Reduced von Willebrand factor survival in type Vicenza von Willebrand disease

Abstract

Type Vicenza variant of von Willebrand disease (VWD) is characterized by a low plasma von Willebrand factor (VWF) level and supranormal VWF multimers. Two candidate mutations, G2470A and G3864A at exons 17 and 27, respectively, of the VWF gene were recently reported to be present in this disorder. Four additional families, originating from northeast Italy, with both mutations of type Vicenza VWD are now described. Like the original type Vicenza subjects, they showed a mild bleeding tendency and a significant decrease in plasma VWF antigen level and ristocetin cofactor activity but normal platelet VWF content. Unlike the original patients, ristocetin-induced platelet aggregation was found to be normal. Larger than normal VWF multimers were also demonstrated in the plasma. Desmopressin (DDAVP) administration increased factor VIII (FVIII) and VWF plasma levels, with the appearance of even larger multimers. However, these forms, and all VWF oligomers, disappeared rapidly from the circulation. The half-life of VWF antigen release and of elimination was significantly shorter than that in healthy counterparts, so that at 4 hours after DDAVP administration, VWF antigen levels were close to baseline. Similar behavior was demonstrated by VWF ristocetin cofactor activity and FVIII. According to these findings, it is presumed that the low plasma VWF levels of type Vicenza VWD are mainly attributed to reduced survival of the VWF molecule, which, on the other hand, is normally synthesized. In addition, because normal VWF-platelet GPIb interaction was observed before or after DDAVP administration, it is proposed that type Vicenza VWD not be considered a 2M subtype. (Blood. 2002;99:180-184)

An Experimental Model to Study the in Vivo Survival of von Willebrand Factor

“…The involvement of the DЈ-D3 region in VWF clearance is supported by a recent report by Casonato and co-workers (19). They observed that patients harboring an Arg-1205 to His mutation within the D3 domain display an increased disappearance of their endogenous VWF upon desmopressin treatment.…”

“…For instance, mutation of the D3-domain residue Arg-1205 to His has been suggested to modulate the survival of VWF in patients (19). To study the direct contribution of Arg-1205 to the clearance of VWF, recombinant VWF/ R1205H was expressed in baby hamster kidney-furin cells.…”

“…In contrast, little is known about the mechanism by which VWF is cleared from the circulation. However, this issue is becoming increasingly important, as illustrated by several recent reports suggesting that modified clearance plays a role in the pathogenesis of VWD type 1 (19,20).…”

Pregnancy and delivery in women with von Willebrand's disease and different von Willebrand factor mutations

“…These patients have a shortened VWF survival after desmopressin, but they are able to attain very high levels shortly after infusion. 14,15 Thus, despite the fact that no significant changes of FVIII/VWF levels were observed during pregnancy, delivery was successfully covered with desmopressin infusions. A schedule of 24-hour intervals was chosen to minimize the risk of tachyphylaxis and the compound was administered soon after delivery to avoid possible risks to the newborn.…”

How I treat von Willebrand disease

“…39 Assessment at 4 hours from infusion is advised to identify patients with increased clearance who are possible candidates for alternative treatments. 39,[41][42][43] However, patients with VWD Vicenza, which is associated with the R1205H mutation, and who show the shortest half-life of FVIII and VWF after desmopressin, can be effectively treated with desmopressin for most instances, including parturition. 43,44 Patients with type 3 VWD are usually unresponsive to desmopressin, although some patients do experience an increase of FVIII:C to effective hemostatic levels, even without a change in the bleeding time (BT).…”