Allo-antibodies are mainly of the IgG class and contain both types of chains, indicating that most of the known

allo-antibodies against VWF are of polyclonal origin. They can not only inhibit the activities Autophagy Compound Library of VWF (neutralizing antibody) but they are also able to precipitate VWF once the immuno-complexes are formed (precipitating antibody). These inhibitors tested in vitro in VWD3 cases did not inactivate FVIII: the reduced FVIII:C after VWF concentrates is probably due to steric hindrance of the FVIII molecule bound to VWF. In most reported cases, antibody development was heralded by poor clinical response to replacement therapy accompanied by lower than expected recovery of VWF with absence of delayed and sustained rise of FVIII (secondary response of FVIII). When inhibitor titre is relatively low therefore, it is not difficult to treat soft-tissue bleeds and to prevent bleeding in surgery. In patients with high titres, replacement learn more therapy is not only ineffective but it may also trigger life-threatening anaphylactic reactions, associated with activation of the complement system. A rise in antibody levels is usually seen 5–10 days after replacement therapy with VWF concentrates, with features typical of a secondary response to a foreign antigen. A VWD3

patient undergoing emergency abdominal surgery was treated with recombinant FVIII (no VWF), because this product could not cause anaphylactic

reactions. Because of the short half-life of FVIII without its VWF carrier, recombinant FVIII had to be administered by continuous intravenous infusion, at very large doses, to keep FVIII levels above 50 IU dL−1 for 10 days after surgery [84]. Another possible therapeutic approach is recombinant activated factor VII (rFVIIa) that can be used in VWD with allo-antibodies according to the same dosage and regimens as for haemophilia A with inhibitors. Type 3 VWD INTErnational RegistrieS and Inhibitor Prospective Study (3WINTERS–IPS, 2011–2016) has been set up to record clinical and laboratory MCE公司 data on a large cohort (at least 250 VWD3) collected locally from a network of European and Iranian Centres [85]. Plasma and DNA of VWD3 patients enrolled will be sent for centralized laboratory investigations. There will also be centralized evaluation of clinical and laboratory parameters (FVIII and VWF). Standardized methods for gene screening and for inhibitors against VWF in plasma will be used. In those patients with confirmed diagnosis of VWD3, there will be a 2-year clinical follow-up to evaluate frequency and risk of bleeding. The study is a prospective, multicentre, international, non-interventional 5-year clinical study. It is promoted by the AB BONOMI Foundation, a non-profit organization with funds obtained from unrestricted grants of five companies.