Bleeding Symptoms and Laboratory Correlation in 150 Patients with Severe von Willebrand Disease.

Severe von Willebrand disease (VWD) is a rare bleeding disorder with markedly decreased or absent von Willebrand factor (VWF) protein, with a parallel decrease in VWF function and FVIII activity. Patients experience excessive mucosal bleeding, characteristic of VWD, but may also experience joint bleeding, a phenotype more typical of hemophilia A. The CDC sponsored Universal Data Collection (UDC) project collects joint range of motion (ROM) as well as other clinical data on patients with blood disorders followed at Hemophilia Treatment Centers (HTCs) in the U.S. As of 1/07, 253 patients in the UDC were classified as having severe VWD. The goal of this study was to further characterize these patients and assess relations between levels of FVIII/VWF and joint bleeding and function.

Methods: To validate the diagnosis of severe VWD, HTCs were contacted to obtain baseline laboratory values. Patients with VWF:Ag < 10%, and consistent VWF:RCo and FVIII levels, were considered to have severe VWD. Of 253 patients, laboratory values were obtained in 201, 162 were confirmed to have severe VWD and 150 had joint ROM data. For the analyses, joint bleeding was categorized as either present or absent at each visit. In addition, the joint function measure was calculated for each patient as the overall proportion of normal joint ROM based on measures taken of 10 joints.

Results: The 150 severe VWD subjects consisted of 73 females (49%) and 77 males (51%), with a mean age of 25 yrs (2–75). Racial distribution was Caucasian: 121; African-American: 8; Hispanic: 8, and other: 13. 86/150 gave a family history of a bleeding disorder. 147/150 subjects reported bleeding episodes. Mean age of first documented bleed was 3, but first use of an HTC was not until a mean age of 8. Of the first bleeding episodes, 79 were mucosal, 10 during circumcision, 12 joint, 6 cranial, 7 were from I.M. injections, 21 were other sites, and 12 were unknown. 137/150 subjects had received blood/factor products and 75 had received them at home. 12 subjects had experienced an ICH. Patients with FVIII levels ≤ 5% (n=105) had a lower mean age of first bleed than those with FVIII > 5% (1.5 vs. 6.1 yrs, p=0.0005), but there was no significant association with VWF:Ag level (p=0.08). Lower FVIII and VWF levels were associated with higher risk of joint bleeding [OR 2.95 (p=0.006) and OR 3 (p=0.02), respectively] but not with non-muscle other bleeding. In a longitudinal multivariate analysis, lower FVIII level (p=0.02), increasing age (p<0.0001), joint bleeding (p<0.0001), and higher BMI (p<0.0001) were all significantly negatively associated with joint function. In a separate analysis of 88 patients with complete information on VWF:Ag, low levels were negatively associated with joint function after adjusting for age, BMI, gender and joint bleeding (p=0.002).

Conclusion: Patients with severe VWD in the U.S. have bleeding symptoms beginning at an early age, with mucosal bleeding most common, but also joint and intracranial bleeding, consistent with a severe bleeding phenotype. Our results verify the strong associations between low levels of FVIII and VWF and both joint bleeding and joint function in this disorder. Further analyses will examine whether levels of these proteins are responsible for the phenotypic similarity between severe VWD and hemophilia A.