However, despite these critical events for patients there have been no advances so far about the causes,

laboratory diagnosis and the best treatment of this rare complication of VWD. Studies need to be set up selleck to identify the following: Definition of anti-VWF inhibitors Genetic defects Laboratory tests to search for inhibitors Therapeutic approaches . Compared to patients with severe-moderate haemophilia A developing inhibitors in about 20–30% of cases, anti-VWF inhibitors are a rare complication of replacement therapy in VWD, mainly occurring in patients with severe inherited type 3 VWD. These inhibitors are allo-antibodies and might be related to deletions in the VWF gene. However, it is known that not all gene deletions are associated

with these inhibitors. Inhibitors have not ever been identified in patients with discrete amounts of circulating VWF such as VWD1, VWD2A, VWD2B, VWD2M and VWD2N (normal or abnormal VWF). In the late 1980s, the first gene defects were identified using the Southern blot technique. A study by Shelton-Inloes et al. showed that homozygous complete VWF gene deletions were identified in 2 of 19 VWD3 patients [78]. Another study showed that complete homozygous and heterozygous deletions were found in six VWD3 patients [79]. In the 1990s, one complete homozygous and one partial heterozygous deletion were detected among 28 VWD3 GS-1101 German patients, whereas one complete heterozygous

VWF gene deletion was identified among five VWD3 Italian patients [80]. The occurrence of an alloantibody directed against VWF in multi-transfused patients with severe VWD3 was first reported in 1974. An incidence of 7.5–9.5% was found in one retrospective international survey based on the 150 cases tested [81]. In the retrospective analysis of the Italian Association of Haemophilia Centres, 96/1650 VWD3 patients (5.8%) were identified among those included in the registry with a prevalence of 1.6 VWD3/million population. Anti-VWF inhibitors were identified in seven VWD3 patients from only three families, Table 2 [82]. The Bethesda method with the Nijmegen modification (with results expressed in Bethesda Unit, BU) is currently used to characterize these inhibitors in patients with haemophilia A. Unfortunately, no general consensus has been reached for click here diagnosing anti-VWF inhibitors. Mix experiments with VWF/FVIII activities were tested after 1–4 h incubation at 37°C. Several solid phase tests have been proposed by different authors, but they are not frequently used. In VWD several assays should be used to assess the inhibitory activities of these allo-antibodies: RIPA in normal PRP; anti-VWF:Ag, anti-VWF:RCo; anti-VWF:CB, anti-FVIII. Antibodies might also occur against ‘mute’ regions of VWF molecules: therefore the inhibiting activity cannot be identified with anti:VWF:RCo, anti-VWF:CB, anti-VWF:Ag and anti-FVIII activities.