Desmopressin aggravates
thrombocytopenia in
type 2B von Willebrand disease (VWF type 2B) by release of large and hyper-adhesive
von Willebrand Factor (VWF) multimers. This pilot study investigated whether the anti-VWF aptamer
ARC1779 can prevent
desmopressin-induced
thrombocytopenia and interferes with the excessive VWF turnover in patients with VWF type 2B. Concentration effect curves of
ARC1779 were established for five patients in vitro and two patients with VWF type 2B were treated by infusion of
ARC1779,
desmopressin, or their combination in a randomised, controlled, double-blind design.
ARC1779 concentrations in the range of 1-3 microg/ml blocked free A1 domain binding sites by 90% in vitro. In vivo,
desmopressin alone induced a profound (-90%) drop in platelet counts in one of the patients.
ARC1779 (4-5 microg/ml) completely inhibited VWF A1 domains and prevented this
desmopressin-induced platelet drop.
Desmopressin alone increased VWF
antigen two- to three-fold, accompanied by concordant changes in VWF
Ristocetin cofactor activity (RCo) and
coagulation factor VIII activity.
ARC1779 substantially enhanced the
desmopressin-induced maximal increase in these parameters, and improved multimer patterns. No treatment related adverse events were observed and no
bleeding occurred despite marked
thrombocytopenia. These data provide first proof of concept in humans and evidence that
ARC1779 is a potent inhibitor of VWF.
ARC1779 prevented the rapid consumption of VWF multimers together with agglutinated platelets that occurred in response to
desmopressin challenge in patients with VWD type 2B.