DECREASED VON WILLEBRAND FACTOR SURVIVAL AS CAUSE OF VON WILLEBRAND DISEASE: ROLE OF MUTATIONS IN VON WILLEBRAND FACTOR GENE AND OF ABO BLOOD GROUPS

Von Willebrand disease (VWD) is the most frequent inherited bleding disorder characterized by great complexity and significant heterogeneity, aspects that affect diagnosis and therapy. VWD is dependent on quantitative defect or abnormalities of VWF, with consequential reduced plug fromation at the vessel wall site. Therefore, patients affected by VWD suffer bleeding tendencies, more or less severe, after trauma. VWD is sometimes not diagnosed and often poorly diagnosed with great consequences in terms of therapy. In this project, we will study new mechanisms responsible for VWD, in particular verifying the contribution of reduction in survival in the VWD development. In our study a great number of well characterized VWD patients and normal subjects will be infused with DDAVP, an analogue of vasopressin (the antidiuretic hormon) which is the only non hemoderivate drug capable of curing most VWD and some Haemophilia A patients. Furthermore, in this study we will express in vitro recombinant VWF carrying the mutations present in Vicenza VWD, the first variant that our group has demonstrated to depend on reduced VWF survival. Furthermore, we will investigate the contribution of ABO blood groups in determining the major or minor phenotypic expression of VWD, since most VWD patients (75%) have O blood type. The present project will also clarify physiologic mechansims of ABO contribution on VWD penetrance. All these findings have great implications not only in VWD diagnosis, but also on prognosis in terms of therapeutic requirements. The comprehension of these mechanisms also adds to understanding Haemophilia A, since O blood type would be recognized as a more sever criteria for the disease. Moreover, the therapy, mainly when recombinant FVIII concentrates are employed, in O blood group patients, could have less therapeutic efficacy and duration in respect to non-O ones.