baseline by mean 3.6 weeks (SD 1.9) PP. 59 data points were available for the gestational, and 61 for the PP analyses. Variables associated with increased EBL include higher BMI (r, p; 0.88, 0.01), C-section (0.79, 0.03), genital laceration (0.79, 0.01), and manual placenta delivery (0.79, 0.01). Variables correlating with increased hemoglobin loss from 36 weeks to 24 h PP include episiotomy (0.75, 0.03) and degree of tear (0.99, 0.01). Cord blood obtained on 9 infants revealed a mean (SD) VWF:Ag, VWF:RCo, and FVIII level (%) 97.9 (35.8), 96.2 (34.8), 67.7 (22.6) at birth. None of 3 infants bled with procedures (1 circumcision, 2 blood draws). Infant VWD levels did not significantly correlate with respective maternal VWD levels at either baseline or labor. In conclusion, subjects with Type 1 VWD appear to have highly individual and heterogeneous rates of rise and decline of VWF levels during gestation and postpartum. Only one of 12 women in this study experienced PPH, attributed to atonic uterus. An exponential growth and decay model best fit the VWF:Ag peripartum levels. Variables correlating with blood loss include higher BMI, C-section, genital laceration, episiotomy, and degree tear. Although this study is small and the population homogenous, it demonstrates the importance of monitoring factor levels in women with Type 1 VWD, as the rise and fall in VWF levels are variable. Mutation analysis may help further explain the heterogeneity of individual responses. Additional studies are needed to better define risk factors associated with PPH in this population. Disclosures: James: CSL Behring: Consultancy, Research Funding. Shapiro:Baxter BioScience: Consultancy. Konkle:CSL Behring: Consultancy, Research Funding.

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The Von Willebrand Disease Aging and Bleeding Correlation (VWD ABC) Study

Blood ◽

10.1182/blood-2021-152755 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1044-1044

Author(s):

Craig D. Seaman ◽

Margaret V. Ragni ◽

Peter A. Kouides ◽

Eric H. Kraut ◽

Rajiv K. Pruthi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Bleeding Risk ◽

