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August 23-24, 2018 | London, UK
Hematology and Oncology
2
nd
International Conference on
Journal of Hematology and Blood Disorder | Volume 2
Molecular and laboratory characteristics of recessive von Willebrand Disease 2N anno 2018
Jan Michiels
Good Heart Centre, The Netherlands
Introduction
: The FVIII binding site on von Willebrand factor
(VWF) is located in the D’ (766-864) and D3 (1054-1060) regions
of theVWF gene. The cysteine residues in theD’ domainCys767-
Cys808;Cys776-Cys804;Cys810-Cys821 form disulfide bridges
between two D’ trypsin-inhibitor-like (TIL’) and E’ regions, which
areofcriticallyimportanceforthebindingbetweenTil’E’andFVIII.
Aims:
To study the genotype phenotype relationship of VWF in
von Willebrand disease (VWD) 2N
Methods:
We critically analyzed the molecular and laboratory
characteristicsofVWD2Nreported inthe literatureanddescribe
experiences from three VWF Research Centers in Europe.
Results:
Homozygous non-cysteine R854Q/R854Q mutation
and of R854Q double heterozygous with non-cysteine E787K,
T791M and R816Wmutations in the D’ domain result in a mild
FVIII binding defect (FVIII:BD) (about 30%) featured by mild
to moderate hemophilia A with normal bleeding time and
normal VWF functions and multimers. The FVIII:BD is markedly
decreased (less than 10%) in E787K, T791M, R816W, 869 and
C1060 either homozygous or double heterozygous with a
null allele. FVIII:BD due to 2N non-cysteine mutations in the
D’ domain of VWF gene and FVIII mutations in the C1 and C2
domain in FVIII gene have no influence on synthesis, storage,
secretion and multimerization of VWF. The VWD type 2N
cysteinemutationsC788R/Y; Y795CandC804F inTIL’; C858C/F in
E’ are associated with aberrant multimerization, poor secretion
and reduced FVIII binding to VWF. Homozygous R760W/R760
(D2 domain) and R788/R788 (D’ domain) induce a pronounced
secretionandmultimerizationconsistentwith recessiveVWD2C
inwhich amild FVIII:BD of about 35%does not contribute to the
severity of bleeding phenotype. The combination of R854Q and
R760 in the D’D2 domains produce VWD type 2Nwith a smeary
pattern of VWF multimers due to a mixture of normal VWF
and of proVWF. Heterozygous R763/WT mutated VWD type 1
and VWD 2N double heterozygous for R854Q and R763 (Furin
cleavage site) show a smeary VWF multimeric pattern due to a
mixture of normal VWF and pro-VWF protein. The homozygous
C1060R/C1060R and the double heterozygous D879N/null,
C1060R/R854Q and C1060R/null mutations in the D3 domain
are associated with a hybrid phenotype of 2N/2E VWD.
Conclusion:
Classical VWD 2N due to the homozygous non-
cysteinemutations in D’ Domain of the VWF R854Q and R816W
impair the binding of FVIII capacity of VWF (FVIII binding
defect: FVIII-BD) but do not impair the multimeric structure of
VWF. The cysteine mutations inside the D’ domain C788R/Y,
C788T and C804F in TiL’, and C858S/F in E’ and outside the D’
domain C760C in D2, R763C Furin cleavage site only produce
VWD 2N when combined with the R854Q mutation and are
associated with aberrant multimerization of VWF. Homozygous
C1060R/C1060R mutation in the D3 domain, and the double
heterozygous D879N/null, C1060R/R854Q or C1060//null
mutationsareassociatedwithahybridphenotypeof2N/2EVWD.
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:
goodheartcenter@outlook.com