Relative contributions of bleeding scores and iron status on health-related quality of life in von Willebrand disease: a cross-sectional study.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder known in humans. Currently, studies investigating the health-related quality of life (HR-QoL) in VWD using standardized tools are limited, particularly among patients with mild decreases in von Willebrand factor or activity. AIM: To determine HR-QoL and its predictors among patients with mild, moderate and severe forms of VWD. METHODS: Patients with clinical diagnosis of VWD were recruited from a tertiary Inherited Bleeding Disorder Clinic. Upon informed consent, bleeding scores were obtained via a standardized, self-administered tool. Each participant also completed a HR-QoL questionnaire (SF-36). Analyses included paired t-test, independent t-test, one-way anova and multivariate regression. RESULTS: A total of 102 patients were recruited (consent rate = 95%). Participants were 38 years on average (SD 14.8), 78% were female and 80% were diagnosed with VWD Type 1. Compared to age- and sex-matched normative data, VWD patients had clinically and statistically significant reductions in seven of eight HR-QoL domains and the physical and mental component summaries. Adjusted for age, sex, socioeconomic status and rurality, there was a trend towards lower physical component summary with increasing bleeding score, and lower mental domains with iron deficiency status (P = 0.07 and P = 0.08 respectively). CONCLUSION: This study is the first to examine the impact of VWD on HR-QoL across disease severity while incorporating socioeconomic status and rurality. Significant reductions in HR-QoL among VWD patients, especially the relationship between iron status and mental HR-QoL, strengthen the rationale for prospective studies to evaluate the efficacy of iron replacement in this setting.

Let's Talk Period! Preliminary results of an online bleeding awareness knowledge translation project and bleeding assessment tool promoted on social media.

INTRODUCTION: Undiagnosed bleeding disorders are common and can pose significant health risks, especially for women. Recently, a self-administered bleeding assessment tool (Self-BAT) was validated in von Willebrand disease. AIM: To increase awareness of undiagnosed bleeding disorders through the use of an informational website (http://letstalkperiod.ca) targeted at women in their reproductive years. METHODS: The Let's Talk Period website was built in consultation with a medical communications company and focus groups of women, with the aim of clearly presenting key messages around menstrual bleeding. The website was promoted through social media and local and national interviews. Upon completion of the online Self-BAT available at http://letstalkperiod.ca, the result is displayed to the user along with a recommendation to seek medical attention if the score is abnormal. RESULTS: During the initial 3-month period, there were 5158 page views from 64 countries. A total of 489 individuals, 95% female, completed the online Self-BAT. The mean Self-BAT score was 6, range 0-44. Abnormal Self-BAT scores were reported in 45% of the respondents, of whom 96% were female. The most commonly reported bleeding symptoms were menorrhagia (98%) and postpartum haemorrhage (82%). Bleeding symptoms were similar across different geographical areas. CONCLUSION: An online screening tool is an effective method of identifying individuals concerned with abnormal bleeding. A significant portion of the general population report experiencing symptoms of abnormal bleeding. In women, the most frequently reported bleeding symptoms were menorrhagia and postpartum haemorrhage.

Obstetric bleeding among women with inherited bleeding disorders: a retrospective study.

