VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease

Abstract

During posttranslational modifications of von Willebrand factor (VWF), the VWF propeptide (VWFpp) is cleaved. The ratio between VWFpp and VWF antigen (VWF:Ag) and the ratio between factor VIII (FVIII:C) and VWF:Ag may be used to assess synthesis and clearance of VWF. We analyzed the contribution of VWFpp and ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag in the pathophysiological characterization of type 1 von Willebrand disease (VWD) in the Molecular and Clinical Markers for the Diagnosis and Management of Type 1 VWD (MCMDM-1VWD) study. The VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios were increased among patients compared with unaffected family members and healthy controls. The VWFpp/VWF:Ag ratio was higher in individuals heterozygous for missense mutations than in those heterozygous for null alleles. In contrast, the FVIII:C/VWF:Ag ratio was highest among heterozygotes for VWF null alleles. The ratios of VWFpp/VWF:Ag and FVIII:C/VWF:Ag indicate that the pathophysiological mechanisms of type 1 VWD include reduced production and accelerated clearance of VWF, but that often a combination of both mechanisms is implicated.

Figures

Figure 1

Ratios of VWF, VWFpp, and FVIII:C. (A) Ratios of VWFpp/VWF:Ag, FVIII:C/VWF:Ag, and VWF:RCo/VWF:Ag are shown for HCs, patients without a mutation identified (No mutation), and patients with a mutation identified in the VWF gene (Mutation). Patients represent the combined results of ICs and affected family members (IC + AFM); the ICs and AFMs were combined as there were no significant differences between the groups. The horizontal gray lines indicate median ratios. The dashed lines indicate the upper limit of the normal range for VWFpp/VWF:Ag (97.5th percentile is 2.2) and FVIII:C/VWF:Ag (97.5th percentile is 1.9) and the lower limit of the normal range for VWF:RCo/VWF:Ag (2.5th percentile is 0.6). For a better graphic representation, 4 outliers with very high ratios in the Mutation group for VWFpp/VWF:Ag and 2 in the Mutation group for FVIII:C/VWF:Ag were omitted. All groups differed significantly from each other (all comparisons P < .001 with the exception of VWF:RCo/VWF:Ag HC vs No mutation, P = .0224). (B) Scatter plots of FVIII:C/VWF:Ag vs VWFpp/VWF:Ag for missense mutations (n = 224, 4 outliers were omitted for better graphic representation), null mutations (n = 20), other mutations (n = 42), and for patients with no mutation (n = 115). The group of “other mutations” comprises putative splice site mutations and changes in the 5′ untranslated region that have not yet been proven by molecular studies to result in null alleles; however, the FVIII:C/VWF:Ag suggests indeed a defect of synthesis in many of them. (C) For all individuals heterozygous for a single missense mutation, the mean (+SD) VWFpp/VWF:Ag ratio is shown. At a few codons, different substitutions were identified (p.C1130F/R/G, p.R1374H/C, p.C2477S/Y) that are listed separately as the VWFpp/VWF:Ag ratio differed for each amino acid substitution. The number of individuals carrying a specific mutation ranged from 1 to 27.