Family History Of Von Willebrand Disease Research Articles

Real-World Use of Recombinant Von Willebrand Factor in People with Clinically Severe Congenital Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe VWD

Background: People with von Willebrand disease (VWD) present with a spectrum of bleeding patterns and clinical symptoms, independent of subtype (Rugeri. Haematologica. 2007; Kalot. Haemophilia. 2021). In certain situations, prophylaxis may be appropriate, particularly when there is recurrent and severe bleeding (Connell, Blood Advances, 2021). There are limited real-world data on the use of recombinant von Willebrand factor (rVWF) in the United States. Aim: To characterize the safety and real-world effectiveness of routine prophylaxis with rVWF in people with clinically severe congenital VWD. Study Design and Methods:This is an interim analysis of a phase 4, longitudinal, prospective, observational cohort study (NCT03853486). Participants with severe VWD types 1, 2, and 3 (≤30% of normal) or “clinically severe VWD” (≤40% of normal with severe bleeding and requiring prophylaxis with factor concentrates) were identified from the ATHNdataset. The American Thrombosis & Hemostasis Network (ATHN) is the steward of the ATHNdataset, a Health Insurance Portability and Accountability Act-compliant, de-identified patient health dataset containing data from individuals with bleeding disorders receiving care through ATHN affiliates who opt in to contribute. Treatment regimens were at the discretion of each participant's respective bleeding disorder provider. Participants are followed for 2 years from the time of enrollment. Safety was measured using definitions from the European Haemophilia Safety Surveillance program. Bleeding events (BEs) were measured by individual bleeding components and calculated per the International Society on Thrombosis and Haemostasis Bleed Assessment Tool and/or the Pictorial Bleeding Assessment Chart. Health-related quality of life measures, including an ATHN9 rVWF substudy form, were used to describe real-world effectiveness of rVWF treatment. Descriptive statistics were used to analyze study outcomes. This study was not designed to detect differences in safety or efficacy between individual treatment products. Interim Results:As of June 16, 2023, 23 participants enrolled in the ATHN9 study were receiving rVWF; 14 participants have been prescribed rVWF for at least 1 full year, 13 of whom received continuous prophylaxis. This abstract reports on those 13 participants in the first year of the study. Mean (SD) age was 42.9 (29.2) years; 69.2% (n=9) of participants were female. Most participants had no comorbidities. As expected, most participants had a family history of VWD (84.6%; n=11) and no documented VWF inhibitors (84.6%; n=11); inhibitor status for the remaining 2 participants was unknown. Baseline VWF and factor VIII measurements were reported for most participants ( Table 1). The majority had type 2 VWD (84.6%; n=11), 92.3% (n=12) had identifiable genetic sequence defects in VWF, and 30.8% (n=4) had an abnormal VWF multimer profile. As dictated by the local investigator, rVWF prophylactic regimens ranged from 36.6 IU/kg once weekly to 57.6 IU/kg every 3 days; 7 (53.8%) participants received 40-60 IU/kg at a frequency of 2-3 times per week. Twenty-one BEs occurred in 5 (38.5%) of the participants receiving rVWF prophylaxis during the first year ( Table 2). Most BEs were spontaneous (61.9%; 13/21), occurring in the nose (n=7), gastrointestinal tract (n=5), or ankle (n=1). The remaining BEs were associated with activity with no known trauma (n=4), trauma (n=2), or unknown cause (n=2). One participant reported 3 rVWF treatment-unrelated adverse events (AEs) of humerus shaft closed fracture, metabolic encephalopathy, and acute exacerbation of chronic obstructive airways disease. When surveyed about their experience with rVWF, participants reported very or extremely satisfied as follows: 76.9% (n=10) with infusion time, 84.6% (n=11) with breakthrough bleed control time, 46.2% (n=6) with number of infusions required for breakthrough bleed control, and 69.2% (n=9) with frequency of achieving bleed control without concomitant hemostatic medication. Discussion:In participants with clinically severe congenital VWD, continuous prophylaxis with rVWF was associated with minimal AEs. Most participants receiving rVWF prophylaxis experienced no BEs during the first year of the study. Most participants expressed overall satisfaction with the use of rVWF.

Immunogenicity of a Plasma-Derived Von Willebrand Factor/Factor VIII Concentrate during the Wil-31 Prophylaxis Study in Patients with Von Willebrand Disease

