Abstract

Type 3 von Willebrand Disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) antigen, and a parallel decrease in FVIII activity and VWF function. In addition to mucocutaneous bleeding, hemarthrosis and limited joint range of motion (ROM) have been reported. We have previously shown that lower FVIII level, increasing age, history of joint bleeding, and higher body mass index (BMI) are negatively associated with joint function in the Type 3 VWD population. The goal of this study was to compare subjects with similar FVIII levels (Type 3 VWD versus moderate Hemophilia A) in order to further isolate the role of FVIII and other variables in joint ROM loss. A previously validated cohort of subjects with Type 3 VWD and FVIII ≤ 5% were compared to subjects with moderate Hemophilia A (FVIII 1–5%) within the CDC-sponsored Universal Data Collection (UDC) database, which contains information on subjects with bleeding disorders followed at Hemophilia Treatment Centers in the U.S. Subjects with a history of an inhibitor were excluded. At each visit, a joint function score was calculated for each subject as the overall proportion of normal joint ROM based on measures taken of 10 joints. Longitudinal data analysis was performed to identify factors affecting joint ROM loss over time.

Clinical characteristics of the two cohorts are as follows:

 Moderate Hemophilia A (n=1814) Type 3 VWD (n=100) p-value 
* Includes mucosal 
** 4 patients with VWD did not have explicit FVIII levels and were excluded from this analysis. 
Gender (F:M) 17:1797 49:51 < 0.001 
Age at 1st visit (mean, range) 19.1 (2–69) 21.9 (3–69) 0.09 
History of bleed (%) 1773 (97.7%) 99 (99.0%) 0.72 
Age of 1st bleed (mean, SD) 2.5 (4.7) 2.0 (5.6) 0.45 
# joint bleeds (mean, SD) 3.0 (6.9) 1.6 (4.3) 0.09 
# muscle bleeds (mean, SD) 0.9 (2.5) 0.4 (1.2) 0.07 
# other bleeds (mean, SD)* 1.2 (4.6) 4.0 (14.5) <0.001 
Home Infusion (%) 1056 (58.2%) 53 (53.0%) 0.03 
Prophylaxis (%) 379 (20.9%) 12 (12.0%) 0.03 
FVIII level (mean, SD)** 2.9 (1.3) 2.6 (1.4) 0.12 
 Moderate Hemophilia A (n=1814) Type 3 VWD (n=100) p-value 
* Includes mucosal 
** 4 patients with VWD did not have explicit FVIII levels and were excluded from this analysis. 
Gender (F:M) 17:1797 49:51 < 0.001 
Age at 1st visit (mean, range) 19.1 (2–69) 21.9 (3–69) 0.09 
History of bleed (%) 1773 (97.7%) 99 (99.0%) 0.72 
Age of 1st bleed (mean, SD) 2.5 (4.7) 2.0 (5.6) 0.45 
# joint bleeds (mean, SD) 3.0 (6.9) 1.6 (4.3) 0.09 
# muscle bleeds (mean, SD) 0.9 (2.5) 0.4 (1.2) 0.07 
# other bleeds (mean, SD)* 1.2 (4.6) 4.0 (14.5) <0.001 
Home Infusion (%) 1056 (58.2%) 53 (53.0%) 0.03 
Prophylaxis (%) 379 (20.9%) 12 (12.0%) 0.03 
FVIII level (mean, SD)** 2.9 (1.3) 2.6 (1.4) 0.12 

Longitudinal data analysis revealed no significant difference in joint ROM loss over time between the Type 3 VWD and moderate Hemophilia A cohorts. Age, non-white race, lower FVIII level, BMI, use of prophylaxis, and history of an invasive joint procedure or orthopedic appliance were significantly associated with joint ROM loss over time. In the subgroup with age < 20 years old, only increasing age, non-white race and male gender were significantly associated with increased joint ROM loss. A predictive model confirmed the significance of a lower FVIII level as a risk factor for the development of increased joint ROM loss over time. A lower FVIII value was found to significantly contribute to both joint and muscle bleeding, but not other (including mucosal) bleeding in the combined cohort. In conclusion, subjects with Type 3 VWD and moderate Hemophilia A both demonstrate a strong bleeding phenotype, with bleeding symptoms beginning at a young age and frequently requiring home therapy. In addition to reporting similar numbers of joint bleeds, subjects with Type 3 VWD and FVIII ≤ 5% have a similar rate of joint ROM loss over time compared to subjects with moderate Hemophilia A. Both longitudinal data analysis and predictive modeling demonstrate that a lower FVIII level significantly contributes to increased joint ROM loss over time. These results help confirm the similarity of the joint bleeding phenotype between subjects with Type 3 VWD and moderate hemophilia A and support that the FVIII level plays an important role in the loss of joint ROM over time in patients with Type 3 VWD. As the ROM loss over time in the two groups was indistinguishable, and patients with hemophilia are known to have normal VWF levels, it suggests that a low VWF antigen may not contribute any additional risk to joint function limitation in the Type 3 VWD population. Further studies are warranted to further define risk factors for joint function limitation in the Type 3 VWD population in order to identify a subgroup that may benefit from prophylactic therapy.

Disclosures: No relevant conflicts of interest to declare.

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