Efficacy and Safety of High-Intermediate-Purity VWF/FVIII Concentrates Given Repeatedly to Severe Patients with Von Willebrand Disease: An Italian Cohort Study on 32 Intensively Treated Cases.

Background and Objectives. Patients with severe forms of von Willebrand’s disease (VWD) may have frequent episodes of mucocutaneous bleeding and also of hemarthrosis or hematomas. They are usually unresponsive to desmopressin (DDAVP) and must be treated with high- or intermediate-purity VWF/FVIII concentrates (VWFc). Due to the different VWF/FVIII composition of the VWFc, timing and dosage of infusions are still not completely standardized. Aim of this study was to evaluate the efficacy and safety of repeated infusions of VWFc given on demand, for bleeds and surgery, and on secondary long-term prophylaxis to our cohort of severe VWD patients.

Design and Methods. This is a cohort study on 473 VWD patients regularly followed up at our Center for more than two years. Inclusion criteria: patients proven to be unresponsive to DDAVP and treated with VWFc with > 25 exposure days (ED)/year (> 50,000 FVIII U/year) during the previous 2 years. All patients were characterized by a bleeding severity score derived from a detailed history of 11 symptoms. Since VWFc available in Italy are still labeled in FVIII IU, patients were given 60 or 40 FVIII IU/Kg of high- (Alphanate, Fanhdi) or intermediate-purity (Haemate-P) in case of on demand or long term prophylaxis, respectively. Efficacy of VWFc used on demand versus prophylaxis (every other day or twice a week) regimens was based on resolution/reduction of bleeds and rated as excellent/good versus partial/poor clinical responses. Safety was measured by monitoring side effects and pre-post infusion FVIII levels during the first two weeks of treatment.

Results. 32/473 (7%) patients only met the inclusion criteria. They were severe (bleeding scores >15; VWF:RCo baseline levels <10 U/dL), with confirmed VWD diagnosis (case n) of types 3 (7), 2A (8), 2B (6), 2M (5) and 1 (6). High (n= 9) and intermediate (n=12) VWFc were used on demand therapy in 21 VWD cases. Prophylaxis was started because of recurrent GI bleeds in 7 patients with VWD types 3 (n=1), 2A (n=4), 2M (n=1) and 1 (n=1) and for joint bleeds only in VWD type 3 (n= 4). Total amounts of FVIII:C Units (mean values with ranges ×1000 U/year) transfused were: on demand = 66.4 (51–123); secondary prophylaxis = 297 (117–720). Clinical response was excellent/good in >95%, >85%, >90% surgeries, bleeds, prophylaxis, respectively. Prophylaxis could stop bleeding in 8 patients and largely reduced hospitalization for PRBC transfusions in the remaining 3. As far as safety, FVIII levels were always <180 U/dL during bleeds and prophylaxis and <210 U/dL during surgeries in all intensively treated VWD. No side effects, including thrombosis, were observed Interpretations and Conclusions. High- and intermediate-purity VWFc are effective and safe in severe forms of VWD also in patients exposed to intensive regimens of therapy, on demand or on prophylaxis. The use of pre-post infusion levels of FVIII is very useful to prevent unnecessary treatment with VWFc. Cost-effectiveness of prophylaxis regimens versus on demand therapy should be further investigated in large prospective studies.