Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study.

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 (VWFAg) and factor (F)VIII coagulant activity (FVIIIC) over VWFAg. OBJECTIVE: To investigate whether the VWFpp/VWFAg and FVIIIC/VWFAg 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. VWFAg, VWFpp, FVIIIC, and genetic analyses were performed centrally, to confirm patients' diagnoses. VWFpp/VWFAg and FVIIIC/VWFAg 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/VWFAg ratio than homozygosity/compound heterozygosity for null variants ([VWFpp median difference, 1.4 IU/dl; 95% CI, 0.2-2.7; P = .016]; [VWFpp/VWFAg median difference, 1.4; 95% CI, 0-4.2; P = .054]). FVIII C/VWFAg ratio was similarly increased in both. VWFpp level did not correlate with the bleeding symptoms (r = .024; P = .778). CONCLUSIONS: An increased VWFpp/VWFAg ratio is indicative of missense variants, whereas FVIIIC/VWFAg ratio does not discriminate missense from null alleles. The VWFpp level was not associated with the severity of bleeding phenotype.