Background: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in people with von Willebrand disease (VWD) with a history of frequent and severe bleeds. The WIL-31 study demonstrated the efficacy of prophylaxis with a plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate containing VWF and FVIII in a 1:1 activity ratio (wilate ®) in adults and children with VWD of all types. The primary endpoint was met, showing a decrease in mean total annualized bleeding rate (ABR) of 84% compared with prior on-demand treatment. Aim: To assess the immunogenicity of pdVWF/FVIII when used during the WIL-31 study in children and adults with VWD of all types. Methods: WIL-31 (NCT04052698) was a prospective, non-controlled, international, multicenter phase 3 trial that enrolled male/female patients aged ≥6 years with VWD type 1 (VWF: RCo <30 IU/dL), type 2 (except 2N) or type 3. Prior to entering the WIL-31 study, all patients had received on-demand treatment with a VWF-containing product during a 6-month, prospective, observational, run-in study (WIL-29); patients who experienced at least 6 bleeding episodes (BEs), excluding menstrual bleeds, of which ≥2 were treated with a VWF-containing product, were eligible to enter WIL-31. During WIL-31, patients received regular pdVWF/FVIII (containing VWF and FVIII in a 1:1 activity ratio) prophylaxis 2-3 times per week at a dose of 20-40 IU/kg for 12 months. FVIII (chromogenic and one-stage assays) and VWF (VWF:RCo assay) activities were assessed at baseline and throughout the study. Retention samples were collected at screening and baseline visits for possible later inhibitor testing (to be performed at a central laboratory using the Nijmegen-Bethesda assay for FVIII inhibitors and the mixing study based on VWF:RCo for VWF inhibitors). Inhibitor testing was also performed if inhibitor development was suspected. Results: Inhibitor testing was performed in 2 of 33 patients because of unusual pharmacokinetic results at the 6-month visits, even though neither patient had any clinical signs of an inhibitor. The VWF inhibitors were detected in samples from two brothers taken at their 6-month visits. However, when retained blood samples from the screening visits of both boys were tested, both samples tested inhibitor-positive, demonstrating that both boys had developed the inhibitors prior to starting prophylaxis during WIL-31. During and before the WIL-29 run-in study, both boys had been treated on demand with another pdVWF/FVIII concentrate. The boys had both been diagnosed with VWD shortly after birth, and it was suspected that they had type 2A based on family history and were 15 (patient A) and 11 years old (patient B) at the start of WIL-31. They had a family history of VWD (both parents were diagnosed with VWD), but no family history of inhibitors. After the completion of WIL-31, both patients were reclassified to type 3 VWD following further investigation including next-generation sequencing. Baseline VWF activity indicated low VWF:RCo levels (Patient A: 0.092 IU/mL and Patient B: 0.65 IU/mL; Figure 1). The boys received 38 (patient A) and 34 IU/kg (patient B) pdVWF/FVIII respectively, twice weekly during WIL-31, and their mean total ABRs decreased by 85% and 91%, respectively, during WIL-31 compared with WIL-29. All bleeding episodes during WIL-31 were spontaneous nose bleeds. Both boys continued the same prophylactic regimen until the end of WIL-31. In one patient the inhibitor titer was negative by the end of the study. Conclusion: VWF inhibitors were detected in 2 of the 33 patients on prophylaxis with pdVWF/FVIII in the WIL-31 study and subsequent investigation revealed that both patients were already positive for VWF inhibitors prior to the study start. In one of the patients, the inhibitor resolved during continued prophylaxis. Despite the inhibitors, prophylaxis was effective in both patients with an ≥85% reduction in ABR compared to on demand treatment.

Symptoms in Infants and Toddlers With von Willebrand Disease

Source: Dupervil B, Abe K, O’Brien SH, et al. Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD. Blood Adv. 2021;5(8):2079-2086; doi:10.1182/bloodadvances.2020004141Investigators from multiple institutions conducted a retrospective study to describe the diagnosis and bleeding history among infants and toddlers with von Willebrand disease (VWD). For the study, data from the CDC Universal Data Collection (UDC) surveillance system established in the US Hemophilia Treatment Center (HTC) Network were reviewed. Children <24 months old, diagnosed with VWD and treated at one of 135 HTCs from 2003 to 2011 were enrolled. For the UDC, data on demographics, VWD diagnosis, family history of bleeding disorders, and history and treatment of bleeding episodes were collected at enrollment and regularly scheduled visits in a systematic manner. VWD type (1, 2, or 3) was classified based on the diagnosis made by the treating physician at the HTC. Descriptive statistics were used to characterize demographics, age at diagnosis, reason for diagnosis (family history or unusual bleeding), and number and anatomic location of bleeding episodes. Chi-square, Fisher exact, or Wilcoxon rank sum tests were used to assess differences when groups were compared.Data on 105 infant and toddlers were analyzed. The mean age of enrollment was 14 months, and 61 (58%) of the patients were male. Among these infants and toddlers, 63% had VWD type 1, 28% type 2, and 9% type 3. There was a family history of bleeding disorders in 79.1%. A family history of VWD prompted diagnostic testing in 68% of study patients; 93% of children diagnosed with type 2 disease had a family history of VWD, compared to 77% of those with type 1 and 44% of those with type 3 (P = 0.02). The mean age at diagnosis of all study patients was 7 months. Children with type 2 VWD were diagnosed at a significantly younger age than those with types 1 and 3 (mean age, 4.7, 8.0, and 6.8 months, respectively; P = 0.04).Among study participants, 22% experienced a bleeding episode before the diagnosis of VWD, 22% were diagnosed at the time of an episode, and approximately 50% were diagnosed before their first notable bleeding event (with testing done because of a family history). Overall, 274 bleeding events were documented in 73 patients. The most common types of bleeding episodes were oral/nasal bleeds (166 episodes, 60.6%) and soft-tissue hematomas (57 episodes, 20.8%); 9 boys (14.8%) experienced unusual bleeding with circumcision. There were 7 episodes of subdural hemorrhages among the study children, occurring both after trauma and spontaneously.The authors conclude that the majority of infants and toddlers with VWD have a family history of the disease, and bleeding episodes are common.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Von Willebrand disease affects up to 1% of the U.S. population.1 Von Willedbrand Factor (VWF) is an acute-phase reactive glycoprotein that aggregates and adheres platelets to damaged blood vessel walls.2 Many with Type 1 VWD, a partial VWF deficiency associated with autosomal dominant inheritance, are unaware of their bleeding disorder due to mild gum bleeding, epistaxis, petechiae, bruising, gastrointestinal bleeding, and heavy menses often attributable to co-morbidities, medications, or trauma (See AAP Grand Rounds. 2020;44[5]:54.)3 Those with subtypes of type 2 VWD, due to different qualitative VWF defects, have variable inheritance and bleeding symptoms.4 Those with the rarest, type 3 VWD, due to an autosomal recessive inheritance manifesting with an absence of VWF, have severe bleeding symptoms.4In older children, teens, and adults, screening for bleeding disorders includes family history and symptom scores using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.5 Falsely abnormal or normal blood test results for CBC, PT, PTT, VWF antigen, VWF activity, Factor VIII, and multimeric analysis arise due to issues with phlebotomy, specimen handling, and assay variability.6 Interpretation of diagnostic test results are affected by blood type, hormones, and concurrent stressors such as fear, exercise, or infection.2 Currently, complex genetic testing plays a limited role in diagnosis and clinical severity in some type 2 VWD cases.7The current investigators review a large cohort of newborns, infants, and toddlers with VWD and describe bleeding episodes, which occur most often before 1 year of age. Limitations of this study include overrepresentation of non-Hispanic whites and missing data for bleeding characteristics or scores, VWF antigen/activity levels, and vitamin K administration at birth. No control cohort with or without bleeding symptoms was available for comparison.A family history of VWD or personal history of oropharyngeal, circumcision-related, hematomas, or intracranial bleeds in children <2 years of age indicate the need for evaluation for VWD.

Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD

AbstractData on infants and toddlers (ITs) with von Willebrand disease (VWD) are lacking. We used data collected in the US Hemophilia Treatment Center Network (USHTCN) to describe birth characteristics, bleeding episodes, and complications experienced by 105 patients with VWD who were <2 years of age. In 68% of the patients, the reason for diagnostic testing was a family history of a bleeding disorder. The mean age at diagnosis was 7 months, with little variation by sex. Patients with type 2 VWD were diagnosed earlier than those with types 1 or 3 (P = .04), and those with a family history were diagnosed ∼4 months earlier than those with none (P < .001). Among the patients who experienced a bleeding event (70%), oral mucosa was the most common site of the initial bleeding episode (32%), followed by circumcision-related (12%) and intracranial/extracranial bleeding (10%). Forty-one percent of the initial bleeding events occurred before 6 months of age, and 68% of them occurred before the age of 1 year. Approximately 5% of the cohort experienced an intracranial hemorrhage; however, none was associated with delivery at birth. Bleeding patterns and rates were similar by sex (P = .40) and VWD type (P = .10). Forty-seven percent were treated with plasma-derived von Willebrand factor VIII concentrates. The results of this study indicate that a high percentage of ITs diagnosed with VWD and receiving care within the multidisciplinary structure of the USHTCN have a family history of VWD. In addition, bleeding events such as circumcision-related, oropharyngeal, and intracranial or extracranial episodes are common and are leading indicators for treatment.

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)

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)

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

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

VWF and FVIII Levels after Desmopressin Are Associated with the Bleeding Phenotype in Type 1 VWD

Introduction The bleeding phenotype of type 1 von Willebrand disease (VWD) patients is very heterogeneous. We hypothesized that part of this heterogeneity is explained by variability in response of von Willebrand factor (VWF) and factor VIII (FVIII) levels to stress during hemostatic challenges. Patients who have a strong increase in VWF and FVIII levels during hemostatic challenges, may have less frequent or less severe bleeding episodes compared to patients who have a smaller increase in VWF and FVIII levels. Therefore, we investigated whether VWF and FVIII levels after desmopressin, which mimic in vivo hemostatic response during hemostatic challenges, are associated with the bleeding score, and therefore may explain part of the heterogeneity in bleeding phenotype of type 1 VWD patients. Methods In this retrospective cohort study, we included type 1 VWD patients of all ages who were diagnosed and treated in the Erasmus University Medical Center. All patients had a hemorrhagic diathesis or family history of VWD and historically lowest VWF antigen (VWF:Ag) and/or VWF Ristocetin Cofactor activity (VWF:RCo) ≤ 0.30 IU/mL with VWF activity/ VWF antigen ratio above 0.60. All patients participated in the Willebrand in the Netherlands (WiN) study, in which a self-administered Tosetto bleeding score was assessed. Results We identified 173 eligible type 1 VWD patients in our treatment center who participated in the WiN study. After exclusion of 50 patients who did not receive a desmopressin test dose, and 1 patient who did not have a bleeding score assessment, we included 122 type 1 VWD patients. Table 1 shows the patient characteristics. Higher FVIII activity during the complete time course (i.e. one, three and 5-6 hours) after desmopressin, and higher VWF and FVIII levels combined at three hours after desmopressin, were associated with a lower bleeding score, respectively β=-0.9 (95% CI: -1.7; -0.1) and β=-1.2 (-1.9; -0.5), both adjusted for age, sex, BMI and comorbidities. FVIII:C at three hours after desmopressin was significantly associated with a lower bleeding score: β=-1.5 (-3.0; -0.1), whereas VWF levels were not associated (Figure 1). Moreover, patients with VWF and FVIII levels in the highest quartile three hours after desmopressin administration had a lower bleeding score compared to other patients (Figure 2). The largest difference was found for FVIII:C: β=-5.1 (-8.4; -1.8), adjusted for age, sex, BMI, comorbidities and baseline FVIII:C. These patients also less often had an abnormal bleeding score: OR=0.1 (0.0-0.5), adjusted for age, sex, BMI, comorbidities and baseline FVIII:C. Lastly, patients with an increased clearance of VWF, defined as VWF propeptide/VWF:Ag ratio &gt;2.2, had lower VWF:Ag (β=-0.3, -0.6; -0.1), VWF:Act (β=-0.5, -0.7; -0.2), VWF:CB (β=-0.5, -1.0; -0.1) and FVIII:C (β=-0.7, -1.0; -0.4) at three hours after desmopressin administration compared to other type 1 VWD patients, all adjusted for age, sex, BMI and comorbidities. An increased clearance of VWF was also associated with a higher bleeding score: β=3.2 (0.2; 6.2), adjusted for age, sex, BMI, comorbidities and baseline VWF and FVIII levels. Discussion In type 1 VWD patients, the desmopressin induced increase of VWF and FVIII levels is associated with a lower bleeding score. Especially higher VWF and FVIII levels at three hours after desmopressin were associated with a milder bleeding phenotype, suggesting that sustained VWF and FVIII levels after a hemostatic challenge may be important to prevent bleeding. This was strengthened by an association between increased clearance of VWF and a higher bleeding score. Furthermore, patients with VWF and FVIII levels in the highest quartile three hours after desmopressin had 5 points lower bleeding score, and patients with FVIII:C in the highest quartile had 10 times less often an abnormal bleeding score. These results indicate that a good hemostatic response may have important and clinically relevant consequences on the bleeding phenotype, and may compensate for the low baseline VWF and FVIII levels in type 1 VWD patients. In conclusion, VWF and FVIII levels after desmopressin administration, which mimic in vivo hemostatic response to hemostatic challenges, are associated with the bleeding phenotype in type 1 VWD patients. This may partly explain the well-known variability in bleeding phenotype of type 1 VWD patients. Disclosures Atiq: Sobi: Other: Travel grant (ISTH 2019); Professor Heimburger Award 2018 (CSL Behring): Research Funding. Schütte:CSL Behring: Other: Travel grant. Boender:Sobi: Employment; Professor Heimburger Award 2016 (CSL Behring): Research Funding. Kruip:Bayer: Research Funding; Pfizer: Research Funding; Daiichy Sankyo: Research Funding; Boehringer Ingelheim: Research Funding. Leebeek:Shire/Takeda: Consultancy; UniQure: Consultancy; Novo Nordisk: Consultancy; Shire/Takeda: Research Funding; Sobi: Other: Travel grant; CSL Behring: Research Funding.

