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. 2022 Jul;20(7):1576-1588.
doi: 10.1111/jth.15713. Epub 2022 Apr 6.

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

Pamela A Christopherson  1 , Sandra L Haberichter  1   2   3 , Veronica H Flood  1   2   3 , Crystal L Perry  1 , Brooke E Sadler  4 , Daniel B Bellissimo  5 , Jorge Di Paola  4 , Robert R Montgomery  1   2   3 ; Zimmerman Program Investigators
Collaborators, Affiliations

Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program

Pamela A Christopherson et al. J Thromb Haemost. 2022 Jul.

Abstract

Background: Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF).

Objectives: As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families.

Patients/methods: 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs.

Results: 75% of subjects (46) had central testing confirming type 3, while 25% were re-classified as type 1-Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co-dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous.

Conclusion: This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co-dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

Keywords: bleeding; genotype-phenotype association; inherited blood coagulation disorders; type 3 VWD.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors do not have any relevant conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
von Willebrand factor type 3 subjects enrolled in the Zimmerman Program. Sixty-two subjects with a pre-existing diagnosis of type 3 VWD were enrolled and evaluated in the Zimmerman Program. Nine subjects (15%) had a significantly increased VWFpp/VWF:Ag and were re-classified as type 1 clearance (1C) and six subjects (10%) had detectable VWF:Ag and VWFpp levels between 2–5 IU/dl and were re-classified as type 1-Severe (1S). 46 (75%) of the subjects had central laboratory testing confirming type 3 (absence of VWF). Two of the 46 confirmed type 3 cases did not have DNA available. Therefore 44 subjects were evaluated by genotypic analysis; 39 subjects had additional family members available to study
FIGURE 2
FIGURE 2
Distribution of the 60 different genetic variants identified in the Zimmerman Program type 3 VWD subjects by VWF domain. Variants included deletions, nonsense, splice site, missense and intronic changes throughout the gene. Candidate variants not previously reported are in bold and recurrent variants are underlined. (VWF domain structure credit Springer 2014)
FIGURE 3
FIGURE 3
Abnormal bleeding score in type 3 subjects. Forty-three type 3 subjects reported an abnormal bleeding score (ISTH BS) according to age and gender published cutoffs (one subject was unreported). There was no significant difference seen in total BS between adult females and males, however there was a difference amongst adult and pediatric (Ped <18 years of age) subjects
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