"Outgrowing" the Laboratory Diagnosis of Type 1 Von Willebrand's Disease: A Two Decade Study

Introduction: In the general population, von Willebrand factor (VWF) and factor VIII (FVIII) levels are known to increase with age. However, in patients with bleeding disorders such as von Willebrand's disease (VWD), the effect of ageing is unclear. With a growing population of elderly patients with bleeding disorders, it is important to understand these changes and their effects on hemostasis, which may preclude the need for hemostatic therapy. The results of two prior studies conducted in the Netherlandsand Canada suggest that VWF levels increase with age in patients with VWD. Our study looks at the trends of VWF with age and the extent of normalization of levels in patients with Type 1VWD. It is the first to be conducted in a United States (U.S.) population, and the largest of its kind to date.

Methods: In a retrospective cohort study, we reviewed the medical records of 266 patients registered at the Mary M. Gooley Hemophilia Center between 1996 and 2016 with a laboratory (lab) diagnosis of presumed Type 1 VWD based on normal multimers and/or ristocetin cofactor (VWF:RCo)/VWF antigen (VWF:Ag) ratio ≥ 0.6. The diagnosis of VWD was based on symptoms of bleeding episodes in conjunction with lab data of either VWF:Ag level < 30 U dL^-1 or VWF:RCo level < 30 U dL^-1, whereas the diagnosis of "Low VWF" was made for levels between 30-50 IU/dL (per NHLBI definition). Lab diagnosis required two subnormal sets taken at a minimum of 2 weeks apart. We collected all their historically documented VWF:Ag, VWF:RCo, and FVIII levels over time. We excluded patients whose levels were followed for less than 5 years, and we excluded all lab data that were related to the effects of desmopressin, products containing VWF or FVIII, pregnancy, or other acute stress situations.

The primary outcome studied was complete normalization of most recent levels, defined as both VWF:Ag > 50 U dL^-1 and VWF:RCo > 50 U dL^-1 on two consecutive occasions separated at least 2 weeks apart. Furthermore, we defined "possible normalization" if only the last set of levels was normal, and "partial normalization" if only one level (either VWF:Ag or VWF:RCo alone) became normal for two consecutive times.

Results: A total of 125 patients were analyzed (n=125), with an average duration of follow-up of 10.4 ± 3.7 years (SD) between the first set of values obtained until the most recent. Forty-five patients (26.4%) initially met the criteria for Type 1 VWD, while 80 patients (73.6%) had Low VWF. In the VWD group, 20.0% patients exhibited complete normalization, 11.1% showed possible normalization, and 55.6% had no normalization. The Low VWF cohort had complete normalization in 36.3% of patients, and possible normalization in 35.0% of patients. The total population had complete normalization in 30.4% of patients (Figure 1). An additional 13.3% and 3.8% had partial normalization in the VWD and Low VWF cohorts respectively.

Only five patients, all of whom had "partial normalization", exhibited "relapse" where a normalized level dropped again. None of the other normalization groups had any incidence of relapse over the studied period of time.

Conclusion: Our preliminary findings suggest that in about one third of patients with Type 1 von Willebrand's disease or Low VWF, the VWF:Ag and VWF:RCo levels completely normalize on repeat testing with age, over an average period of 10 years. Our study population is the largest to date whose levels were followed over time, and appears to be the first in a U.S. population. The rate and degree of normalization with time, as well as correlation with bleeding symptoms, are still being investigated. This may help determine whether rescinding the lab diagnosis precludes pre-operative hemostatic therapy. At the very least, clinicians should consider repeat testing in their Type 1 VWD patients 5 to 10 years post initial lab diagnosis.

Figure 1

View largeDownload slide

Stacked columns showing percentages of complete, possible, partial and no normalization in the total, VWD, and Low VWF cohorts.

Figure 1

View largeDownload slide

Stacked columns showing percentages of complete, possible, partial and no normalization in the total, VWD, and Low VWF cohorts.

Close modal