Utility of Repeat Testing in the Evaluation for Von Willebrand Disease in Pediatric Patients

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is diagnosed via 3 cardinal features: 1) personal history of bleeding, 2) laboratory assays and 3) family history of VWD. The diagnosis of VWD in pediatric patients is complicated by von Willebrand factor (VWF) inter- and intra-assay variability, phlebotomy-induced physiologic stress increasing VWF levels from baseline, and a lack of prior hemostatic challenges. Given these challenges, NHLBI guidelines recommend repeated testing in patients with mildly low or normal levels and a high suspicion of VWD. However, no studies to date have evaluated the utility of repeat VWF testing in pediatric patients. Currently, our center's standard of care is to complete 3 separate sets of VWF testing to rule out VWD. The primary objective of this study was to determine the clinical variables associated with requiring more than 1 test to diagnose VWD and to establish a cutoff value for the first set of VWF assays above which further testing would not be informative.This single center retrospective cohort study included patients ≤ 18 years of age who either had a diagnosis of or evaluation for VWD between January 2012 and July 2017. Patients were excluded if the VWD laboratory evaluation was completed at another institution or due to the presence of another bleeding disorder. Medical charts were abstracted for demographic information, medications, reason for testing, family history of VWD, results of VWF assays, and other illness at time of evaluation. All patients had a retrospective ISTH BAT score completed. Data were analyzed using SAS and are reported as median (IQR). Statistical analysis was done with non-parametric tests (Mann-Whitney or Wilcoxon sign-rank) for two groups comparisons. Odds ratios were calculated using Fisher's Exact test for clinical factors associated with a VWD diagnosis. Univariate logistic regression was performed, modeling the odds of requiring more than 1 diagnostic test to diagnose VWD.One thousand unique patients were evaluated and 189 excluded, yielding a final cohort of 811 patients. Of these, 631 (77.8%) did not have VWD and 180 (22.2%) were diagnosed with VWD. Patients diagnosed with VWD were younger than those without (median age 5.8 vs 8.5 years, p=0.0019) and were more likely to have a family history of VWD (38% vs 22%, p < 0.0001) but there was no difference in race or sex between cohorts. As expected, patients in the VWD cohort had lower VWF activity (34 vs 78 IU/dl, p < 0.0001), VWF antigen (45 vs 89 IU/dL, p < 0.0001) and FVIII (57 vs 100 IU/dL, p < 0.0001) than those without VWD. ISTH BAT scores were higher in the VWD cohort (2.47 vs. 2.07, p = 0.027).As shown in Table 1 and Figure 1, increased odds of VWD diagnosis were noted in those tested due to a family history of VWD (OR 1.75, 95% CI 1.21-2.51) or abnormal coagulation studies (OR 1.61, 95% CI 1.07-2.24). Subjects with VWD required fewer tests than those without VWD (median 1 vs 2, p < 0.001).Univariate analysis failed to identify any significant associations with needing > 1 test for the diagnosis of VWD (Table 1), so a multivariable model was not performed. In 69.4% (125/180) of subjects with VWD, the first test was diagnostic.In receiver-operating curve analysis, the first VWF antigen and activity have a high power for diagnosis of VWD with AUC of 0.88 and 0.92, respectively (Fig 1). A cutoff of 100 IU/dL for VWF antigen or activity on first test yielded a sensitivity of 95%, specificity of 38% and negative predictive value of 96.6% for VWF antigen compared to 98%, 38% and 98.6% for VWF activity, respectively.Here we demonstrate that the majority of pediatric subjects had diagnostic VWF values on the first set of testing. Unfortunately, no clinical variables were identified for patients with VWD who required > 1 test for diagnosis. However increased odds of VWD diagnosis were noted in those with a family history of VWD and abnormal coagulation studies. A cutoff of 100 IU/dL for VWF activity or antigen on the first test resulted in > 95% negative predictive value to rule out the diagnosis. Pediatric patients without a family history of VWD and VWF levels > 100 IU/dL on initial test may not need further testing to rule out the diagnosis of VWD. DisclosuresDoshi:Bayer Hemophilia Awards Program: Research Funding. Butler:Pfizer: Consultancy; Genentech: Consultancy; HemaBiologics: Consultancy.