INTRODUCTION: Women with inherited bleeding disorders are at increased risk for bleeding complications during pregnancy and the postpartum period, particularly postpartum haemorrhage (PPH). AIM: This retrospective study evaluates pregnancy management through the Inherited Bleeding Disorders Clinic of Southeastern Ontario, the clinical factors associated with pregnancy-related abnormal bleeding and assesses tranexamic acid use in the postpartum treatment of bleeding disorder patients. METHODS: A chart review of 62 pregnancies, from 33 women, evaluated patient characteristics (age, haemostatic factor levels) and delivery conditions (mode of delivery, postpartum treatment) in relation to abnormal postpartum bleeding. RESULTS: This cohort revealed increased risk of immediate PPH with increased age at delivery (mean age: 30.1 years with PPH, 26.5 years without PPH, P < 0.013), and birth by vaginal delivery (P < 0.042). Low von Willebrand factor (VWF) antigen or factor VIII (FVIII) in the third trimester was not associated with an increased risk of PPH; however, low VWF:RCo was associated with increased immediate PPH despite treatment with continuous factor infusion (P < 0.042). Women treated with tranexamic acid postpartum had less severe bleeding in the 6-week postpartum (P < 0.049) with no thrombotic complications. CONCLUSIONS: This study contributes to the growing body of work aimed at optimizing management of bleeding disorder patients through pregnancy and the postpartum period, showing patients are at a higher risk of PPH as they age. Risk factors such as low third trimester VWF:RCo have been identified. Treatment with tranexamic acid in the postpartum period is associated with a reduced incidence of abnormal postpartum bleeding.

Evaluation of the utility of the ISTH-BAT in haemophilia carriers: a multinational study.

INTRODUCTION: There has been increasing recognition in recent years that female carriers of haemophilia manifest abnormal bleeding; however, data on the use of bleeding assessment tools in this population are lacking. AIM: Our objective was to validate the ISTH-BAT in haemophilia carriers to describe bleeding symptoms and allow for comparisons with factor levels and other patient groups. METHODS: This was a prospective, observational, cross-sectional study performed by members of Global Emerging HEmostasis Panel (GEHEP). Unselected consecutive haemophilia carriers were recruited and a CRF and the ISTH-BAT were completed by study personnel. RESULTS: A total of 168 haemophilia carriers were enrolled: 155 haemophilia A and 13 haemophilia B. The mean age was 40 years (range: 20-82). Carriers had higher mean bleeding scores (BS) compared with age-matched controls (n = 46; 5.7 vs. 1.43; P < 0.0001) and Type 3 VWD OC (n = 32; 3.0; P = 0.009), but lower BS compared with women with Type 1 VWD (n = 83; 8.7; P < 0.0001). Fifteen carriers reported haemarthrosis, and of those six had normal FVIII/FIX levels. There was a significant but weak negative correlation between BS and factor level (Spearman's r2  = -0.36, P < 0.001). CONCLUSION: Our results show that haemophilia carriers experience abnormal bleeding, including haemarthrosis. Overall, BS in women with Type 1 VWD > haemophilia carriers > Type 3 VWD OC > controls. Understanding the performance of the ISTH-BAT in this population is a critical step in future research aimed at investigating the underlying pathophysiology of abnormal bleeding, with the ultimate goal of optimizing treatment.

Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease.

In a normal population, VWF plasma levels (VWF:Ag) and VWF activity (VWF:RCo) increase by approximately 0.17 and 0.15 IU mL(-1) per decade, but the influence of age is unknown in patients with type 1 von Willebrand disease (VWD). In a retrospective cohort study, the medical records of 31 type 1 VWD patients over the age of 30, who had been followed for ≥5 years, were reviewed for baseline clinical data and previously performed VWF:Ag, VWF:RCo and factor VIII levels ( FVIII: C). VWF multimer analysis was normal in 28/31 cases performed. Mean age at diagnosis was 33 (range 16-60 years), and duration of follow-up ranged from 5 to 26 years (mean 11 years). Patients had 2-10 time points of VWD testing (mean of 5.2). The mean VWF:Ag, VWF:RCo and FVIII: C at time of diagnosis were 0.44 IU mL(-1) 0.34 IU mL(-1) and 0.75 IU mL(-1) . At last follow-up, the mean VWF:Ag, VWF:RCo and FVIII: C were significantly increased to 0.71 IU L(-1) , 0.56 IU mL(-1) and 0.90 IU mL(-1) (P ≤ 0.001, <0.001, and 0.0081 respectively). Here 18/31 patients had VWF:Ag, VWF:RCo and FVIII: C levels that increased into the normal range. The rate of change in VWF:Ag, VWF:RCo and FVIII was 0.30 IU mL(-1) (0.21-0.39, CI 95%, P < 0.0001), 0.20 IU mL(-1) per decade (0.13-0.27, CI 95%, P = 0.0001) and 0.20 IU mL(-1) (0.11-0.29, CI 95%, P = 0.0011). Patients with type 1 VWD experience age-related increases to VWF:Ag and VWF:RCo which can result in normalization of VWF levels. Further studies are required to determine if the bleeding phenotype resolves with the increases in VWF:Ag and VWF:RCo levels.

