Phenotypic classification of von Willebrand disease

Von Willebrand disease (VWD) is caused by quantitative and/or qualitative defects of the von Willebrand factor (VWF), a multimeric high molecular weight glycoprotein. Typically it affects the primary hemostatic system, which is reflected by a mucocutaneous bleeding tendency simulating a platelet function defect. VWD is the most common inherited coagulation disorder. The current classification comprises the main types 1, 2 and 3. The qualitative type 2 variants are differentiated into the subtypes 2A, 2B, 2M and 2M. Among these, type 2A is very heterogeneous, consisting of several phenotypically different disease entities with the diagnostic hallmark of a loss of the large multimers. Up to now, the quantitative type 1 variants were considered the most prevalent with frequencies of 70% to 80%, compared to type 2 (15-25%) and type 3 (<5%). Phenotypic characterisation of our patients was done by a battery of tests that included VWF:AG, VWF:CB, VWF:FVIIIB, the RIPA-test, and multimer analysis combined with luminescent visualisation of the electrophoretic bands by means of a sensitive video system. Among 634 patients with inherited VWD, studied during 2003, 51% had VWD type 1 compared to 47% with type 1 and 2% with type 3. Most of the type 2 variants were type 2A (75%), while type 2M (16%), type 2B (6%) and type 2N (3%) were infrequent. Thus, many patients with presumed VWD type 1 and bleeding symptoms have VWD type 2 instead. The diagnosis of VWD type 2A subtypes depends on a standardised multimer analysis as the critical method.