Bleeding Patterns in Type I VWD in Effect of VWF Levels: An Individual Participant Data Meta-Analysis of Three Cohorts

Type I von Willebrand disease (VWD) is the most frequent bleeding disorder, with a prevalence of 10-50 cases per 10,000 persons. VWD usually shows an autosomal dominant inheritance pattern, at least in families having VWF:Ag levels below 30 IU/dL. There is considerable uncertainty whether patients having only mildly reduced VWF levels (in the range 30-50 IU/dL) should be diagnosed as having VWD or if they should be considered as a separate clinical entity, broadly referred to as “reduced VWF patients.” We hypothesize that these patients may have a clinically distinct bleeding pattern, in terms of presenting symptoms at diagnosis, bleeding severity, and possibly even clinical.We pooled data from three cohorts of patients. The MCMDM-1 VWD Study is a multicenter survey on type 1 VWD that recruited 154 type 1 VWD families from nine European countries. The Kingston cohort recruited consecutive patients with type 1 VWD diagnosed in Kingston, Canada and includes patients screened because of bleeding symptoms or family history of VWD over a 10 year period. The Zimmerman Program for the Molecular and Clinical Biology of VWD is a multicenter study that enrolled VWD patients mostly from US clinical centres, primarily carrying a diagnosis of type 1 VWD (315 families) but also including type 2 and type 3 subjects. For the present study, only patients with a confirmed diagnosis of type 1 VWD were retained. From the three cohorts, demographic, laboratory and clinical data were abstracted, including severity of bleeding symptoms classified according to the MCMDM-1 study criteria. Only data from index cases and affected family members were retained for the present analysis. Bleeding symptoms receiving a score >=2 (and therefore requiring some type of medical intervention) were classified as “clinically relevant”. VWF:Ag and VWF:RCo were measured centrally by the reference core lab of each of the three studies, against the WHO International Standard. For this purpose of the present study, Type 1 VWD is defined as VWF:Ag levels (or VWF:RCo for the Zimmerman Program) below 30 IU/dL; affected family members and index cases with VWF:Ag levels equal or above 30 IU/dL were classified as “low-VWF” patients.Pooled data from the three studies resulted in 1411 patients. At multivariate analysis, blood group O females with lower bleeding scores were the characteristics associated with the “low-VWF” patients; interestingly, the number of clinically relevant bleeding symptoms was associated with the phenotype independently from the total bleeding score. For all considered bleeding symptoms, VWD patients had a higher prevalence of relevant bleeding, with the notable exception of menorrhagia. Particularly in index cases, menorrhagia but also post-surgical bleeding was increased in patients having the “low-VWF” phenotype, although only for menorrhagia the difference was statistically significant (p=0.022).Unsupervised cluster analysis of symptom distribution disclosed three subgroups of patients. The first two were composed by males (first group) or females (second group), both having few or none bleeding symptoms. The third identified by unsupervised cluster analysis group was composed of highly symptomatic patients, predominantly women. In these patients, mucous (“wet”) bleeding (epistaxis and menorrhagia) was common together with post-surgical or extraction bleeding. This pattern was not correlated with mean VWF:Ag level or “low-VWF” or Type 1 VWD phenotype. We conclude that “low-VWF” patients are more frequently blood group O, older females, with lower average bleeding scores and number of symptoms and possibly selected because of menorrhagia. A group of “severe bleeders” may be identified (n=270, 19%), having a similar distribution of “low VWF” and “VWD” phenotypes. DisclosuresTosetto:Stago, Novo-Nordisk, BMS: Speakers Bureau; Werfen: Other: Member of Advisory Board, Speakers Bureau. Eikenboom:CSL: Research Funding. James:CSL Behring: Research Funding; Shire: Research Funding; Bayer: Research Funding. Montgomery:BCW: Patents & Royalties: GPIbM assay patent to the BloodCenter of Wisconsin.

Who Are the Type 2 Von Willebrand Disease Patients? Results from Interim Analysis of the French HRQoL Study: Wish-Qol.

Type 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor (VWF) function and structure resulting in various bleeding phenotypes. Variants 2A, 2B and 2M are mainly related to abnormal interaction of VWF with platelets and/or the subendothelium. Mucocutaneous bleeds such as epistaxis, menorrhagia and gastro-intestinal bleedings are the most frequently reported in these subtypes, while in patients with type 2N VWD characterized by a defective binding of VWF to FVIII, a phenotype with symptoms suggestive of mild/moderate hemophilia A is common.Are type 2 VWD female patients' bleeding score, clinical phenotype and impairment of Quality of Life (QoL) more severe than the males' ones? To answer this question, we report here results of VWD type 2 patients enrolled in the French Heath related Quality of Life study: WiSH-QoL.This study is conducted with the French Reference Centre for von Willebrand Disease (CRMW). Clinical phenotype such as bleeding score (Tosetto score), biological profile and genotype are documented. Clinical characteristics and therapeutic approach are also recorded. Patients are treated with WILFACTIN®, triple-secured plasma-derived VWF with a low factor VIII content. Information on socio-demographic and resources consumption are gathered by patients in their diary. HRQoL is assessed with the generic SF-36 (for adults), the chronic-generic DISABKIDS Short Form (for children and adolescents), the VWD-specific HRQoL questionnaire VWD-QoL (for adults, children, adolescents and parents with a proxy version), the VWD-specific treatment satisfaction assessment VWD-Sat (for adults and parents with a proxy version). The Impact on Family (IOF) Scale is dedicated to caregivers of children with VWD. At least 350 patients will be followed during 2 years.During the recruitment period (Oct. 2014 - Nov. 2017), 357 patients were enrolled. At the time of this analysis, data at inclusion on 355 patients were evaluable. Focus was made on the 226 type 2 VWD patients: 141 (62.4%) females and 85 (37.6%) males, median age and range at study entry 32.7 (1-78) and 26.4 (1-83) years, respectively. The majority of them were adults with 101 (71.6%) females and 49 (57.6%) males. 76 patients were below 18 years (40 (28.4%) females and 36 (42.4%) males). In the female subgroup, 81 were women of child-bearing age (15-50 y.o), 27 under 15 years with 21 prepubertal children and 33 above 50 years.The median age at diagnosis was 11.5 years (range 0-78) associated with a family history of VWD in the majority of patients (178, 78.8%), earlier in males' life (6 y) than in females (15 y). The first substitutive treatment by VWF was administered at a median age of 19.0 years (range 0-78), with 13.0 years for males compared to 23.5 y for females.At baseline, 23 (10.2%) patients (12 females and 11 males) had reported GI manifestations.The patients were 64 patients with type 2A, 52 with type 2B, 68 with type 2M, 12 with type 2N and 30 with type 2 unspecified.The median Tosetto bleeding score (BS) reported for 202 patients was +7.0 (range -1 to 25), higher +8.0 (range -1 to 25) in female compared to +5.0 (range 0 to 21) in male patients. It was also able to distinguish disease severity by variants as shown in table1. Whatever the variants (2A, 2B, 2M and 2N VWD,) the women of child-bearing age group had the highest BS.At enrollment, 62 female patients (44.0%) have already received a concomitant treatment with Iron, oral contraceptive, intra-uterine device. In the group of 64 women who had experienced a total of 136 deliveries (mainly vaginal deliveries (107, 78.7%) and C. Section (29, 21.3%)), the mean number of childbirth was 2.1 (range 1-5). Post-Partum Hemorrhages occured in 42 of these cases (31.3%), mainly within 48 hours after giving birth in 27 cases (67.5%) out of the 40 cases with available data.Were also found differences in both Physical and Mental Component Score of the generic SF-36 with higher impairments in HRQoL in adults females than in males (PCS 54.04 vs 55.22) MCS (44.71 vs. 47.85). The same tendency was seen with the Normalized Global score VWD-Specific in adults with higher score in females than in males (17.26 vs 13.91).This study with HRQoL results will bring a deeper insight into type 2 VWD patients' real daily life. These findings may teach us what would be the best care for VWD patients and especially for females who need definitely specific health care throughout their fertile life. [Display omitted] DisclosuresBorel-Derlon:Octapharma: Other: Clinical Research Investigator; LFB: Membership on an entity's Board of Directors or advisory committees; Shire: Other: Principal investigator; Novonordisk: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Desprez:LFB: Other: Investigator. Volot:LFB: Other: Investigator. Pan-Petesch:LFB: Other: Investigator. Chatelanaz:LFB: Employment. Doriat-Robin:LFB: Employment. Veyradier:LFB: Other: Investigator. Von Mackensen:LFB: Membership on an entity's Board of Directors or advisory committees.

