An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees

Kunicki, Thomas J.; Federici, Augusto B.; Salomon, Daniel R.; Koziol, James A.; Head, Steven R.; Mondala, Tony; Chismar, Jeffrey D.; Baronciani, Luciano; Canciani, Maria Teresa; Peake, I. R.

doi:10.1182/blood-2004-01-0349

Cited by 62 publications

(50 citation statements)

References 45 publications

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“…Even though no additional hemostatic defects were evident, nevertheless we can not exclude that cosegregation with prohemorrhagic polymorphisms in other hemostatic gene(s) might be responsible for this pattern, as recently observed in Type 1 von Willebrand disease [19]. Whatever the explanation is, these results again emphasize the lack of a strict correlation between FXI plasma level and bleeding tendency.…”

Section: Discussionmentioning

confidence: 36%

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

et al. 2008

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Factor XI (FXI) deficiency is an autosomal inherited coagulation disorder characterized by bleeding symptoms mainly associated with injury or surgery. Although most of the FXI gene mutations in Ashkenazi Jews are represented by the Glu117stop or Phe283Leu mutations, considerable genetic heterogeneity has been reported in other populations. We report here the genotypic characterization of four families with severe inherited FXI deficiency from the Czech Republic. Seven different gene mutations (three novel) were identified, thus, excluding the existence of a major founder effect in this population. Interestingly, both Glu117-stop and Phe283Leu were detected once, further demonstrating the occurrence of these mutations also outside the Jewish populations. In conclusion, we confirm that FXI deficiency in non-Jewish populations is because of different gene mutations; however, the presence of the Glu117stop and Phe283Leu mutations suggests that genetic testing in FXI-deficient patients can start with these two point mutations. Am. J. Hematol. 83:916-919, 2008. V

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Section: Discussionmentioning

confidence: 36%

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

et al. 2008

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“…In a previous study of VWD type 1 pedigrees [12], we found a significant association between haplotype 2 (807C) and severity of bleeding (high score), while a modest and not statistically insignificant association was seen with -52T. In the case of the type 2 pedigrees in this study, the influence of -52T and its association with increased bleeding score was greater than had been found in the previous type 1 study, while statistical significance was not observed with haplotype 2.…”

Section: Discussionmentioning

confidence: 99%

“…The severity of bleeding episodes was ranked from 0 to 5, as shown in Table 2, in each of 11 bleeding manifestation categories: epistaxis; cutaneous symptomatic bleeding; bleeding from minor wounds; oral cavity bleeding; gastrointestinal bleeding; bleeding associated with tooth extraction; surgery; muscle hematoma; hemarthrosis; postpartum hematoma; and menorrhagia. The bleeding score used in this study, in which a ranking from 0 to 5 is employed, is a modification of the previous scoring method used in our study of VWD type 1 patients [12] in order to more fully describe the severity of bleeding in all 11 categories. The numerical sum of the scores for each category was then divided by the age of the individual and multiplied by 100 to arrive at the bleeding severity score adjusted for age.…”

Section: Standardized Criteria To Evaluate Bleeding Historymentioning

confidence: 99%

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Kunicki

Baronciani

Canciani

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P ¼ 0.012) or when genderspecific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit a 2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.

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“…14 Genotypes were determined using primer sequences in a primer extension based assay 15 or a customized Nanogen-based single nucleotide polymorphism (SNP) analysis (Nanogen Inc., San Diego, CA, USA). 16 SNPs were confirmed by direct Sanger sequencing.…”

Section: Design and Methodsmentioning

confidence: 99%