Responsiveness of patients with VWD to DDAVP

Since the early discovery that desmopressin (DDAVP) would release von Willebrand factor (VWF) from vascular endothelium,¹  DDAVP has been considered a treatment option for those with type 1 von Willebrand disease (VWD), with the proviso that an adequate biologic response was demonstrated after administration of a trial dose. Surprisingly, there have been few studies that have examined the frequency of this adequate response. In this issue of Blood, Federici and colleagues (page 2032) report on a careful assessment that was carried out on a large cohort of patients studied prospectively in a European multicenter trial. Although these patients' cases were defined on clinical grounds as being severe, many of the patients had laboratory levels of VWF that we would anticipate to be responsive to DDAVP therapy. While the lack of adequate biologic response in patients with type 2 VWD was not surprising, the response rate of 26.27% in patients with type 1 VWD was surprisingly low and seemed not to correlate with the basal level of VWF. One possible explanation was the requirement in their study for a demonstrable beneficial effect on the bleeding time. Many centers have felt that the bleeding time is an inadequate surrogate marker for hemostatic effectiveness and have ceased measuring it as part of the clinical trial of DDAVP in patients with VWD. But other tests of primary hemostasis also have poor clinical utility or clinical correlation and do not provide a “gold standard” for clinical assessment of primary hemostasis.

When this group of patients with type 1 VWD was subdivided according to their ratios of ristocetin cofactor activity (VWF: RCo) to VWF antigen (VWF:Ag), those with low ratios demonstrated only 12.5% responsiveness, compared with 33% responsiveness in patients with type 1 VWD with normal VWF:RCo/VWF:Ag ratios (> 0.6). Studies in other laboratories suggest that this ratio can be used to define type 2M VWD.²  Whether the former group, with a low ratio, represents patients with type 2M disease may require a more complete understanding of the genetic mutations in this group of patients with type 1 disease.

Recent studies of patients with VWD,³  including patients with the “Vicenza VWD variant” (R1205H),^4,5  suggest that some patients with type 1 VWD may have low VWF levels because the mutant VWF has a shortened survival. Such patients might have exhibited a strong post-DDAVP response at 30 or 60 minutes but had an inadequate hemostatic level at 2 hours. Such an assessment would require more than just a pre-DDAVP and a one-hour post-DDAVP laboratory assessment to determine plasma half-life.

The study by Federici and coworkers reaffirms the continued clinical need for a careful clinical trial of DDAVP to establish clinical laboratory responsiveness. Many assume that this clinical responsiveness will clearly correlate with the ultimate clinical improvement, but this has not been established and needs further study. This study suggests that a rigorous clinical assessment of DDAVP responsiveness is indicated—particularly in those patients who are clinically labeled as having severe or moderately severe VWD. Whether the bleeding time should be part of this laboratory assessment is not clear and may require further study.

Von Willebrand disease continues to be a complex disorder that requires more careful definition at both a molecular and a clinical level. This study emphasizes the importance of continued clinical assessment of therapeutic efficacy in both type 1 and type 2 VWD and the need for clinical correlation.