Von Willebrand Factor Propeptide and Pathophysiological Mechanisms in European and Iranian Patients With Type 3 Von Willebrand Disease Enrolled in the 3Winters-Ips Study Publisher Pubmed



Pagliari MT¹ ; Rosendaal FR² ; Ahmadinejad M^{3, 4} ; Badiee Z⁵ ; Baghaipour MR⁶ ; Baronciani L⁷ ; Benitez Hidalgo O⁸ ; Bodo I⁹ ; Budde U¹⁰ ; Castaman G¹¹ ; Eshghi P⁴ ; Goudemand J¹² ; Karimi M¹³ ; Keikhaei B¹⁴ Show All Authors
Source: Journal of Thrombosis and Haemostasis Published:2022

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 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. © 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.