Abstract Number: OC 22.4
Meeting: ISTH 2022 Congress
Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » von Willebrand Factor Biology
Background: Patients suffering from von Willebrand disease (VWD) have reduced quality-of-life despite current treatment options. Moreover, innovation in VWD therapeutic strategies has essentially stalled and available treatments have remained unchanged for decades. Therefore, there is an unmet need to develop new therapeutic strategies for VWD-patients.
Aims: To develop original mouse models to expedite pre-clinical studies of innovative therapeutic approaches for VWD.
Methods: Mice expressing human von Willebrand factor (hVWF), either wild-type or carrying the type 2A (p.R1597W) variant, and human GPIbalpha, but not the corresponding murine proteins, have been generated on an 129Sv genetic background (hVWF+/+/hGP1BA+/+ and hVWF(p.R1597W)+/+/hGP1BA+/+). VWF antigen (VWF:Ag), propeptide, multimer pattern and factor VIII (FVIII) activity were analyzed. Tail clip and tail vein transection (TVT) models were applied to assess bleeding tendency.
Results: hVWF+/+/hGP1BA+/+ -mice expressed 15±4% VWF:Ag, 44±8% FVIII activity and normal VWF multimers. hVWF(p.R1597W)+/+/hGP1BA+/+-mice expressed 3±1% VWF:Ag and 7±1% FVIII activity combined with an abnormal multimer pattern, with only low multimers and few degradation bands visible. VWF propeptide/antigen ratio was higher in these mice, suggesting an accelerated VWF clearance. Antigen levels increased upon histamine-treatment, evidencing the presence of a releasable VWF pool in both models. Despite the relatively low VWF:Ag levels, hVWF+/+/hGP1BA+/+ -mice displayed normal haemostatic responses in both the severe- (tail-clip) and milder- (TVT) bleeding assays. In contrast, hVWF(p.R1597W)+/+/hGP1BA+/+-mice had a severe bleeding phenotype. Interestingly, in the TVT model, although the amount of blood shed was consistent with severe bleeding, 57% of type 2A mice were capable of forming an occlusive, although unstable clot within 15 minutes of the injury, differing from the bleeding profile of VWF-deficient mice.
Conclusion(s): We have developed unique humanized mouse models for VWD-type 1 and VWD-type 2A, which will be useful to test innovative therapeutic strategies for VWD.
To cite this abstract in AMA style:
Casari C, Heestermans M, Mc Cuskey G, Peyron I, Reperant C, Christophe O, Denis C, Lenting P. Unique humanized mouse models of von Willebrand disease to implement the need for innovative therapeutic strategies [abstract]. https://abstracts.isth.org/abstract/unique-humanized-mouse-models-of-von-willebrand-disease-to-implement-the-need-for-innovative-therapeutic-strategies/. Accessed March 21, 2024.« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/unique-humanized-mouse-models-of-von-willebrand-disease-to-implement-the-need-for-innovative-therapeutic-strategies/