Validation Study of the Composite Score to Identify Von Willebrand Disease in Children.

The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD. Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined. A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%. The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.

An approach to outreach patients with von Willebrand disease in Egypt by targeting women with heavy menstrual bleeding and/or bleeding symptoms

von Willebrand disease (VWD) is frequently ignored as a cause of menorrhagia. We investigated Egyptian women complaining of heavy menstrual bleeding (HMB) and/or other bleeding symptoms to detect potential VWD cases. Seventy-five female patients complaining of HMB and/or bleeding symptoms and 38 age-matched healthy female controls went through a family history questionnaire, a physical examination and were evaluated for bleeding score, pictorial blood assessment chart (PBAC), complete blood count, serum ferritin, blood group, prothrombin time, activated partial thromboplastin time, factor VIII (FVIII) activity, von Willebrand factor (VWF) ristocetin cofactor (RCo) activity, antigen (Ag), and RCo/Ag ratio. Sixty-eight of 75 patients presented with HMB, out of which 46 had no organic pathology and 7 presented other bleeding symptoms. Six patients were diagnosed with VWD, three with HMB, two with other bleeding symptoms and one with family history of VWD. Two related VWD patients were diagnosed in the control group. There were significant differences in bleeding and PBAC scores, ferritin level, FVIII activity, VWF:RCo and VWF:Ag between VWD patients and controls. This study indicated a high prevalence of VWD among patients with HMB without organic pathology (6.5%) and demonstrated the sensitivity of diagnostic parameters of VWD patients in an outreach campaign. The inexpensive bleeding and PBAC scoring systems are valuable to exclude cases without objective bleeding symptoms. Raising gynaecologists awareness about hereditary bleeding disorders is important to ensure a proper diagnosis and possible referral of these patients. Management of these patients with comprehensive medical care services under a multidisciplinary team would be ideal.

Validation Study Of The Composite Score To Identify Von Willebrand Disease in Children

BackgroundThe diagnosis of type 1 von Willebrand disease (VWD), the most common inherited bleeding disorder, presents a diagnostic challenge in children. In the absence of a prior hemostatic challenge in children, a VWD diagnosis may be missed by the Tosetto bleeding score, as it is based, in part, on bleeding symptoms, i.e. with surgery, menses, or childbirth, that may not occur until after childhood. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. Other bleeding scores, such as the James score, which assesses early life bleeding, e.g. cephalohematoma, macroscopic hematuria, and umbilical stump, post-circumcision, post-venipuncture bleeding, has been validated in children with VWD, but early life bleeding events are uncommon in VWD. We previously described a 4-variable Composite Score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children < 11 years of age, when at least two of four criteria are positive: 1) Tosetto bleeding score ≥ 1; 2) family history of VWD or bleeding; 3) personal history of iron deficiency anemia; and/or 4) positive James early bleeding score. The purpose of this study was to validate a Composite Score of ≥ 2 (i.e. at least 2 of 4 variables positive) for identifying children with VWD. MethodsWe designed and conducted a prospective validation study to determine the accuracy of the Composite Score for identification of children (<11 years of age) with VWD. Following parental consent, children without a prior history of VWD undergoing VWD testing were enrolled, and survey data were collected including personal bleeding history (including Tosetto and James scores), history of iron deficiency anemia, and family history of VWD or bleeding. Results of VWD testing were collected, including VWF:RCo, VWF:Ag, and VIII:C in addition to VWF multimers, if performed. Survey data and bleeding scores were compared between those with and without VWD, defined by VWF:RCo <30 (NIH 2008 criteria), or <40, or <50 IU/dL. Prior to study, it was determined that a Composite Score ≥ 2 would have 90% power to identify VWD defined by VWF:RCo <0.30 IU/dL, and 80% power to identify VWD by VWF:RCo <40 IU/dL. Categorical variables were compared using chi-square or Fischer's exact test. Continuous variables were compared using two-sample t-test or Wilcoxon's rank sum test. Sensitivity, specificity, positive and negative predictive value of the Composite Score of ≥ 2 to diagnose VWD were determined. ResultsA total of 195 subjects were enrolled from 12 participating centers from 2010-2013, of whom 193 patients with no missing data were included in the analysis. A total of 81 (41.9%) children had type 1 VWD, including 11 (5.7%) with VWF:RCo <30 IU/dL (Group A), 24 (12.4%) with VWF:RCo <40 IU/dL (Group B), and 46 (23.8%) with VWF:RCo <50 IU/dL (Group C); the remainder with VWF:RCo ≥50 IU/dL were unaffected. There were no significant demographic differences between groups: overall 54.9% were male, 82.4% were Caucasian, and the mean age was 4.7 years. A composite score of ≥ 2 had 63.6%, 75%, and 67.4% sensitivity in diagnosing type 1 VWD in Groups A, B, and C respectively; 33.5%, 34.9%, and 34% specificity in diagnosing type 1 VWD, respectively; and 93.8%, 90.8%, and 76.9% negative predictive value, respectively. Based on the performance of the composite, with VWD being defined by a VWF:RCo of <30, <40, or <50 IU/dL, 31.6%, 30.6%, and 25.9% of subjects, respectively, had a negative composite score and therefore would not have required VWD testing. DiscussionThis is the first study to prospectively validate the Composite Score to identify children with type 1 VWD. Although the sensitivity and specificity of the Composite Score were lower than in the original study (above), the latter included only VWD subjects, while this validation study included all, VWD and non-VWD, undergoing testing. The negative predictive value of the Composite Score was robust, especially at lower VWF:RCo, and indicates that VWD testing could be eliminated in nearly a third of children referred for VWD testing. Given the difficulty of diagnosing VWD in children, the Composite Score may be an important screening tool for diagnosis of type 1 VWD in children. Disclosures:Kerlin:Bayer Healthcare US: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk A/S: Consultancy, Honoraria.