Cross Sectional Study ◽

Von Willebrand Disease ◽

Blood Type ◽

Advisory Committees ◽

Cross Sectional ◽

Von Willebrand

Abstract Introduction It is well established that von Willebrand factor (VWF) levels increase with age among healthy adults. Recently, there is emerging research demonstrating this may also occur in patients with von Willebrand disease (VWD), particularly type 1 VWD, and may be related to comorbidities. Despite increasing VWF levels, it remains unclear as to whether or not this alters bleeding phenotype. It is also unclear why this occurs most commonly in patients with type 1 VWD, but VWF mutation status may play a role. Older patients commonly undergo invasive procedures, and all VWD patients require periprocedural VWD-specific therapy to ensure appropriate hemostasis. If older type 1 VWD patients have experienced normalization of VWF levels, and no longer have an increased risk of bleeding, VWD-specific therapy may increase thrombosis risk, especially among patients with underlying cardiovascular disease or related risk factors, subject the patient to other adverse reactions such as hyponatremia, and is unnecessarily costly. For these reasons, investigation into the effect of age on VWF levels and bleeding risk in type 1 VWD patients is sorely needed. Methods This is an NHLBI-funded K23 multicenter, cross-sectional study to determine the effect of age on VWF levels and bleeding risk in patients with type 1 VWD, and to determine if pathogenic VWF mutations alter this effect.Individuals with a new or historical diagnosis of type 1 VWD (defined as clinical symptoms consistent with VWD and VWF antigen level or ristocetin cofactor activity <0.50 IU/mL) and age 18 or older are enrolled during routine clinic visits at participating Hemophilia Treatment Centers (HTCs). Following enrollment, pertinent medical history is obtained; the condensed MCMDM-1 VWD Bleeding Assessment Tool is administered, with bleeding history based on bleeding symptoms during the past 5 years; and blood samples are collected for the following: VWF antigen (VWF:Ag) level, VWF ristocetin cofactor activity, factor VIII activity, blood type, and VWF gene sequencing. We hypothesize age is associated with increased VWF:Ag levels and lower condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD, and this association is weaker among those with a pathogenic VWF mutation. In addition, we hypothesize multimorbidity partially explains the association between age and VWF:Ag levels, and VWF:Ag levels partially explain the association between age and condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD. A sample size of 250 participants provides 90% power to detect an effect size of Beta=±0.032 points per year of age, which is much smaller than the observed effect size, Beta=-0.080, from preliminary data. The primary analyses will be based on multivariable linear regression models with adjustment for blood type O, exogenous estrogen therapy, multimorbidity (defined as 2 or more of the core set of 20 chronic conditions, i.e., cancer, hypertension, stroke, etc., as selected by the United States Department of Health and Human Services), and medications (aspirin, nonsteroidal antiinflammatory drugs, and anticoagulants). In the regression models, two-sided t-tests will be used with an alpha=0.05. Results This multicenter, cross-sectional study consists of seven HTCs: Hemophilia Center of Western Pennsylvania, Children's Hospital of Pennsylvania, Mary M. Gooley Hemophilia Center, Ohio State University, Bleeding & Clotting Disorders Institute, Mayo Clinic, and University of California, San Diego. During the first year of the study, site initiation visits were conducted, regulatory approval obtained, and contracts executed. Delays in these activities occurred in large part due to the COVID-19 pandemic. As the first year of the study concludes, all sites are now active and enrolling participants. Thus far, 43 participants have been enrolled (Table 1). No barriers to enrollment have been encountered and very few patients have declined study participation. Discussion In conclusion, this ongoing multicenter, cross-section study seeks to determine the effect age has on VWF levels and bleeding risk in patients with type 1 VWD while exploring the role of VWF mutations and multimorbidity in this process. The results will be used to justify a longitudinal study, which is the ideal approach to research the effects of aging in this population. Figure 1 Figure 1. Disclosures Seaman: Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; HEMA Biologics: Consultancy, Honoraria. Ragni: Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Kraut: Uniqure: Consultancy. Pruthi: CSL Behring: Honoraria; Bayer Healthcare AG: Honoraria; Instrumentation Laboratory: Honoraria; Genentech: Honoraria; HEMA Biologics: Honoraria; Merck: Honoraria. Raffini: CSL Behring: Consultancy; HEMA Biologics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; XaTek: Consultancy. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. von Drygalski: Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa.

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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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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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Diagnostic Fidelity of Historically Diagnosed Patients with VWD Enrolled from 27 Centers in the ZPMCB-VWD

Blood ◽

10.1182/blood.v118.21.381.381 ◽

2011 ◽

Vol 118 (21) ◽

pp. 381-381 ◽

Cited By ~ 1

Author(s):

Robert R. Montgomery ◽

Pamela A. Christopherson ◽

Sandra L Haberichter ◽

Veronica H Flood ◽

Joan Cox Gill ◽

...

Keyword(s):

