Article

Biologic response to desmopressin in patients with severe type 1 and type 2 von Willebrand disease: results of a multicenter European study

University of Milan, Milano, Lombardy, Italy
Blood (Impact Factor: 9.78). 04/2004; 103(6):2032-8. DOI: 10.1182/blood-2003-06-2072
Source: PubMed

ABSTRACT This study prospectively evaluated the rate of biologic response to desmopressin (DDAVP) in 66 patients with type 1 or 2 von Willebrand disease (VWD), each of whom had, on the basis of available records, a clinically significant bleeding history and at least one of the following laboratory abnormalities: bleeding time (BT) longer than 15 minutes, ristocetin cofactor activity (VWF:RCo) less than 10 IU/dL, factor VIII coagulant activity (FVIII:C) less than 20 IU/dL (severe VWD). Before the study, responsive patients were defined as those who, 2 hours after infusion of 0.3 microg/kg DDAVP, had increased baseline values of VWF:RCo and FVIII:C by at least 3-fold and achieved levels of at least 30 IU/dL for both and a BT of 12 minutes or less. The rate of biologic response varied according to VWD types and was higher in type 1 (7 of 26, 27%) than in type 2 (7 of 40, 18%) (type 2A [1 of 15, 7%], type 2M [3 of 21, 14%], type 2N [3 of 4, 75%]). Mutations in the VWF gene were previously known or newly identified in most patients with types 2A (n = 15 of 15), 2M (n = 15 of 21), and 2N (n = 4 of 4), but in none of those with type 1 VWD. Genotype provided more information than phenotype in predicting individual responses to DDAVP only in patients with 2A and 2N VWD. This prospective study showed that the rate of biologic response to DDAVP is relatively low not only in type 2 but also in type 1 VWD when uniform and stringent criteria for patient selection and responsiveness are applied.

0 Followers
 · 
71 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 von Willebrand disease includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, four different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment for the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared to patients with actual quantitative deficiency (Type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-Factor VIII concentrates represents the safe mainstay of treatment for all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal anti-hemorrhagic prophylaxis in the individual patient. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; 125(6). DOI:10.1182/blood-2014-08-551960 · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Following the recognition of von Willebrand disease (VWD) in 1926 and the cloning of the gene for von Willebrand factor (VWF) in 1985, significant advances have been made in our fundamental knowledge of both the disease and the protein. Some of this new knowledge has also begun to impact the clinical management of VWD. First, the progressive increase in our understanding of the molecular genetic basis of VWD has resulted in rational applications of molecular testing to complement the current range of phenotypic tests for VWD. These molecular genetic strategies are most effectively directed at the prenatal diagnosis of type 3 VWD and confirmatory testing for types 2B and 2N disease. In contrast, the use of molecular testing to clarify the diagnosis of type 1 VWD is of marginal benefit, at best. In terms of VWD therapies, a new recombinant VWF concentrate has recently completed successful clinical trials and is now awaiting more widespread application. There have even been some preclinical successes with VWF gene transfer although the clinical rationale for this therapeutic strategy needs careful consideration. Much more remains to be learnt about the biology of VWF and further translational advances for the enhancement of VWD care will inevitably be realized.
    Journal of Thrombosis and Haemostasis 06/2013; 11(s1). DOI:10.1111/jth.12257 · 5.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Von Willebrand disease (VWD) is a bleeding disorder characterized by reduced plasma von Willebrand factor (VWF) levels or functionally abnormal VWF. Low VWF plasma levels in VWD patients are the result of mutations in the VWF gene that lead to decreased synthesis, impaired secretion, increased clearance or a combination thereof. However, expression studies of variants located in the A domains of VWF are limited. We therefore characterized the biosynthesis of VWF mutations, located in the VWF A1–A3 domains, that were found in families diagnosed with VWD. Human Embryonic Kidney 293 (HEK293) cells were transiently transfected with plasmids encoding full-length wild-type VWF or mutant VWF. Six mutations in the A1–A3 domains were expressed. We found that all mutants, except one, showed impaired formation of elongated pseudo-Weibel-Palade bodies (WPB). In addition, two mutations also showed reduced numbers of pseudo-WPB, even in the heterozygous state, and increased endoplasmic reticulum retention, which is in accordance with the impaired regulated secretion seen in patients. Regulated secretion upon stimulation of transfected cells reproduced the in vivo situation, indicating that HEK293 cells expressing VWF variants found in patients with VWD can be used to properly assess defects in regulated secretion.
    British Journal of Haematology 08/2014; 167(4). DOI:10.1111/bjh.13074 · 4.96 Impact Factor

Preview