Incidence and Determinants of Bleeding in Different Types of von Willebrand Disease: Results of the First Prospective Multicenter Study on 814 Italian Patients.
Authors: Federici Augusto B. , Bucciarelli Paolo , Castaman Giancarlo , Mazzucconi Maria G. , Morfini Massimo , Rocino Angiola , Schiavoni Mario , Rodeghiero Francesco , Mannucci Pier M. 
Published: October 2019

Abstract
Background. von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disorder, no data on the incidence and determinants of bleedings requiring specific treatments have been available thus far. Aims and design of the study: to determine the incidence and determinants of bleedings requiring therapy with DDAVP and/or VWF concentrates in VWD, a national registry was organized by using a database devised to collect detailed retrospective information. Patients included in the registry were followed up for one year and prospective data on number, type and management of bleeding episodes were analyzed.
Methods: all patients were diagnosed following recommendations of the ISTH-SSC-SC on VWF with bleeding severity score (BSS) calculated at enrollment. Diagnoses of VWD were confirmed by the coordinating center using also multimeric analysis in plasma and mutations of VWF gene in all types 2 and 3. For different risk categories the incidence of bleeding (mucosal and non-mucosal bleeding) was calculated. Bleeding-free survival was computed with the Kaplan-Meier method and a Cox’s proportional hazard model was used to calculate the risk of bleeding (hazard ratio = HR)
Results: In the retrospective study, 1,234/1,529 (81%) cases satisfied the inclusion criteria and were enrolled in the registry as types 1 (54%), 2 (40%) and 3 (6%).VWD diagnosis occurs in young adults (83%), mainly in women (57%). Mucosal bleeding (64%) are more frequent than hematomas or hemarthrosis (15%) but 73% of patients did not require transfusions. In the prospective study based on 814/1,234 (66%) cases of the registry (type 1=47%, 2=47%, 3=6%) 147/815 (18%) were treated in a year for 318 bleeding episodes and 87 minor or major surgeries. BSS >10 (6.8, 3.8–12.3), bleeding time >20 min (BT = 5.5, 3.1–9.8), VWF:RCo <10 U/dL (3.2, 1.7–5.9) and FVIII:C <20 U/dL (4.1, 2.4–7) were significantly associated with high risk of bleeding. By multivariate model including all the variables, BSS (5.5, 2.8–10.8) was the most significant determinant of bleeding. The bleeding-free survival at one year was significantly different in type 3 (52%) versus types 1 (96%) and 2 (91%) VWD. On the other hands, patients with VWF.RCo >30 U/dL and FVIII:C > 40 U/dL showed always BSS <5 with the lowest incidence of bleeding. A total of 292 DDAVP injections were used to manage bleeding and surgeries in types 1 (65%) and 2 (35%) VWD and 452 injections of VWF concentrates were used to treat bleeding and surgeries in type 3 (75%), type 2 (34%) and type 1 (15%) VWD.
Conclusions: This prospective study confirms that BSS is an important predictive factor for clinical bleeding and the need for treatment. In cases with VWF.RCo >30 U/dL and FVIII:C >40 U/dL bleeding episodes are very rare, in agreement with their relatively low BSS.