Spectrum of Type 2 Von Willebrand Disease in the Zimmerman Program

Abstract While von Willebrand disease (VWD) is the most common inherited bleeding disorder, most patients have quantitative defects in von Willebrand factor (VWF). The qualitative variants, collectively termed type 2 VWD, are less common, but also in general more severe than type 1 VWD. However, despite a common laboratory phenotype of decreased VWF:RCo/VWF:Ag ratio for types 2A, 2B, and 2M VWD, the clinical phenotype is highly variable. We examined index cases and affected family members enrolled in the Zimmerman Program with a phenotypic diagnosis of type 2 VWD. All subjects had factor VIII (FVIII), VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and multimer distribution analyzed in a central laboratory. For calculation of mean VWF:RCo values, a level of 5 was assigned to subjects with VWF:RCo below the laboratory lower limit of detection of 10 IU/dL. A platelet binding assay was also performed using a gain of function GPIb containing 2 mutations that enable spontaneous binding to VWF in the absence of ristocetin (VWF:GPIbM). Full length VWF gene sequencing was performed for all index cases. Targeted sequencing was performed for family members to ascertain the presence or absence of sequence variations found in the index case. Bleeding symptoms were quantified using the ISTH bleeding assessment tool and reported as bleeding scores (BS). Mean FVIII, VWF:Ag, VWF:RCo, and BS are listed in the table below for each type 2 variant. For type 2A VWD, 113 subjects have been enrolled to date. All had an abnormal multimer distribution with loss of high molecular weight multimers. 6 type 2A subjects had a VWF:RCo/VWF:Ag ratio of ≤0.7. The lowest VWF:RCo levels were seen in the type 2A cohort with 60% <10. 98% of type 2A subjects had an identified sequence variation on full length sequencing. 25% had the p.R1597W sequence variation and an additional 4 subjects had p.R1597Q. The mean bleeding score for the subjects with sequence variations at 1597 was 10.6. 11% of subjects had p.R1374H, which correlated with a higher mean bleeding score of 12.4. Mean bleeding score for the remainder of the type 2A subjects was lower, at 6.6, suggesting that differences in VWF genetics may account for differences in phenotype, despite the common type 2A laboratory presentation of reduced VWF:RCo and loss of high molecular weight multimers. 44 type 2B subjects have been enrolled to date, all with abnormal multimer distribution and either documented abnormal VWF-platelet binding or a presence of a known type 2B sequence variation. Sequence variations were found in 100% of subjects. The most common sequence variations were p.V1316M (20%), p.R1306W (18%), p.R1341Q (11%), and p.H1268Y (9%). Mean VWF:RCo/VWF:Ag ratios ranged from 0.32-1.12, suggesting that a normal VWF:RCo/VWF:Ag ratio cannot completely exclude the possibility of type 2B VWD. Most (94%) had increased VWF:GPIbM. Subjects with p.V1316M and p.R1306W/Q sequence variations had lower VWF:RCo compared to subjects with p.R1341Q/W but mean bleeding scores did not differ. 59 type 2M subjects have been enrolled to date. Mean VWF:RCo/VWF:Ag ratio was 0.46 (range 0.14-0.7). Sequence variations were found in 93% of subjects. R1374C was found in 13 members from one family. While mean VWF levels were similar to the entire 2M group, a wide range in VWF:Ag and VWF:RCo/VWF:Ag ratio was observed, accompanied by a corresponding range in BS from 0-8. This suggests that other modifiers of phenotype may be present aside from the VWF sequence variation. 11 type 2N subjects have been enrolled to date, all with low VWF binding to FVIII. Sequence variations were found in 100% of this cohort. R854Q was present in 89% of subjects. Bleeding scores were highest for homozygous 2N sequence variations. Overall, the mean BS for type 1 VWD subjects was 6.3, the mean BS for type 2 VWD subjects was 7.5, and the mean BS for type 3 VWD subjects was 16.8. Types 2A and 2N had higher bleeding scores on average than type 2B, and type 2M subjects had on average the lowest bleeding scores. Although heterogeneity was seen across all the type 2 variants, both laboratory testing and genetic testing are useful in categorizing and phenotyping type 2 VWD. Table. FVIII (mean) VWF:Ag (mean) VWF:RCo (mean) BS (mean) Type 2A 47 34 12 8.7 Type 2B 45 36 23 7.1 Type 2M 62 54 21 5.4 Type 2N 30 69 76 8.3 Disclosures Montgomery: Immucor: Patents & Royalties.

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The Power of a Standardized Bleeding Score in Diagnosing Pediatric Type 1 Von Willebrand Disease.