Generation and optimization of the self-administered bleeding assessment tool and its validation as a screening test for von Willebrand disease.

INTRODUCTION/AIM: Our aim was to generate, optimize and validate a self-administered bleeding assessment tool (self-BAT) for von Willebrand disease (VWD). METHODS: In Phase 1, medical terminology in the expert-administered International Society on Thrombosis and Haemostasis (ISTH)-BAT was converted into a Grade 4 reading level to produce the first version of the Self-BAT which was then optimized to ensure agreement with the ISTH-BAT. In Phase 2, the normal range of bleeding scores (BSs) was determined and test-retest reliability analysed. In Phase 3, the optimized Self-BAT was tested as a screening tool for first time referrals to the Haematology clinic. RESULTS: Bleeding score from the final optimized version of the Self-BAT showed an excellent intra-class correlation coefficient (ICC) of 0.87 with ISTH-BAT BS in Phase 1. In Phase 2, the normal range of BSs for the optimized Self-BAT was determined to be 0 to +5 for females and 0 to +3 for males and excellent test-retest reliability was shown (ICC = 0.95). In Phase 3, we showed that a positive Self-BAT BS (≥6 for females, ≥4 for males) has a sensitivity of 78%, specificity of 23%, positive predictive value (PPV) of 0.15 and negative predictive value (NPV) of 0.86 for VWD; these figures improved when just the females were analysed; sensitivity of 100%, specificity of 21%, PPV = 0.17 and NPV = 1.0. CONCLUSION: We show an optimized Self-BAT can generate comparable BS to the expert-administered ISTH-BAT and is a reliable, effective screening tool to incorporate into the assessment of individuals, particularly women, referred for a possible bleeding disorder.

Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project.

Bleeding Assessment Tools (BATs) have been developed to aid in the standardized evaluation of bleeding symptoms. The Vicenza Bleeding Questionnaire (BQ), published in 2005, established a common framework and scoring key that has undergone subsequent modification over the years, culminating in the publication of the ISTH-BAT in 2010. Understanding the normal range of bleeding scores is critical when assessing the utility of a BAT. Within the context of The Merging Project, a bioinformatics system was created to facilitate the merging of legacy data derived from four different (but all Vicenza-based) BATs; the MCMDM1-VWD BQ, the Condensed MCMDM-1VWD BQ, the Pediatric Bleeding Questionnaire and the ISTH-BAT. Data from 1040 normal adults and 328 children were included in the final analysis, which showed that the normal range is 0-3 for adult males, 0-5 for adult females and 0-2 in children for both males and females. Therefore, the cut-off for a positive or abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children. This information can now be used to objectively assess bleeding symptoms as normal or abnormal in future studies.

Quantification of perioperative changes in von Willebrand factor and factor VIII during elective orthopaedic surgery in normal individuals.

