von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease

The ratios between von Willebrand factor propeptide (VWFpp) or FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) reflect synthesis, secretion and clearance of VWF. We aimed to define the pathophysiology of 658 types 1, 2 and 3 von Willebrand disease (VWD) patients with VWF levels ≤30 U/dL from the "Willebrand in the Netherlands" (WiN-)study using the VWFpp/VWF:Ag and FVIII:C/VWF:Ag ratios. We also evaluated the use of VWFpp in the classification and diagnosis of VWD. Based on the ratios, reduced VWF synthesis was observed in 18% (67/380) of type 1 patients and in only 2% (5/240) of type 2 patients. A significant proportion of type 3 patients had detectable VWFpp (14/37, 41%). These patients had a lower bleeding score than type 3 patients with complete absence of both VWF:Ag and VWFpp: 14.0 vs. 19.5, p=0.025. The majority of these patients had missense mutations with rapid VWF clearance, whereas type 3 patients with absence of VWFpp were homozygous for null alleles. In conclusion, VWFpp identified severe type 1 VWD with very low VWF levels in patients who had previously been classified as type 3 VWD. This study underlines the clinical significance of the VWFpp assay in the diagnosis and classification of VWD.