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Blood, 1 June 2002, Vol. 99, No. 11, pp. 4243-4245
CORRESPONDENCE
To the editor:
The elusive pathogenesis of von Willebrand disease
Vicenza
In the paper by Casonato et al1 on
reduced von Willebrand factor (VWF) survival in type 2M Vicenza von
Willebrand disease (VWD), the authors reported 4 additional
families who had the same peculiar phenotype and candidate
mutations (2470G>A in exon 17 and 3864G>A in exon 27 of the
VWF gene) previously identified by our group in the original
families2 and other families from the same geographical
area.3 However, Casonato et al1 reported 2 important phenotypic differences. First, ristocetin-induced platelet
agglutination (RIPA) was normal, whereas it was invariably reduced in
the original cases.4 This led the authors to speculate that VWF Vicenza interacts normally with platelets, even though they
did not perform binding studies. Second, their patients showed an
aberrant multimeric pattern of plasma VWF on high-resolution agarose
gels, characterized by the presence of doublets instead of the typical
triplet pattern. Barring methodological differences, these findings
support the views that some of the patients reported by Casonato et al
do not have typical VWD Vicenza. The authors state that the "pathognomonic" aspect of VWD
Vicenza is the very low level of plasma VWF contrasting with normal levels of platelet VWF. There are cases of VWD other than VWD Vicenza with this discrepant pattern. For instance, heterozygotes with
type 1 VWD as a result of the Cys1130Phe mutation also have low plasma levels of VWF but normal platelet levels.5 As
the original Vicenza patients, these type 1 patients are responsive to
desmopressin treatment with brisk transient normalization of VWF
measurements, shortening of the bleeding time (not shown), and
postinfusion disappearance rate of FVIII/VWF measurements (Figure
1). We believe that the appropriate
controls for the studies done by Casonato et al should be patients with
type 1 with similar baseline levels of VWF, not
healthy individuals. Furthermore, at variance with them, we
believe that the fact that VWF is normal in platelets does not
necessarily demonstrate that this protein is secreted normally. If
synthesis is normal but there is a dominant-negative intracellular
retention due to impaired production and secretion, the platelet VWF
content would be expected to be normal as in the example demonstrated
in type 1 VWD for the Cys1149Arg mutation and the very similar
Cys1130Phe mutation.6 Should the constitutive pathway be
mainly affected in VWD Vicenza, as suggested by Schneppenheim et
al,7 then studies on the survival of desmopressin-released VWF, which originates from the secretory pathway, are largely irrelevant.
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| Figure 1.
Factor VIII/von Willebrand factor measurements after
desmopressin in type 2M Vicenza and Cys1130Phe mutation.
The figure shows the mean of the results of FVIII:C (A), VWF:Ag (B),
and VWF:RCo (C) in 2 patients for each group infused intravenously with
0.3 µg/kg of desmopressin.  indicates Vicenza;  ,
Cys1130Phe.
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In conclusion, Casonato et al1 describe 4 additional
families of VWD Vicenza with an unusual phenotype without providing definite experimental evidence as to the possible pathogenetic mechanism of the disease. Only expression studies and cotransfection of
the mutant gene and wild-type gene could perhaps explain the basis of
this subtype of VWD. Further studies are needed prior to dismissal of
this subtype from type 2M VWD, which includes cases with defective
VWF-platelet interaction accompanied by intact VWF multimers in plasma.
Giancarlo Castaman, Francesco Rodeghiero, and Pier Mannuccio Mannucci
Correspondence: Giancarlo Castaman, Department of Hematology,
San Bortolo Hospital, Vicenza, Italy
References
1.
Casonato A, Pontara E, Sartorello F, et al.
Reduced von Willebrand factor survival in type Vicenza von Willebrand disease.
Blood.
2002;99:180-184[Abstract/Free Full Text].
2.
Castaman G, Missiaglia E, Federici AB, Schneppenheim R, Rodeghiero F.
An additional unique candidate mutation (G2470A; M740I) in the original families with von Willebrand disease type 2 M Vicenza and the G3864A (R1205H) mutation.
Thromb Haemost.
2000;84:350-351[Medline]
[Order article via Infotrieve].
3.
Castaman G, Novella E, Rodeghiero F.
Nine additional families with type 2 M von Willebrand disease (VWD) Vicenza from Vicenza area show segregation of the G2470A (M740I) and the G3864A (R1205H) mutations in the von Willebrand factor gene with the abnormal phenotype.
Thromb Haemost.
2001;86(suppl1):1808.
4.
Mannucci PM, Lombardi R, Castaman G, et al.
Von Willebrand disease "Vicenza" with larger-than-normal (supranormal) von Willebrand factor multimers.
Blood.
1988;71:65-70[Abstract/Free Full Text].
5.
Castaman G, Eikenboom JCJ, Missiaglia E, Rodeghiero F.
Autosomal dominant type 1 von Willebrand disease due to G3639T mutation (C1130F) in exon 26 of von Willebrand factor gene: description of five Italian families and evidence for a founder effect.
Br J Haematol.
2000;108:876-879[CrossRef][Medline]
[Order article via Infotrieve].
6.
Bodo' I, Katsumi A, Tuley EA, Eikenboom JCJ, Dong Z, Sadler JE.
Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins.
Blood.
2001;98:2973-2979[Abstract/Free Full Text].
7.
