Prospective Observation on the Use of Von Willebrand Factor (VWF) Concentrates in a Large Cohort of Type 3 Von Willebrand Disease (VWD): Interim (18-months) Analyses on 149 Cases Enrolled into the 3Winters-Ips Project

Although rare, type 3 von Willebrand disease (VWD3) is of major interest because of its severe clinical presentation, the need for replacement therapy with von Willebrand Factor (VWF) concentrates and the risk of anti-VWF inhibitors. To better characterize the clinical and laboratory features of this rare inherited bleeding disorder, a large cohort of VWD3 patients has been enrolled into the type 3 Von Willebrand International RegistrieSInhibitor Prospective Study. 3WINTERS-IPS is a no-profit, investigators initiated, multicenter, European-Iranian (EU-IR) observational, retrospective and prospective study on patients with VWD3 diagnosis. One of the aims of 3WINTERS-IPS is to assess the efficacy and safety of VWF concentrates with or without FVIII, including the risk of anti-VWF antibodies, in a large cohort of centrally confirmed VWD3 patients. A total of 260 previously diagnosed VWD3 cases were enrolled into the study from 18-EU and 7-IR investigation sites (retrospective registries) and reassessed by 5 expert labs for phenotypic and genotypic analyses to confirm VWD3 diagnosis (central confirmation). Only 201/260 (77%) cases with centrally confirmed VWD3 diagnosis were included into the 24-month clinical observation (prospective phase) registered as NCT02460458 into Clinical-Trials.gov. All the clinical and laboratory data were reported by investigators into the database online organized by a CRO under the direct supervision of the Scientific Coordinators. Clinical results on the efficacy and safety of VWF concentrates during the first 18-month observation are currently available on 149/201 (74%) VWD3 patients (EU=62/IR=87) with the following sex (M/F) and age (Mean-SD, Median) distribution: 86/115 and 28.9-18, 27. Anti-VWF antibodies were confirmed in 16/201 (8%) VWD3: these patients are under treatment with recombinant FVIII without VWF or recombinant activated Factor VII. Being 3WINTERS-IPS a non-interventional study, the therapeutic approaches such as on demand (OD) or secondary long-term prophylaxis (SLTP) with the assigned VWF concentrates with or without FVIII (FANHDI, HAEMATE-P, WILATE, WILFACTIN) were decided by local investigators. The number of VWD3 treated OD/SLTP were 106/43 with more cases under SLTP at EU than at IR sites (28/15). Cases under OD/SLTP with bleeds were 73/106(69%) of OD and 21/43(48%) of SLTP. To compare the results of OD/SLTP groups, data obtained were divided by case number and by months to calculate the mean (range) annual bleeding rate (ABR). ABR observed so far in OD/SLTP is 4.3 (2.8-5.8)/3.1(1.4-3.8) with nose (29/28%), joint (19/24%), uterus (13/23%) bleeds being the most frequent sites. To manage (OD) or prevent (SLTP) bleeds the mean (range) consumption of VWF:RCo units of VWF concentrates per patient were 4800 (1800-15.500) and 8000 (5000-10.500) units, respectively. During follow-up VWD3 patients under OD/SLTP were exposed to 17/10 minor/major surgeries with 14.900 (9.500-22.000)/17.200 (12.800-31.000) VWF:RCo Units used per surgery. Efficacy of the different VWF concentrates was reported as good/excellent during bleeds and surgeries. No side effects related to VWF concentrates were reported by investigators: no additional anti-VWF antibodies were found after the use of VWF concentrates. Based on this interim analyses on the largest cohort of VWD3 currently under prospective observation, the frequency of spontaneous bleeds assessed by ABR seems lower than expected by the severe VWF defect of VWD3. So far, the use of SLTP seems to reduce the ABR. However, a longer prospective observation (from 2 to 5 years) with 3WINTERS-IPS-EXTENDED is required to characterize bleeding phenotype of VWD3 patients and to prepare recommendations on the appropriate use (OD/SLTP) of the VWF concentrates