Type 1 von Willebrand disease: a possible novel mechanism.

ADAMTS13 (a disintegrin and metalloprotease with thrombospondin motifs) catalyses the proteolysis of von Willebrand factor (vWF). Recent research has indicated that the rate of vWF proteolysis by ADAMTS13 is greater for group O than non-O groups, in the order: group O >/= group B > group A >/= group AB. This, together with the observation that vWF levels are lower for group O than non-O groups, suggested a possible inverse relationship between vWF proteolysis and vWF level. We studied four patients with von Willebrand disease type 1 and found that the ADAMTS13 activity in their cryo-depleted plasma was similar and comparable with a normal control. In contrast, the vWF from one patient was significantly more susceptible to proteolysis than that of the others, which were comparable with a normal control. The increased susceptibility to proteolysis was associated with heterozygosity for tyrosine/cysteine 1584 (Tyr/Cys1584). A preliminary cohort study (n = 200) indicated an allele frequency of 0.005 for G 24/1282 encoding Cys1584. In vitro, heterozygous vWF showed an increase in proteolysis of 13.1-23.5% compared with homozygous Tyr/Tyr vWF. These data suggest that increased vWF proteolysis may be implicated in type 1 von Willebrand disease in some patients and that Cys1584 may, in part, exert its effect through this mechanism.