Schneppenheim R, Federici AB, Budde U, et al.
Von Willebrand disease type 2M Vicenza in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families.
Thromb Haemost.
2000;82:136-140.
Response:
The reduced survival of type Vicenza von Willebrand
factor
Type Vicenza von Willebrand disease (VWD) was first
described by Mannucci's group in patients coming from Northeast
Italy1; its phenotype was characterized by significantly
reduced plasma levels of von Willebrand factor (VWF), a normal platelet
VWF content, and the presence of unusually large VWF multimers. The
original type Vicenza patients were also characterized by a normal
response to DDAVP infusion with normal T1/2 survival, as compared with type 1 VWD.1 Recently, 2 candidate mutations were
described; 2470G>A in exon 17 and 3864G>A in exon 27 of VWF
gene.2,3 Why plasma VWF levels are significantly reduced
despite the normal platelet VWF content is a matter of discussion.
Schneppenheim et al2 suggest a defect in the constitutive
release of Vicenza VWF, in contrast with the normal acute one. We
instead advance that a reduced survival of a normally synthesized VWF
underlies the significant reduction in plasma VWF.4 Castaman et al suggest in their letter that our patients may not have a
typical type Vicenza phenotype. Indeed, they have all the peculiar
haemostatic findings and the 2 candidate mutations associated with type
Vicenza VWD, but differ in that they have normal or borderline
ristocetin-induced platelet agglutination (RIPA) values and a multimer
pattern characterized by the presence of doublets instead of the
typical triplet pattern. As far as RIPA is concerned, we know that this
test may be affected by variations in the plasma VWF concentrations
during physiologic or pathologic conditions. Even though we did not
perform binding studies, this observation prompted us to speculate
about the normality of platelet glycoprotein Ib (GPIb) and
type Vicenza VWF. Regarding the multimer pattern, it appears to be
evident only under electrophoretic conditions that require high
resolution gel. Should our patients not be type Vicenza VWD, we must
presume that the 2 candidate Vicenza mutations are not involved in
determining the Vicenza phenotype or, alternatively, that our patients
also have other mutation(s) affecting their phenotype. However, this
seems unlikely as our patients belonged to 4 unrelated families.
Regardless of the usual and unusual nature of our type Vicenza VWD
patients, we think that the novelty of our report is the demonstration
of a reduced VWF survival in patients having the genotype/phenotype of
type Vicenza VWD. Our results show that the acutely released type
Vicenza VWF has a significantly reduced time of persistence in
circulation compared to normal, thereby offering a plausible
explanation for its reduced plasma VWF levels. Moreover, Castaman et al
suggest that our survival results should have been compared with those
of type 1 VWD, having similar baseline VWF levels, rather than a
normal counterpart. Since there are many type 1 VWD with
different VWF gene mutations, which type should we choose in order to
evaluate whether the survival of Vicenza VWF is reduced or normal?
Furthermore, when we investigate a laboratory result to decide whether
it is normal or pathologic, we have to compare it with findings in a
normal population not a pathologic one. Finally, the finding that
Vicenza and Cys1130Phe VWF have a similar T1/2 elimination as
documented by Castaman's results is not surprising. It is likely that
other VWD variants will be identified in the future due to reduced VWF
survival. Instead the question should be are Vicenza and Cys1130Phe VWF survivals similar to or different from the normal counterpart! Castaman et al state that we concluded that VWF is normally secreted
because platelet VWF is normal. This is not so; we only said that VWF
is normally synthesized because platelet VWF is normal, as is the VWF
release because of the normal VWF response to DDAVP administration.
That type Vicenza VWF acutely released by DDAVP has a shortened
survival remains an incontrovertible, and we suspect not an irrelevant
finding, as suggested by Castaman et al. Alternatively, we should
presume that the fates of constitutively and acutely secreted VWF are
different. Whether or not the constitutive release of Vicenza VWF might
also be defective as advanced by Schneppenheim will be clarified by our
ongoing expression studies. In the mean time, we have no objection to
classifying type Vicenza in the heterogeneous type 2M VWD group.
Alessandra Casonato, Elena Pontara, Francesca Sartorello, Maria Grazia Cattini, and Antonio Girolami
Correspondence: A. Casonato, University of Padua Medical School,
Dept of Medical and Surgical Science, Second Chair of Internal
Medicine, Padua, Italy
References
1.
Mannucci PM, Lombardi R, Castaman G, et al.
Von Willebrand disease "Vicenza" with larger-than-normal (supranormal) von Willebrand factor multimers.
Blood.
1988;71:65-70[Abstract/Free Full Text].
2.
Castaman G, Missiaglia E, Federici AB, Rodeghiero F.
An additional unique candidate mutation (G2470A; M740I) in the original families with von Willebrand disease type 2 M Vicenza and the G3864A (R1205H) mutation.
Thromb Haemost.
2000;84:350-351[Medline]
[Order article via Infotrieve].
3.
Schneppenheim R, Federici AB, Budde U, et al.
Von Willebrand disease type 2M Vicenza in Italian and German patients: identification of the first candidate mutation (G3864A; R1205H) in 8 families.
Thromb Haemost.
2000;82:136-140.
4.
Casonato A, Pontara E, Sartorello F, et al.
Reduced von Willebrand factor survival in type Vicenza von Willebrand disease.
Blood.
2002;99:180-184[Abstract/Free Full Text].
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