We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels ≤30 U/dl. Menorrhagia (85%), cutaneous bleeding (77%), bleeding from minor wounds (77%) and oral-cavity bleeding (62%) occurred most frequently. Higher age was associated with a higher bleeding score (BS), determined according to Tosetto, in females. A 10 year increase in age was associated with 0.8 point (95% confidence interval [CI] 0.4-1.1) higher BS. Females had higher BS than males (median 12 vs. 10, p=0.012). BS differed significantly between VWD type 1, 2 and 3: median 9 (-2-31), 13 (-1-33) and 19.5 (1-35), respectively (p<0.001). BS was strongly associated with VWF and FVIII levels: individuals with VWF:Ag levels ≤10 IU/dl, VWF:Act ≤10 IU/dl and FVIII:C ≤10 IU/dl had, respectively, 5.3 point (95%CI 3.2-7.3), 4.3 point (95%CI 2.9-5.8) and 9.6 point (95%CI 6.5-12.7) higher BS, than those with levels >30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels.

Summary. Background: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. Objectives: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate or severe VWD, and assessed whether bleeding severity and type of VWD are associated with HR-QoL. Methods: HR-QoL was assessed using the Short Form (SF)-36, and bleeding severity was measured using the Bleeding Score (BS). Results: Five hundred and nine patients participated; 192 males and 317 females, median age and range 45 (16-87) and 47 (16-84) years, respectively. Compared with the general population, HR-QoL in VWD patients was lower in the vitality domain (61 vs. 66 P < 0.001 for females, 67 vs. 72 P < 0.001 for males). Patients with the most severe bleeding phenotype (highest quartile BS, BS > 17) had a lower HR-QoL in eight domains than patients with a less severe bleeding type (lowest quartile BS, BS < 7) in the univariate analysis. After adjustment for age, gender, comorbidity and employment/educational status, a more severe bleeding phenotype was associated with lower scores on the domains of physical functioning, role limitations due to physical functioning, bodily pain, general health, social functioning and physical component summary. Conclusions: HRQoL is lower in VWD patients compared with the general population. HR-QoL is strongly associated with bleeding phenotype.

Summary. Background: High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. Objectives: To investigate the prevalence of arterial thrombosis in VWD patients relative to the general population. Patients/Methods: We included 635 adult patients with VWF levels 30 U dL À1 , aged 16-85 years, from the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN) study and compared the prevalence of arterial thrombosis with two reference populations from the general Dutch population adjusted for age and sex as standardized morbidity ratios (SMRs).Results: Twenty-nine arterial thrombotic events occurred in 21 patients (3.3%). Five patients suffered an acute myocardial infarction and three an ischemic stroke. Unstable angina pectoris was recorded 12 times, transient ischemic attack nine. The prevalence of all arterial thrombotic events combined (acute myocardial infarction, ischemic stroke and coronary heart disease) was 39% and 63% lower than in the two reference populations. The prevalence of cardiovascular disease in VWD was lower than in the general population, SMR 0.60 (95% CI, 0.32-0.98) for coronary heart disease and SMR 0.40 (95% CI, 0.13-0.83) for acute myocardial infarction. For ischemic stroke the prevalence was 35-67% lower compared with two reference populations, SMR 0.65 (95% CI, 0.12-1.59) and 0.33 (95% CI, 0.06-0.80), respectively. Conclusions: This is the first study showing that VWD patients have a reduced prevalence of arterial thrombosis and provides important insights into the role of VWF in the pathogenesis of arterial thrombosis.

A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged ≥16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of ≥2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD.

Summary. Background: Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder. Whether VWD is associated with health-related quality of life (HR-QoL) in children is unknown. Objectives: This nationwide crosssectional study measured HR-QoL in children with moderate or severe VWD. Our primary aim was to compare HR-QoL of VWD patients with that of reference populations. Additionally, we studied the impact of bleeding phenotype and VWD type on HR-QoL. Methods: HR-QoL was assessed with the Infant/ Toddler QoL Questionnaire (0-5 years) and Child Health Questionnaire (6-15 years), and compared with reference population scores. Multivariate analysis was used to evaluate the influence of type of VWD and bleeding phenotype on HRQoL scores. Results: Preschool children (0-5 years, n = 46) with VWD had lower HR-QoL scores for general health perceptions and parental time than reference populations. School children (6-15 years, n = 87) with VWD had lower scores for physical functioning, role functioning -emotional/ behavioral, general health perceptions, and physical summary. Type of VWD was associated with HR-QoL in school children for bodily pain, general health perceptions, parental emotion, family activities, and physical summary. Scores of children with type 3 VWD were, on average, 15 points lower than those of the reference population on the above-mentioned scales. A more severe bleeding phenotype was associated with a lower score on 11/15 physical, emotional and social scales.Conclusion: HR-QoL is lower in VWD children than in reference populations, in particular in school children. The negative impact of VWD is sensitive to type of VWD and bleeding phenotype; as well as physical scales, emotional and social scales are affected.