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www.vwfassays-in-vwd.com Background Von Willebrand factor (VWF) is a multifunctional glycoprotein which circulates in plasma as a multimeric form in a complex with factor VIII (FVIII/VWF complex). VWF plays a pivotal role in hemostasis, by promoting platelet adhesion to subendothelium, through two different functional domains (the VWF receptor for platelet GpIb/IX complex in the A1 domain and the VWF receptors for subendothelial/collagens in the A2 and A3 domains) as well as platelet-platelet interactions (the VWF receptor for platelet GpIIb/IIIa complex). VWF is also the carrier for FVIII and is essential for its function by protecting it from early proteolysis in the circulation (the VWF receptor for FVIII in the D' domain). Moreover, since the VWF is a multimeric glycoprotein, and its native subunit is organized in dimers by disulphide bonds at the carboxy-terminal part of the molecule, the C-terminal (CK domain) should be considered an additional important side of VWF activity. Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder and is due to quantitative (type 1 and 3 VWD) or qualitative defects of VWF. VWD can be very heterogeneous because VWD patients can show molecular defects of VWF in virtually more than one of the functional domains of this multimeric glycoprotein. Compared to patients with hemophilia A (HA), the other most frequent inherited bleeding disorder, who are characterized by reduced plasma levels of a single factor (FVIII levels < 1 U/dL = severe HA; 1-10 U/dL = moderate HA; 10-30 U/dL = mild HA), patients with VWD need more than one test to be correctly diagnosed. According to the role of VWF in hemostasis, tests for a correct diagnosis of VWD should explore the most important VWF activities, namely the antigenic levels of VWF (VWF:Ag), the VWF-platelet GpIb interactions (VWF:RCo), the VWF-subendothelium-collagen interactions (VWF:CB), the VWF-factor VIII interactions (VWF:FVIIIB), the capacity of VWF to be organized in normal multimers (VWF:MULT). A proposal has been made by a Steering Committee on behalf of the ISTH-SSC on VWF to organize an international collaborative effort to determine the best approach to the diagnosis of VWD. Aims of this WP This is not a quality control exercise, but is trying to establish the best diagnostic repertoire currently available for VWD diagnosis by means of the following specific aims: a) to review all the methods used until now for VWD diagnosis with available tests for VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF collagen binding assay (VWF:CB), VWF multimers (VWF:MULT), VWF/FVIII binding assays (VWF:FVIIIB); b) to select the methods which appear to be the most suitable for an International Survey; c)to test these methods in the identification of specific VWD VARIANTS already characterized by various phenotypic tests and identification of VWF gene mutations; d) to involve laboratories from all over the world which will perform these assays blindly to assess the potency in making correct diagnosis of these VWD variants; e) to prepare guidelines for minimal requirements for correct VWD diagnosis
Augusto B. Federici, MD On behalf of the Members of the Steering Committee: Ulrich Budde, Giancarlo Castaman, Emanuel Favaloro, Ken Friedmam, Anthony Hubbard, Christine A. Lee, Claudine Mazurier, Robert R. Montgomery, Alok Shrivastava, Mark Weinstein |
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