Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study
(2022) In Journal of Thrombosis and Haemostasis 20(5). p.1106-1114- Abstract
Background: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. Objective: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. Methods: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats... (More)
Background: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. Objective: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. Methods: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients’ diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman’s rank correlation. Results: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2–2.7; P =.016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0–4.2; P =.054]). FVIII:C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r =.024; P =.778). Conclusions: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.
(Less)
- author
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- bleeding, mutation, propeptide, von Willebrand disease, von Willebrand factor
- in
- Journal of Thrombosis and Haemostasis
- volume
- 20
- issue
- 5
- pages
- 1106 - 1114
- publisher
- Wiley-Blackwell
- external identifiers
-
- scopus:85125078712
- pmid:35092343
- ISSN
- 1538-7933
- DOI
- 10.1111/jth.15658
- language
- English
- LU publication?
- no
- id
- 284f22f7-7533-4f0d-8173-27b19c8f52d4
- date added to LUP
- 2022-04-19 11:08:10
- date last changed
- 2024-04-20 14:37:07
@article{284f22f7-7533-4f0d-8173-27b19c8f52d4,
abstract = {{<p>Background: Type 3 von Willebrand disease (VWD) is a severe bleeding disorder caused by the virtually complete absence of von Willebrand factor (VWF). Pathophysiological mechanisms of VWD like defective synthesis, secretion, and clearance of VWF have previously been evaluated using ratios of VWF propeptide (VWFpp) over VWF antigen (VWF:Ag) and factor (F)VIII coagulant activity (FVIII:C) over VWF:Ag. Objective: To investigate whether the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios may also be applied to understand the pathophysiological mechanism underlying type 3 VWD and whether VWFpp is associated with bleeding severity. Methods: European and Iranian type 3 patients were enrolled in the 3WINTERS-IPS study. Plasma samples and buffy coats were collected and a bleeding assessment tool was administered at enrolment. VWF:Ag, VWFpp, FVIII:C, and genetic analyses were performed centrally, to confirm patients’ diagnoses. VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were compared among different variant classes using the Mann-Whitney test. Median differences with 95% confidence intervals (CI) were estimated using the Hodges-Lehmann method. VWFpp association with bleeding symptoms was assessed using Spearman’s rank correlation. Results: Homozygosity/compound heterozygosity for missense variants showed higher VWFpp level and VWFpp/VWF:Ag ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2–2.7; P =.016]; [VWFpp/VWF:Ag median difference, 1.4; 95% CI, 0–4.2; P =.054]). FVIII:C/VWF:Ag ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r =.024; P =.778). Conclusions: An increased VWFpp/VWF:Ag ratio is indicative of missense variants, whereas FVIII:C/VWF:Ag ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.</p>}},
author = {{Pagliari, Maria Teresa and Rosendaal, Frits R. and Ahmadinejad, Minoo and Badiee, Zahra and Baghaipour, Mohammad Reza and Baronciani, Luciano and Benítez Hidalgo, Olga and Bodó, Imre and Budde, Ulrich and Castaman, Giancarlo and Eshghi, Peyman and Goudemand, Jenny and Karimi, Mehran and Keikhaei, Bijan and Lassila, Riitta and Leebeek, Frank W.G. and Lopez Fernandez, Maria Fernanda and Mannucci, Pier Mannuccio and Marino, Renato and Oldenburg, Johannes and Peake, Ian and Santoro, Cristina and Schneppenheim, Reinhard and Tiede, Andreas and Toogeh, Gholamreza and Tosetto, Alberto and Trossaert, Marc and Yadegari, Hamideh and Zetterberg, Eva M.K. and Peyvandi, Flora and Federici, Augusto B. and Eikenboom, Jeroen}},
issn = {{1538-7933}},
keywords = {{bleeding; mutation; propeptide; von Willebrand disease; von Willebrand factor}},
language = {{eng}},
number = {{5}},
pages = {{1106--1114}},
publisher = {{Wiley-Blackwell}},
series = {{Journal of Thrombosis and Haemostasis}},
title = {{Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study}},
url = {{http://dx.doi.org/10.1111/jth.15658}},
doi = {{10.1111/jth.15658}},
volume = {{20}},
year = {{2022}},
}