Clinical Joint Outcome after Joint Bleeds in Patients with Von Willebrand Disease Is Comparable to Moderate and Severe Hemophilia A Despite Fewer Joint Bleeds
Authors: van Galen Karin PM , Timmer Merel , de Kleijn Piet , Leebeek Frank W.G. , Schutgens Roger E.G. , Fischer Kathelijn , Mauser-Bunschoten Eveline 
Published: October 2019

Abstract
Background
Recurrent joint bleeds are the main cause of joint deterioration (hemophilic arthropathy) in patients with hemophilia. To what extent arthropathy occurs following joint bleeds in patients with Von Willebrand disease (VWD) compared to hemophilia has never been studied.
Objectives
The primary objective was to compare joint outcome by physical examination between adults with VWD and moderate and severe hemophilia A (HA). The main secondary objectives were to compare joint bleed frequency, radiological joint damage and self-reported functional limitations between VWD and moderate and severe HA.
Methods
We selected adult patients with VWD (VWF activity <30%) and moderate or severe HA, who had a medical history of treatment for joint bleeds, for this post hoc analysis. To compare joint outcome we used the Hemophilia Joint Health Score (HJHS range 0-124, obtained by physical examination), X-ray Pettersson scores of ankles, knees and elbows (PS range 0-13 per joint) and Hemophilia Activities List scores, a patient administered questionnaire measuring functional limitations (HAL range 0-100). Univariate analyses were performed using Mann Whitney U and Chi2. For multivariate analysis we used negative binomial regression analysis (HJHS) and logistic regression (dichotomized PS>3 and HAL<95) adjusted for age. We performed a subgroup analysis of the patients with type 3 VWD.
Results
We included 48 patients with VWD, 39 with moderate and 59 with severe HA. The mean age was 45, 38 and 26 years, respectively. Fewer patients with VWD than HA had a lifetime history of more than 5 joint bleeds (56% VWD vs. 77% moderate HA vs. 98% severe HA, p<0.001). Joint dysfunction at physical examination was comparable between the patients with VWD and moderate HA (median HJHS 5 vs. 5.5, p=0.65) but slightly better in VWD compared to severe HA (median HJHS 5 vs. 9, p=0.02). Apparent joint damage on X rays (PS>3 of one or more joints) occurred in 12/46 patients with VWD compared to 27/40 patients with severe HA (26% vs. 68%: OR 0.09; 95%CI 0.03-0.34, p<0.001). In moderate HA insufficient X rays were available for analyses. Functional limitations according to the HAL were comparable between patients with VWD and moderate and severe HA (VWD median HAL total score 88 vs. 95 in both moderate and severe HA, p=0.35).
The subgroup analysis of joint dysfunction in patients with type 3 VWD (n=19, median age 40) showed clinical changes comparable to severe HA (median HJHS 14 vs. 9, p=0.83). We found a trend towards less radiological joint damage in type 3 VWD compared to severe HA (PS>3: 47% vs. 68%, OR 0.28; 95%CI 0.07-1.12, p=0.07). However, patients with type 3 VWD reported more functional limitations compared to those with moderate or severe HA (median HAL total score 77 vs. 95, p=0.01; adjusted for age OR 0.38; 95%CI 0.1-1.2, p=0.10).
Conclusions
Despite fewer joint bleeds, joint function according to the HJHS was comparable between adult patients with VWD and moderate HA with a history of treatment for joint bleeds. Apparent X ray joint damage occurred less often in patients with VWD compared to those with severe HA. The HJHS of patients with type 3 VWD was comparable to those with severe HA, but the patients with type 3 VWD reported more functional limitations, partly explained by their higher age. Knowledge of similarities and differences in joint outcome between VWD and hemophilia can be helpful to improve the awareness and treatment of joint bleeds in VWD to prevent arthropathy and functional limitations.

Disclosures
van Galen: Bayer: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Leebeek:CSL Behring: Research Funding; Baxter: Research Funding. Schutgens:Sanquin: Research Funding; CSL Behring: Research Funding. Fischer:Baxalta/Baxter: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Wyeth: Research Funding; Biogen: Consultancy; Biotest: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy. Mauser-Bunschoten:CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Griffols: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Biovitrum: Research Funding; Saquin: Research Funding.