Prevalence and Determinants of Bleeding in Severe Von Willebrand Disease Type 3: Results of Retro/Prospective Studies in a Cohort of 105/52 Italian Patients.

von Willebrand disease type 3 (VWD3) is due to virtually complete deficiency of the von Willebrand factor (VWF) and, for this reason, has been also described as “severe VWD”. Although rare (1-5 cases per million population), VWD3 is of major interest because of its severe clinical presentation, the need for replacement therapy with VWF/FVIII concentrates and the risk of occurrence of anti-VWF inhibitors after the infusion of VWF/FVIII concentrates.

to determine the prevalence and determinants of bleedings requiring therapy with VWF/FVIII concentrates in VWD3 patients, data were collected from the Italian registry on Hemophilia and Allied Disorders organized on behalf of the Italian Association of Hemophilia Centers (AICE). The VWD3 patients included in the registry were then followed up for one year by six Italian Centers and prospective data on number, type and management of bleeding episodes were analyzed.

VWD3 patients were diagnosed when VWF antigen was undetectable and factor VIII (FVIII) levels were reduced in plasma. Bleeding severity score (BSS) was calculated at enrollment. Gene deletions and mutations were searched for in all available DNA. 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)

In the Italian registry, 105 VWD3 patients (5.7%) were identified among the 1850 VWD (Italian prevalence=1.75 per million). The entire cohort of VWD3 was characterized by the following demographic, clinical and laboratory parameters (median, range): gender (M/F)= 50/55; age=37 (3-65); BSS=18 (3-35); FVIII= 4 (2-18); anti-VWF inhibitors= 7 cases (6.7%) from 3 families. Molecular diagnosis was available in 65/105 cases with the following gene defects (pt-n): large deletion (7); small deletions and insertions (23); nonsense (9); splice site (8) and missense mutations (17). Mucosal bleedings (64%) were more frequent than hematomas and hemarthrosis (24%). At the time of the enrollment in the registry 95/105 (91%) VWD3 had been already exposed to VWF/FVIII concentrates because of bleeding and/or minor or major surgeries. In the prospective study, 52 VWD3 patients could be enrolled and 46 (88%) were treated in a year for 118 bleeding episodes and 27 minor or major surgeries. BSS>10 (6.8, 3.8-12.3) and FVIII<10U/dL (4.1, 2.4-7) were significantly associated with high risk of bleeding. The bleeding-free survival at one year calculated according to values of BSS and FVIII levels showed 4 different KM curves with the following results:

89% (BSS=5-10&FVIII>10U/dL); 64%(BSS>10&FVIII=5-10U/dL);

59% (BSS=5-10&FVIII<10U/dL); 18%(BSS>10&FVIII<5U/dL). A total of 192 injections of VWF/FVIII concentrates were used to treat bleeding and surgeries in VWD3. Patients with anti-VWF inhibitors were off therapy during this follow-up.

these retro/prospective studies performed for the first time in a relative large cohort of patients show that also VWD3 can be very heterogeneous. BSS & FVIII levels are good predictors of bleeding. Larger multicenter studies should be organized to identify possible additional modifiers influencing the risk of bleeding in VWD3.

No relevant conflicts of interest to declare.