Blood ◽

10.1182/blood.v114.22.1293.1293 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1293-1293

Author(s):

Paul D Marcus ◽

Kidan G Nire ◽

Linda Grooms ◽

Jennifer Klima ◽

Sarah O'Brien

Keyword(s):

Platelet Function ◽

Predictive Value ◽

Care Setting ◽

Tertiary Care ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

The Mean ◽

Bleeding Score ◽

Von Willebrand

Abstract Abstract 1293 Poster Board I-315 INTRODUCTION Type I von Willebrand disease (VWD) is the most common inherited bleeding disorder. Repetitive testing of von Willebrand factor (VWF) levels is necessary before the diagnosis can be safely ruled out, as VWF levels fluctuate in response to genetic and environmental factors. A predictive bleeding score (BS) could reveal individuals that may benefit from repetitive testing and those for whom repetitive testing is unlikely to be of benefit. While a standardized questionnaire (the Vicenza score) was developed to evaluate hemorrhagic symptoms, it was never prospectively validated for a pediatric population in a tertiary care setting. SUBJECTS The study targeted children, ages 0 to 17 years, referred to the Hemostasis and Thrombosis Center (HTC) of Nationwide Children's Hospital for a coagulation evaluation as a result of bleeding symptoms, family history of a bleeding disorder and/or abnormal coagulation labs found during pre-operative screening. Children were excluded if they had a previously diagnosed bleeding disorder, if their caregiver did not speak English or if the child did not undergo VWF:Ag and VWF:RCo testing. METHODS Prior to the diagnosis or exclusion of a bleeding disorder in the child, caregivers consented to answer the questionnaire over the telephone. Descriptions of the Vicenza score are available online (http://www.euvwd.group.shef.ac.uk/bleed_score.htm). LABORATORY TESTING A single VWF:Ag or VWF:RCo <30 IU/dL was classified as “Definite Type 1 VWD” while levels from 30-50 IU/dL were classified as “Low VWF” (http://www.nhlbi.nih.gov/guidelines/vwd). Platelet function analysis (PFA-100) screened for platelet function defects, with some patients undergoing follow-up platelet aggregation studies and/or platelet electron microscopy. Laboratory studies from other institutions were excluded from analysis. Patients' medical records were reviewed after hematologic evaluation, and the resultant data was analyzed with STATA 10.1 (Stata Corp., College Station, TX). RESULTS A total of 104 children (52 females and 52 males) with a mean age of 7.53 years (range 1 month to 17 years) were included. At least one hemorrhagic symptom was present in 99 of the 104 children (95%) with the mean number of symptoms being 2.87 (range 0 to 7). The mean Vicenza score was 3.24 (range -1 to 13). Of the 104 children, 8 met criteria for “Definite Type 1 VWD,” 23 met criteria for “Low VWF,” 14 were diagnosed with a “Platelet Function Defect,” and 2 children had bleeding secondary to Ehlers Danlos syndrome. Children with non-bleeding disorders (e.g. Factor XII deficiency) or no laboratory evidence of a bleeding disorder were classified as “No Bleeding Disorder.” In general, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive diagnostic likelihood ratio of the bleeding questionnaire demonstrated poor predictive value in our patient population with the exception of high specificity in ruling out “Definite Type 1 VWD” (Table). The NPV was comparably high with both qualitative (>2 bleeding symptoms) and quantitative (BS ≥2) criteria. CONCLUSIONS The Vicenza score, previously validated in adults and in a pediatric primary care setting, appears to have limited predictive value in a pediatric tertiary care setting when evaluating patients with platelet function defects or low VWF levels. While the Vicenza score has a high NPV to exclude “Definite Type 1 VWD,” the use of simpler qualitative criteria is similarly predictive. Disclosures No relevant conflicts of interest to declare.

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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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The Management of Bleeding Risk in Von Willebrand Disease: Should Blood Group O Make a Difference?

Blood ◽

10.1182/blood.v124.21.2829.2829 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2829-2829

Author(s):

Joan Cox Gill ◽

Veronica H Flood ◽

Pamela A Christopherson ◽

Daniel B Bellissimo ◽

Kenneth D Friedman ◽

...

Keyword(s):