Prospective Comparison of the Pediatric Bleeding Questionnaire (PBQ) and the International Society On Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) in Children Referred to a Tertiary-Care Pediatric Centre.

AbstractAbstract 2229Mucocutaneous bleeding symptoms, such as epistaxis and bruising, are frequent complaints in childhood; a detailed bleeding history is a crucial initial step in determining whether a child presenting with such symptoms has an underlying bleeding disorder. A Pediatric Bleeding Questionnaire (PBQ), based on the MCMDM-1 VWD Bleeding Questionnaire, incorporates 6 pediatric-specific bleeding symptoms (see below) to quantify bleeding severity in children. Bleeding symptoms are scored in a −1 to +4 range, with a −1 score assigned for tooth extraction or surgery if bleeding did not occur in at least 2 procedures, and are summed for all symptoms. An overall PBQ score of ≥2 predicts a diagnosis of von Willebrand disease (VWD). The PBQ has also been used to quantify the severity of bleeding symptoms in children with VWD or platelet function disorders (Bowman et al, J Thromb Haemost 2009;7:1418; Biss et al, J Thromb Haemost 2010;8:950; Biss et al, J Thromb Haemost 2010;8:1416). The ISTH has developed a Bleeding Assessment Tool (ISTH-BAT) to standardize the reporting of bleeding symptoms in adult and pediatric populations; bleeding symptoms are scored in a 0 to +4 range, and are summed (Rodeghiero et al, J Thromb Haemost 2010;8:2063). Criteria for scoring of each symptom are similar between the two questionnaires, but not identical.Here, we have performed a detailed comparison between PBQ and ISTH-BAT scores in a prospective study of children with mucocutaneous bleeding and/or a family history of VWD or a platelet function disorder referred to our tertiary-care pediatric bleeding disorders clinic. To date, we have enrolled 75 subjects, with a mean age of 9.9 yrs (range: 0.5–17.8 yrs), of whom 36 are males. The median overall PBQ score of these children was 3 (range: 0–12), as was the median overall ISTH-BAT score (range: 0–13).In 37/75 children (49%), the overall PBQ score was identical to the overall ISTH-BAT score. In the majority of these children (34/37; 92%), the individual scores for each symptom were identical. However, in 3 children, there were differences in the individual scores that balanced out, resulting in identical overall scores.For 38/75 children (51%), the overall PBQ and ISTH-BAT scores were different. In the majority of these children (33/38; 87%), the difference between the scores was only 1, with the ISTH-BAT being lower in 19/38 children, and higher in 14/38 children. In 2/38 children, the overall ISTH-BAT was lower by 2, in 2/38, higher by 2 and in 1/38, higher by 3. A lower overall ISTH-BAT score was mainly due to a lower score for cutaneous bleeding symptoms (14/21 children). A higher overall ISTH-BAT score was mainly due to a −1 PBQ score for a child who did not bleed on at least 2 tooth extractions or surgeries (observed in 11/17 children) and/or a higher ISTH-BAT score for menorrhagia (observed in 6/17 children, specifically, 6/9 postmenarchal adolescent females).10/75 (13%) children had a normal overall PBQ score of 0 or 1 (median: 1). The median overall ISTH-BAT score in these children was also 1 (range: 0–3), but 5 children had a score of 2 or 3. In the remaining 65/75 children (87%) with a positive, abnormal PBQ score, the median score was 3 (range: 2–12), as was the median overall ISTH-BAT score (range: 2–13).In contrast with previous prospective studies using the PBQ/ISTH-BAT in which pediatric-specific symptoms were not observed (Bowman et al, J Thromb Haemost 2009;7:1418; Bidlingmaier et al, J Thromb Haemost 2012;10:1335), 12/75 children (16%) received scores for macroscopic hematuria, post-circumcision bleeding, cephalohematoma, umbilical stump bleeding, post-venipuncture bleeding, or conjunctival hemorrhage.In summary, in this prospective study, we have observed similar, but not identical, overall PBQ and ISTH-BAT scores and the occurrence of pediatric-specific bleeding symptoms in children referred to a tertiary-care bleeding disorders clinic with mucocutaneous bleeding and/or a family history of VWD or platelet dysfunction. Thus, the inclusion of pediatric-specific bleeding symptoms in the standardized questionnaires is useful, and if the ISTH-BAT is to be adopted for general use to aid in the evaluation of whether a child has an underlying bleeding disorder, it will be essential to determine the cut-off for an abnormal ISTH-BAT bleeding score in children <18 yrs of age. Disclosures:James:CSL-Behring, Baxter, Bayer: Honoraria, Research Funding.

