Clinical and laboratory versus molecular markers for a correct classification of von Willebrand disease

Abstract

von Willebrand disease (VWD) is the most common inherited bleeding disorder. In this perspective article, Drs. Federici and Canciani review how correlating the clinical, laboratory and genetic features of von Willebrand disease has led to improved understanding of its pathophysiology. They show how this has rationalized classification, which in turn can be used to improve treatment of these patients.

Figure 1.

Flow-chart proposed for the correct diagnosis and classification of different VWD types. Once bleeding history of the suspected patients with VWD is collected and family history of bleeding investigated (Table 1), a reduced level of VWF should be measured by using VWF:RCo (a). First level of diagnosis : VWD3 can be diagnosed in case of undetectable VWF:Ag (b). FVIII (c) is always reduced in VWD3 and in VWD2N: it can be reduced or normal in all the other VWD types. VWD2B can be identified (d) in case of heightened RIPA (< 0.8 mg/mL) whereas VWD1, VWD2A and VWD2M cause low RIPA (> 1.2 mg/mL). A proportionate reduction of both VWF:Ag and VWF:RCo with a VWF:RCo/Ag ratio > 0.6 suggests VWD1 (e). If the VWF:RCo/Ag ratio is < 0.6, VWD2A, VWD2B, and VWD2N should be suspected. VWD2N can be suspected in case of FVIII/VWF ratio (f) < 1 while a FVIII/VWF ratio is > 1 is usually associated with VWD1. Second level of diagnosis: Multimeric analysis in plasma (g) is necessary to distinguish between VWD2A (lack of the largest and intermediate multimers) and VWD2M (all the multimers present). VWFpp/VWF:Ag (h) is increased in VWD1 with short half-life of VWF. DDAVP infusion test (i) can identify patients with no biological response, short biological response or response to this drug. VWF:FVIIIB () should i be performed to confirm VWD2N. This figure is modified and updated from that reported previously. Once phenotypic diagnosis is performed, mutations should be searched for (molecular diagnosis) to confirm VWF defects within the family of VWD patients (Figure 2).

Figure 2.

Schematic representation of the VWF gene located in chromosome 12: the main exons are indicated with the number of base pairs from 5’ to 3’ (upper panel). The structure of VWF functional domains: the pre-pro-VWF is indicated with amino acids numbered from the amino- (aa 1) to carboxy-terminal portions (aa 2813) of VWF. Note the important CK and D3 domains for formation of VWF dimers and multimers. The native mature subunit of VWF, after the cleaving of the pre-pro-VWF, is described with its functional domains: the VWF binding sites for factor VIII (D’ and D3), GpIb, botrocetin, heparin, sulfatide, collagen (A1), collagen (A3) and the RGD sequence for binding to ·IIb‚3 (intermediate panel). Distribution of VWF mutations in patients with VWD2: the positions of mutations causing VWD2A, VWD2B, VWD2M, VWD2N are indicated with black bars throughout the VWF domains (lower panel).