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Journal of Hematology and Blood Disorder | Volume 2
allied
academies
August 23-24, 2018 | London, UK
Hematology and Oncology
2 nd International Conference on
The European Clinica Laboratory and Molecular (ECLM)
criteria define 10 distinct von Willebrand diseases (VWD)
due to mutations in the D1, D2, D’, D3, A1, A2, A3, D4, C1-6 and
CK domains of the von Willebrand factor (VWF) gene: recessive
VWD type 3, severe type 1, 2C and 2N; dominant VWD type
1 clearance (C), secretion (SD) or clearance/secretion defect
(CSD); dominant VWD 2A, 2B, 2E, 2M and 2D; and mild type
1 (Low VWF) frequentl carriers of recessive VWD. Recessive
VWD type 3 is caused by homozygous or heterozygous double
null mutations as the cause of recessive pseudo-hemophilia
first described by Erik von Willebrand. Recessive VWDs type
1 are mainly caused by homozygous or double heterozygous
missense secretion defective mutations in the D1, D2, D4
or C1-6 domains of the VWF gene. Recessive VWD due to
mutations in the D1 domain is featured by persistence of pro-
VWF and characterized by severe secretion and FVIII binding
defect and therefore mimicking VWD type 3. Recessive VWD 2C
due to mutations in the D2 domain are featured by secretion
and multimerization defect and no clearance defect. Recessive
VWD 2N is a mild hemophilia due to mutations in the D’-FVIII
binding domain. The VWF function and multimers are normal
in noncysteine 2N mutations and defective in cystein 2N
mutations in the D’domain, whereas the 1060 2N mutation in
the D3 show a hybrid 2N/2E VWD phenotype. Dominant VWD
1E or 2E are caused by heterozygous missense mutations in the
D3 domain and are featured by variable degrees of secretion
(SD) multimerization and clearance (C ) defects. VWD 1C as the
most pronounced clearance defect is caused by the Vincenza
mutation R1205H in the D3 domain. Dominant VWD 2B is
caused by a gain of functionmutation in the A1 domain showing
spontaneous interaction between VWD 2B mutant and platelet
glycoprotein Ib (GPIb) with the consequence of increased
ristocetine-induced platelet aggregation (RIPA) followed by
increased proteolysis at the VWF cleavage site leading to the
loss of large VWFmultimersmimicking VWD type 2A. Dominant
VWD 2M is due to loss of RIPA function mutations in the A1
domain and characterized by decreased (RIPA), decreased
VWF:RCo as compared to VWF:CB (I-III), with normal or smeary
VWFmultimers or some loss of largemutimers, a poor response
of VWF:RCo and normal response of VWF:CB to DDAVP.
Dominant VWD type 2A are hypersensitive to ADAMTS13 (VWF
cleavage protein) caused by mutations in the A2 domain of the
VWF gene, which results in proteolysis of large VWF multimers
by ADAMTS13 into VWF degradation products resulting in the
loss of large VWF multimers, triplet structure of VWF bands
and decreased ratios of both VWF:RCo/Ag and VWF:CB/Ag. A
new category of secretion and/or clearance defects are due
to mutations in the D4 and C1-6 domains. The D4 and C1-6
mutations in theVWF genemainly consist of two groups of VWD
type 1 secretion defects (SD) those with normal VWF multimers
and thosewitha smearyVWFmultimericpattern. Homozygosity
or double heterozygosity null or missense mutation in the C1-6
domain produce recessive severe type 1 VWD with smeary
VWF multimers (eg mutation 2362). VWD mutations in the CK
dimerization domain of the VWF gene produce dominant or
recessive VWD type 2D (or even recessive type 1) featured by
the loss of large VWFmultimers and intervening VWF subbands.
Speaker Biography
Jan Michiels Professor of Nature Medicine & Health Blood Coagulation & Vascular
Medicine Center in Netherlands. He also serves as an Editorial board member for many
scientific journals
e:
Jan Michiels
Good Heart Centre, The Netherlands
Novel insights in the diagnosis and classification of autosomal recessive and dominant
von Willebrand diseases anno 2018