1. Genetic determinants of enhanced von Willebrand factor clearance from plasma.
- Author
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Seidizadeh O, Baronciani L, Pagliari MT, Cozzi G, Colpani P, Cairo A, Siboni SM, Biguzzi E, and Peyvandi F
- Subjects
- Humans, von Willebrand Factor genetics, von Willebrand Factor chemistry, Protein Precursors, von Willebrand Diseases diagnosis, von Willebrand Diseases genetics, von Willebrand Disease, Type 1 diagnosis, von Willebrand Disease, Type 1 genetics
- Abstract
Background: Enhanced von Willebrand factor (VWF) clearance from plasma is associated with von Willebrand disease (VWD). However, the genetic background of this disease mechanism is not well defined., Objective: To determine VWF variants that are associated with reduced VWF survival., Methods: Two hundred fifty-four patients with VWD (type 1 = 50 and type 2 = 204) were investigated, and the results were compared with 120 healthy controls. The patients were comprehensively characterized for phenotypic and genetic features. The ratio of VWF propeptide (VWFpp)/VWF antigen (VWFpp ratio) was used to establish in each patient the VWF clearance state., Results: Out of 92 variants associated with type 1 (7 were novel) and type 2 VWD, 19 had a VWFpp ratio ranging from 1.7 to 2.2, 24 had a VWFpp ratio between 2.3 and 2.9, and 24 variants had a ratio of ≥3. The VWFpp median ratio in healthy controls was 0.98 (0.55-1.6) so that a cut-off value of >1.6 was considered an indicator of accelerated VWF clearance from plasma. An enhanced VWF clearance was observed in 34% of type 1 cases, 100% of type 1 Vicenza cases, 81% of 2A cases, 77% of 2B cases, 88% of 2M cases, and 36% of 2N cases., Conclusions: An accelerated VWF clearance was found in most patients with type 2A, 2B, and 2M VWD, with a lower proportion of type 1 and 2N. Sixty-seven different variants alone or in combination with other variants were associated with an increased VWFpp ratio. The variants with the highest VWFpp ratio were mostly located in the D3-A1 VWF domains., Competing Interests: Declaration of competing interests F.P. has participated in educational meetings and the advisory board of Sanofi, Sobi, Takeda, Roche, and Biomarin. O.S. received congress support from Kedrion. All other authors report no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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