PB0812 - Lack of Congruent VWF Levels, Genetics, and Bleeding Symptoms in Families with a Type 1 von Willebrand Disease Diagnosis

Background: Type 1 von Willebrand Disease (VWD) is a common bleeding disorder defined by partial quantitative deficiency of von Willebrand factor (VWF). Inheritance is reported as autosomal dominant with variable penetrance.

Aims: To determine the percentage of families who show complete congruence of type 1 VWD diagnosis, VWF genotype, and bleeding phenotype.

Methods: Index cases (IC) and their family members were enrolled at 35 centers across the United States (310 families, 1402 individuals). Diagnosis of type 1 VWD was defined as VWF:Ag < 50 IU/dL or VWF:RCo < 54 IU/dL with normal activity/antigen ratio. Sanger sequencing of the VWF coding region (± comparative genomic hybridization) was performed for ICs with assessment of variant pathogenicity by ACMG criteria. Family members were analyzed for presence of variant(s) in IC for that family. Bleeding scores were calculated using the ISTH bleeding assessment tool.

Results: Familial congruence was determined across the three categories (presence/absence of genetic variant, low VWF levels, and abnormal bleeding score). Average family size was 4.5 individuals. Only 24% of families showed complete congruence of laboratory values, genotype, and bleeding phenotype. The proportion of congruent and incongruent families with or without a VWF variant did not differ (p=0.24). Furthermore, the mean VWF:Ag was similar between those with and without a genetic variant (p=0.15). The mean IC bleeding score was significantly higher in families with congruency of genetic variants, bleeding score, and VWF levels (p < 0.001).

Conclusion(s): Most families affected by type 1 VWD do not show complete congruence of VWF levels, genotype, and bleeding phenotype. Congruence was associated with higher bleeding scores in the IC affirming importance of symptoms in VWD diagnosis. Genetic changes outside the VWF coding region or locus or other explanations for bleeding phenotypes may be important in this population. Our study demonstrates the complicated nature of VWD inheritance.