Sequence Variation ◽

Von Willebrand Disease ◽

Blood Type ◽

Similar Process ◽

Central Laboratory ◽

Type 3 ◽

Von Willebrand ◽

Normal Controls

Abstract Abstract 381FN2 The TS Zimmerman Program for the Molecular and Clinical Biology of von Willebrand Disease (ZPMCB-VWD) is a large NIH PPG to study existing subjects with von Willebrand Disease in the United States and to contrast these with prior and ongoing studies in Canada and the UK. 569 index cases (ICs) and 1732 family members were recruited from 8 Primary Clinical Centers and 19 Secondary Clinical Center. The inclusion criteria were that the subjects had a historical diagnosis of VWD and were registered as ongoing patients in the local HTC. 247 normal controls (NCs) were studied for comparison. Data included pre-existing diagnosis, historical diagnostic VWD testing, detailed bleeding history using a modified MCMDM-1VWD QBS, and subjects had plasma and DNA drawn for studies at a central laboratory for VWD, VWF phenotyping, and full length VWF exon sequencing. ICs included 391 type 1, 105 type 2, 43 type 3, and 30 unclassified. The recent HLBI Guidelines suggested that the diagnosis of VWD be based on a VWF level of <30 IU/dL (either VWF:Ag or VWF:RCo). Using the historical data, only 39.4% of ICs had either VWF:Ag or VWF:RCo of <30. Since historic data were studied using various lower limits of normal, we found 80% of subjects had either an Ag or RCO of <60. Central Laboratory testing of NCs and ICs was performed. While 7 of 247 NCs had reduced VWF:Ag or VWF:RCo, none of the NCs had <30 by either assay. Of the NCs with low VWF, 6 of 7 were blood type O and none had an abnormal bleeding score. While 372 of 569 ICs (65.4%) had reduced VWF assays by either method, only 201 (35.3%) had VWF assays that were below the NHLBI Guidelines of <30. Among ICs the correlation between current and historic VWF levels was an r2=0.199 for VWF:RCo and r2=0.268 for VWF:Ag. The current VWF:RCo correlated with the current VWF:Ag with an r2=0.827. The VWF:Ag and VWF:RCo were also restudied in a second laboratory with an r2=0.849 for VWF:Ag and r2=0.854 for VWF:RCo. The MCMDM-1VWD QBS was normal in all normal controls. In contrast, 350 of the ICs born prior to 1996, 247 (70.5%) had an abnormal QBS. Evaluated by pre-existing diagnosis, 65% of type 1 VWD, 78.6% of type 2 VWD and 100% of type 3 VWD had abnormal QBS. Interestingly, of the 351 VWD subjects born before 1996, the QBS was abnormal in 83.5% of males and 67.7% of females. In this age group, there were 248 females and 103 males followed with the diagnosis of VWD. VWF sequencing was carried out on all ICs and compared to the VWF Database maintained at the University of Sheffield. Sequence variations were present in 100% of the 391 type 1 VWD subjects with VWF levels of <10, 96% with VWF 11–20, 77% with VWF 21–30, 70% with VWF 31–40, 39% with VWF 41–50, and 42% of those with VWF 51–60. The decrease in VWF sequence variation between those <40 and those >40 seemed to be striking. The mean VWF:Ag levels of type 1 ICs with a VWF sequence variation was significantly lower (p<0.0001) than those with normal VWF sequence. More than 20 years ago, we demonstrated that besides blood type, age had the most significant effect on level of VWF in normal blood donors. We evaluated the VWF:Ag levels in our 247 NCs and VWF:Ag levels rose about 5% for each 10 years of age from age 20 to 60. In VWD it is not known if a similar process results in reduced bleeding symptoms with age or if this increase is related to the aging process or progressive vascular pathology. Stress is a significant confounding variable in the hemostatic evaluation of children – particularly for the diagnosis of VWD, but the effect of aging has not been defined. We therefore have demonstrated that the diagnosis of VWD was not consistently substantiated in a large group of patients diagnosed with VWD – particularly if using the VWF levels recommended by the NHLBI Guidelines. Historic VWF levels do not correlate with current levels of VWF. Moreover, 35% of these VWD subjects do not have evidence even of reduced VWF levels upon retesting. A number of questions remain. Are the NHLBI recommendations too strict? Is there an effect of aging on the normal level of VWF that affects the correct diagnosis of VWD? Will more rigid initial diagnostic testing improve the fidelity of the diagnosis of VWD? Is the diagnosis of VWD applied to a group of individuals with clinical bleeding with only some of these being associated with low VWF? Further longitudinal study of these VWD subjects is important. In those with significant clinical bleeding, other hemostatic abnormalities must be sought. The fidelity of the diagnosis of VWD needs improvement. Disclosures: Montgomery: GTI Diagnostics: Consultancy; CSL Behring: Consultancy; Biogen IDEC: Honoraria; Bayer: Consultancy; Baxter: Consultancy.

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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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