von Willebrand's disease (VWD) patients undergoing major surgery are prophylactically treated to promote haemostasis. There is variability in perioperative clinical practice; however, most guidelines suggest replacing the deficient factor to a level of 1.0 IU mL(-1) (or 100%). A review of the literature reveals a paucity of well constructed descriptive data quantifying the changes in coagulation that occur in response to surgical stress. The aim of this study was to quantify the changes in haemostatic variables occurring in response to elective orthopaedic surgery in normal individuals. Eligible subjects >18 years of age undergoing total hip or knee replacement were recruited. Blood samples were drawn at five time points: baseline, preoperatively, 30 min after surgical incision, 30 min postoperatively, postoperative day (POD) 1. Analyses included t-tests and repeated measures anova. Overall 30 patients, 21 women and 9 men, with a mean age of 65 were included in the final analysis. All von Willebrand factor (VWF) variables were seen to significantly decrease intraoperatively and increase postoperatively. VWF multimers showed a statistically significant decrease in high molecular weight multimers intraoperatively and an increase postoperatively. On subgroup analysis, age, gender and anaesthesia type were significantly correlated with changes in VWF parameters. Data presented in the current study establish a physiological baseline for VWF parameters in the normal population and demonstrate mean VWF/factor VIII levels greater than 1.0 IU mL(-1) intraoperatively. As such, current management in VWD patients does not appear to mimic the normal physiological response to surgery.

Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms.

UNLABELLED: Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. SUMMARY: Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (ß = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (ß = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (ß = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly influenced by the presence of the other.

Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human AMPA receptors in vitro.

The present study describes the activity of two novel potent and selective AMPA receptor potentiator molecules LY392098 and LY404187. LY392098 and LY404187 enhance glutamate (100 microM) stimulated ion influx through recombinant homomeric human AMPA receptor ion channels, GluR1-4, with estimated EC(50) values of 1.77 microM (GluR1(i)), 0.22 microM (GluR2(i)), 0.56 microM (GluR2(o)), 1.89 microM (GluR3(i)) and 0.20 microM (GluR4(i)) for LY392098 and EC(50) values of 5.65 microM (GluR1(i)), 0.15 microM (GluR2(i)), 1.44 microM (GluR2(o)), 1.66 microM (GluR3(i)) and 0.21 microM (GluR4(i)) for LY404187. Neither compound affected ion influx in untransfected HEK293 cells or GluR transfected cells in the absence of glutamate. Both compounds were selective for activity at AMPA receptors, with no activity at human recombinant kainate receptors. Electrophysiological recordings demonstrated that glutamate (1 mM)-evoked inward currents in human GluR4 transfected HEK293 cells were potentiated by LY392098 and LY404187 at low concentrations (3-10 nM). In addition, both compounds removed glutamate-dependent desensitization of recombinant GluR4 AMPA receptors. These studies demonstrate that LY392098 and LY404187 allosterically potentiate responses mediated by human AMPA receptor ion channels expressed in HEK 293 cells in vitro.

Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease.

BACKGROUND: Given the challenges involved in obtaining accurate bleeding histories, attempts at standardization have occurred and the value of quantifying hemorrhagic symptoms has been recognized. PATIENTS/METHODS: An extensive validated bleeding questionnaire (MCMDM-1VWD) was condensed by eliminating all details that did not directly affect the bleeding score (BS) and the correlation between the two versions was tested. Additionally, the diagnostic utility of the condensed version was prospectively tested. RESULTS: Data on 259 individuals who were administered the questionnaire are presented here; 217 being prospectively investigated for von Willebrand disease (VWD) (group 1) and 42 previously known to have type 1, 2 or 3 VWD (group 2). Of the 217 prospectively investigated, 35 had positive BS (> or =4) and 182 had negative scores. Seven individuals (all with positive BS) had laboratory results consistent with type 1 VWD. This results in a sensitivity of 100% and a specificity of 87%. The positive predictive value is 0.20 and the negative predictive value is 1. The correlation between the full MCMDM-1VWD and condensed versions is excellent (Spearman's 0.97, P < 0.001, linear regression r(2) = 96.4). Inter-observer reliability for the condensed version is reasonable (Spearman's 0.72, P < 0.001 and intra-class correlation coefficient 0.805, P < 0.001). There was a significant difference in BS between subtypes of VWD, with type 3 >> type 2 >> type 1 VWD (anova P < 0.001). There is a strong inverse relationship between VWF:Ag level and BS (Spearman's -0.411, P < 0.001). CONCLUSIONS: The Condensed MCMDM-1VWD Bleeding Questionnaire is an efficient, effective tool in the evaluation of patients for VWD.