Type 1 von Willebrand disease (VWD), the most common form of this disease, is defined by quantitative deficiency of von Willebrand factor (VWF) and bleeding symptoms in a proband who also has family members with the same features. A major discrepancy between VWF antigen (VWF:Ag) and ristocetin cofactor activity (VWF:RCo), or a manifestly abnormal VWF multimer profile, points toward an abnormal VWF molecule and suggests a diagnosis of VWD type 2 rather than VWD type 1. Although simple in concept, this definition can be difficult to translate into operational steps to diagnose individual patients correctly. This difficulty is due to several factors that have been increasingly clarified during recent years. Type 1 VWD, although generally transmitted in a dominant way, is variably penetrant in different families and may be variably expressed in the same family. The VWF levels in affected patients and healthy controls overlap considerably and there is no strong relationship between plasma VWF levels and bleeding manifestations, apart from very severe cases. Furthermore, VWF levels are 25–30% lower in O blood group individuals, and blood group O is over-represented among VWD patients. Also, mucocutaneous bleeding symptoms are more common in the healthy population than is often recognized. All of these factors interfere with the evaluation of the three main criteria used to diagnose VWD: reduced VWF level, bleeding symptoms, and inheritance [1–3].
During 1995–1996, an ad hoc working party (Chair J. E. Sadler, Co-chair F. Rodeghiero) of the Subcommittee on VWF of SSC/ISTH proposed consensus criteria for the diagnosis of VWD type 1. They were formulated taking into consideration the opinion and the experience of the members of the working party (WP) through a structured questionnaire and ranking the preferred choices or criteria in response to several questions concerning bleeding symptoms, inheritance and laboratory investigations. The normal range of VWF was differentiated according to O and non-O blood groups. The problem of diagnosis in young children or in patients lacking a convincing personal or family bleeding history was recognized, and therefore a distinction was made between ‘type 1 VWD’ and ‘possible type 1 VWD’. These criteria were approved at the 42nd Annual SSC Meeting held in Barcelona as provisional criteria, with the caveat that they should represent a starting point for further investigation and validation by appropriate clinical studies.
These criteria were never published and have not been easily available, although they have been used in several studies of VWD type 1 prevalence or diagnosis [4–6]. Multicenter studies using modifications of these provisional criteria are underway to better define markers for diagnosis and to clarify the association of bleeding symptoms with specific molecular defects at the VWF locus.
Each of these criteria and their combination needs to be evaluated with respect to sensitivity and specificity in order to produce clinically useful guidelines for the diagnosis and management of VWD type 1. Experience during the last 10 years indicates that most mild VWD cases could simply represent coincidental association of low VWF level with bleeding symptoms, even if all of the provisional criteria for diagnosing ‘VWD type 1’ are satisfied . Well-controlled epidemiological criteria considering the combination of bleeding symptoms and reduced VWF values in more than one family member could produce a diagnosis of VWD in up to 1% of a screened population of school children . As a matter of fact, only one of the 10 patients identified in this investigation has sought medical assistance for bleeding during the past 15 years, indicating that diagnosing very mild cases may not be helpful . Clearly, we need different criteria in order to make clinically meaningful diagnoses. These diagnoses should benefit patients by improving the prevention or treatment of significant bleeding; they should not just label them with a congenital disorder that entails unmerited negative social and personal consequences .
Despite the limitations discussed above, the provisional consensus criteria developed by the Subcommittee on VWF may provide a useful point of reference for studies of how to diagnose VWD type 1 or manage patients with low VWF levels. Therefore we have included them here (Appendix) in case they may be useful for such investigations.