Julie Grabell

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

Summary.  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 (≥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 r2 = 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 (anovaP < 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.

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.

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

Our aim was to generate, optimize and validate a self‐administered bleeding assessment tool (self‐BAT) for von Willebrand disease (VWD).

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.

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

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.

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

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.

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

Women with inherited bleeding disorders are at increased risk for bleeding complications during pregnancy and the postpartum period, particularly postpartum haemorrhage (PPH).

Generation and optimization of the self‐administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease

Our objective was to generate, optimize, and validate a self‐administered pediatric bleeding questionnaire (Self‐PBQ) as a screening tool for von Willebrand disease (VWD) in children referred to the hematology clinic for the first time.

Rapid acquisition of immunologic tolerance to factor VIII and disappearance of anti-factor VIII IgG4 after prophylactic therapy in a hemophilia A patient with high-titer factor VIII inhibitor.

We report an 11-month-old boy with severe hemophilia A who had regular exposure to factor VIII (FVIII) intended to reduce the risk of developing an inhibitor. He developed a high-titer inhibitor (peak titer 19 BU) that disappeared within 6 weeks of starting immune tolerance induction (ITI). Anti-FVIII IgG4 peaked briefly compared with anti-FVIII IgG1 and the Bethesda titer. Neither rapid resolution of an inhibitor after prophylaxis nor this behavior of anti-FVIII IgG4 has been previously reported. Transient anti-FVIII IgG4 may be a marker of an attenuated anti-FVIII response induced by prophylactic FVIII therapy.

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

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.