Secondary Long-Term Prophylaxis in Severe Patients with von Willebrand’s Disease: An Italian Cohort Study.

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. However, little retrospective or prospective data on secondary long term prophylaxis in VWD are available. Aim of this study was to evaluate the efficacy and safety of fixed regimens of prophylaxis with factor VIII/VWF concentrates in our cohort of VWD patients with recurrent joint and gastrointestinal (GI) bleeds. Design and Methods. This is a cohort study on 452 VWD patients regularly followed up at our Center for at least three years. 89/452 cases (20%) were treated with FVIII/VWF concentrates during the last two years because of one or more bleedings and 11/89 (12%) were included in a long term prophylaxis program because of frequent recurrence of bleeds at the same sites. All patients were characterized by a bleeding severity score derived from a detailed history of 11 symptoms. Since concentrates available in Italy are still labelled in FVIII IU, patients were given 40 FVIII IU/Kg of high- (Alphanate, Fanhdi) or intermediate-purity (Haemate-P) concentrates, two times a week (joint bleeds) or every other day (GI bleeds) to maintain FVIII/VWF levels higher than baseline during prophylaxis. Effectiveness of prophylaxis was based on resolution/reduction of bleeding as well as on numbers of transfused packed red blood cells (PRBC) and days of hospitalization. Safety was measured by monitoring side effects and FVIII levels before and after every injection during the first three weeks of prophylaxis. Results. All the 11 patients were severe, as shown by high bleeding scores (> 20) and VWF:RCo baseline levels <10 U/dL. Prophylaxis was started because of GI bleeds in 7 patients with VWD type 3 (n=1), 2A (n=4), 2M (n=1) and 1 (n=1) and for joint bleeds only in VWD type 3 (n= 4). Prophylaxis could stop bleeding in 8 patients and largely reduced hospitalization for PRBC transfusions in the remaining 3. When prophylaxis was compared with previous on demand regimen in all 11 cases, the annual total FVIII IU (x 1000) of concentrate (a) as well as number of PRBC used (b) and days of hospitalization (c) were significantly reduced (mean ± SD, with * p < 0.01): a * = 239±207 versus 385±247; b* = 9±11 versus 3±4; c* = 18±13 versus 4±3. As far as safety, FVIII levels were always <180 U/dL in all VWD and no side effects, including thrombosis, were observed. Interpretations and Conclusions. Secondary long-term prophylaxis by high-and intermediate purity FVIII/VWF concentrates is effective and safe in severe forms of VWD. Cost-effectiveness of these prophylaxis regimens versus on demand therapy should be further investigated in large prospective studies.