Biological effect of desmopressin in eight patients with type 2n (‘Normandy’) von Willebrand disease

Abstract

It is generally thought that the plasma increase in factor VIII (FVIII) after desmopressin (dDAVP) infusion is related to the plasma increase in von Willebrand factor (vWF), which is the plasma carrier for FVIII. The aim of this study was to evaluate the FVIII and vWF responses in patients with type 2N vWD, characterized by the mild FVIII deficiency related to markedly decreased affinity of vWF for FVIII. At different times after one intravenous dose of dDAVP (0.3 or 0.4 microgram/kg) we measured the FVIII coagulant activity, FVIII antigen, vWF antigen and ristocetin cofactor activity, in eight patients with either Arg91Gln or Arg53Trp amino acid substitution in mature vWF. In all the patients, whatever their mutation, the dDAVP infusion resulted in a 2.3 +/- 0.7-fold increase of vWF and a variable rise (9.5 +/- 7.7 times) of FVIII, whereas the vWF capacity to bind FVIII was not improved. The FVIII response was more transient than vWF response, and FVIII half disappearance time was evaluated to be approximately 3 h. The data indicate that the stabilizing effect of vWF on FVIII is not responsible for the FVIII increase induced by dDAVP. The clinical implication of this study is that, in the 2N vWD patients, dDAVP may be a useful prophylactic or curative treatment when the test dose has been shown to be effective to reach a haemostatic FVIII level.

Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A

“…However, DDAVP induces release of both VWF and FVIII, but following release the FVIII half-life is 2 hours whereas VWF has a normal half-life of 12 hours in type 2N VWD. 41 This suggests that intracellularly, in the acidic environment of the late Golgi, there is normal association and storage of the VWF-FVIII noncovalent complex that is disrupted at the neutral pH of plasma following release.…”

Von Willebrand Disease: Range of the Disease, and Management

“…For types 2M and 3 there is, typically, an inadequate response to desmopressin because of the respective loss-of-function and complete absence of VWF protein. For type 2N, desmopressin increases VWF and FVIII levels by two to ninefold; however FVIII increases for an average of 3 h. Thus for patients with type 2N, desmopressin should be used when a very transient rise in FVIII is required [40]. Because of the variability of response to DDAVP, response data from a DDAVP challenge test could be used to overcome phenotypic assay limitations.…”

Optimizing treatment of von Willebrand disease by using phenotypic and molecular data

“…28 Type 2M is caused by a variety of unique mutations in exon 28, usually with dominant negative effects, and with heterogeneous responses to desmopressin. 29,30 Missense mutations in the FVIII-binding domain at the Nterminus of VWF are responsible for type 2N. 29 These mutations may cause significant symptoms only in the homozygous or compound heterozygous state.…”