The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles:reply to a rebuttal

We thank Dr. Shetty and colleagues for their interest in our work and for providing comparative data from the Indian Type 3 VWD population. They provide results on 77 Type 3 VWD patients, and in contrast to our study, did not see higher bleeding scores (BS) in those with mutations in the VWF propeptide. In the Canadian study, the BS in those with VWF propeptide mutations is BS = 21 vs. BS = 11 for those with non-propeptide mutations compared with BS = 10 for propeptide and BS = 8 for non-propeptide in the Indian study. It is unclear which bleeding questionnaire was used to assess the Indian patients; the reference provided is for a review paper, not an original article. In this review, Dr. O’Brien primarily discusses questionnaires descended from the Rodeghiero et al “Vicenza Bleeding Questionnaire” published in 2005.¹ Therefore, we acknowledge that the tool used to assess the Indian Type 3 VWD patients is likely to be very comparable to our Condensed MCMDM-1VWD Bleeding Questionnaire (which is a Vicenza descendent).

We suggest three possible reasons for the discrepant results. The first is that the age of the patients in the two studies is very different. The mean age of the Type 3 VWD patients in the Canadian study is 29 years compared to ~13 years in the Indian study. It is well known that BS is age dependent, particularly in Type 3 VWD.² The fact that the Canadian patients were, on average, 16 years older, may have allowed time for further discrimination of bleeding severity. The second potential reason for the different results is that the frequency of both type and location of mutation varies between studies. There are more non-propeptide null mutations in the Indian study compared with the Canadian (34/77 vs. 9/31), which may impact bleeding severity. Additionally, the Canadian population is more heterogeneous, and we suspect that the rates of both consanguinity and homozygosity are higher in the patients. Lastly, there may be unrecognized genetic modifiers that differ between the two populations that impact their bleeding phenotype.

Dr. Shetty and colleagues correctly point out that 4 of the cases that we included in the propeptide group for our analysis were compound heterozygotes with mutations outside of the propeptide. When we restrict our analysis to those with both mutant alleles in the propeptide, the results show a similar, although not statistically significant trend (median BS = 21 (propeptide) vs. 11 (non-propeptide) (p value = 0.09)).

Finally, we disagree that the BS derived from Vicenza-based questionnaires cannot be compared between pediatric and adults. Given that the framework and scoring key for both the Condensed MCMDM-1VWD Bleeding Questionnaire, and the PBQ (Pediatric Bleeding Questionnaire) are essentially the same, we feel the scores are highly comparable.^3,4 Certainly, we all seem to agree that children may not have had exposure to hemostatic challenges to the same degree as adults, and given the cumulative nature of the Vicenza-based scores, the BS in adults will generally be higher than in children.

This is a commentary on article Kasatkar P, Ghosh K, Shetty S. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles: a rebuttal. J Thromb Haemost. 2013;11(9):1784-5. and Bowman M, Tuttle A, Notley C, Brown C, Tinlin S, Deforest M, Leggo J, Blanchette VS, Lillicrap D, James P; Association of Hemophilia Clinic Directors of Canada. The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles. J Thromb Haemost. 2013;11(3):512-20.