Predictors of Von Willebrand Disease In Children: A Case-Control Study

AbstractAbstract 712 Background:Von Willebrand disease (VWD) is the single most common congenital bleeding disorder. The Tosetto Bleeding Score (BS), a quantitative measure of bleeding, has improved specificity of diagnosis, but symptoms are variable, and, among children a diagnosis of VWD may be missed as they may not have lived long enough to experience symptoms on which the score is based. As many as 25% of affected children come to clinical attention after postoperative bleeding: thus, a better diagnostic tool is needed in children. A Tosetto BS modified for children by one additional question on early life bleeding, known as the James BS, has been validated for a small cohort of VWD children, but its utility in type 1 VWD diagnosed by the 2008 NHLBI-defined VWF:RCo<30 or in children <11 years of age remains unknown. Further, the role of family bleeding history or personal history of anemia in VWD diagnosis has not been studied. Methods:We conducted a case-control study to determine predictors of VWD in children younger than 11 years of age. Cases included 40 children with VWF:RCo<30 IU/dL (Group A) and 39 children with VWF:RCo=30-50 IU/dL (Group B). Controls included 80 children without VWD, age-, sex-, race-matched to CASES<30. Tosetto and James bleeding scores, family history of VWD or bleeding, and personal history of anemia were determined by prospective data extraction from charts of cases at the time of VWD diagnosis, and by parental interview of controls. Results:Group A included 52% male, 90% Caucasian, and age 7.5 years (median), not different from Group B, p=0.91, p=0.67, and p=0.26; or controls, p=0.90; p=1.00, and p=0.78, respectively. The median Tosetto BS in Group A was 2, greater than in controls, median 0, p<0.0001, but similar to Group B, median 1, p=0.10. The median James BS in Group A was 2, greater than in controls, median 0, p<0.0001, but not different from Group B, median 1, p=0.06. The majority of Group A had a family history of VWD or bleeding, 97%, similar to Group B, 85.0%, p=0.06; but higher than in controls, 0%, p<0.0001. In Group A, 47.5% had a personal history of iron deficiency anemia (by history and/or MCV<80), higher than Group B, 18%, p=0.005, and higher than controls, 1.3%, p<0.0001. The most common bleeding symptom in Group A was cutaneous bleeding, in 60%, similar to Group B, 44%, p=0.14, but higher than controls, 2.5%, p<0.0001. Comparing Group A with controls, a composite score of four variables, 1) Tosetto BS>1, 2) a family history of VWD or bleeding, 3) a personal history of iron deficiency (by history and/or MCV<80), and/or 4) a James ‘other’ early event bleeding, was predictive of VWD, p<0.0001, with 100% specificity and 75% sensitivity if at least 2 variables were present; similarly, a composite of three variables, excluding Tosetto BS>1, was also predictive of VWD, p<0.0001, with 98.8% specificity and 100% sensitivity if at least one variable was present. Comparing Groups A and B (all cases) with controls, a composite score of all four variables, was predictive of VWD, p<0.0001, with 100% specificity and 58.2% sensitivity if at least 2 variables were present; similarly, a composite of three variables, excluding Tosetto BS >1, was predictive of VWD, p<0.0001, with 98.8% specificity and 92.4% sensitivity if at least 1 variable was present. The area under the curve for diagnosing VWD in Group A by the Tosetto BS was AUC=0.872, Wald 95% CI (0.804−0.940), and by the James BS was AUC=0.885 (Wald 95% CI 0.820–0.950), and not different from the area under the curve for diagnosing VWD in Group B, AUC=0.801, Wald 95% CI (0.721−0.881), for each score. Conclusion:The AUC for the Tosetto bleeding score for diagnosing VWD in children < 11 years of age, exceeds 0.87, and the James exceeds 0.80, and both appear to be independent of VWF level <30 vs. 30–50. Combining a family history of VWD or bleeding, a personal history of iron deficiency anemia (by history or MCV<80) improves the Tosetto BS in children, independent of VWF level. These findings should be validated in a larger group of children. Disclosures:Kulkarni:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Participate in clinical trials. Yee:Novo Nordisk: Consultant. Ragni:Novo Nordisk, Inc.: Research Support for this study.

Platelet von Willebrand factor determination does not improve the diagnosis of patients with suspected Type 1 von Willebrand disease

Establishing a laboratory diagnosis of a bleeding disorder can be challenging for some patients who present with mucocutaneous bleeding symptoms. A common clinical scenario is an older patient with a prior diagnosis of von Willebrand disease (VWD) or a family history of VWD, who now has von Willebrand factor (VWF) values repeatedly within the normal range. Plasma VWF antigen levels have been shown to increase with age. Whether platelet VWF increases with age is unknown. We hypothesized that platelet VWF does not increase with age and low platelet VWF levels, despite normal plasma levels, could be a reason for continued bleeding symptoms in some patients. Therefore, we compared the platelet and plasma VWF antigen and activity as well as the platelet function analyzer (PFA)-100 closure times in 35 patients with a history of mucocutaneous bleeding symptoms and consistently normal levels of VWF antigen and activity, despite a prior history of a VWD diagnosis and/or a positive family history of VWD. Overall in our patients (bleeders), the platelet VWF values correlated with the plasma values and only three patients had reduced platelet VWF. In the bleeding group, the PFA-100 results showed an inverse correlation with plasma and platelet values, which was stronger for the plasma values. Therefore, platelet VWF determination was not helpful in the diagnosis of suspected mild type 1 VWD.