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

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

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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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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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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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Bleeding in Patients with Clinically Severe Von Willebrand Disease: Preliminary Results of Athn 9, a Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Severe Von Willebrand Disease (VWD)

Blood ◽

10.1182/blood-2020-137124 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Angela C. Weyand ◽

Kenneth D Friedman ◽

Sweta Gupta ◽

Kristina M. Haley ◽

Chunla He ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Von Willebrand Disease ◽

Heavy Menstrual Bleeding ◽

Severe Bleeding ◽

Advisory Committees ◽

Type 3 ◽

Von Willebrand

Background: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, thought to occur in ~0.1% of the population. VWD results from a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multifunctional plasma protein involved in primary and secondary hemostasis. Diagnosis of VWD can be difficult due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Treatment of VWD is aimed at replacement of the defective or missing protein through plasma derived or recombinant VWF, release of endogenous VWF through desmopressin (DDAVP) or clot stabilization with anti-fibrinolytic therapy. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding individuals with VWD and a clinically severe bleeding phenotype. Aims: To characterize the bleeding phenotype and treatment regimens in patients with clinically severe VWD in the United States. Study Design and Methods: ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at ATHN-affiliated sites across the US. Participants were identified by the site investigators with the projected goal to enroll 130 individuals. Inclusion criteria were patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GPIbM or VWF:Ag≤ 30% or patients with "clinically severe VWD" defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% a with severe bleeding phenotype (need for recurrent use of factor concentrates) and prior enrollment in the ATHN dataset national surveillance data collection project. Patients with platelet-type or acquired VWD were excluded. Laboratory assessment including a standardized diagnostic battery, VWF genetic analysis, and inhibitor testing, was performed by a central laboratory. Bleeding was assessed using the International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (normal adult 0-4, normal score <18 years 0-2) and the Pictorial Bleeding Assessment Chart (PBAC) if applicable. Results: Initial data on 35 participants was analyzed. Most were adult (69%), female (66%), Caucasian (86%) and non-Hispanic (89%). Just less than half (16/35, 45.7%) have completed diagnostic testing (Table 1). Half of the patients had Type 1, a quarter Type 3, and the remaining had Type 2 or unknown. The majority of patients (69%) had VWF GPIbM activity <30IU/dL, while 44% had an abnormally low FVIII level as well. The majority (26/35, 74.3%) had a known family history of VWD. Slightly over half (19/35, 54.2%) had previous surgery. Few participants (4/35, 11.4%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was significant but variable with a mean ISTH BAT score of 10.6 (range 0-39). With the exception of the youngest cohort (0-5 years of age, mean BAT score of 6, range 3-8), bleeding scores increased with age and all participants had abnormal scores. The most commonly endorsed symptoms were epistaxis, heavy menstrual bleeding (HMB), and post-surgical bleeding. The PBAC was performed on 4/10 participants in reference to their last period with a median score of 36 and range of 0-112 (>150 is abnormal). The majority (3/4) of participants filling out the PBAC received VWF concentrate prophylaxis for HMB. The majority (23 participants, 66%) utilized factor concentrates for prophylaxis or on-demand treatment; six patients (17%) were on continuous prophylaxis, while 12 (34%) were on event-based or HMB prophylaxis while the remainder received episodic treatment. Participants most commonly used plasma derived VWF concentrate (93.9%) with the remainder using recombinant VWF. Discussion: Initial evaluation of 35 participants with clinically severe VWD demonstrated a predominance of mucosal bleeding with a minority of participants endorsing joint bleeds at enrollment. Despite abnormal ISTH BAT scores in all participants, PBAC scores were within normal range, likely reflecting appropriate management of HMB with most participants receiving VWF concentrate for HMB prophylaxis. In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on laboratory evaluation, bleeding phenotype, response to factor replacement therapy and quality of life. Disclosures Weyand: Shire: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Aptevo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Friedman:Alexion: Speakers Bureau; Bayer: Consultancy; Instrumentation Laboratories: Consultancy; Alexion: Consultancy. Haley:ATHN: Research Funding. Roberts:Sanofi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy, Research Funding, Speakers Bureau; uniQure: Consultancy; Octapharma: Consultancy, Speakers Bureau. Sidonio:Genentech: Membership on an entity's Board of Directors or advisory committees; Sanofi/Bioverativ: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Catalyst Sciences: Membership on an entity's Board of Directors or advisory committees; Emergent Solutions: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Octapharma: Research Funding; Grifols: Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: VWF concentrates used for heavy menstrual bleeding

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Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1722864 ◽

2021 ◽

Vol 47 (02) ◽

pp. 192-200

Author(s):

James S. O'Donnell

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Personalized Treatment ◽

Treatment Plans ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

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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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Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients

Thrombosis and Haemostasis ◽

10.1160/th12-02-0089 ◽

2012 ◽

Vol 108 (10) ◽

pp. 662-671 ◽

Cited By ~ 29

Author(s):

Hamideh Yadegari ◽

Julia Driesen ◽

Anna Pavlova ◽

Arijit Biswas ◽

Hans-Jörg Hertfelder ◽

...

Keyword(s):

Von Willebrand Factor ◽

Splice Site ◽

Von Willebrand Disease ◽

Missense Mutations ◽

Large Deletions ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon Willebrand disease (VWD) is the most common inherited bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (VWF). VWD is classified into three types – type 1 (partial quantitative deficiencies), type 2 (qualitative defects) and type 3 (complete deficiency of VWF). In this study we explored genotype and phenotype characteristics of patients with VWD with the aim of dissecting the distribution of mutations in different types of VWD. One hundred fourteen patients belonging to 78 families diagnosed to have VWD were studied. Mutation analysis was performed by direct sequencing of the VWF. Large deletions were investigated by multiplex ligation-dependent probe amplification (MLPA) analysis. The impact of novel candidate missense mutations and potential splice site mutations was predicted by in silico assessments. We identified mutations in 66 index patients (IPs) (84.6%). Mutation detection rate was 68%, 94% and 94% for VWD type 1, 2 and 3, respectively. In total, 68 different putative mutations were detected comprising 37 missense mutations (54.4%), 10 small deletions (14.7%), two small insertions (2.9%), seven nonsense mutations (10.3%), five splice-site mutations (7.4%), six large deletions (8.8%) and one silent mutation (1.5%). Twenty-six of these mutations were novel. Furthermore, in type 1 and type 2 VWD, the majority of identified mutations (74% vs. 88.1%) were missense substitutions while mutations in type 3 VWD mostly caused null alleles (82%). Genotyping in VWD is a helpful tool to further elucidate the pathogenesis of VWD and to establish the relationship between genotype and phenotype.

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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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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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