D. Rapson

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.

The prevalence of symptomatic von Willebrand disease in primary care practice

The adjusted HR for the development of PTS in thrombophilic as compared with non-thrombophilic patients was 1.23 (95% CI, 0.92–1.64; P = 0.15). In comparison to non-carriers of thrombophilia, the adjusted HR for the development of PTS was 0.42 (95% CI, 0.20–0.88; P = 0.02) in carriers of FVL, 0.81 (0.36–1.37) in carriers of lupus anticoagulant, 0.96 (0.29–3.82) in carriers of protein C deficiency, 1.08 (0.29–2.70) in carriers of protein S deficiency, and 1.33 (0.68–2.58) in carriers of the prothrombin gene mutation. Neither of the two patients with antithrombin deficiency developed PTS. In the subgroup of the 85 patients with FVL, PTS developed in 11 of the 50 patients (22.0%) with involvement of the popliteal vein only, and in 18 of the 35 (51.4%; P = 0.01) with more proximal thrombosis location, irrespective of the modality of clinical presentation (idiopathic or secondary to risk factors). The main limitation of our investigation lies in the failure to assess the role of other thrombophilic abnormalities such as hyperhomocysteinemia and increased levels of factors VIII, IX or XI. Nevertheless, based on our results the PTS rate in carriers of the most common thrombophilic abnormalities who develop an episode of proximal DVT does not seem to exceed that expected in non-carriers, and is likely to be even diminished by the carriage of FVL, most probably because of the more distal location of the thrombotic episode in carriers as compared with non-carriers of this abnormality [3,8]. The main implication of our study results is that awareness of a thrombophilic status should not influence the strategy that is commonly recommended for prevention of late post-thrombotic sequelae in patients with proximal DVT. Disclosure of Conflict of Interests

The effect of exercise on von Willebrand factor and ADAMTS‐13 in individuals with type 1 and type 2B von Willebrand disease

Summary.  Background: The effect of exercise on von Willebrand factor (VWF) and ADAMTS‐13 levels in individuals with von Willebrand disease (VWD) has never been reported.

Challenges in defining type 2M von Willebrand disease: results from a Canadian cohort study

Summary.  Background/methods: In order to better characterize the genotype–phenotype correlation in type 2M von Willebrand disease (VWD), we sequenced the coding region for the mature subunit of the von Willebrand factor (VWF) gene (exons 18–52, including exon/intron boundaries) in 16 index cases originally submitted to the Canadian Type 1 VWD Study as type 1 VWD, but reclassified as type 2M VWD on the basis of phenotype (excessive mucocutaneous bleeding and von Willebrand factor: antigen (VWF:Ag) and/or von Willebrand factor: ristocetin cofactor (VWF:RCo) between 0.05 and 0.50 IU mL–1 on at least two occasions and RCo/Ag ratio < 0.6 and no loss of high molecular weight multimers). Available family members (16 affected, 23 unaffected and six unknown) were sequenced for identified mutations. Results: We identified eight different missense mutations (R854Q, T1054M, R1315C, R1374C, R1374H, L1382P, S2179F, and T2647M) within these 16 families. We were significantly more likely to identify a VWF mutation in cases with RCo/Ag ratios < 0.50 (P < 0.05, chi‐squared test). Importantly, every index case with an RCo/Ag ratio < 0.40 (4/4 index cases) had a mutation identified within the A1 domain, in contrast to 1/12 cases with an RCo/Ag ratio > 0.40. Difficulties with the standardization of the VWF:RCo may be responsible for the heterogeneity in cases with RCo/Ag ratios between 0.40 and 0.60. Conclusions: The genotype–phenotype correlation for cases with RCo/Ag ratios < 0.40 is clear. On the basis of our results, the phenotypic definition of type 2M VWD may need to be more stringent, and should be the subject of an international standardization initiative.

A prospective evaluation of the prevalence of symptomatic von Willebrand disease (VWD) in a pediatric primary care population.

The prevalence of von Willebrand disease (VWD) is reported as ∼1%; however, these estimates were not based on individuals with significant symptoms. Four thousand five hundred ninety‐two unselected parents/children were asked: “Does your child have a problem with bleeding/bruising?”; 223 (5%) answered yes, 41 of whom were administered the validated Pediatric Bleeding Questionnaire and had VWF testing. Five were diagnosed with VWD (three type 1, one type 2A, one type 2B). The prevalence of bleeding/bruising in a general pediatric population is 5%; the prevalence of symptomatic VWD at the level of pediatric primary care is at least 1 in 1,000. Pediatr Blood Cancer 2010;55:171–173.

A novel type 2A (Group II) von Willebrand disease mutation (L1503Q) associated with loss of the highest molecular weight von Willebrand factor multimers

Summary.  Type 2A von Willebrand disease (VWD) is characterized by decreased platelet‐dependent function of von Willebrand factor (VWF) associated with an absence of high‐molecular‐weight multimers. In this study, sequence analysis of the VWF gene from a Type 2A VWD patient showed a novel, heterozygous T→A transversion at nucleotide 4510, resulting in the non‐conservative substitution of L1503Q in the mature VWF subunit. This substitution, which was not found in 55 unrelated normal individuals, was reproduced by in vitro site directed mutagenesis of a full‐length VWF cDNA and was subsequently expressed in COS‐7 cells. The corresponding recombinant mutant VWF protein was partially retained in COS‐7 cells yet the full spectrum of multimers was observed, suggesting that the absence of the highest molecular weight multimers results from increased proteolysis. The recombinant mutant VWF protein was digested with the ADAMTS13 protease from VWF‐depleted plasma and the aberrant VWF multimer pattern was observed. These results suggest that the L1503Q substitution induces a conformational change in the VWF protein, which increases the proteins susceptibility to proteolysis. A three‐dimensional model of the A2 domain demonstrates that the L1503Q mutation and the physiological proteolytic cleavage site for ADAMTS13 (Y1605‐M1606) are localized close together in two adjacent parallel β‐sheets. The mutation L1503Q does not significantly disrupt the conformation of the protein; thus the subtle loss of multimers in this patient may be due to altered interactions with the ADAMTS13 protease.