Blood Group ◽

Von Willebrand Factor ◽

Sequence Variation ◽

Gene Sequence ◽

Von Willebrand Disease ◽

Sequence Change ◽

Bleeding Score ◽

Von Willebrand ◽

Willebrand Factor

Abstract Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by a quantitative deficiency of von Willebrand factor (VWF) and excessive mucocutaneous bleeding. It is well known that von Willebrand factor (VWF) levels are significantly lower in persons with ABO blood group O and that there is a significantly higher prevalence of blood group O in patients with a diagnosis of type 1 VWD. This raises a question important to the clinical care of patients with low VWF; is there a difference in bleeding risk in patients with a deficiency of VWF on the basis of blood group O versus those with a deficiency of VWF due to a sequence variation in the VWF gene. To explore this question, we examined index cases enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD with a quantitative deficiency of VWF including those with a phenotypic diagnosis of low VWF [von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo)≤ 50 U/dL and >40 U/dL], type 1 VWD (VWF:Ag or VWF:RCo≤40 U/dL) and type 1C VWD (VWF:Ag ≤30 U/dL and VWF propeptide/Ag ratio >3 indicating increased clearance of VWF). VWF:Ag, VWF:RCo, VWF propeptide and multimer distribution were analyzed in the clinical hemostasis laboratory at the BloodCenter of Wisconsin. Full length VWF gene sequencing including intron-exon boundaries was performed for all index cases. Bleeding symptoms were scored utilizing the ISTH, MCMDM1 and PBQ bleeding assessment tools. Since there was a high correlation among bleeding scores with these three methods, the ISTH score was utilized for this analysis. Complete data were available for 91 subjects with low VWF, 161 subjects with type 1 VWD, 53 subjects with type 1C VWD and 74 normal control subjects. Median ages were not different among the diagnostic groups. As expected based on previous reports, the groups of VWD patients with lower VWF:Ag values (Mean±1SD) had an increased percentage of subjects with an identified sequence variation; low VWF group, VWF:Ag 50.4±8.4, 38% with sequence variation; Type 1 VWD, VWF:Ag 30.8±11.6, 70% with sequence variation; and Type 1C VWD, VWF:Ag 9.8±5.9, 83% with sequence variation. The low VWF group and the type 1 VWD groups both had a significantly increased frequency of subjects with blood group O (70 – 80%) vs. nonO (19-30%) in comparison to those with type 1C in whom the frequency of blood group O (57% ) vs. nonO (43%) was not different than that in the normal control population (43% O vs. 57% nonO). This suggests that the type 1 and low VWF groups have a significant proportion of subjects with low VWF on the basis of blood group O alone. Since those subjects with a diagnosis of low VWF or Type 1 VWD who have no identifiable sequence variation are more likely to be affected by blood group O alone, we examined the ISTH bleeding scores in subjects with similar VWF levels and blood group O with and without an identifiable VWF gene sequence variation. We found that there was no difference in the ISTH bleeding scores in blood group O subjects regardless of the presence of a VWF gene sequence variation; low VWF, no sequence change (N=45), median bleeding score 6.0 vs. 5.0 with sequence change (N=27); type 1 VWD, no sequence change (N=39), median bleeding score 5.0 vs. 5.0 with sequence change (N=73); type 1C VWD, no sequence change (N=6), median bleeding score 7.0 vs. 7.0 with sequence change (N=24). There were no differences in median bleeding scores in blood group O vs. nonO groups, and none in the nonO groups with or without sequence variation in any of the VWD phenotypic diagnostic categories. There were no significant differences in bleeding scores by gender in any of the diagnostic categories. In conclusion, we found no differences in ISTH bleeding scores in the groups of subjects most likely to have low VWF on the basis of blood group O alone, i.e., those with blood group O and no identifiable VWF gene sequence variation compared to those with VWF gene sequence variations. Thus, management of persons with VWF deficiency should be based on baseline VWF levels and not modified in those with blood group O. Disclosures No relevant conflicts of interest to declare.

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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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The Association of Aging With Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029617724232 ◽

2017 ◽

Vol 24 (3) ◽

pp. 434-438 ◽

Cited By ~ 2

Author(s):

Craig D. Seaman ◽

Margaret V. Ragni

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Antigen Level ◽

Age Related ◽

The Mean ◽

Bleeding Score ◽

Von Willebrand ◽

Willebrand Factor

Little is known about aging in von Willebrand disease (VWD). It is uncertain whether VWD patients experience an age-related increase in von Willebrand factor (VWF) levels, and if so, it is unknown whether normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the association of age with VWF levels and bleeding risk in patients with type 1 VWD. This is a retrospective chart review of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinic visits. Data collected included VWF antigen level and condensed molecular and clinical markers for the diagnosis and management of Type 1 (MCMDM-1) VWD bleeding assessment tool (BAT) bleeding score based on bleeding symptoms during the previous 3 years. Thirty-nine patients participated in the study, and 32 were female. The average age of participants was 41.8 ± 18.0 years. The mean VWF antigen level was 0.83 ± 0.37 IU/mL, and the mean bleeding score was 2.51 ± 2.90. The bleeding score was inversely associated with age, β = −0.080 (SE = 0.023), P < .01. There was a nonsignificant association between VWF antigen levels and age. To our knowledge, this is the first report showing an association between aging and decreased bleeding symptoms in patients with type 1 VWD. Determining whether or not bleeding risk is reduced in older patients with type 1 VWD is essential for optimal clinical management. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of health-care dollars. These findings warrant further investigation.

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Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease

Thrombosis and Haemostasis ◽

10.1160/th10-09-0616 ◽

2011 ◽

Vol 105 (04) ◽

pp. 597-604 ◽

Cited By ~ 21

Author(s):

Susan Halimeh ◽

Anne Krümpel ◽

Hannelore Rott ◽

Nadja Bogdanova ◽

Ulrich Budde ◽

...

Keyword(s):

Replacement Therapy ◽

Von Willebrand Disease ◽

Recurrent Bleeding ◽

On Demand ◽

Bleeding Episodes ◽

Bleeding Score ◽

Type 3 ◽

Von Willebrand

SummaryIn patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P→ or Wilate→ (n=24). Median [min-max] dose [vWF:RCo] was 40 [20–47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the preprophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy.

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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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